CN110099682B - 偶联连接体,含有此连接体的细胞结合分子-药物偶联物及其制备和应用 - Google Patents
偶联连接体,含有此连接体的细胞结合分子-药物偶联物及其制备和应用 Download PDFInfo
- Publication number
- CN110099682B CN110099682B CN201680090956.2A CN201680090956A CN110099682B CN 110099682 B CN110099682 B CN 110099682B CN 201680090956 A CN201680090956 A CN 201680090956A CN 110099682 B CN110099682 B CN 110099682B
- Authority
- CN
- China
- Prior art keywords
- cell
- conjugate
- group
- cancer
- antibody
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003814 drug Substances 0.000 title claims description 137
- 229940079593 drug Drugs 0.000 title claims description 133
- 230000027455 binding Effects 0.000 title abstract description 55
- 238000002360 preparation method Methods 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- -1 linker compound Chemical class 0.000 claims description 309
- 206010028980 Neoplasm Diseases 0.000 claims description 80
- 201000011510 cancer Diseases 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 20
- 229940127089 cytotoxic agent Drugs 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 208000023275 Autoimmune disease Diseases 0.000 claims description 15
- 208000015181 infectious disease Diseases 0.000 claims description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 7
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 7
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 6
- 208000035473 Communicable disease Diseases 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 4
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims description 4
- 229960000455 brentuximab vedotin Drugs 0.000 claims description 4
- 229960003787 sorafenib Drugs 0.000 claims description 4
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 3
- 108010036949 Cyclosporine Proteins 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- 229960000548 alemtuzumab Drugs 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229960001265 ciclosporin Drugs 0.000 claims description 3
- 229960002087 pertuzumab Drugs 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 229960001603 tamoxifen Drugs 0.000 claims description 3
- 229960000575 trastuzumab Drugs 0.000 claims description 3
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 2
- 239000005536 L01XE08 - Nilotinib Substances 0.000 claims description 2
- 239000003798 L01XE11 - Pazopanib Substances 0.000 claims description 2
- 239000002118 L01XE12 - Vandetanib Substances 0.000 claims description 2
- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 claims description 2
- 229960003697 abatacept Drugs 0.000 claims description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 2
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 claims description 2
- 229960003094 belinostat Drugs 0.000 claims description 2
- 229960003008 blinatumomab Drugs 0.000 claims description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 2
- 229960001467 bortezomib Drugs 0.000 claims description 2
- 229960005107 darunavir Drugs 0.000 claims description 2
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 claims description 2
- 229960001251 denosumab Drugs 0.000 claims description 2
- 229960004137 elotuzumab Drugs 0.000 claims description 2
- 229960004891 lapatinib Drugs 0.000 claims description 2
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims description 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims description 2
- 229960004942 lenalidomide Drugs 0.000 claims description 2
- 229960003907 linezolid Drugs 0.000 claims description 2
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 claims description 2
- 229960001346 nilotinib Drugs 0.000 claims description 2
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims description 2
- 229960003347 obinutuzumab Drugs 0.000 claims description 2
- 229960000470 omalizumab Drugs 0.000 claims description 2
- 229960000402 palivizumab Drugs 0.000 claims description 2
- 229960005184 panobinostat Drugs 0.000 claims description 2
- FWZRWHZDXBDTFK-ZHACJKMWSA-N panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 claims description 2
- 229960000639 pazopanib Drugs 0.000 claims description 2
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229960002633 ramucirumab Drugs 0.000 claims description 2
- 229960003876 ranibizumab Drugs 0.000 claims description 2
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 claims description 2
- 229960000620 ranitidine Drugs 0.000 claims description 2
- 229930002330 retinoic acid Natural products 0.000 claims description 2
- 229960004641 rituximab Drugs 0.000 claims description 2
- 229960003452 romidepsin Drugs 0.000 claims description 2
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 claims description 2
- 108010091666 romidepsin Proteins 0.000 claims description 2
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 claims description 2
- 229960003323 siltuximab Drugs 0.000 claims description 2
- 229960001796 sunitinib Drugs 0.000 claims description 2
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims description 2
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 claims description 2
- 229960003433 thalidomide Drugs 0.000 claims description 2
- 229960001727 tretinoin Drugs 0.000 claims description 2
- 229960000241 vandetanib Drugs 0.000 claims description 2
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 claims description 2
- 229960003862 vemurafenib Drugs 0.000 claims description 2
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 claims description 2
- 229960000237 vorinostat Drugs 0.000 claims description 2
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 claims description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims 2
- 229960002052 salbutamol Drugs 0.000 claims 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 claims 2
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 claims 2
- RWRDJVNMSZYMDV-SIUYXFDKSA-L (223)RaCl2 Chemical compound Cl[223Ra]Cl RWRDJVNMSZYMDV-SIUYXFDKSA-L 0.000 claims 1
- YFGHCGITMMYXAQ-UHFFFAOYSA-N 2-[(diphenylmethyl)sulfinyl]acetamide Chemical compound C=1C=CC=CC=1C(S(=O)CC(=O)N)C1=CC=CC=C1 YFGHCGITMMYXAQ-UHFFFAOYSA-N 0.000 claims 1
- VERWQPYQDXWOGT-LVJNJWHOSA-N 4-amino-5-fluoro-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one;[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate;(e)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VERWQPYQDXWOGT-LVJNJWHOSA-N 0.000 claims 1
- NEZNLHNPLRCSOG-FNZDRVHOSA-N 4-amino-5-fluoro-1-[(2r,5s)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one;[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate;(e)-but-2-enedioic acid;4-[[4-[4-[(e)-2-cyanoe Chemical compound Cl.OC(=O)\C=C\C(O)=O.C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1.CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N NEZNLHNPLRCSOG-FNZDRVHOSA-N 0.000 claims 1
- SJVQHLPISAIATJ-ZDUSSCGKSA-N 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1 SJVQHLPISAIATJ-ZDUSSCGKSA-N 0.000 claims 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims 1
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 claims 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims 1
- 108010019673 Darbepoetin alfa Proteins 0.000 claims 1
- 108010065920 Insulin Lispro Proteins 0.000 claims 1
- 108010005716 Interferon beta-1a Proteins 0.000 claims 1
- 108010005714 Interferon beta-1b Proteins 0.000 claims 1
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 claims 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 claims 1
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 claims 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 claims 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims 1
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 claims 1
- 108010019598 Liraglutide Proteins 0.000 claims 1
- DUGOZIWVEXMGBE-UHFFFAOYSA-N Methylphenidate Chemical compound C=1C=CC=CC=1C(C(=O)OC)C1CCCCN1 DUGOZIWVEXMGBE-UHFFFAOYSA-N 0.000 claims 1
- 239000005480 Olmesartan Substances 0.000 claims 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 claims 1
- 108010082455 Sebelipase alfa Proteins 0.000 claims 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 claims 1
- 229940124925 Zostavax Drugs 0.000 claims 1
- RUGAHXUZHWYHNG-NLGNTGLNSA-N acetic acid;(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5, Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 RUGAHXUZHWYHNG-NLGNTGLNSA-N 0.000 claims 1
- 108010081667 aflibercept Proteins 0.000 claims 1
- 229960005475 antiinfective agent Drugs 0.000 claims 1
- 239000004599 antimicrobial Substances 0.000 claims 1
- 229960003852 atezolizumab Drugs 0.000 claims 1
- 229950002916 avelumab Drugs 0.000 claims 1
- 229960001573 cabazitaxel Drugs 0.000 claims 1
- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 claims 1
- 229960001292 cabozantinib Drugs 0.000 claims 1
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 claims 1
- 229960002438 carfilzomib Drugs 0.000 claims 1
- 108010021331 carfilzomib Proteins 0.000 claims 1
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 claims 1
- 229960003315 cinacalcet Drugs 0.000 claims 1
- VDHAWDNDOKGFTD-MRXNPFEDSA-N cinacalcet Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 VDHAWDNDOKGFTD-MRXNPFEDSA-N 0.000 claims 1
- 229940010466 cosentyx Drugs 0.000 claims 1
- 229960005061 crizotinib Drugs 0.000 claims 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 claims 1
- 229960002204 daratumumab Drugs 0.000 claims 1
- 229960005029 darbepoetin alfa Drugs 0.000 claims 1
- 229960002923 denileukin diftitox Drugs 0.000 claims 1
- 108010017271 denileukin diftitox Proteins 0.000 claims 1
- 229940075925 depakote Drugs 0.000 claims 1
- 235000014113 dietary fatty acids Nutrition 0.000 claims 1
- 229960004497 dinutuximab Drugs 0.000 claims 1
- 229950004949 duvelisib Drugs 0.000 claims 1
- 229940029486 emtricitabine / rilpivirine / tenofovir disoproxil Drugs 0.000 claims 1
- 229960004671 enzalutamide Drugs 0.000 claims 1
- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 claims 1
- 229930195729 fatty acid Natural products 0.000 claims 1
- 239000000194 fatty acid Substances 0.000 claims 1
- 229960002003 hydrochlorothiazide Drugs 0.000 claims 1
- 229960001507 ibrutinib Drugs 0.000 claims 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 claims 1
- 229960003445 idelalisib Drugs 0.000 claims 1
- YKLIKGKUANLGSB-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2[C]3N=CN=C3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 YKLIKGKUANLGSB-HNNXBMFYSA-N 0.000 claims 1
- 239000002955 immunomodulating agent Substances 0.000 claims 1
- 229960004461 interferon beta-1a Drugs 0.000 claims 1
- 229960003161 interferon beta-1b Drugs 0.000 claims 1
- 229960005386 ipilimumab Drugs 0.000 claims 1
- 229960001361 ipratropium bromide Drugs 0.000 claims 1
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 claims 1
- 229940041615 kanuma Drugs 0.000 claims 1
- 108010021336 lanreotide Proteins 0.000 claims 1
- 229960001739 lanreotide acetate Drugs 0.000 claims 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 claims 1
- 229960003881 letrozole Drugs 0.000 claims 1
- 229950008325 levothyroxine Drugs 0.000 claims 1
- 229960004194 lidocaine Drugs 0.000 claims 1
- 229960002701 liraglutide Drugs 0.000 claims 1
- VOBHXZCDAVEXEY-JSGCOSHPSA-N lisdexamfetamine Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)CC1=CC=CC=C1 VOBHXZCDAVEXEY-JSGCOSHPSA-N 0.000 claims 1
- 229960001451 lisdexamfetamine Drugs 0.000 claims 1
- 229940083118 mekinist Drugs 0.000 claims 1
- 229960004640 memantine Drugs 0.000 claims 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 claims 1
- 229960005558 mertansine Drugs 0.000 claims 1
- 229960003105 metformin Drugs 0.000 claims 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims 1
- 229960001344 methylphenidate Drugs 0.000 claims 1
- 229960002237 metoprolol Drugs 0.000 claims 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 claims 1
- 229960001165 modafinil Drugs 0.000 claims 1
- 229960001664 mometasone Drugs 0.000 claims 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 claims 1
- 229950011068 niraparib Drugs 0.000 claims 1
- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 claims 1
- 229960003301 nivolumab Drugs 0.000 claims 1
- 229960000572 olaparib Drugs 0.000 claims 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 claims 1
- 229960005117 olmesartan Drugs 0.000 claims 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 claims 1
- 229960003752 oseltamivir Drugs 0.000 claims 1
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 claims 1
- 229960002085 oxycodone Drugs 0.000 claims 1
- 229960004390 palbociclib Drugs 0.000 claims 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 claims 1
- 229960005079 pemetrexed Drugs 0.000 claims 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 claims 1
- 229940031999 pneumococcal conjugate vaccine Drugs 0.000 claims 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims 1
- 229960001233 pregabalin Drugs 0.000 claims 1
- 229960003712 propranolol Drugs 0.000 claims 1
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 claims 1
- 229960004431 quetiapine Drugs 0.000 claims 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 claims 1
- 229960004157 rabeprazole Drugs 0.000 claims 1
- 238000001959 radiotherapy Methods 0.000 claims 1
- 229960004622 raloxifene Drugs 0.000 claims 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 claims 1
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 claims 1
- 229960001148 rivaroxaban Drugs 0.000 claims 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims 1
- 229960000672 rosuvastatin Drugs 0.000 claims 1
- ZNSIZMQNQCNRBW-UHFFFAOYSA-N sevelamer Chemical compound NCC=C.ClCC1CO1 ZNSIZMQNQCNRBW-UHFFFAOYSA-N 0.000 claims 1
- 229960003693 sevelamer Drugs 0.000 claims 1
- 229960003310 sildenafil Drugs 0.000 claims 1
- 229960004034 sitagliptin Drugs 0.000 claims 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 claims 1
- 229960003855 solifenacin Drugs 0.000 claims 1
- FBOUYBDGKBSUES-VXKWHMMOSA-N solifenacin Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(O[C@@H]2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-VXKWHMMOSA-N 0.000 claims 1
- 229960000835 tadalafil Drugs 0.000 claims 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 claims 1
- 229960002935 telaprevir Drugs 0.000 claims 1
- 108010017101 telaprevir Proteins 0.000 claims 1
- 229960000235 temsirolimus Drugs 0.000 claims 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 claims 1
- 229960003604 testosterone Drugs 0.000 claims 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 claims 1
- 229960000257 tiotropium bromide Drugs 0.000 claims 1
- 108010078373 tisagenlecleucel Proteins 0.000 claims 1
- 229960005026 toremifene Drugs 0.000 claims 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 claims 1
- 229960004066 trametinib Drugs 0.000 claims 1
- 229960004699 valsartan Drugs 0.000 claims 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims 1
- 229950011257 veliparib Drugs 0.000 claims 1
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 claims 1
- 229960002760 ziv-aflibercept Drugs 0.000 claims 1
- 125000005647 linker group Chemical group 0.000 abstract description 119
- 238000010168 coupling process Methods 0.000 abstract description 21
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 abstract description 20
- 230000008878 coupling Effects 0.000 abstract description 20
- 238000005859 coupling reaction Methods 0.000 abstract description 20
- 231100000433 cytotoxic Toxicity 0.000 abstract description 10
- 230000001472 cytotoxic effect Effects 0.000 abstract description 10
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 abstract description 4
- 210000004027 cell Anatomy 0.000 description 130
- 239000000562 conjugate Substances 0.000 description 97
- 230000015572 biosynthetic process Effects 0.000 description 57
- 238000003786 synthesis reaction Methods 0.000 description 57
- 239000011230 binding agent Substances 0.000 description 52
- 229910052757 nitrogen Inorganic materials 0.000 description 48
- 125000003396 thiol group Chemical class [H]S* 0.000 description 45
- 108090000765 processed proteins & peptides Proteins 0.000 description 43
- 239000000427 antigen Substances 0.000 description 40
- 108091007433 antigens Proteins 0.000 description 40
- 102000036639 antigens Human genes 0.000 description 40
- 125000000217 alkyl group Chemical group 0.000 description 37
- 150000001413 amino acids Chemical class 0.000 description 36
- 125000003118 aryl group Chemical group 0.000 description 34
- 229940024606 amino acid Drugs 0.000 description 33
- 235000001014 amino acid Nutrition 0.000 description 33
- 238000000034 method Methods 0.000 description 32
- 125000001072 heteroaryl group Chemical group 0.000 description 30
- 125000004432 carbon atom Chemical group C* 0.000 description 28
- 102000005962 receptors Human genes 0.000 description 28
- 108020003175 receptors Proteins 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- 241000700605 Viruses Species 0.000 description 27
- 102000004196 processed proteins & peptides Human genes 0.000 description 25
- 108090000623 proteins and genes Proteins 0.000 description 25
- 125000000623 heterocyclic group Chemical group 0.000 description 24
- 235000018102 proteins Nutrition 0.000 description 23
- 102000004169 proteins and genes Human genes 0.000 description 23
- 241000282414 Homo sapiens Species 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- 150000002148 esters Chemical class 0.000 description 21
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 19
- 150000001408 amides Chemical class 0.000 description 18
- 125000000753 cycloalkyl group Chemical group 0.000 description 18
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 18
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 17
- 239000002254 cytotoxic agent Substances 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 125000004404 heteroalkyl group Chemical group 0.000 description 17
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 17
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 229940049595 antibody-drug conjugate Drugs 0.000 description 15
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 15
- 125000000524 functional group Chemical group 0.000 description 15
- 239000003112 inhibitor Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 231100000599 cytotoxic agent Toxicity 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 14
- 208000011580 syndromic disease Diseases 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 206010033128 Ovarian cancer Diseases 0.000 description 12
- 206010035226 Plasma cell myeloma Diseases 0.000 description 12
- 150000008064 anhydrides Chemical class 0.000 description 12
- 201000001441 melanoma Diseases 0.000 description 12
- 229920001184 polypeptide Polymers 0.000 description 12
- 229910052717 sulfur Inorganic materials 0.000 description 12
- 150000003568 thioethers Chemical class 0.000 description 12
- 206010009944 Colon cancer Diseases 0.000 description 11
- 102000003886 Glycoproteins Human genes 0.000 description 11
- 108090000288 Glycoproteins Proteins 0.000 description 11
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 11
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 11
- 206010061535 Ovarian neoplasm Diseases 0.000 description 11
- 206010060862 Prostate cancer Diseases 0.000 description 11
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 11
- 102100040112 Tumor necrosis factor receptor superfamily member 10B Human genes 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 11
- 239000003446 ligand Substances 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 230000003612 virological effect Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 208000034578 Multiple myelomas Diseases 0.000 description 10
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 10
- 229910052736 halogen Inorganic materials 0.000 description 10
- 150000007857 hydrazones Chemical class 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 9
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 9
- 102100040247 Tumor necrosis factor Human genes 0.000 description 9
- 206010017758 gastric cancer Diseases 0.000 description 9
- 125000005179 haloacetyl group Chemical group 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 9
- 229960005190 phenylalanine Drugs 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 102100031940 Epithelial cell adhesion molecule Human genes 0.000 description 8
- 206010025323 Lymphomas Diseases 0.000 description 8
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 8
- 102100034256 Mucin-1 Human genes 0.000 description 8
- 125000005262 alkoxyamine group Chemical group 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 239000000611 antibody drug conjugate Substances 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 229920001223 polyethylene glycol Polymers 0.000 description 8
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 8
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 7
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 7
- 239000002202 Polyethylene glycol Substances 0.000 description 7
- 208000005718 Stomach Neoplasms Diseases 0.000 description 7
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- 125000004450 alkenylene group Chemical group 0.000 description 7
- 125000002947 alkylene group Chemical group 0.000 description 7
- 125000004419 alkynylene group Chemical group 0.000 description 7
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 7
- 229960004679 doxorubicin Drugs 0.000 description 7
- 208000006454 hepatitis Diseases 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 7
- 201000005202 lung cancer Diseases 0.000 description 7
- 208000020816 lung neoplasm Diseases 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 7
- 201000011549 stomach cancer Diseases 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 7
- DLKUYSQUHXBYPB-NSSHGSRYSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[3-methylbutanoyloxymethyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-(4-methylphenyl)pentanoic acid Chemical class N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C DLKUYSQUHXBYPB-NSSHGSRYSA-N 0.000 description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 229940045513 CTLA4 antagonist Drugs 0.000 description 6
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 description 6
- 229930186147 Cephalosporin Natural products 0.000 description 6
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 102000001301 EGF receptor Human genes 0.000 description 6
- 241000709661 Enterovirus Species 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 6
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000006751 Mitsunobu reaction Methods 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 210000001744 T-lymphocyte Anatomy 0.000 description 6
- 102100033579 Trophoblast glycoprotein Human genes 0.000 description 6
- 230000001154 acute effect Effects 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 125000000033 alkoxyamino group Chemical group 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 229940124587 cephalosporin Drugs 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 235000018417 cysteine Nutrition 0.000 description 6
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical class NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 6
- 206010014599 encephalitis Diseases 0.000 description 6
- 150000002170 ethers Chemical class 0.000 description 6
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 231100000283 hepatitis Toxicity 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 150000002466 imines Chemical class 0.000 description 6
- 230000001024 immunotherapeutic effect Effects 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 208000032839 leukemia Diseases 0.000 description 6
- 230000003211 malignant effect Effects 0.000 description 6
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 238000001542 size-exclusion chromatography Methods 0.000 description 6
- 229940126586 small molecule drug Drugs 0.000 description 6
- 150000007970 thio esters Chemical class 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 229960001612 trastuzumab emtansine Drugs 0.000 description 6
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical class CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 description 5
- 108010006654 Bleomycin Proteins 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 241000701022 Cytomegalovirus Species 0.000 description 5
- 108010066687 Epithelial Cell Adhesion Molecule Proteins 0.000 description 5
- 208000017604 Hodgkin disease Diseases 0.000 description 5
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 5
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 5
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 5
- 108010038453 Interleukin-2 Receptors Proteins 0.000 description 5
- 102000010789 Interleukin-2 Receptors Human genes 0.000 description 5
- 102000004889 Interleukin-6 Human genes 0.000 description 5
- 108090001005 Interleukin-6 Proteins 0.000 description 5
- 102100037792 Interleukin-6 receptor subunit alpha Human genes 0.000 description 5
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 5
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 5
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 5
- 206010037742 Rabies Diseases 0.000 description 5
- 208000002474 Tinea Diseases 0.000 description 5
- 102100029675 Tumor necrosis factor receptor superfamily member 13B Human genes 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 230000001363 autoimmune Effects 0.000 description 5
- 210000000481 breast Anatomy 0.000 description 5
- 239000004202 carbamide Substances 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 229960002173 citrulline Drugs 0.000 description 5
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 5
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 5
- 235000004554 glutamine Nutrition 0.000 description 5
- 229960003180 glutathione Drugs 0.000 description 5
- 229930182470 glycoside Natural products 0.000 description 5
- 150000002338 glycosides Chemical class 0.000 description 5
- 208000002672 hepatitis B Diseases 0.000 description 5
- 210000004408 hybridoma Anatomy 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 229940100601 interleukin-6 Drugs 0.000 description 5
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 5
- 230000000813 microbial effect Effects 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- JSHOVKSMJRQOGY-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-(pyridin-2-yldisulfanyl)butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCSSC1=CC=CC=N1 JSHOVKSMJRQOGY-UHFFFAOYSA-N 0.000 description 4
- BQWBEDSJTMWJAE-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-[(2-iodoacetyl)amino]benzoate Chemical compound C1=CC(NC(=O)CI)=CC=C1C(=O)ON1C(=O)CCC1=O BQWBEDSJTMWJAE-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 4
- FDKWRPBBCBCIGA-REOHCLBHSA-N (2r)-2-azaniumyl-3-$l^{1}-selanylpropanoate Chemical compound [Se]C[C@H](N)C(O)=O FDKWRPBBCBCIGA-REOHCLBHSA-N 0.000 description 4
- AGGWFDNPHKLBBV-YUMQZZPRSA-N (2s)-2-[[(2s)-2-amino-3-methylbutanoyl]amino]-5-(carbamoylamino)pentanoic acid Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCNC(N)=O AGGWFDNPHKLBBV-YUMQZZPRSA-N 0.000 description 4
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 4
- 241000193738 Bacillus anthracis Species 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 4
- 241000589562 Brucella Species 0.000 description 4
- 108700012439 CA9 Proteins 0.000 description 4
- 102100038078 CD276 antigen Human genes 0.000 description 4
- 241000222122 Candida albicans Species 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 description 4
- 102100025466 Carcinoembryonic antigen-related cell adhesion molecule 3 Human genes 0.000 description 4
- 241000711573 Coronaviridae Species 0.000 description 4
- FDKWRPBBCBCIGA-UWTATZPHSA-N D-Selenocysteine Natural products [Se]C[C@@H](N)C(O)=O FDKWRPBBCBCIGA-UWTATZPHSA-N 0.000 description 4
- 108060006698 EGF receptor Proteins 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- 208000007465 Giant cell arteritis Diseases 0.000 description 4
- 102100041003 Glutamate carboxypeptidase 2 Human genes 0.000 description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
- 102100022662 Guanylyl cyclase C Human genes 0.000 description 4
- 101710154606 Hemagglutinin Proteins 0.000 description 4
- 241000700721 Hepatitis B virus Species 0.000 description 4
- 101000914337 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 3 Proteins 0.000 description 4
- 101000892862 Homo sapiens Glutamate carboxypeptidase 2 Proteins 0.000 description 4
- 101000801433 Homo sapiens Trophoblast glycoprotein Proteins 0.000 description 4
- 101000610604 Homo sapiens Tumor necrosis factor receptor superfamily member 10B Proteins 0.000 description 4
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 4
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- 102000000588 Interleukin-2 Human genes 0.000 description 4
- 108010038501 Interleukin-6 Receptors Proteins 0.000 description 4
- RWSXRVCMGQZWBV-PHDIDXHHSA-N L-Glutathione Natural products OC(=O)[C@H](N)CCC(=O)N[C@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-PHDIDXHHSA-N 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 4
- 102000000440 Melanoma-associated antigen Human genes 0.000 description 4
- 108050008953 Melanoma-associated antigen Proteins 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- FDJKUWYYUZCUJX-UHFFFAOYSA-N N-glycolyl-beta-neuraminic acid Natural products OCC(O)C(O)C1OC(O)(C(O)=O)CC(O)C1NC(=O)CO FDJKUWYYUZCUJX-UHFFFAOYSA-N 0.000 description 4
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 4
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 4
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 4
- 206010034277 Pemphigoid Diseases 0.000 description 4
- 101710176177 Protein A56 Proteins 0.000 description 4
- 208000006265 Renal cell carcinoma Diseases 0.000 description 4
- 241000725643 Respiratory syncytial virus Species 0.000 description 4
- 241000606701 Rickettsia Species 0.000 description 4
- 241000130764 Tinea Species 0.000 description 4
- 108010009583 Transforming Growth Factors Proteins 0.000 description 4
- 102000009618 Transforming Growth Factors Human genes 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 101710178278 Tumor necrosis factor receptor superfamily member 10B Proteins 0.000 description 4
- 101710178302 Tumor necrosis factor receptor superfamily member 13B Proteins 0.000 description 4
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 125000003172 aldehyde group Chemical group 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 230000003097 anti-respiratory effect Effects 0.000 description 4
- 239000012736 aqueous medium Substances 0.000 description 4
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 210000001185 bone marrow Anatomy 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical compound NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 150000001780 cephalosporins Chemical class 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 230000021615 conjugation Effects 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 4
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 4
- 235000019152 folic acid Nutrition 0.000 description 4
- 239000011724 folic acid Substances 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 125000003827 glycol group Chemical group 0.000 description 4
- 150000004820 halides Chemical group 0.000 description 4
- 239000000185 hemagglutinin Substances 0.000 description 4
- 125000002883 imidazolyl group Chemical group 0.000 description 4
- 206010022000 influenza Diseases 0.000 description 4
- 102000006495 integrins Human genes 0.000 description 4
- 108010044426 integrins Proteins 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 208000028454 lice infestation Diseases 0.000 description 4
- 210000004698 lymphocyte Anatomy 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229960003151 mercaptamine Drugs 0.000 description 4
- GBCAVSYHPPARHX-UHFFFAOYSA-M n'-cyclohexyl-n-[2-(4-methylmorpholin-4-ium-4-yl)ethyl]methanediimine;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.C1CCCCC1N=C=NCC[N+]1(C)CCOCC1 GBCAVSYHPPARHX-UHFFFAOYSA-M 0.000 description 4
- 229960001972 panitumumab Drugs 0.000 description 4
- 238000002823 phage display Methods 0.000 description 4
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical group OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 4
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 4
- 229920000768 polyamine Polymers 0.000 description 4
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 4
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical compound C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 4
- 229960001225 rifampicin Drugs 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- ZKZBPNGNEQAJSX-UHFFFAOYSA-N selenocysteine Natural products [SeH]CC(N)C(O)=O ZKZBPNGNEQAJSX-UHFFFAOYSA-N 0.000 description 4
- 229940055619 selenocysteine Drugs 0.000 description 4
- 235000016491 selenocysteine Nutrition 0.000 description 4
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 4
- 150000003852 triazoles Chemical class 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 4
- 239000004474 valine Substances 0.000 description 4
- 229910052727 yttrium Inorganic materials 0.000 description 4
- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 description 3
- FFILOTSTFMXQJC-QCFYAKGBSA-N (2r,4r,5s,6s)-2-[3-[(2s,3s,4r,6s)-6-[(2s,3r,4r,5s,6r)-5-[(2s,3r,4r,5r,6r)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2-[(2r,3s,4r,5r,6r)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(e)-3-hydroxy-2-(octadecanoylamino)octadec-4-enoxy]oxan-3-yl]oxy-3-hy Chemical compound O[C@@H]1[C@@H](O)[C@H](OCC(NC(=O)CCCCCCCCCCCCCCCCC)C(O)\C=C\CCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@@H]([C@@H](N)[C@H](O)C2)C(O)C(O)CO[C@]2(O[C@@H]([C@@H](N)[C@H](O)C2)C(O)C(O)CO)C(O)=O)C(O)=O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](CO)O1 FFILOTSTFMXQJC-QCFYAKGBSA-N 0.000 description 3
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 3
- RULKYXXCCZZKDZ-UHFFFAOYSA-N 2,3,4,5-tetrachlorophenol Chemical compound OC1=CC(Cl)=C(Cl)C(Cl)=C1Cl RULKYXXCCZZKDZ-UHFFFAOYSA-N 0.000 description 3
- RPEPGIOVXBBUMJ-UHFFFAOYSA-N 2,3-difluorophenol Chemical compound OC1=CC=CC(F)=C1F RPEPGIOVXBBUMJ-UHFFFAOYSA-N 0.000 description 3
- UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-UHFFFAOYSA-N 0.000 description 3
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 3
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 3
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 3
- 102100031585 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Human genes 0.000 description 3
- OMNVYXHOSHNURL-WPRPVWTQSA-N Ala-Phe Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 OMNVYXHOSHNURL-WPRPVWTQSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- 102100034605 Atrial natriuretic peptide receptor 3 Human genes 0.000 description 3
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 3
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 3
- 102100032412 Basigin Human genes 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000589968 Borrelia Species 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 3
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 3
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 3
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 3
- 108050005493 CD3 protein, epsilon/gamma/delta subunit Proteins 0.000 description 3
- 101150013553 CD40 gene Proteins 0.000 description 3
- 102100025221 CD70 antigen Human genes 0.000 description 3
- 206010007134 Candida infections Diseases 0.000 description 3
- 206010008761 Choriomeningitis lymphocytic Diseases 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 3
- 102100037241 Endoglin Human genes 0.000 description 3
- 241000991587 Enterovirus C Species 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 208000001640 Fibromyalgia Diseases 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 206010061192 Haemorrhagic fever Diseases 0.000 description 3
- 241000711549 Hepacivirus C Species 0.000 description 3
- 101000777636 Homo sapiens ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 Proteins 0.000 description 3
- 101000924488 Homo sapiens Atrial natriuretic peptide receptor 3 Proteins 0.000 description 3
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 3
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 3
- 101000798441 Homo sapiens Basigin Proteins 0.000 description 3
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 3
- 101000934356 Homo sapiens CD70 antigen Proteins 0.000 description 3
- 101000914324 Homo sapiens Carcinoembryonic antigen-related cell adhesion molecule 5 Proteins 0.000 description 3
- 101000920667 Homo sapiens Epithelial cell adhesion molecule Proteins 0.000 description 3
- 101000899808 Homo sapiens Guanylyl cyclase C Proteins 0.000 description 3
- 101001046677 Homo sapiens Integrin alpha-V Proteins 0.000 description 3
- 101000578784 Homo sapiens Melanoma antigen recognized by T-cells 1 Proteins 0.000 description 3
- 101000623901 Homo sapiens Mucin-16 Proteins 0.000 description 3
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 3
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 description 3
- 101001094545 Homo sapiens Retrotransposon-like protein 1 Proteins 0.000 description 3
- 101000716102 Homo sapiens T-cell surface glycoprotein CD4 Proteins 0.000 description 3
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 3
- 241001502974 Human gammaherpesvirus 8 Species 0.000 description 3
- 241000711920 Human orthopneumovirus Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- 102100022337 Integrin alpha-V Human genes 0.000 description 3
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 description 3
- 108010074328 Interferon-gamma Proteins 0.000 description 3
- 102000008070 Interferon-gamma Human genes 0.000 description 3
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 3
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 208000007764 Legionnaires' Disease Diseases 0.000 description 3
- 241000222722 Leishmania <genus> Species 0.000 description 3
- 208000016604 Lyme disease Diseases 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- 229930126263 Maytansine Natural products 0.000 description 3
- 239000000637 Melanocyte-Stimulating Hormone Substances 0.000 description 3
- 108010007013 Melanocyte-Stimulating Hormones Proteins 0.000 description 3
- 102100028389 Melanoma antigen recognized by T-cells 1 Human genes 0.000 description 3
- 102100023123 Mucin-16 Human genes 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 3
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 3
- SUHQNCLNRUAGOO-UHFFFAOYSA-N N-glycoloyl-neuraminic acid Natural products OCC(O)C(O)C(O)C(NC(=O)CO)C(O)CC(=O)C(O)=O SUHQNCLNRUAGOO-UHFFFAOYSA-N 0.000 description 3
- FDJKUWYYUZCUJX-KVNVFURPSA-N N-glycolylneuraminic acid Chemical compound OC[C@H](O)[C@H](O)[C@@H]1O[C@](O)(C(O)=O)C[C@H](O)[C@H]1NC(=O)CO FDJKUWYYUZCUJX-KVNVFURPSA-N 0.000 description 3
- PRXGMEURJXGKOP-UHFFFAOYSA-N NP(N)=O Chemical compound NP(N)=O PRXGMEURJXGKOP-UHFFFAOYSA-N 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 3
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 description 3
- 241000187654 Nocardia Species 0.000 description 3
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 3
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 108091000054 Prion Proteins 0.000 description 3
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010037660 Pyrexia Diseases 0.000 description 3
- 206010061603 Respiratory syncytial virus infection Diseases 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- 108020004459 Small interfering RNA Proteins 0.000 description 3
- 102100035721 Syndecan-1 Human genes 0.000 description 3
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 3
- 108010000449 TNF-Related Apoptosis-Inducing Ligand Receptors Proteins 0.000 description 3
- 241000244155 Taenia Species 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 3
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 3
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 description 3
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 3
- 208000018756 Variant Creutzfeldt-Jakob disease Diseases 0.000 description 3
- 241000700647 Variola virus Species 0.000 description 3
- 102100023543 Vascular cell adhesion protein 1 Human genes 0.000 description 3
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 3
- 206010047115 Vasculitis Diseases 0.000 description 3
- 241000607598 Vibrio Species 0.000 description 3
- 241000607479 Yersinia pestis Species 0.000 description 3
- 206010061418 Zygomycosis Diseases 0.000 description 3
- 125000002015 acyclic group Chemical group 0.000 description 3
- 150000001266 acyl halides Chemical class 0.000 description 3
- 229960003767 alanine Drugs 0.000 description 3
- 235000004279 alanine Nutrition 0.000 description 3
- 108010011559 alanylphenylalanine Proteins 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 150000001345 alkine derivatives Chemical class 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 3
- 229960000723 ampicillin Drugs 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 230000002529 anti-mitochondrial effect Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 235000009697 arginine Nutrition 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 235000009582 asparagine Nutrition 0.000 description 3
- 229960001230 asparagine Drugs 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- 210000003719 b-lymphocyte Anatomy 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- 229960001561 bleomycin Drugs 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000002798 bone marrow cell Anatomy 0.000 description 3
- 201000003984 candidiasis Diseases 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 229960002129 cefixime Drugs 0.000 description 3
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 3
- 230000015861 cell surface binding Effects 0.000 description 3
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 3
- 229940106164 cephalexin Drugs 0.000 description 3
- 229960005395 cetuximab Drugs 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- 229930013356 epothilone Natural products 0.000 description 3
- 150000003883 epothilone derivatives Chemical class 0.000 description 3
- 229960000390 fludarabine Drugs 0.000 description 3
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 229960000304 folic acid Drugs 0.000 description 3
- VGGRCVDNFAQIKO-UHFFFAOYSA-N formic anhydride Chemical compound O=COC=O VGGRCVDNFAQIKO-UHFFFAOYSA-N 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- 210000003714 granulocyte Anatomy 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 3
- 125000004475 heteroaralkyl group Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 229960003130 interferon gamma Drugs 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000004255 ion exchange chromatography Methods 0.000 description 3
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 3
- 229950000518 labetuzumab Drugs 0.000 description 3
- 208000001419 lymphocytic choriomeningitis Diseases 0.000 description 3
- 230000036210 malignancy Effects 0.000 description 3
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 3
- 238000012737 microarray-based gene expression Methods 0.000 description 3
- 238000012243 multiplex automated genomic engineering Methods 0.000 description 3
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 3
- 229960000951 mycophenolic acid Drugs 0.000 description 3
- 201000005962 mycosis fungoides Diseases 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 150000002923 oximes Chemical class 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 3
- 201000000317 pneumocystosis Diseases 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229920002635 polyurethane Polymers 0.000 description 3
- 239000004814 polyurethane Substances 0.000 description 3
- 229960002429 proline Drugs 0.000 description 3
- 210000002307 prostate Anatomy 0.000 description 3
- 229960000885 rifabutin Drugs 0.000 description 3
- 201000005404 rubella Diseases 0.000 description 3
- HXCHCVDVKSCDHU-PJKCJEBCSA-N s-[(2r,3s,4s,6s)-6-[[(2r,3s,4s,5r,6r)-5-[(2s,4s,5s)-5-(ethylamino)-4-methoxyoxan-2-yl]oxy-4-hydroxy-6-[[(2s,5z,9r,13e)-9-hydroxy-12-(methoxycarbonylamino)-13-[2-(methyltrisulfanyl)ethylidene]-11-oxo-2-bicyclo[7.3.1]trideca-1(12),5-dien-3,7-diynyl]oxy]-2-m Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-PJKCJEBCSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000011669 selenium Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000004055 small Interfering RNA Substances 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- 150000003456 sulfonamides Chemical class 0.000 description 3
- 206010043207 temporal arteritis Diseases 0.000 description 3
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 3
- FPZLLRFZJZRHSY-HJYUBDRYSA-N tigecycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O FPZLLRFZJZRHSY-HJYUBDRYSA-N 0.000 description 3
- 229960004089 tigecycline Drugs 0.000 description 3
- 229960003989 tocilizumab Drugs 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- 241001529453 unidentified herpesvirus Species 0.000 description 3
- 241000712461 unidentified influenza virus Species 0.000 description 3
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 3
- AADVCYNFEREWOS-UHFFFAOYSA-N (+)-DDM Natural products C=CC=CC(C)C(OC(N)=O)C(C)C(O)C(C)CC(C)=CC(C)C(O)C(C)C=CC(O)CC1OC(=O)C(C)C(O)C1C AADVCYNFEREWOS-UHFFFAOYSA-N 0.000 description 2
- UIFGGABIJBWRMG-FMQUCBEESA-N (4-chlorophenyl)methyl (ne)-n-[(4-chlorophenyl)methoxycarbonylimino]carbamate Chemical compound C1=CC(Cl)=CC=C1COC(=O)\N=N\C(=O)OCC1=CC=C(Cl)C=C1 UIFGGABIJBWRMG-FMQUCBEESA-N 0.000 description 2
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical class C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 2
- OMRPLUKQNWNZAV-CONSDPRKSA-N (6as)-3-[3-[[(6as)-2-methoxy-8-(4-methoxyphenyl)-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-8-(4-aminophenyl)-2-methoxy-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical class C1=CC(OC)=CC=C1C1=CN2C(=O)C3=CC(OC)=C(OCCCOC=4C(=CC=5C(=O)N6C=C(C[C@H]6C=NC=5C=4)C=4C=CC(N)=CC=4)OC)C=C3N=C[C@@H]2C1 OMRPLUKQNWNZAV-CONSDPRKSA-N 0.000 description 2
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 2
- QXYLYYZZWZQACI-UHFFFAOYSA-N 2,3,4,5-tetrafluorophenol Chemical compound OC1=CC(F)=C(F)C(F)=C1F QXYLYYZZWZQACI-UHFFFAOYSA-N 0.000 description 2
- UMPSXRYVXUPCOS-UHFFFAOYSA-N 2,3-dichlorophenol Chemical compound OC1=CC=CC(Cl)=C1Cl UMPSXRYVXUPCOS-UHFFFAOYSA-N 0.000 description 2
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- QZDDFQLIQRYMBV-UHFFFAOYSA-N 2-[3-nitro-2-(2-nitrophenyl)-4-oxochromen-8-yl]acetic acid Chemical compound OC(=O)CC1=CC=CC(C(C=2[N+]([O-])=O)=O)=C1OC=2C1=CC=CC=C1[N+]([O-])=O QZDDFQLIQRYMBV-UHFFFAOYSA-N 0.000 description 2
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical group OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 description 2
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 2
- QBLRHWLVSHLMSP-UHFFFAOYSA-N 3-bromopyrrole-2,5-dione Chemical compound BrC1=CC(=O)NC1=O QBLRHWLVSHLMSP-UHFFFAOYSA-N 0.000 description 2
- QXZBMSIDSOZZHK-DOPDSADYSA-N 31362-50-2 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C(C)C)C1=CNC=N1 QXZBMSIDSOZZHK-DOPDSADYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- MFRZPLYKVDHOSN-UHFFFAOYSA-N 4-(2-isocyanoethyl)morpholine Chemical compound [C-]#[N+]CCN1CCOCC1 MFRZPLYKVDHOSN-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- 102100033400 4F2 cell-surface antigen heavy chain Human genes 0.000 description 2
- 102100030310 5,6-dihydroxyindole-2-carboxylic acid oxidase Human genes 0.000 description 2
- SSPYSWLZOPCOLO-UHFFFAOYSA-N 6-azauracil Chemical compound O=C1C=NNC(=O)N1 SSPYSWLZOPCOLO-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- XKJMBINCVNINCA-UHFFFAOYSA-N Alfalone Chemical compound CON(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XKJMBINCVNINCA-UHFFFAOYSA-N 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 102100025677 Alkaline phosphatase, germ cell type Human genes 0.000 description 2
- 206010001935 American trypanosomiasis Diseases 0.000 description 2
- 102100022749 Aminopeptidase N Human genes 0.000 description 2
- 102000008076 Angiogenic Proteins Human genes 0.000 description 2
- 108010074415 Angiogenic Proteins Proteins 0.000 description 2
- 102000004145 Annexin A1 Human genes 0.000 description 2
- 108090000663 Annexin A1 Proteins 0.000 description 2
- 108010032595 Antibody Binding Sites Proteins 0.000 description 2
- 101710145634 Antigen 1 Proteins 0.000 description 2
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 2
- 241000244186 Ascaris Species 0.000 description 2
- 108010028006 B-Cell Activating Factor Proteins 0.000 description 2
- 241000223836 Babesia Species 0.000 description 2
- 102100038341 Blood group Rh(CE) polypeptide Human genes 0.000 description 2
- 108010051479 Bombesin Proteins 0.000 description 2
- 102000013585 Bombesin Human genes 0.000 description 2
- 208000003508 Botulism Diseases 0.000 description 2
- 241001453380 Burkholderia Species 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- 102100037853 C-C chemokine receptor type 4 Human genes 0.000 description 2
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 description 2
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 2
- 108010049990 CD13 Antigens Proteins 0.000 description 2
- 102100027207 CD27 antigen Human genes 0.000 description 2
- 108010065524 CD52 Antigen Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000589876 Campylobacter Species 0.000 description 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 2
- 208000005024 Castleman disease Diseases 0.000 description 2
- 108010001857 Cell Surface Receptors Proteins 0.000 description 2
- 102000000844 Cell Surface Receptors Human genes 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 208000024699 Chagas disease Diseases 0.000 description 2
- 241000606153 Chlamydia trachomatis Species 0.000 description 2
- 101800001982 Cholecystokinin Proteins 0.000 description 2
- 102100025841 Cholecystokinin Human genes 0.000 description 2
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 2
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 2
- 102100040835 Claudin-18 Human genes 0.000 description 2
- 241000193403 Clostridium Species 0.000 description 2
- 208000037384 Clostridium Infections Diseases 0.000 description 2
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 2
- 201000007336 Cryptococcosis Diseases 0.000 description 2
- 241000221204 Cryptococcus neoformans Species 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- AADVCYNFEREWOS-OBRABYBLSA-N Discodermolide Chemical compound C=C\C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C\C(C)=C/[C@H](C)[C@@H](O)[C@@H](C)\C=C/[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C AADVCYNFEREWOS-OBRABYBLSA-N 0.000 description 2
- 241000605314 Ehrlichia Species 0.000 description 2
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 2
- 108010036395 Endoglin Proteins 0.000 description 2
- 241000224432 Entamoeba histolytica Species 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102400001368 Epidermal growth factor Human genes 0.000 description 2
- 101800003838 Epidermal growth factor Proteins 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- 208000007985 Erythema Infectiosum Diseases 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical group C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 2
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 2
- 201000006353 Filariasis Diseases 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- 102100035139 Folate receptor alpha Human genes 0.000 description 2
- 102100028875 Formylglycine-generating enzyme Human genes 0.000 description 2
- 101710192607 Formylglycine-generating enzyme Proteins 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- IECPWNUMDGFDKC-UHFFFAOYSA-N Fusicsaeure Natural products C12C(O)CC3C(=C(CCC=C(C)C)C(O)=O)C(OC(C)=O)CC3(C)C1(C)CCC1C2(C)CCC(O)C1C IECPWNUMDGFDKC-UHFFFAOYSA-N 0.000 description 2
- WMBWREPUVVBILR-UHFFFAOYSA-N GCG Natural products C=1C(O)=C(O)C(O)=CC=1C1OC2=CC(O)=CC(O)=C2CC1OC(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-UHFFFAOYSA-N 0.000 description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 2
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 description 2
- AIJTTZAVMXIJGM-UHFFFAOYSA-N Grepafloxacin Chemical compound C1CNC(C)CN1C(C(=C1C)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 AIJTTZAVMXIJGM-UHFFFAOYSA-N 0.000 description 2
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 description 2
- 102100030595 HLA class II histocompatibility antigen gamma chain Human genes 0.000 description 2
- 108010036449 HLA-DR10 antigen Proteins 0.000 description 2
- 208000020061 Hand, Foot and Mouth Disease Diseases 0.000 description 2
- 208000025713 Hand-foot-and-mouth disease Diseases 0.000 description 2
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 2
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 2
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 2
- 241000724675 Hepatitis E virus Species 0.000 description 2
- 208000037262 Hepatitis delta Diseases 0.000 description 2
- 241000724709 Hepatitis delta virus Species 0.000 description 2
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 2
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 2
- 241000709721 Hepatovirus A Species 0.000 description 2
- 208000007514 Herpes zoster Diseases 0.000 description 2
- 102100026122 High affinity immunoglobulin gamma Fc receptor I Human genes 0.000 description 2
- 241000228404 Histoplasma capsulatum Species 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000800023 Homo sapiens 4F2 cell-surface antigen heavy chain Proteins 0.000 description 2
- 101000773083 Homo sapiens 5,6-dihydroxyindole-2-carboxylic acid oxidase Proteins 0.000 description 2
- 101000574440 Homo sapiens Alkaline phosphatase, germ cell type Proteins 0.000 description 2
- 101000666610 Homo sapiens Blood group Rh(CE) polypeptide Proteins 0.000 description 2
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 2
- 101001023230 Homo sapiens Folate receptor alpha Proteins 0.000 description 2
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 2
- 101001082627 Homo sapiens HLA class II histocompatibility antigen gamma chain Proteins 0.000 description 2
- 101000913074 Homo sapiens High affinity immunoglobulin gamma Fc receptor I Proteins 0.000 description 2
- 101001055308 Homo sapiens Immunoglobulin heavy constant epsilon Proteins 0.000 description 2
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 description 2
- 101001076292 Homo sapiens Insulin-like growth factor II Proteins 0.000 description 2
- 101001078133 Homo sapiens Integrin alpha-2 Proteins 0.000 description 2
- 101000935040 Homo sapiens Integrin beta-2 Proteins 0.000 description 2
- 101000960936 Homo sapiens Interleukin-5 receptor subunit alpha Proteins 0.000 description 2
- 101000605020 Homo sapiens Large neutral amino acids transporter small subunit 1 Proteins 0.000 description 2
- 101000777628 Homo sapiens Leukocyte antigen CD37 Proteins 0.000 description 2
- 101000622137 Homo sapiens P-selectin Proteins 0.000 description 2
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 2
- 101000650590 Homo sapiens Roundabout homolog 4 Proteins 0.000 description 2
- 101000874179 Homo sapiens Syndecan-1 Proteins 0.000 description 2
- 101000934346 Homo sapiens T-cell surface antigen CD2 Proteins 0.000 description 2
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 2
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 2
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 2
- 101000800116 Homo sapiens Thy-1 membrane glycoprotein Proteins 0.000 description 2
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 2
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 2
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 2
- 241000046923 Human bocavirus Species 0.000 description 2
- 241000342334 Human metapneumovirus Species 0.000 description 2
- 241000701806 Human papillomavirus Species 0.000 description 2
- 241000829111 Human polyomavirus 1 Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 102000004157 Hydrolases Human genes 0.000 description 2
- 108090000604 Hydrolases Proteins 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 102100026212 Immunoglobulin heavy constant epsilon Human genes 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 2
- 101710184277 Insulin-like growth factor 1 receptor Proteins 0.000 description 2
- 102100025947 Insulin-like growth factor II Human genes 0.000 description 2
- 102100025305 Integrin alpha-2 Human genes 0.000 description 2
- 102100025390 Integrin beta-2 Human genes 0.000 description 2
- 108010064593 Intercellular Adhesion Molecule-1 Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000004388 Interleukin-4 Human genes 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 108010002616 Interleukin-5 Proteins 0.000 description 2
- 102100039897 Interleukin-5 Human genes 0.000 description 2
- 102100039881 Interleukin-5 receptor subunit alpha Human genes 0.000 description 2
- 208000003456 Juvenile Arthritis Diseases 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- 208000011200 Kawasaki disease Diseases 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 241000588748 Klebsiella Species 0.000 description 2
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 108090001090 Lectins Proteins 0.000 description 2
- 102000004856 Lectins Human genes 0.000 description 2
- 208000004023 Legionellosis Diseases 0.000 description 2
- 208000035353 Legionnaires disease Diseases 0.000 description 2
- 102100031586 Leukocyte antigen CD37 Human genes 0.000 description 2
- 208000012309 Linear IgA disease Diseases 0.000 description 2
- 241000712899 Lymphocytic choriomeningitis mammarenavirus Species 0.000 description 2
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 201000005505 Measles Diseases 0.000 description 2
- 102100022430 Melanocyte protein PMEL Human genes 0.000 description 2
- 201000009906 Meningitis Diseases 0.000 description 2
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 2
- 102000003735 Mesothelin Human genes 0.000 description 2
- 108090000015 Mesothelin Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010049567 Miller Fisher syndrome Diseases 0.000 description 2
- 241000700560 Molluscum contagiosum virus Species 0.000 description 2
- 208000003445 Mouth Neoplasms Diseases 0.000 description 2
- 108010008707 Mucin-1 Proteins 0.000 description 2
- 241000235395 Mucor Species 0.000 description 2
- 208000005647 Mumps Diseases 0.000 description 2
- 241000711386 Mumps virus Species 0.000 description 2
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 2
- 108010056852 Myostatin Proteins 0.000 description 2
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
- UGJBHEZMOKVTIM-UHFFFAOYSA-N N-formylglycine Chemical compound OC(=O)CNC=O UGJBHEZMOKVTIM-UHFFFAOYSA-N 0.000 description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 2
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 2
- 241000588653 Neisseria Species 0.000 description 2
- 102000003729 Neprilysin Human genes 0.000 description 2
- 108090000028 Neprilysin Proteins 0.000 description 2
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 2
- 102100021010 Nucleolin Human genes 0.000 description 2
- GXLFYVWQXRNZON-UHFFFAOYSA-N O1N=NC(C=2C=CC=CC=2)=C1S(=O)(=O)C Chemical compound O1N=NC(C=2C=CC=CC=2)=C1S(=O)(=O)C GXLFYVWQXRNZON-UHFFFAOYSA-N 0.000 description 2
- 239000004104 Oleandomycin Substances 0.000 description 2
- RZPAKFUAFGMUPI-UHFFFAOYSA-N Oleandomycin Natural products O1C(C)C(O)C(OC)CC1OC1C(C)C(=O)OC(C)C(C)C(O)C(C)C(=O)C2(OC2)CC(C)C(OC2C(C(CC(C)O2)N(C)C)O)C1C RZPAKFUAFGMUPI-UHFFFAOYSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 102000043276 Oncogene Human genes 0.000 description 2
- 208000010195 Onychomycosis Diseases 0.000 description 2
- 101710160107 Outer membrane protein A Proteins 0.000 description 2
- 102100023472 P-selectin Human genes 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 241000606860 Pasteurella Species 0.000 description 2
- 241000517307 Pediculus humanus Species 0.000 description 2
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 2
- 208000007452 Plasmacytoma Diseases 0.000 description 2
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 description 2
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 description 2
- 206010035718 Pneumonia legionella Diseases 0.000 description 2
- 206010035737 Pneumonia viral Diseases 0.000 description 2
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 2
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 2
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 241000605861 Prevotella Species 0.000 description 2
- 102000029797 Prion Human genes 0.000 description 2
- 102100023832 Prolyl endopeptidase FAP Human genes 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 102100035703 Prostatic acid phosphatase Human genes 0.000 description 2
- 101710194807 Protective antigen Proteins 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 2
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 2
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
- 241000702670 Rotavirus Species 0.000 description 2
- 102100027701 Roundabout homolog 4 Human genes 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 241000242678 Schistosoma Species 0.000 description 2
- 241000242677 Schistosoma japonicum Species 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- 101710192761 Serine-type anaerobic sulfatase-maturating enzyme Proteins 0.000 description 2
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 2
- 108010079723 Shiga Toxin Proteins 0.000 description 2
- 241000607768 Shigella Species 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000006045 Spondylarthropathies Diseases 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 206010061372 Streptococcal infection Diseases 0.000 description 2
- 241000193996 Streptococcus pyogenes Species 0.000 description 2
- XBPJBGYZBLYHLT-WSMHCRMLSA-N Streptomyces coelicolor calcium-dependent antibiotic CDA4b Chemical compound CCCC1OC1C(=O)N[C@@H](CO)C(=O)N[C@@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C=2C=CC(O)=CC=2)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H]([C@H](O)C(N)=O)C(=O)N[C@@H](C(C)CC(O)=O)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)OC1C XBPJBGYZBLYHLT-WSMHCRMLSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108091008874 T cell receptors Proteins 0.000 description 2
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 2
- 206010042971 T-cell lymphoma Diseases 0.000 description 2
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 2
- 102100025237 T-cell surface antigen CD2 Human genes 0.000 description 2
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 description 2
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 2
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 description 2
- 206010057644 Testis cancer Diseases 0.000 description 2
- 206010043376 Tetanus Diseases 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- 102100033523 Thy-1 membrane glycoprotein Human genes 0.000 description 2
- 241000223997 Toxoplasma gondii Species 0.000 description 2
- 201000005485 Toxoplasmosis Diseases 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 108060008539 Transglutaminase Proteins 0.000 description 2
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 2
- 241000224526 Trichomonas Species 0.000 description 2
- 241000223229 Trichophyton rubrum Species 0.000 description 2
- 101710190034 Trophoblast glycoprotein Proteins 0.000 description 2
- 241000223105 Trypanosoma brucei Species 0.000 description 2
- 241000223109 Trypanosoma cruzi Species 0.000 description 2
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 description 2
- 102100036922 Tumor necrosis factor ligand superfamily member 13B Human genes 0.000 description 2
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 101800003344 Vaccinia growth factor Proteins 0.000 description 2
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 2
- IUKLSMSEHKDIIP-BZMYINFQSA-N Verticine Chemical compound C([C@@H]1[C@@H](O)C[C@H]2[C@@H]3CC[C@@H]4[C@]5(C)O)[C@@H](O)CC[C@]1(C)[C@H]2C[C@H]3[C@@H]4CN1[C@H]5CC[C@H](C)C1 IUKLSMSEHKDIIP-BZMYINFQSA-N 0.000 description 2
- 241000607734 Yersinia <bacteria> Species 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 229960000446 abciximab Drugs 0.000 description 2
- 229930183665 actinomycin Natural products 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000005377 adsorption chromatography Methods 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000004422 alkyl sulphonamide group Chemical group 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 2
- 102000013529 alpha-Fetoproteins Human genes 0.000 description 2
- 108010026331 alpha-Fetoproteins Proteins 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 235000008206 alpha-amino acids Nutrition 0.000 description 2
- 229960004821 amikacin Drugs 0.000 description 2
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 2
- 208000006730 anaplasmosis Diseases 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 230000001512 anti-cytomegaloviral effect Effects 0.000 description 2
- 230000001986 anti-endotoxic effect Effects 0.000 description 2
- 230000003432 anti-folate effect Effects 0.000 description 2
- 229940127074 antifolate Drugs 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 201000009361 ascariasis Diseases 0.000 description 2
- 244000309743 astrovirus Species 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 108010044540 auristatin Proteins 0.000 description 2
- 229960003005 axitinib Drugs 0.000 description 2
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 2
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 2
- 229960002170 azathioprine Drugs 0.000 description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 2
- 201000008680 babesiosis Diseases 0.000 description 2
- 229940065181 bacillus anthracis Drugs 0.000 description 2
- 150000001557 benzodiazepines Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- PPKJUHVNTMYXOD-PZGPJMECSA-N c49ws9n75l Chemical compound O=C([C@@H]1N(C2=O)CC[C@H]1S(=O)(=O)CCN(CC)CC)O[C@H](C(C)C)[C@H](C)\C=C\C(=O)NC\C=C\C(\C)=C\[C@@H](O)CC(=O)CC1=NC2=CO1.N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2C[C@@H](CS[C@H]3C4CCN(CC4)C3)C(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O PPKJUHVNTMYXOD-PZGPJMECSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229930195731 calicheamicin Natural products 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 229960004117 capecitabine Drugs 0.000 description 2
- 238000000738 capillary electrophoresis-mass spectrometry Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- MQLRYUCJDNBWMV-GHXIOONMSA-N cefetamet Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 MQLRYUCJDNBWMV-GHXIOONMSA-N 0.000 description 2
- 229960004041 cefetamet Drugs 0.000 description 2
- 229960004261 cefotaxime Drugs 0.000 description 2
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 2
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 2
- 229960005090 cefpodoxime Drugs 0.000 description 2
- 229960002580 cefprozil Drugs 0.000 description 2
- 229960000484 ceftazidime Drugs 0.000 description 2
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 2
- 229960001991 ceftizoxime Drugs 0.000 description 2
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 description 2
- 229960001668 cefuroxime Drugs 0.000 description 2
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 150000001782 cephems Chemical class 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 239000007806 chemical reaction intermediate Substances 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 229940038705 chlamydia trachomatis Drugs 0.000 description 2
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 2
- 229940107137 cholecystokinin Drugs 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 235000013477 citrulline Nutrition 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 description 2
- PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 229960000684 cytarabine Drugs 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 2
- 239000000412 dendrimer Substances 0.000 description 2
- 229920000736 dendritic polymer Polymers 0.000 description 2
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- 125000005879 dioxolanyl group Chemical group 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 2
- VHJLVAABSRFDPM-ZXZARUISSA-N dithioerythritol Chemical compound SC[C@H](O)[C@H](O)CS VHJLVAABSRFDPM-ZXZARUISSA-N 0.000 description 2
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 2
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 2
- 229960005501 duocarmycin Drugs 0.000 description 2
- 229930184221 duocarmycin Natural products 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 229940007078 entamoeba histolytica Drugs 0.000 description 2
- 208000028104 epidemic louse-borne typhus Diseases 0.000 description 2
- 229940116977 epidermal growth factor Drugs 0.000 description 2
- 229940030275 epigallocatechin gallate Drugs 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 108010072257 fibroblast activation protein alpha Proteins 0.000 description 2
- 229940126864 fibroblast growth factor Drugs 0.000 description 2
- 102000006815 folate receptor Human genes 0.000 description 2
- 108020005243 folate receptor Proteins 0.000 description 2
- 239000004052 folic acid antagonist Substances 0.000 description 2
- 229960002737 fructose Drugs 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 229960004675 fusidic acid Drugs 0.000 description 2
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical compound O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 208000010749 gastric carcinoma Diseases 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- UXFJYSFCCBPXED-UHFFFAOYSA-N gostatin Chemical compound NC1CNC(C(O)=O)=C(CC(O)=O)C1=O UXFJYSFCCBPXED-UHFFFAOYSA-N 0.000 description 2
- 208000024908 graft versus host disease Diseases 0.000 description 2
- 229960000642 grepafloxacin Drugs 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 201000005787 hematologic cancer Diseases 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 229940084986 human chorionic gonadotropin Drugs 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- IFSDAJWBUCMOAH-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 IFSDAJWBUCMOAH-HNNXBMFYSA-N 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 229940127121 immunoconjugate Drugs 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 201000006747 infectious mononucleosis Diseases 0.000 description 2
- 229960000598 infliximab Drugs 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 229940068935 insulin-like growth factor 2 Drugs 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 229960003350 isoniazid Drugs 0.000 description 2
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 239000002523 lectin Substances 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000001617 migratory effect Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 229950003063 mitumomab Drugs 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 2
- 201000007524 mucormycosis Diseases 0.000 description 2
- 208000010805 mumps infectious disease Diseases 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- GPXLMGHLHQJAGZ-JTDSTZFVSA-N nafcillin Chemical compound C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C(O)=O)=O)C(OCC)=CC=C21 GPXLMGHLHQJAGZ-JTDSTZFVSA-N 0.000 description 2
- 229960000515 nafcillin Drugs 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 201000003631 narcolepsy Diseases 0.000 description 2
- 201000009240 nasopharyngitis Diseases 0.000 description 2
- 230000001613 neoplastic effect Effects 0.000 description 2
- 229960000808 netilmicin Drugs 0.000 description 2
- ZBGPYVZLYBDXKO-HILBYHGXSA-N netilmycin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@]([C@H](NC)[C@@H](O)CO1)(C)O)NCC)[C@H]1OC(CN)=CC[C@H]1N ZBGPYVZLYBDXKO-HILBYHGXSA-N 0.000 description 2
- 208000008795 neuromyelitis optica Diseases 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- 229950010203 nimotuzumab Drugs 0.000 description 2
- 108010044762 nucleolin Proteins 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 229960002450 ofatumumab Drugs 0.000 description 2
- 229960002351 oleandomycin Drugs 0.000 description 2
- RZPAKFUAFGMUPI-KGIGTXTPSA-N oleandomycin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C RZPAKFUAFGMUPI-KGIGTXTPSA-N 0.000 description 2
- 235000019367 oleandomycin Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 108010071584 oxidized low density lipoprotein Proteins 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 201000002530 pancreatic endocrine carcinoma Diseases 0.000 description 2
- 230000003071 parasitic effect Effects 0.000 description 2
- 229960003330 pentetic acid Drugs 0.000 description 2
- IUKLSMSEHKDIIP-UHFFFAOYSA-N petine Natural products CC1(O)C2CCC3C4CC(O)C5CC(O)CCC5(C)C4CC3C2CN2C1CCC(C)C2 IUKLSMSEHKDIIP-UHFFFAOYSA-N 0.000 description 2
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 2
- 125000004437 phosphorous atom Chemical group 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 229960001221 pirarubicin Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000001023 pro-angiogenic effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 206010036807 progressive multifocal leukoencephalopathy Diseases 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 239000005297 pyrex Substances 0.000 description 2
- 229960002026 pyrithione Drugs 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 229940052337 quinupristin/dalfopristin Drugs 0.000 description 2
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical compound C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 description 2
- 208000030925 respiratory syncytial virus infectious disease Diseases 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 229960000329 ribavirin Drugs 0.000 description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 2
- ATEBXHFBFRCZMA-VXTBVIBXSA-N rifabutin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC(=C2N3)C(=O)C=4C(O)=C5C)C)OC)C5=C1C=4C2=NC13CCN(CC(C)C)CC1 ATEBXHFBFRCZMA-VXTBVIBXSA-N 0.000 description 2
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 229960000268 spectinomycin Drugs 0.000 description 2
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
- 201000005671 spondyloarthropathy Diseases 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 201000000498 stomach carcinoma Diseases 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- SUVMJBTUFCVSAD-UHFFFAOYSA-N sulforaphane Chemical compound CS(=O)CCCCN=C=S SUVMJBTUFCVSAD-UHFFFAOYSA-N 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 238000002626 targeted therapy Methods 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 description 2
- 229960003865 tazobactam Drugs 0.000 description 2
- 229960003250 telithromycin Drugs 0.000 description 2
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 2
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 2
- 230000002381 testicular Effects 0.000 description 2
- 201000003120 testicular cancer Diseases 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 125000000101 thioether group Chemical group 0.000 description 2
- 229940104230 thymidine Drugs 0.000 description 2
- 201000004647 tinea pedis Diseases 0.000 description 2
- 201000005882 tinea unguium Diseases 0.000 description 2
- 229960000707 tobramycin Drugs 0.000 description 2
- NLVFBUXFDBBNBW-PBSUHMDJSA-S tobramycin(5+) Chemical compound [NH3+][C@@H]1C[C@H](O)[C@@H](C[NH3+])O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H]([NH3+])[C@H](O)[C@@H](CO)O2)O)[C@H]([NH3+])C[C@@H]1[NH3+] NLVFBUXFDBBNBW-PBSUHMDJSA-S 0.000 description 2
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 239000012581 transferrin Substances 0.000 description 2
- 102000003601 transglutaminase Human genes 0.000 description 2
- 108091005703 transmembrane proteins Proteins 0.000 description 2
- 102000035160 transmembrane proteins Human genes 0.000 description 2
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 2
- 229960001670 trilostane Drugs 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 229960000497 trovafloxacin Drugs 0.000 description 2
- WVPSKSLAZQPAKQ-CDMJZVDBSA-N trovafloxacin Chemical compound C([C@H]1[C@@H]([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F WVPSKSLAZQPAKQ-CDMJZVDBSA-N 0.000 description 2
- 229930184737 tubulysin Natural products 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- 229960004528 vincristine Drugs 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 2
- 229960004355 vindesine Drugs 0.000 description 2
- 208000009421 viral pneumonia Diseases 0.000 description 2
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 229950008250 zalutumumab Drugs 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 2
- 229960000641 zorubicin Drugs 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 description 1
- BSPMWFRGZQDRIU-UHFFFAOYSA-N (2-amino-1h-imidazol-5-yl)methanol Chemical class NC1=NC(CO)=CN1 BSPMWFRGZQDRIU-UHFFFAOYSA-N 0.000 description 1
- NBKZGRPRTQELKX-UHFFFAOYSA-N (2-methylpropan-2-yl)oxymethanone Chemical compound CC(C)(C)O[C]=O NBKZGRPRTQELKX-UHFFFAOYSA-N 0.000 description 1
- DENYZIUJOTUUNY-MRXNPFEDSA-N (2R)-14-fluoro-2-methyl-6,9,10,19-tetrazapentacyclo[14.2.1.02,6.08,18.012,17]nonadeca-1(18),8,12(17),13,15-pentaen-11-one Chemical compound FC=1C=C2C=3C=4C(CN5[C@@](C4NC3C1)(CCC5)C)=NNC2=O DENYZIUJOTUUNY-MRXNPFEDSA-N 0.000 description 1
- NIFKPNXQOJGPCM-MNCSTQPFSA-N (2R,3S,4R,5R)-2-ethyl-2,3,4,5,6-pentahydroxyhexanoic acid Chemical compound C(C)[C@@](C(=O)O)(O)[C@@H](O)[C@H](O)[C@H](O)CO NIFKPNXQOJGPCM-MNCSTQPFSA-N 0.000 description 1
- FWFGIHPGRQZWIW-SQNIBIBYSA-N (2S)-2-[[(2R)-2-[(1S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methyl-1-oxopentyl]amino]-2-phenylacetic acid cyclopentyl ester Chemical compound O=C([C@@H](NC(=O)[C@@H]([C@H](O)C(=O)NO)CC(C)C)C=1C=CC=CC=1)OC1CCCC1 FWFGIHPGRQZWIW-SQNIBIBYSA-N 0.000 description 1
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 1
- JPSHPWJJSVEEAX-OWPBQMJCSA-N (2s)-2-amino-4-fluoranylpentanedioic acid Chemical compound OC(=O)[C@@H](N)CC([18F])C(O)=O JPSHPWJJSVEEAX-OWPBQMJCSA-N 0.000 description 1
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 1
- TVIRNGFXQVMMGB-OFWIHYRESA-N (3s,6r,10r,13e,16s)-16-[(2r,3r,4s)-4-chloro-3-hydroxy-4-phenylbutan-2-yl]-10-[(3-chloro-4-methoxyphenyl)methyl]-6-methyl-3-(2-methylpropyl)-1,4-dioxa-8,11-diazacyclohexadec-13-ene-2,5,9,12-tetrone Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H](O)[C@@H](Cl)C=2C=CC=CC=2)C/C=C/C(=O)N1 TVIRNGFXQVMMGB-OFWIHYRESA-N 0.000 description 1
- OFPZNTXZCGKCMU-VXBOPZJTSA-N (3z,5e,7r,8s,10s,11z,13s,14r,15s,17s,20r,21s,22s)-22-[(2s,3z)-hexa-3,5-dien-2-yl]-8,10,14,20-tetrahydroxy-7,13,15,17,21-pentamethyl-1-oxacyclodocosa-3,5,11-trien-2-one Chemical compound C=C\C=C/[C@H](C)[C@@H]1OC(=O)\C=C/C=C/[C@@H](C)[C@@H](O)C[C@H](O)\C=C/[C@H](C)[C@H](O)[C@@H](C)C[C@@H](C)CC[C@@H](O)[C@@H]1C OFPZNTXZCGKCMU-VXBOPZJTSA-N 0.000 description 1
- XIYOPDCBBDCGOE-IWVLMIASSA-N (4s,4ar,5s,5ar,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methylidene-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C=C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1[C@H](O)[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O XIYOPDCBBDCGOE-IWVLMIASSA-N 0.000 description 1
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 1
- JTCJHLLFFDVSII-BYPYZUCNSA-N (5S)-6-oxa-4-thia-1-azabicyclo[3.2.0]hept-2-en-7-one Chemical compound O=C1O[C@H]2SC=CN12 JTCJHLLFFDVSII-BYPYZUCNSA-N 0.000 description 1
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 description 1
- XSPUSVIQHBDITA-KXDGEKGBSA-N (6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(5-methyltetrazol-2-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CN1N=NC(C)=N1 XSPUSVIQHBDITA-KXDGEKGBSA-N 0.000 description 1
- YWKJNRNSJKEFMK-PQFQYKRASA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-8-oxo-3-(5,6,7,8-tetrahydroquinolin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 YWKJNRNSJKEFMK-PQFQYKRASA-N 0.000 description 1
- MWWSFMDVAYGXBV-MYPASOLCSA-N (7r,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.O([C@@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-MYPASOLCSA-N 0.000 description 1
- INAUWOVKEZHHDM-PEDBPRJASA-N (7s,9s)-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-7-[(2r,4s,5s,6s)-5-hydroxy-6-methyl-4-morpholin-4-yloxan-2-yl]oxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.N1([C@H]2C[C@@H](O[C@@H](C)[C@H]2O)O[C@H]2C[C@@](O)(CC=3C(O)=C4C(=O)C=5C=CC=C(C=5C(=O)C4=C(O)C=32)OC)C(=O)CO)CCOCC1 INAUWOVKEZHHDM-PEDBPRJASA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- MINDHVHHQZYEEK-UHFFFAOYSA-N (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid Natural products CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-UHFFFAOYSA-N 0.000 description 1
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 1
- UQVNRKBFAXNOGA-LWTNMJDUSA-N (E)-tomaymycin Chemical compound CO[C@H]1NC2=CC(O)=C(OC)C=C2C(=O)N2C\C(=C\C)C[C@@H]12 UQVNRKBFAXNOGA-LWTNMJDUSA-N 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- QKDHBVNJCZBTMR-LLVKDONJSA-N (R)-temafloxacin Chemical compound C1CN[C@H](C)CN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1F QKDHBVNJCZBTMR-LLVKDONJSA-N 0.000 description 1
- LAMIXXKAWNLXOC-INIZCTEOSA-N (S)-HDAC-42 Chemical compound O=C([C@@H](C(C)C)C=1C=CC=CC=1)NC1=CC=C(C(=O)NO)C=C1 LAMIXXKAWNLXOC-INIZCTEOSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- PRJHDVZYWLTOOE-UHFFFAOYSA-N (methoxyamino)oxymethane;hydrochloride Chemical compound Cl.CONOC PRJHDVZYWLTOOE-UHFFFAOYSA-N 0.000 description 1
- NCCJWSXETVVUHK-ZYSAIPPVSA-N (z)-7-[(2r)-2-amino-2-carboxyethyl]sulfanyl-2-[[(1s)-2,2-dimethylcyclopropanecarbonyl]amino]hept-2-enoic acid;(5r,6s)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1r)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Chemical compound C1C(SCC\N=C/N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21.CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O NCCJWSXETVVUHK-ZYSAIPPVSA-N 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- ITWBWJFEJCHKSN-UHFFFAOYSA-N 1,4,7-triazonane Chemical compound C1CNCCNCCN1 ITWBWJFEJCHKSN-UHFFFAOYSA-N 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- SWQQELWGJDXCFT-PNHWDRBUSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-ethynylimidazole-4-carboxamide Chemical compound C#CC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 SWQQELWGJDXCFT-PNHWDRBUSA-N 0.000 description 1
- SPMVMDHWKHCIDT-UHFFFAOYSA-N 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC=1C=C(C)ON=1 SPMVMDHWKHCIDT-UHFFFAOYSA-N 0.000 description 1
- MBDUIEKYVPVZJH-UHFFFAOYSA-N 1-ethylsulfonylethane Chemical compound CCS(=O)(=O)CC MBDUIEKYVPVZJH-UHFFFAOYSA-N 0.000 description 1
- GPAAEZIXSQCCES-UHFFFAOYSA-N 1-methoxy-2-(2-methoxyethoxymethoxymethoxy)ethane Chemical compound COCCOCOCOCCOC GPAAEZIXSQCCES-UHFFFAOYSA-N 0.000 description 1
- SDTORDSXCYSNTD-UHFFFAOYSA-N 1-methoxy-4-[(4-methoxyphenyl)methoxymethyl]benzene Chemical compound C1=CC(OC)=CC=C1COCC1=CC=C(OC)C=C1 SDTORDSXCYSNTD-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- CTLOSZHDGZLOQE-UHFFFAOYSA-N 14-methoxy-9-[(4-methylpiperazin-1-yl)methyl]-9,19-diazapentacyclo[10.7.0.02,6.07,11.013,18]nonadeca-1(12),2(6),7(11),13(18),14,16-hexaene-8,10-dione Chemical compound O=C1C2=C3C=4C(OC)=CC=CC=4NC3=C3CCCC3=C2C(=O)N1CN1CCN(C)CC1 CTLOSZHDGZLOQE-UHFFFAOYSA-N 0.000 description 1
- PBYIIRLNRCVTMQ-UHFFFAOYSA-N 2,3,5,6-tetrafluorophenol Chemical compound OC1=C(F)C(F)=CC(F)=C1F PBYIIRLNRCVTMQ-UHFFFAOYSA-N 0.000 description 1
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- RUPDGJAVWKTTJW-UHFFFAOYSA-N 2,3-dinitropyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1[N+]([O-])=O RUPDGJAVWKTTJW-UHFFFAOYSA-N 0.000 description 1
- 125000003764 2,4-dimethylpentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- KZDCMKVLEYCGQX-UDPGNSCCSA-N 2-(diethylamino)ethyl 4-aminobenzoate;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical compound O.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 KZDCMKVLEYCGQX-UDPGNSCCSA-N 0.000 description 1
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical compound O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- WVHGJJRMKGDTEC-WCIJHFMNSA-N 2-[(1R,4S,8R,10S,13S,16S,27R,34S)-34-[(2S)-butan-2-yl]-8,22-dihydroxy-13-[(2R,3S)-3-hydroxybutan-2-yl]-2,5,11,14,27,30,33,36,39-nonaoxo-27lambda4-thia-3,6,12,15,25,29,32,35,38-nonazapentacyclo[14.12.11.06,10.018,26.019,24]nonatriaconta-18(26),19(24),20,22-tetraen-4-yl]acetamide Chemical compound CC[C@H](C)[C@@H]1NC(=O)CNC(=O)[C@@H]2Cc3c([nH]c4cc(O)ccc34)[S@](=O)C[C@H](NC(=O)CNC1=O)C(=O)N[C@@H](CC(N)=O)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H]([C@@H](C)[C@H](C)O)C(=O)N2 WVHGJJRMKGDTEC-WCIJHFMNSA-N 0.000 description 1
- ACTOXUHEUCPTEW-BWHGAVFKSA-N 2-[(4r,5s,6s,7r,9r,10r,11e,13e,16r)-6-[(2s,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-10-[(2s,5s,6r)-5-(dimethylamino)-6-methyloxan-2-yl]oxy-4-hydroxy-5-methoxy-9,16-dimethyl-2-o Chemical compound O([C@H]1/C=C/C=C/C[C@@H](C)OC(=O)C[C@@H](O)[C@@H]([C@H]([C@@H](CC=O)C[C@H]1C)O[C@H]1[C@@H]([C@H]([C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(O)C2)[C@@H](C)O1)N(C)C)O)OC)[C@@H]1CC[C@H](N(C)C)[C@@H](C)O1 ACTOXUHEUCPTEW-BWHGAVFKSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- BGFTWECWAICPDG-UHFFFAOYSA-N 2-[bis(4-chlorophenyl)methyl]-4-n-[3-[bis(4-chlorophenyl)methyl]-4-(dimethylamino)phenyl]-1-n,1-n-dimethylbenzene-1,4-diamine Chemical compound C1=C(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C(N(C)C)=CC=C1NC(C=1)=CC=C(N(C)C)C=1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 BGFTWECWAICPDG-UHFFFAOYSA-N 0.000 description 1
- FIDMEHCRMLKKPZ-YSMBQZINSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;[2-methoxy-5-[(z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl] dihydrogen phosphate Chemical compound OCC(N)(CO)CO.C1=C(OP(O)(O)=O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 FIDMEHCRMLKKPZ-YSMBQZINSA-N 0.000 description 1
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- RTJUXLYUUDBAJN-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-fluoro-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1C[C@H](F)[C@@H](CO)O1 RTJUXLYUUDBAJN-KVQBGUIXSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- FDAYLTPAFBGXAB-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)ethanamine Chemical compound ClCCN(CCCl)CCCl FDAYLTPAFBGXAB-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-n-methyl-1,3,5-triazine-2,4,6-triamine Chemical compound CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- ZBAPTBRNNCVUFB-UHFFFAOYSA-N 2h-imidazo[4,5-g][1,2,3]benzothiadiazole Chemical compound C1=CC2=NNSC2=C2N=CN=C21 ZBAPTBRNNCVUFB-UHFFFAOYSA-N 0.000 description 1
- BIKSKRPHKQWJCW-UHFFFAOYSA-N 3,4-dibromopyrrole-2,5-dione Chemical compound BrC1=C(Br)C(=O)NC1=O BIKSKRPHKQWJCW-UHFFFAOYSA-N 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 description 1
- LKKMLIBUAXYLOY-UHFFFAOYSA-N 3-Amino-1-methyl-5H-pyrido[4,3-b]indole Chemical compound N1C2=CC=CC=C2C2=C1C=C(N)N=C2C LKKMLIBUAXYLOY-UHFFFAOYSA-N 0.000 description 1
- MAUCONCHVWBMHK-UHFFFAOYSA-N 3-[(dimethylamino)methyl]-N-[2-[4-[(hydroxyamino)-oxomethyl]phenoxy]ethyl]-2-benzofurancarboxamide Chemical compound O1C2=CC=CC=C2C(CN(C)C)=C1C(=O)NCCOC1=CC=C(C(=O)NO)C=C1 MAUCONCHVWBMHK-UHFFFAOYSA-N 0.000 description 1
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- GSCPDZHWVNUUFI-UHFFFAOYSA-N 3-aminobenzamide Chemical compound NC(=O)C1=CC=CC(N)=C1 GSCPDZHWVNUUFI-UHFFFAOYSA-N 0.000 description 1
- IEDIKTABXQYWBL-UHFFFAOYSA-N 3-aminopropanoic acid Chemical compound NCCC(O)=O.NCCC(O)=O IEDIKTABXQYWBL-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 102100040842 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase FUT3 Human genes 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- GJMPSRSMBJLKKB-UHFFFAOYSA-N 3-methylphenylacetic acid Chemical compound CC1=CC=CC(CC(O)=O)=C1 GJMPSRSMBJLKKB-UHFFFAOYSA-N 0.000 description 1
- QHSXWDVVFHXHHB-UHFFFAOYSA-N 3-nitro-2-[(3-nitropyridin-2-yl)disulfanyl]pyridine Chemical compound [O-][N+](=O)C1=CC=CN=C1SSC1=NC=CC=C1[N+]([O-])=O QHSXWDVVFHXHHB-UHFFFAOYSA-N 0.000 description 1
- INZOTETZQBPBCE-NYLDSJSYSA-N 3-sialyl lewis Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]([C@H](O)CO)[C@@H]([C@@H](NC(C)=O)C=O)O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 INZOTETZQBPBCE-NYLDSJSYSA-N 0.000 description 1
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 1
- MSTDXOZUKAQDRL-UHFFFAOYSA-N 4-Chromanone Chemical compound C1=CC=C2C(=O)CCOC2=C1 MSTDXOZUKAQDRL-UHFFFAOYSA-N 0.000 description 1
- SUVMJBTUFCVSAD-JTQLQIEISA-N 4-Methylsulfinylbutyl isothiocyanate Natural products C[S@](=O)CCCCN=C=S SUVMJBTUFCVSAD-JTQLQIEISA-N 0.000 description 1
- HSBKFSPNDWWPSL-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@@H]1C=C[C@H](CO)O1 HSBKFSPNDWWPSL-VDTYLAMSSA-N 0.000 description 1
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 1
- 108010068327 4-hydroxyphenylpyruvate dioxygenase Proteins 0.000 description 1
- MDOJTZQKHMAPBK-UHFFFAOYSA-N 4-iodo-3-nitrobenzamide Chemical compound NC(=O)C1=CC=C(I)C([N+]([O-])=O)=C1 MDOJTZQKHMAPBK-UHFFFAOYSA-N 0.000 description 1
- YVMBAUWDIGJRNY-BESUKNQGSA-N 4o8o7q7iu4 Chemical compound C1C(=O)C[C@H](O)\C=C(/C)\C=C\CNC(=O)\C=C\[C@@H](C)[C@@H](C(C)C)OC(=O)C2=CCCN2C(=O)C2=COC1=N2.N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2CCC(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O YVMBAUWDIGJRNY-BESUKNQGSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 1
- 229940000681 5-hydroxytryptophan Drugs 0.000 description 1
- MJZJYWCQPMNPRM-UHFFFAOYSA-N 6,6-dimethyl-1-[3-(2,4,5-trichlorophenoxy)propoxy]-1,6-dihydro-1,3,5-triazine-2,4-diamine Chemical compound CC1(C)N=C(N)N=C(N)N1OCCCOC1=CC(Cl)=C(Cl)C=C1Cl MJZJYWCQPMNPRM-UHFFFAOYSA-N 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 1
- HGGAKXAHAYOLDJ-FHZUQPTBSA-N 6alpha-[(R)-1-hydroxyethyl]-2-[(R)-tetrahydrofuran-2-yl]pen-2-em-3-carboxylic acid Chemical compound S([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1[C@H]1CCCO1 HGGAKXAHAYOLDJ-FHZUQPTBSA-N 0.000 description 1
- WUWFMDMBOJLQIV-UHFFFAOYSA-N 7-(3-aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid Chemical compound C1C(N)CCN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1F WUWFMDMBOJLQIV-UHFFFAOYSA-N 0.000 description 1
- MPORYQCGWFQFLA-ONPDANIMSA-N 7-[(7s)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1r,2s)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid;trihydrate Chemical compound O.O.O.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 MPORYQCGWFQFLA-ONPDANIMSA-N 0.000 description 1
- PLIVFNIUGLLCEK-UHFFFAOYSA-N 7-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]oxy-n-hydroxyheptanamide Chemical compound C=12C=C(OCCCCCCC(=O)NO)C(OC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 PLIVFNIUGLLCEK-UHFFFAOYSA-N 0.000 description 1
- WLCZTRVUXYALDD-IBGZPJMESA-N 7-[[(2s)-2,6-bis(2-methoxyethoxycarbonylamino)hexanoyl]amino]heptoxy-methylphosphinic acid Chemical compound COCCOC(=O)NCCCC[C@H](NC(=O)OCCOC)C(=O)NCCCCCCCOP(C)(O)=O WLCZTRVUXYALDD-IBGZPJMESA-N 0.000 description 1
- VGGWNGWXGFWLRK-UHFFFAOYSA-N 8,9-dihydro-1H-[1,3]oxazolo[4,5-i][1,2]benzodiazepine Chemical compound C1=CC=NNC2=C(OCN3)C3=CC=C21 VGGWNGWXGFWLRK-UHFFFAOYSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 1
- 102100040079 A-kinase anchor protein 4 Human genes 0.000 description 1
- 101710109924 A-kinase anchor protein 4 Proteins 0.000 description 1
- 108700022307 A54145 Proteins 0.000 description 1
- 102000020236 ADP-ribosylarginine hydrolase Human genes 0.000 description 1
- 108010079768 ADP-ribosylarginine hydrolase Proteins 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- 206010063409 Acarodermatitis Diseases 0.000 description 1
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 1
- 208000034950 Acinetobacter Infections Diseases 0.000 description 1
- 241000588626 Acinetobacter baumannii Species 0.000 description 1
- 241000186046 Actinomyces Species 0.000 description 1
- 241000186041 Actinomyces israelii Species 0.000 description 1
- 102000018918 Activin Receptors Human genes 0.000 description 1
- 108010052946 Activin Receptors Proteins 0.000 description 1
- 206010000748 Acute febrile neutrophilic dermatosis Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- 208000010370 Adenoviridae Infections Diseases 0.000 description 1
- 206010060931 Adenovirus infection Diseases 0.000 description 1
- 208000002485 Adiposis dolorosa Diseases 0.000 description 1
- 208000016683 Adult T-cell leukemia/lymphoma Diseases 0.000 description 1
- 241000607534 Aeromonas Species 0.000 description 1
- ULXXDDBFHOBEHA-ONEGZZNKSA-N Afatinib Chemical compound N1=CN=C2C=C(OC3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-ONEGZZNKSA-N 0.000 description 1
- 208000000230 African Trypanosomiasis Diseases 0.000 description 1
- 208000008190 Agammaglobulinemia Diseases 0.000 description 1
- 101000994818 Agrotis ipsilon Insulin-related peptide 2 Proteins 0.000 description 1
- AAQGRPOPTAUUBM-ZLUOBGJFSA-N Ala-Ala-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(O)=O AAQGRPOPTAUUBM-ZLUOBGJFSA-N 0.000 description 1
- ZIBWKCRKNFYTPT-ZKWXMUAHSA-N Ala-Asn-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O ZIBWKCRKNFYTPT-ZKWXMUAHSA-N 0.000 description 1
- LIWMQSWFLXEGMA-WDSKDSINSA-N Ala-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](C)N LIWMQSWFLXEGMA-WDSKDSINSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 102100024321 Alkaline phosphatase, placental type Human genes 0.000 description 1
- 208000032671 Allergic granulomatous angiitis Diseases 0.000 description 1
- 102100035248 Alpha-(1,3)-fucosyltransferase 4 Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 102100034452 Alternative prion protein Human genes 0.000 description 1
- 231100000729 Amatoxin Toxicity 0.000 description 1
- 208000004881 Amebiasis Diseases 0.000 description 1
- 241000224489 Amoeba Species 0.000 description 1
- 206010001980 Amoebiasis Diseases 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 241000606646 Anaplasma Species 0.000 description 1
- 241001465677 Ancylostomatoidea Species 0.000 description 1
- 201000002045 Ancylostomiasis Diseases 0.000 description 1
- 102100032187 Androgen receptor Human genes 0.000 description 1
- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000033211 Ankylostomiasis Diseases 0.000 description 1
- 102100023003 Ankyrin repeat domain-containing protein 30A Human genes 0.000 description 1
- 101710099705 Anti-lipopolysaccharide factor Proteins 0.000 description 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 1
- 241001523209 Antissa Species 0.000 description 1
- 241001425476 Apiosporina morbosa Species 0.000 description 1
- 102000006410 Apoproteins Human genes 0.000 description 1
- 108010083590 Apoproteins Proteins 0.000 description 1
- 241000203069 Archaea Species 0.000 description 1
- 201000009695 Argentine hemorrhagic fever Diseases 0.000 description 1
- CKAJHWFHHFSCDT-WHFBIAKZSA-N Asp-Glu Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(O)=O CKAJHWFHHFSCDT-WHFBIAKZSA-N 0.000 description 1
- OAMLVOVXNKILLQ-BQBZGAKWSA-N Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(O)=O OAMLVOVXNKILLQ-BQBZGAKWSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241001225321 Aspergillus fumigatus Species 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 206010060971 Astrocytoma malignant Diseases 0.000 description 1
- 241001533362 Astroviridae Species 0.000 description 1
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 1
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 206010071576 Autoimmune aplastic anaemia Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 208000000659 Autoimmune lymphoproliferative syndrome Diseases 0.000 description 1
- 206010069002 Autoimmune pancreatitis Diseases 0.000 description 1
- 208000031212 Autoimmune polyendocrinopathy Diseases 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 208000004736 B-Cell Leukemia Diseases 0.000 description 1
- 108010008014 B-Cell Maturation Antigen Proteins 0.000 description 1
- 102000006942 B-Cell Maturation Antigen Human genes 0.000 description 1
- 102100027203 B-cell antigen receptor complex-associated protein beta chain Human genes 0.000 description 1
- 102100025218 B-cell differentiation antigen CD72 Human genes 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 206010055181 BK virus infection Diseases 0.000 description 1
- 208000004429 Bacillary Dysentery Diseases 0.000 description 1
- 241000304886 Bacilli Species 0.000 description 1
- 241000193755 Bacillus cereus Species 0.000 description 1
- 206010060976 Bacillus infection Diseases 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 1
- 208000004926 Bacterial Vaginosis Diseases 0.000 description 1
- 241000692822 Bacteroidales Species 0.000 description 1
- 241000606125 Bacteroides Species 0.000 description 1
- 208000034974 Bacteroides Infections Diseases 0.000 description 1
- 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 1
- 239000003840 Bafetinib Substances 0.000 description 1
- MGQLHRYJBWGORO-LLVKDONJSA-N Balofloxacin Chemical compound C1[C@H](NC)CCCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1OC MGQLHRYJBWGORO-LLVKDONJSA-N 0.000 description 1
- 241001518086 Bartonella henselae Species 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 description 1
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 1
- 208000009299 Benign Mucous Membrane Pemphigoid Diseases 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 241000186000 Bifidobacterium Species 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 241000157302 Bison bison athabascae Species 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000228405 Blastomyces dermatitidis Species 0.000 description 1
- 206010005098 Blastomycosis Diseases 0.000 description 1
- 208000009766 Blau syndrome Diseases 0.000 description 1
- 206010005913 Body tinea Diseases 0.000 description 1
- 206010061591 Borrelia infection Diseases 0.000 description 1
- 241000589969 Borreliella burgdorferi Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006143 Brain stem glioma Diseases 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000014698 Brassica juncea var multisecta Nutrition 0.000 description 1
- 235000006008 Brassica napus var napus Nutrition 0.000 description 1
- 240000000385 Brassica napus var. napus Species 0.000 description 1
- 235000006618 Brassica rapa subsp oleifera Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 235000004977 Brassica sinapistrum Nutrition 0.000 description 1
- 201000010424 Brazilian hemorrhagic fever Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- MBABCNBNDNGODA-LTGLSHGVSA-N Bullatacin Natural products O=C1C(C[C@H](O)CCCCCCCCCC[C@@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)=C[C@H](C)O1 MBABCNBNDNGODA-LTGLSHGVSA-N 0.000 description 1
- KGGVWMAPBXIMEM-ZRTAFWODSA-N Bullatacinone Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@H]2OC(=O)[C@H](CC(C)=O)C2)CC1 KGGVWMAPBXIMEM-ZRTAFWODSA-N 0.000 description 1
- KGGVWMAPBXIMEM-JQFCFGFHSA-N Bullatacinone Natural products O=C(C[C@H]1C(=O)O[C@H](CCCCCCCCCC[C@H](O)[C@@H]2O[C@@H]([C@@H]3O[C@@H]([C@@H](O)CCCCCCCCCC)CC3)CC2)C1)C KGGVWMAPBXIMEM-JQFCFGFHSA-N 0.000 description 1
- 241000589513 Burkholderia cepacia Species 0.000 description 1
- 206010073031 Burkholderia infection Diseases 0.000 description 1
- 241001136175 Burkholderia pseudomallei Species 0.000 description 1
- 206010069748 Burkholderia pseudomallei infection Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- UHPQGESRYTWQJW-UHFFFAOYSA-N C(C=C1)=CC2=C1NC1=C2C(C2=NNC=CC=C2)=CC=C1 Chemical compound C(C=C1)=CC2=C1NC1=C2C(C2=NNC=CC=C2)=CC=C1 UHPQGESRYTWQJW-UHFFFAOYSA-N 0.000 description 1
- DGGZCXUXASNDAC-QQNGCVSVSA-N C-1027 chromophore Chemical compound COc1cc2OC(=C)C(=O)Nc2c(c1)C(=O)O[C@H]3COC(=O)C[C@H](N)c4cc(O)c(O[C@@H]5C#C\C=C\3/C#CC6=CC=C[C@]56O[C@@H]7OC(C)(C)[C@H]([C@@H](O)[C@H]7O)N(C)C)c(Cl)c4 DGGZCXUXASNDAC-QQNGCVSVSA-N 0.000 description 1
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 description 1
- 102100025618 C-X-C chemokine receptor type 6 Human genes 0.000 description 1
- 229930182476 C-glycoside Natural products 0.000 description 1
- 150000000700 C-glycosides Chemical class 0.000 description 1
- 102100028668 C-type lectin domain family 4 member C Human genes 0.000 description 1
- VEXYXZYCHUQSBP-UHFFFAOYSA-N C1(=CC=CC=C1)C=1N=NOC1.CS(=O)(=O)C Chemical compound C1(=CC=CC=C1)C=1N=NOC1.CS(=O)(=O)C VEXYXZYCHUQSBP-UHFFFAOYSA-N 0.000 description 1
- 102100032957 C5a anaphylatoxin chemotactic receptor 1 Human genes 0.000 description 1
- 108010008629 CA-125 Antigen Proteins 0.000 description 1
- 102000007269 CA-125 Antigen Human genes 0.000 description 1
- 102000001902 CC Chemokines Human genes 0.000 description 1
- 108010040471 CC Chemokines Proteins 0.000 description 1
- 102100037917 CD109 antigen Human genes 0.000 description 1
- 102100035893 CD151 antigen Human genes 0.000 description 1
- 102100024210 CD166 antigen Human genes 0.000 description 1
- 102100024220 CD180 antigen Human genes 0.000 description 1
- 102100021992 CD209 antigen Human genes 0.000 description 1
- 102000049320 CD36 Human genes 0.000 description 1
- 108010045374 CD36 Antigens Proteins 0.000 description 1
- 108010036239 CD4-IgG(2) Proteins 0.000 description 1
- 102100032937 CD40 ligand Human genes 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- 102100036008 CD48 antigen Human genes 0.000 description 1
- 102100022002 CD59 glycoprotein Human genes 0.000 description 1
- 102100025222 CD63 antigen Human genes 0.000 description 1
- 102100027221 CD81 antigen Human genes 0.000 description 1
- 102100027217 CD82 antigen Human genes 0.000 description 1
- 102100035793 CD83 antigen Human genes 0.000 description 1
- 102100037904 CD9 antigen Human genes 0.000 description 1
- QAGYKUNXZHXKMR-UHFFFAOYSA-N CPD000469186 Natural products CC1=C(O)C=CC=C1C(=O)NC(C(O)CN1C(CC2CCCCC2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-UHFFFAOYSA-N 0.000 description 1
- 229940126609 CR6261 Drugs 0.000 description 1
- 201000002829 CREST Syndrome Diseases 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 108050006947 CXC Chemokine Proteins 0.000 description 1
- 102000019388 CXC chemokine Human genes 0.000 description 1
- NPPYMFIOAPYLBT-LNWHSMOUSA-N C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)S(O)(=O)=O.OC1O[C@H](CS(O)(=O)=O)[C@@H](O)[C@H](O)[C@H]1O Chemical compound C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)S(O)(=O)=O.OC1O[C@H](CS(O)(=O)=O)[C@@H](O)[C@H](O)[C@H]1O NPPYMFIOAPYLBT-LNWHSMOUSA-N 0.000 description 1
- 102100029761 Cadherin-5 Human genes 0.000 description 1
- 101100463133 Caenorhabditis elegans pdl-1 gene Proteins 0.000 description 1
- 101100328884 Caenorhabditis elegans sqt-3 gene Proteins 0.000 description 1
- 208000006339 Caliciviridae Infections Diseases 0.000 description 1
- 241000189662 Calla Species 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 206010051226 Campylobacter infection Diseases 0.000 description 1
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 102000013602 Cardiac Myosins Human genes 0.000 description 1
- 108010051609 Cardiac Myosins Proteins 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 208000003732 Cat-scratch disease Diseases 0.000 description 1
- UQLLWWBDSUHNEB-CZUORRHYSA-N Cefaprin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CSC1=CC=NC=C1 UQLLWWBDSUHNEB-CZUORRHYSA-N 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 208000009846 Central Nervous System Protozoal Infections Diseases 0.000 description 1
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000242722 Cestoda Species 0.000 description 1
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 1
- 102000004003 Chemokine CCL11 Human genes 0.000 description 1
- 108010082548 Chemokine CCL11 Proteins 0.000 description 1
- 102000009410 Chemokine receptor Human genes 0.000 description 1
- 108050000299 Chemokine receptor Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 208000007190 Chlamydia Infections Diseases 0.000 description 1
- 241001647378 Chlamydia psittaci Species 0.000 description 1
- 241000195585 Chlamydomonas Species 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 239000004099 Chlortetracycline Substances 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 206010008748 Chorea Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 208000030939 Chronic inflammatory demyelinating polyneuropathy Diseases 0.000 description 1
- 241000611330 Chryseobacterium Species 0.000 description 1
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 description 1
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 1
- HBBOZFUQJDYASD-UHFFFAOYSA-N Cis-1,3-Dioxide-1,3-Dithiane Natural products OC1C(O)C(O)C(C)OC1OC1C(OC2C(C(O)C(O)C(CO)O2)O)C(CO)OC(O)C1NC(C)=O HBBOZFUQJDYASD-UHFFFAOYSA-N 0.000 description 1
- 108050009324 Claudin-18 Proteins 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 241001327965 Clonorchis sinensis Species 0.000 description 1
- 206010061043 Clostridial infection Diseases 0.000 description 1
- 241001112695 Clostridiales Species 0.000 description 1
- 241000193155 Clostridium botulinum Species 0.000 description 1
- 206010009657 Clostridium difficile colitis Diseases 0.000 description 1
- 206010054236 Clostridium difficile infection Diseases 0.000 description 1
- 241000193468 Clostridium perfringens Species 0.000 description 1
- 102000003780 Clusterin Human genes 0.000 description 1
- 108090000197 Clusterin Proteins 0.000 description 1
- 241000223205 Coccidioides immitis Species 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 208000010007 Cogan syndrome Diseases 0.000 description 1
- 102100035167 Coiled-coil domain-containing protein 54 Human genes 0.000 description 1
- 208000011038 Cold agglutinin disease Diseases 0.000 description 1
- 206010009868 Cold type haemolytic anaemia Diseases 0.000 description 1
- 108010078777 Colistin Proteins 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 102000004266 Collagen Type IV Human genes 0.000 description 1
- 108010042086 Collagen Type IV Proteins 0.000 description 1
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 208000009802 Colorado tick fever Diseases 0.000 description 1
- 241000204955 Colorado tick fever virus Species 0.000 description 1
- 101710184994 Complement control protein Proteins 0.000 description 1
- 102100025680 Complement decay-accelerating factor Human genes 0.000 description 1
- 102100030886 Complement receptor type 1 Human genes 0.000 description 1
- 102100032768 Complement receptor type 2 Human genes 0.000 description 1
- 108091035707 Consensus sequence Proteins 0.000 description 1
- 241000186227 Corynebacterium diphtheriae Species 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 201000003075 Crimean-Congo hemorrhagic fever Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 208000019707 Cryoglobulinemic vasculitis Diseases 0.000 description 1
- 229930188224 Cryptophycin Natural products 0.000 description 1
- 208000008953 Cryptosporidiosis Diseases 0.000 description 1
- 206010011502 Cryptosporidiosis infection Diseases 0.000 description 1
- 241000223935 Cryptosporidium Species 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- 108010060385 Cyclin B1 Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 102100027417 Cytochrome P450 1B1 Human genes 0.000 description 1
- 206010048843 Cytomegalovirus chorioretinitis Diseases 0.000 description 1
- 206010049018 Cytomegalovirus oesophagitis Diseases 0.000 description 1
- 241000235819 Cytospora Species 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- DYDCUQKUCUHJBH-UWTATZPHSA-N D-Cycloserine Chemical compound N[C@@H]1CONC1=O DYDCUQKUCUHJBH-UWTATZPHSA-N 0.000 description 1
- DYDCUQKUCUHJBH-UHFFFAOYSA-N D-Cycloserine Natural products NC1CONC1=O DYDCUQKUCUHJBH-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- WQZGKKKJIJFFOK-CBPJZXOFSA-N D-Gulose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-CBPJZXOFSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-WHZQZERISA-N D-aldose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-WHZQZERISA-N 0.000 description 1
- WQZGKKKJIJFFOK-IVMDWMLBSA-N D-allopyranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-IVMDWMLBSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 102100039128 DNA-3-methyladenine glycosylase Human genes 0.000 description 1
- 101100016370 Danio rerio hsp90a.1 gene Proteins 0.000 description 1
- 101100481408 Danio rerio tie2 gene Proteins 0.000 description 1
- QMLVECGLEOSESV-RYUDHWBXSA-N Danofloxacin Chemical compound C([C@@H]1C[C@H]2CN1C)N2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 QMLVECGLEOSESV-RYUDHWBXSA-N 0.000 description 1
- 108010013198 Daptomycin Proteins 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- UQBOJOOOTLPNST-UHFFFAOYSA-N Dehydroalanine Chemical compound NC(=C)C(O)=O UQBOJOOOTLPNST-UHFFFAOYSA-N 0.000 description 1
- FMTDIUIBLCQGJB-UHFFFAOYSA-N Demethylchlortetracyclin Natural products C1C2C(O)C3=C(Cl)C=CC(O)=C3C(=O)C2=C(O)C2(O)C1C(N(C)C)C(O)=C(C(N)=O)C2=O FMTDIUIBLCQGJB-UHFFFAOYSA-N 0.000 description 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 241000725619 Dengue virus Species 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012468 Dermatitis herpetiformis Diseases 0.000 description 1
- AUGQEEXBDZWUJY-ZLJUKNTDSA-N Diacetoxyscirpenol Chemical compound C([C@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@@H]1C=C(C)CC[C@@]13COC(=O)C)O2 AUGQEEXBDZWUJY-ZLJUKNTDSA-N 0.000 description 1
- AUGQEEXBDZWUJY-UHFFFAOYSA-N Diacetoxyscirpenol Natural products CC(=O)OCC12CCC(C)=CC1OC1C(O)C(OC(C)=O)C2(C)C11CO1 AUGQEEXBDZWUJY-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- OFPZNTXZCGKCMU-QUQSCIKMSA-N Dictyostatin 1 Natural products CC(C=C/C=C)C1OC(=O)C=C/C=C/C(C)C(O)CC(O)C=C/C(C)C(O)C(C)CC(C)CCC(O)C1C OFPZNTXZCGKCMU-QUQSCIKMSA-N 0.000 description 1
- 101100285708 Dictyostelium discoideum hspD gene Proteins 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- 201000003066 Diffuse Scleroderma Diseases 0.000 description 1
- 208000024134 Diffuse cutaneous systemic sclerosis Diseases 0.000 description 1
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 102100024364 Disintegrin and metalloproteinase domain-containing protein 8 Human genes 0.000 description 1
- 208000021866 Dressler syndrome Diseases 0.000 description 1
- 239000012983 Dulbecco’s minimal essential medium Substances 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102100023471 E-selectin Human genes 0.000 description 1
- 102000017930 EDNRB Human genes 0.000 description 1
- 102000012545 EGF-like domains Human genes 0.000 description 1
- 108050002150 EGF-like domains Proteins 0.000 description 1
- 102000012804 EPCAM Human genes 0.000 description 1
- 101150084967 EPCAM gene Proteins 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 102100025137 Early activation antigen CD69 Human genes 0.000 description 1
- 201000011001 Ebola Hemorrhagic Fever Diseases 0.000 description 1
- 241000244160 Echinococcus Species 0.000 description 1
- 102100029722 Ectonucleoside triphosphate diphosphohydrolase 1 Human genes 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- 241000230129 Eisenia <Phaeophyceae> Species 0.000 description 1
- 208000031912 Endemic Flea-Borne Typhus Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 108010090557 Endothelin B Receptor Proteins 0.000 description 1
- 108010032976 Enfuvirtide Proteins 0.000 description 1
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 1
- 208000034801 Enterobacteriaceae Infections Diseases 0.000 description 1
- 108010001687 Enterotoxin Receptors Proteins 0.000 description 1
- 102000000820 Enterotoxin Receptors Human genes 0.000 description 1
- 241001529459 Enterovirus A71 Species 0.000 description 1
- 206010014954 Eosinophilic fasciitis Diseases 0.000 description 1
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 241001379910 Ephemera danica Species 0.000 description 1
- 206010014979 Epidemic typhus Diseases 0.000 description 1
- 206010014989 Epidermolysis bullosa Diseases 0.000 description 1
- 241001480036 Epidermophyton floccosum Species 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 206010015108 Epstein-Barr virus infection Diseases 0.000 description 1
- 208000000832 Equine Encephalomyelitis Diseases 0.000 description 1
- 241000588698 Erwinia Species 0.000 description 1
- 206010015226 Erythema nodosum Diseases 0.000 description 1
- 241001646719 Escherichia coli O157:H7 Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- QGXBDMJGAMFCBF-UHFFFAOYSA-N Etiocholanolone Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 QGXBDMJGAMFCBF-UHFFFAOYSA-N 0.000 description 1
- 208000017259 Extragonadal germ cell tumor Diseases 0.000 description 1
- 206010015993 Eyelid oedema Diseases 0.000 description 1
- 241000272190 Falco peregrinus Species 0.000 description 1
- 241000242711 Fasciola hepatica Species 0.000 description 1
- 108010003471 Fetal Proteins Proteins 0.000 description 1
- 102000004641 Fetal Proteins Human genes 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 102100037362 Fibronectin Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 102000010451 Folate receptor alpha Human genes 0.000 description 1
- 108050001931 Folate receptor alpha Proteins 0.000 description 1
- 102000005698 Frizzled receptors Human genes 0.000 description 1
- 108010045438 Frizzled receptors Proteins 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- FNUPUYFWZXZMIE-UHFFFAOYSA-N Fustin Natural products O1C2=CC(O)=CC=C2C(=O)C(O)C1C1=CC=C(O)C(O)=C1 FNUPUYFWZXZMIE-UHFFFAOYSA-N 0.000 description 1
- 102100032340 G2/mitotic-specific cyclin-B1 Human genes 0.000 description 1
- 241000531123 GB virus C Species 0.000 description 1
- 108700012941 GNRH1 Proteins 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- RVAQIUULWULRNW-UHFFFAOYSA-N Ganetespib Chemical compound C1=C(O)C(C(C)C)=CC(C=2N(C(O)=NN=2)C=2C=C3C=CN(C)C3=CC=2)=C1O RVAQIUULWULRNW-UHFFFAOYSA-N 0.000 description 1
- 201000000628 Gas Gangrene Diseases 0.000 description 1
- 102000004862 Gastrin releasing peptide Human genes 0.000 description 1
- 108090001053 Gastrin releasing peptide Proteins 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 206010017915 Gastroenteritis shigella Diseases 0.000 description 1
- 206010017916 Gastroenteritis staphylococcal Diseases 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 244000168141 Geotrichum candidum Species 0.000 description 1
- 235000017388 Geotrichum candidum Nutrition 0.000 description 1
- 208000021309 Germ cell tumor Diseases 0.000 description 1
- 241000224467 Giardia intestinalis Species 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- BBBXWRGITSUJPB-YUMQZZPRSA-N Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CCC(O)=O BBBXWRGITSUJPB-YUMQZZPRSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 102100035716 Glycophorin-A Human genes 0.000 description 1
- 102000010956 Glypican Human genes 0.000 description 1
- 108050001154 Glypican Proteins 0.000 description 1
- 108050007237 Glypican-3 Proteins 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 206010056559 Graft infection Diseases 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 101710198293 Guanylyl cyclase C Proteins 0.000 description 1
- 208000035895 Guillain-Barré syndrome Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000017891 HER2 positive breast carcinoma Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 206010061190 Haemophilus infection Diseases 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000207963 Harpagophytum Species 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 206010019375 Helicobacter infections Diseases 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 102100031573 Hematopoietic progenitor cell antigen CD34 Human genes 0.000 description 1
- 208000032759 Hemolytic-Uremic Syndrome Diseases 0.000 description 1
- 201000004331 Henoch-Schoenlein purpura Diseases 0.000 description 1
- 206010019617 Henoch-Schonlein purpura Diseases 0.000 description 1
- 108010007712 Hepatitis A Virus Cellular Receptor 1 Proteins 0.000 description 1
- 102100034459 Hepatitis A virus cellular receptor 1 Human genes 0.000 description 1
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 208000005100 Herpetic Keratitis Diseases 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 201000002563 Histoplasmosis Diseases 0.000 description 1
- 101001022185 Homo sapiens Alpha-(1,3)-fucosyltransferase 4 Proteins 0.000 description 1
- 101000757191 Homo sapiens Ankyrin repeat domain-containing protein 30A Proteins 0.000 description 1
- 101000914491 Homo sapiens B-cell antigen receptor complex-associated protein beta chain Proteins 0.000 description 1
- 101000934359 Homo sapiens B-cell differentiation antigen CD72 Proteins 0.000 description 1
- 101000856683 Homo sapiens C-X-C chemokine receptor type 6 Proteins 0.000 description 1
- 101000766907 Homo sapiens C-type lectin domain family 4 member C Proteins 0.000 description 1
- 101000867983 Homo sapiens C5a anaphylatoxin chemotactic receptor 1 Proteins 0.000 description 1
- 101000738399 Homo sapiens CD109 antigen Proteins 0.000 description 1
- 101000980840 Homo sapiens CD166 antigen Proteins 0.000 description 1
- 101000897416 Homo sapiens CD209 antigen Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101000716130 Homo sapiens CD48 antigen Proteins 0.000 description 1
- 101000897400 Homo sapiens CD59 glycoprotein Proteins 0.000 description 1
- 101000934368 Homo sapiens CD63 antigen Proteins 0.000 description 1
- 101000914479 Homo sapiens CD81 antigen Proteins 0.000 description 1
- 101000914469 Homo sapiens CD82 antigen Proteins 0.000 description 1
- 101000946856 Homo sapiens CD83 antigen Proteins 0.000 description 1
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 description 1
- 101000749329 Homo sapiens Claudin-18 Proteins 0.000 description 1
- 101000737052 Homo sapiens Coiled-coil domain-containing protein 54 Proteins 0.000 description 1
- 101000856022 Homo sapiens Complement decay-accelerating factor Proteins 0.000 description 1
- 101000727061 Homo sapiens Complement receptor type 1 Proteins 0.000 description 1
- 101000941929 Homo sapiens Complement receptor type 2 Proteins 0.000 description 1
- 101000725164 Homo sapiens Cytochrome P450 1B1 Proteins 0.000 description 1
- 101000744174 Homo sapiens DNA-3-methyladenine glycosylase Proteins 0.000 description 1
- 101000908391 Homo sapiens Dipeptidyl peptidase 4 Proteins 0.000 description 1
- 101000622123 Homo sapiens E-selectin Proteins 0.000 description 1
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 description 1
- 101001012447 Homo sapiens Ectonucleoside triphosphate diphosphohydrolase 1 Proteins 0.000 description 1
- 101000881679 Homo sapiens Endoglin Proteins 0.000 description 1
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 1
- 101001074244 Homo sapiens Glycophorin-A Proteins 0.000 description 1
- 101000777663 Homo sapiens Hematopoietic progenitor cell antigen CD34 Proteins 0.000 description 1
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 description 1
- 101000972946 Homo sapiens Hepatocyte growth factor receptor Proteins 0.000 description 1
- 101100341519 Homo sapiens ITGAX gene Proteins 0.000 description 1
- 101000878602 Homo sapiens Immunoglobulin alpha Fc receptor Proteins 0.000 description 1
- 101001046687 Homo sapiens Integrin alpha-E Proteins 0.000 description 1
- 101001078143 Homo sapiens Integrin alpha-IIb Proteins 0.000 description 1
- 101001046683 Homo sapiens Integrin alpha-L Proteins 0.000 description 1
- 101001046686 Homo sapiens Integrin alpha-M Proteins 0.000 description 1
- 101000935043 Homo sapiens Integrin beta-1 Proteins 0.000 description 1
- 101001015004 Homo sapiens Integrin beta-3 Proteins 0.000 description 1
- 101000599852 Homo sapiens Intercellular adhesion molecule 1 Proteins 0.000 description 1
- 101001057504 Homo sapiens Interferon-stimulated gene 20 kDa protein Proteins 0.000 description 1
- 101001055144 Homo sapiens Interleukin-2 receptor subunit alpha Proteins 0.000 description 1
- 101001043821 Homo sapiens Interleukin-31 Proteins 0.000 description 1
- 101001018097 Homo sapiens L-selectin Proteins 0.000 description 1
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 description 1
- 101000980823 Homo sapiens Leukocyte surface antigen CD53 Proteins 0.000 description 1
- 101000608935 Homo sapiens Leukosialin Proteins 0.000 description 1
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 1
- 101000917826 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-a Proteins 0.000 description 1
- 101000917824 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor II-b Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101001063392 Homo sapiens Lymphocyte function-associated antigen 3 Proteins 0.000 description 1
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 1
- 101000934372 Homo sapiens Macrosialin Proteins 0.000 description 1
- 101001008874 Homo sapiens Mast/stem cell growth factor receptor Kit Proteins 0.000 description 1
- 101000620359 Homo sapiens Melanocyte protein PMEL Proteins 0.000 description 1
- 101000961414 Homo sapiens Membrane cofactor protein Proteins 0.000 description 1
- 101000694615 Homo sapiens Membrane primary amine oxidase Proteins 0.000 description 1
- 101000628535 Homo sapiens Metalloreductase STEAP2 Proteins 0.000 description 1
- 101000946889 Homo sapiens Monocyte differentiation antigen CD14 Proteins 0.000 description 1
- 101000577540 Homo sapiens Neuropilin-1 Proteins 0.000 description 1
- 101000613490 Homo sapiens Paired box protein Pax-3 Proteins 0.000 description 1
- 101000601724 Homo sapiens Paired box protein Pax-5 Proteins 0.000 description 1
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 1
- 101001043564 Homo sapiens Prolow-density lipoprotein receptor-related protein 1 Proteins 0.000 description 1
- 101001098868 Homo sapiens Proprotein convertase subtilisin/kexin type 9 Proteins 0.000 description 1
- 101001136592 Homo sapiens Prostate stem cell antigen Proteins 0.000 description 1
- 101000880770 Homo sapiens Protein SSX2 Proteins 0.000 description 1
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 1
- 101000633784 Homo sapiens SLAM family member 7 Proteins 0.000 description 1
- 101000650817 Homo sapiens Semaphorin-4D Proteins 0.000 description 1
- 101000884271 Homo sapiens Signal transducer CD24 Proteins 0.000 description 1
- 101000824971 Homo sapiens Sperm surface protein Sp17 Proteins 0.000 description 1
- 101000873927 Homo sapiens Squamous cell carcinoma antigen recognized by T-cells 3 Proteins 0.000 description 1
- 101000946860 Homo sapiens T-cell surface glycoprotein CD3 epsilon chain Proteins 0.000 description 1
- 101000596234 Homo sapiens T-cell surface protein tactile Proteins 0.000 description 1
- 101000835745 Homo sapiens Teratocarcinoma-derived growth factor 1 Proteins 0.000 description 1
- 101000834948 Homo sapiens Tomoregulin-2 Proteins 0.000 description 1
- 101000904724 Homo sapiens Transmembrane glycoprotein NMB Proteins 0.000 description 1
- 101000610602 Homo sapiens Tumor necrosis factor receptor superfamily member 10C Proteins 0.000 description 1
- 101000610609 Homo sapiens Tumor necrosis factor receptor superfamily member 10D Proteins 0.000 description 1
- 101000795167 Homo sapiens Tumor necrosis factor receptor superfamily member 13B Proteins 0.000 description 1
- 101000679903 Homo sapiens Tumor necrosis factor receptor superfamily member 25 Proteins 0.000 description 1
- 101000760337 Homo sapiens Urokinase plasminogen activator surface receptor Proteins 0.000 description 1
- 101000622304 Homo sapiens Vascular cell adhesion protein 1 Proteins 0.000 description 1
- 206010020376 Hookworm infection Diseases 0.000 description 1
- 108010084873 Human Immunodeficiency Virus nef Gene Products Proteins 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- 241000701041 Human betaherpesvirus 7 Species 0.000 description 1
- 241000701027 Human herpesvirus 6 Species 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 241000702617 Human parvovirus B19 Species 0.000 description 1
- 102100027735 Hyaluronan mediated motility receptor Human genes 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- GRRNUXAQVGOGFE-UHFFFAOYSA-N Hygromycin-B Natural products OC1C(NC)CC(N)C(O)C1OC1C2OC3(C(C(O)C(O)C(C(N)CO)O3)O)OC2C(O)C(CO)O1 GRRNUXAQVGOGFE-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020983 Hypogammaglobulinaemia Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 1
- 208000031814 IgA Vasculitis Diseases 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- 108010073816 IgE Receptors Proteins 0.000 description 1
- 102000009438 IgE Receptors Human genes 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102100038005 Immunoglobulin alpha Fc receptor Human genes 0.000 description 1
- 102000012214 Immunoproteins Human genes 0.000 description 1
- 108010036650 Immunoproteins Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000002979 Influenza in Birds Diseases 0.000 description 1
- 108090001117 Insulin-Like Growth Factor II Proteins 0.000 description 1
- 102000048143 Insulin-Like Growth Factor II Human genes 0.000 description 1
- 102100022341 Integrin alpha-E Human genes 0.000 description 1
- 102100025306 Integrin alpha-IIb Human genes 0.000 description 1
- 102100022339 Integrin alpha-L Human genes 0.000 description 1
- 102100022338 Integrin alpha-M Human genes 0.000 description 1
- 102100022297 Integrin alpha-X Human genes 0.000 description 1
- 102100025304 Integrin beta-1 Human genes 0.000 description 1
- 102100032999 Integrin beta-3 Human genes 0.000 description 1
- 102100027268 Interferon-stimulated gene 20 kDa protein Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 102100039064 Interleukin-3 Human genes 0.000 description 1
- 102100021596 Interleukin-31 Human genes 0.000 description 1
- 102000010781 Interleukin-6 Receptors Human genes 0.000 description 1
- 102100021593 Interleukin-7 receptor subunit alpha Human genes 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 0.000 description 1
- 206010073751 Intracranial germ cell tumour Diseases 0.000 description 1
- 206010061252 Intraocular melanoma Diseases 0.000 description 1
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 1
- 241000567229 Isospora Species 0.000 description 1
- 206010023076 Isosporiasis Diseases 0.000 description 1
- 241000701460 JC polyomavirus Species 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- DEFJQIDDEAULHB-IMJSIDKUSA-N L-alanyl-L-alanine Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(O)=O DEFJQIDDEAULHB-IMJSIDKUSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VSOAQEOCSA-N L-altropyranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-VSOAQEOCSA-N 0.000 description 1
- 102100031413 L-dopachrome tautomerase Human genes 0.000 description 1
- 101710093778 L-dopachrome tautomerase Proteins 0.000 description 1
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- DWPCPZJAHOETAG-IMJSIDKUSA-N L-lanthionine Chemical compound OC(=O)[C@@H](N)CSC[C@H](N)C(O)=O DWPCPZJAHOETAG-IMJSIDKUSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- QEFRNWWLZKMPFJ-ZXPFJRLXSA-N L-methionine (R)-S-oxide Chemical compound C[S@@](=O)CC[C@H]([NH3+])C([O-])=O QEFRNWWLZKMPFJ-ZXPFJRLXSA-N 0.000 description 1
- QEFRNWWLZKMPFJ-UHFFFAOYSA-N L-methionine sulphoxide Natural products CS(=O)CCC(N)C(O)=O QEFRNWWLZKMPFJ-UHFFFAOYSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- ZFOMKMMPBOQKMC-KXUCPTDWSA-N L-pyrrolysine Chemical compound C[C@@H]1CC=N[C@H]1C(=O)NCCCC[C@H]([NH3+])C([O-])=O ZFOMKMMPBOQKMC-KXUCPTDWSA-N 0.000 description 1
- 102100033467 L-selectin Human genes 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- 239000002137 L01XE24 - Ponatinib Substances 0.000 description 1
- BPFYOAJNDMUVBL-UHFFFAOYSA-N LSM-5799 Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3N(C)COC1=C32 BPFYOAJNDMUVBL-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010023927 Lassa fever Diseases 0.000 description 1
- 241000589242 Legionella pneumophila Species 0.000 description 1
- 241000222740 Leishmania braziliensis Species 0.000 description 1
- 208000004554 Leishmaniasis Diseases 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 241000589902 Leptospira Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 102000004058 Leukemia inhibitory factor Human genes 0.000 description 1
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 1
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 description 1
- 102100024221 Leukocyte surface antigen CD53 Human genes 0.000 description 1
- 102100039564 Leukosialin Human genes 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 206010062038 Lip neoplasm Diseases 0.000 description 1
- 108010028921 Lipopeptides Proteins 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 241000186779 Listeria monocytogenes Species 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 1
- 102100029204 Low affinity immunoglobulin gamma Fc region receptor II-a Human genes 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 206010067737 Lupus hepatitis Diseases 0.000 description 1
- 108010064548 Lymphocyte Function-Associated Antigen-1 Proteins 0.000 description 1
- 102100030984 Lymphocyte function-associated antigen 3 Human genes 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- NVGBPTNZLWRQSY-UWVGGRQHSA-N Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN NVGBPTNZLWRQSY-UWVGGRQHSA-N 0.000 description 1
- QCZYYEFXOBKCNQ-STQMWFEESA-N Lys-Phe Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 QCZYYEFXOBKCNQ-STQMWFEESA-N 0.000 description 1
- 102000034655 MIF Human genes 0.000 description 1
- 108060004872 MIF Proteins 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- 108700012912 MYCN Proteins 0.000 description 1
- 101150022024 MYCN gene Proteins 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 108010048043 Macrophage Migration-Inhibitory Factors Proteins 0.000 description 1
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 description 1
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 1
- 102100037791 Macrophage migration inhibitory factor Human genes 0.000 description 1
- 102100025136 Macrosialin Human genes 0.000 description 1
- 208000009777 Majeed syndrome Diseases 0.000 description 1
- 206010025538 Malignant ascites Diseases 0.000 description 1
- 206010064281 Malignant atrophic papulosis Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000000932 Marburg Virus Disease Diseases 0.000 description 1
- 201000011013 Marburg hemorrhagic fever Diseases 0.000 description 1
- 241001115401 Marburgvirus Species 0.000 description 1
- 102100027754 Mast/stem cell growth factor receptor Kit Human genes 0.000 description 1
- 241000712079 Measles morbillivirus Species 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 102100039373 Membrane cofactor protein Human genes 0.000 description 1
- 102100027159 Membrane primary amine oxidase Human genes 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- 102100026711 Metalloreductase STEAP2 Human genes 0.000 description 1
- 206010066226 Metapneumovirus infection Diseases 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 201000000090 Microsporidiosis Diseases 0.000 description 1
- 241001480037 Microsporum Species 0.000 description 1
- DMUAPQTXSSNEDD-QALJCMCCSA-N Midecamycin Chemical compound C1[C@](O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C DMUAPQTXSSNEDD-QALJCMCCSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 102100035877 Monocyte differentiation antigen CD14 Human genes 0.000 description 1
- 239000005462 Mubritinib Substances 0.000 description 1
- 108010063954 Mucins Proteins 0.000 description 1
- 102000015728 Mucins Human genes 0.000 description 1
- 208000012192 Mucous membrane pemphigoid Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 206010028282 Murine typhus Diseases 0.000 description 1
- 101100346932 Mus musculus Muc1 gene Proteins 0.000 description 1
- 101100425758 Mus musculus Tnfrsf1b gene Proteins 0.000 description 1
- 241000186362 Mycobacterium leprae Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 241000202934 Mycoplasma pneumoniae Species 0.000 description 1
- 201000008235 Mycoplasma pneumoniae pneumonia Diseases 0.000 description 1
- 108010013731 Myelin-Associated Glycoprotein Proteins 0.000 description 1
- 102100021831 Myelin-associated glycoprotein Human genes 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000006123 Myiasis Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- HRNLUBSXIHFDHP-UHFFFAOYSA-N N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC1=NC=CC(C=2C=NC=CC=2)=N1 HRNLUBSXIHFDHP-UHFFFAOYSA-N 0.000 description 1
- 108700026495 N-Myc Proto-Oncogene Proteins 0.000 description 1
- YALNUENQHAQXEA-UHFFFAOYSA-N N-[4-[(hydroxyamino)-oxomethyl]phenyl]carbamic acid [6-(diethylaminomethyl)-2-naphthalenyl]methyl ester Chemical compound C1=CC2=CC(CN(CC)CC)=CC=C2C=C1COC(=O)NC1=CC=C(C(=O)NO)C=C1 YALNUENQHAQXEA-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- PYUSHNKNPOHWEZ-YFKPBYRVSA-N N-formyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC=O PYUSHNKNPOHWEZ-YFKPBYRVSA-N 0.000 description 1
- FDJKUWYYUZCUJX-AJKRCSPLSA-N N-glycoloyl-beta-neuraminic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@@H]1O[C@](O)(C(O)=O)C[C@H](O)[C@H]1NC(=O)CO FDJKUWYYUZCUJX-AJKRCSPLSA-N 0.000 description 1
- 229930182474 N-glycoside Natural products 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 102100030124 N-myc proto-oncogene protein Human genes 0.000 description 1
- 206010028767 Nasal sinus cancer Diseases 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 102100035486 Nectin-4 Human genes 0.000 description 1
- 101710043865 Nectin-4 Proteins 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 102000005348 Neuraminidase Human genes 0.000 description 1
- 108010006232 Neuraminidase Proteins 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000033383 Neuroendocrine tumor of pancreas Diseases 0.000 description 1
- 102100028762 Neuropilin-1 Human genes 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- AFLXUQUGROGEFA-UHFFFAOYSA-N Nitrogen mustard N-oxide Chemical compound ClCC[N+]([O-])(C)CCCl AFLXUQUGROGEFA-UHFFFAOYSA-N 0.000 description 1
- 241001263478 Norovirus Species 0.000 description 1
- 241000714209 Norwalk virus Species 0.000 description 1
- 208000010505 Nose Neoplasms Diseases 0.000 description 1
- 241001126829 Nosema Species 0.000 description 1
- 108010070047 Notch Receptors Proteins 0.000 description 1
- 102000005650 Notch Receptors Human genes 0.000 description 1
- 229930182473 O-glycoside Natural products 0.000 description 1
- 150000008444 O-glycosides Chemical class 0.000 description 1
- 102100037589 OX-2 membrane glycoprotein Human genes 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 241000243985 Onchocerca volvulus Species 0.000 description 1
- 206010073938 Ophthalmic herpes simplex Diseases 0.000 description 1
- 208000005225 Opsoclonus-Myoclonus Syndrome Diseases 0.000 description 1
- 208000007027 Oral Candidiasis Diseases 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- 241000150452 Orthohantavirus Species 0.000 description 1
- 241000712464 Orthomyxoviridae Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- 108010035042 Osteoprotegerin Proteins 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 206010053869 POEMS syndrome Diseases 0.000 description 1
- 102100040891 Paired box protein Pax-3 Human genes 0.000 description 1
- 102100037504 Paired box protein Pax-5 Human genes 0.000 description 1
- VREZDOWOLGNDPW-ALTGWBOUSA-N Pancratistatin Chemical compound C1=C2[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)[C@@H]3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-ALTGWBOUSA-N 0.000 description 1
- VREZDOWOLGNDPW-MYVCAWNPSA-N Pancratistatin Natural products O=C1N[C@H]2[C@H](O)[C@H](O)[C@H](O)[C@H](O)[C@@H]2c2c1c(O)c1OCOc1c2 VREZDOWOLGNDPW-MYVCAWNPSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- TYMABNNERDVXID-DLYFRVTGSA-N Panipenem Chemical compound C([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1S[C@H]1CCN(C(C)=N)C1 TYMABNNERDVXID-DLYFRVTGSA-N 0.000 description 1
- 208000009608 Papillomavirus Infections Diseases 0.000 description 1
- 206010033767 Paracoccidioides infections Diseases 0.000 description 1
- 201000000301 Paracoccidioidomycosis Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000003937 Paranasal Sinus Neoplasms Diseases 0.000 description 1
- 208000000821 Parathyroid Neoplasms Diseases 0.000 description 1
- UOZODPSAJZTQNH-UHFFFAOYSA-N Paromomycin II Natural products NC1C(O)C(O)C(CN)OC1OC1C(O)C(OC2C(C(N)CC(N)C2O)OC2C(C(O)C(O)C(CO)O2)N)OC1CO UOZODPSAJZTQNH-UHFFFAOYSA-N 0.000 description 1
- 206010034038 Parotitis Diseases 0.000 description 1
- 208000000733 Paroxysmal Hemoglobinuria Diseases 0.000 description 1
- 241000517324 Pediculidae Species 0.000 description 1
- 241000517306 Pediculus humanus corporis Species 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 1
- 229930195708 Penicillin V Natural products 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 108010067902 Peptide Library Proteins 0.000 description 1
- 241000150350 Peribunyaviridae Species 0.000 description 1
- 241001537210 Perna Species 0.000 description 1
- 201000005702 Pertussis Diseases 0.000 description 1
- 240000009164 Petroselinum crispum Species 0.000 description 1
- 102100036050 Phosphatidylinositol N-acetylglucosaminyltransferase subunit A Human genes 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 206010035148 Plague Diseases 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 241000223960 Plasmodium falciparum Species 0.000 description 1
- 241000223821 Plasmodium malariae Species 0.000 description 1
- 241000223810 Plasmodium vivax Species 0.000 description 1
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 1
- 102100030485 Platelet-derived growth factor receptor alpha Human genes 0.000 description 1
- 101710148465 Platelet-derived growth factor receptor alpha Proteins 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 101710164680 Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 208000035109 Pneumococcal Infections Diseases 0.000 description 1
- 241000233870 Pneumocystis Species 0.000 description 1
- 206010035724 Pneumonia mycoplasmal Diseases 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 206010065159 Polychondritis Diseases 0.000 description 1
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 1
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 1
- 108010093965 Polymyxin B Proteins 0.000 description 1
- 206010036105 Polyneuropathy Diseases 0.000 description 1
- 208000031732 Post-Lyme Disease Syndrome Diseases 0.000 description 1
- 208000010366 Postpoliomyelitis syndrome Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 244000308495 Potentilla anserina Species 0.000 description 1
- 235000016594 Potentilla anserina Nutrition 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 108010079780 Pristinamycin Proteins 0.000 description 1
- RLNUPSVMIYRZSM-UHFFFAOYSA-N Pristinamycin Natural products CC1OC(=O)C(C=2C=CC=CC=2)NC(=O)C2CC(=O)CCN2C(=O)C(CC=2C=CC(=CC=2)N(C)C)CCN(C)C(=O)C2CCCN2C(=O)C(CC)NC(=O)C1NC(=O)C1=NC=CC=C1O RLNUPSVMIYRZSM-UHFFFAOYSA-N 0.000 description 1
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 1
- 208000037534 Progressive hemifacial atrophy Diseases 0.000 description 1
- 102100021923 Prolow-density lipoprotein receptor-related protein 1 Human genes 0.000 description 1
- 102100040120 Prominin-1 Human genes 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Chemical group OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000186429 Propionibacterium Species 0.000 description 1
- 102100038955 Proprotein convertase subtilisin/kexin type 9 Human genes 0.000 description 1
- 102100036735 Prostate stem cell antigen Human genes 0.000 description 1
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 1
- 102100038358 Prostate-specific antigen Human genes 0.000 description 1
- 101710180319 Protease 1 Proteins 0.000 description 1
- 101710180313 Protease 3 Proteins 0.000 description 1
- 102100037686 Protein SSX2 Human genes 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010037151 Psittacosis Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 241000517305 Pthiridae Species 0.000 description 1
- 241000411545 Punargentus Species 0.000 description 1
- 208000003670 Pure Red-Cell Aplasia Diseases 0.000 description 1
- 206010037688 Q fever Diseases 0.000 description 1
- 102000014128 RANK Ligand Human genes 0.000 description 1
- 108010025832 RANK Ligand Proteins 0.000 description 1
- 241000711798 Rabies lyssavirus Species 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- KGZHFKDNSAEOJX-WIFQYKSHSA-N Ramoplanin Chemical compound C([C@H]1C(=O)N[C@H](CCCN)C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C)C(=O)N[C@H](C(=O)O[C@@H]([C@@H](C(N[C@@H](C(=O)N[C@H](CCCN)C(=O)N[C@@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N1)[C@H](C)O)C=1C=CC(O)=CC=1)C=1C=CC(O)=CC=1)[C@@H](C)O)C=1C=CC(O)=CC=1)=O)NC(=O)[C@H](CC(N)=O)NC(=O)\C=C/C=C/CC(C)C)C(N)=O)C=1C=C(Cl)C(O)=CC=1)C=1C=CC(O)=CC=1)[C@@H](C)O)C=1C=CC(O[C@@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=1)C1=CC=CC=C1 KGZHFKDNSAEOJX-WIFQYKSHSA-N 0.000 description 1
- 206010071141 Rasmussen encephalitis Diseases 0.000 description 1
- 208000004160 Rasmussen subacute encephalitis Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 101000737809 Rattus norvegicus Cadherin-related family member 5 Proteins 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 1
- 102100037421 Regulator of G-protein signaling 5 Human genes 0.000 description 1
- 101710140403 Regulator of G-protein signaling 5 Proteins 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 241000702263 Reovirus sp. Species 0.000 description 1
- 208000005793 Restless legs syndrome Diseases 0.000 description 1
- 208000004364 Rhinosporidiosis Diseases 0.000 description 1
- 206010061494 Rhinovirus infection Diseases 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 229940127395 Ribonucleotide Reductase Inhibitors Drugs 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- URWAJWIAIPFPJE-UHFFFAOYSA-N Rickamicin Natural products O1CC(O)(C)C(NC)C(O)C1OC1C(O)C(OC2C(CC=C(CN)O2)N)C(N)CC1N URWAJWIAIPFPJE-UHFFFAOYSA-N 0.000 description 1
- 241000606695 Rickettsia rickettsii Species 0.000 description 1
- 241000606726 Rickettsia typhi Species 0.000 description 1
- 229930189077 Rifamycin Natural products 0.000 description 1
- 241000713124 Rift Valley fever virus Species 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 206010039207 Rocky Mountain Spotted Fever Diseases 0.000 description 1
- 206010067470 Rotavirus infection Diseases 0.000 description 1
- 229930182475 S-glycoside Natural products 0.000 description 1
- 241000315672 SARS coronavirus Species 0.000 description 1
- 102100029198 SLAM family member 7 Human genes 0.000 description 1
- 241000059486 Sabo virus Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 206010039438 Salmonella Infections Diseases 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 206010049677 Salpingo-oophoritis Diseases 0.000 description 1
- 241000447727 Scabies Species 0.000 description 1
- 241000242680 Schistosoma mansoni Species 0.000 description 1
- 101100071627 Schizosaccharomyces pombe (strain 972 / ATCC 24843) swo1 gene Proteins 0.000 description 1
- 201000010848 Schnitzler Syndrome Diseases 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 102100034201 Sclerostin Human genes 0.000 description 1
- 108050006698 Sclerostin Proteins 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 102100027744 Semaphorin-4D Human genes 0.000 description 1
- 239000012506 Sephacryl® Substances 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 208000009359 Sezary Syndrome Diseases 0.000 description 1
- 208000021388 Sezary disease Diseases 0.000 description 1
- 101710173694 Short transient receptor potential channel 2 Proteins 0.000 description 1
- 102000003838 Sialyltransferases Human genes 0.000 description 1
- 108090000141 Sialyltransferases Proteins 0.000 description 1
- 102100038081 Signal transducer CD24 Human genes 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 108010029389 Simplexvirus glycoprotein B Proteins 0.000 description 1
- 229930192786 Sisomicin Natural products 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 102000046202 Sodium-Phosphate Cotransporter Proteins Human genes 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 239000004187 Spiramycin Substances 0.000 description 1
- 241000586493 Spirosoma Species 0.000 description 1
- 241001149962 Sporothrix Species 0.000 description 1
- 102100035748 Squamous cell carcinoma antigen recognized by T-cells 3 Human genes 0.000 description 1
- UQZIYBXSHAGNOE-USOSMYMVSA-N Stachyose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](CO[C@@H]2[C@@H](O)[C@@H](O)[C@@H](O)[C@H](CO)O2)O1 UQZIYBXSHAGNOE-USOSMYMVSA-N 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 208000008582 Staphylococcal Food Poisoning Diseases 0.000 description 1
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 1
- 206010072148 Stiff-Person syndrome Diseases 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241001505901 Streptococcus sp. 'group A' Species 0.000 description 1
- 108010034396 Streptogramins Proteins 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- 241000244174 Strongyloides Species 0.000 description 1
- 241000244177 Strongyloides stercoralis Species 0.000 description 1
- 206010042276 Subacute endocarditis Diseases 0.000 description 1
- 208000037065 Subacute sclerosing leukoencephalitis Diseases 0.000 description 1
- 206010042297 Subacute sclerosing panencephalitis Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NHUHCSRWZMLRLA-UHFFFAOYSA-N Sulfisoxazole Chemical compound CC1=NOC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1C NHUHCSRWZMLRLA-UHFFFAOYSA-N 0.000 description 1
- 101800001271 Surface protein Proteins 0.000 description 1
- 108010002687 Survivin Proteins 0.000 description 1
- 208000010265 Sweet syndrome Diseases 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 108090000058 Syndecan-1 Proteins 0.000 description 1
- BXFOFFBJRFZBQZ-QYWOHJEZSA-N T-2 toxin Chemical compound C([C@@]12[C@]3(C)[C@H](OC(C)=O)[C@@H](O)[C@H]1O[C@H]1[C@]3(COC(C)=O)C[C@@H](C(=C1)C)OC(=O)CC(C)C)O2 BXFOFFBJRFZBQZ-QYWOHJEZSA-N 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 102100027208 T-cell antigen CD7 Human genes 0.000 description 1
- 102100025131 T-cell differentiation antigen CD6 Human genes 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- 102100035794 T-cell surface glycoprotein CD3 epsilon chain Human genes 0.000 description 1
- 102100025244 T-cell surface glycoprotein CD5 Human genes 0.000 description 1
- 102100035268 T-cell surface protein tactile Human genes 0.000 description 1
- 101150057140 TACSTD1 gene Proteins 0.000 description 1
- 108010014401 TWEAK Receptor Proteins 0.000 description 1
- 208000001106 Takayasu Arteritis Diseases 0.000 description 1
- 108010053950 Teicoplanin Proteins 0.000 description 1
- 102100026404 Teratocarcinoma-derived growth factor 1 Human genes 0.000 description 1
- HATRDXDCPOXQJX-UHFFFAOYSA-N Thapsigargin Natural products CCCCCCCC(=O)OC1C(OC(O)C(=C/C)C)C(=C2C3OC(=O)C(C)(O)C3(O)C(CC(C)(OC(=O)C)C12)OC(=O)CCC)C HATRDXDCPOXQJX-UHFFFAOYSA-N 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- 101710137710 Thioesterase 1/protease 1/lysophospholipase L1 Proteins 0.000 description 1
- 102100026966 Thrombomodulin Human genes 0.000 description 1
- 108010034949 Thyroglobulin Proteins 0.000 description 1
- 102000009843 Thyroglobulin Human genes 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- 208000007712 Tinea Versicolor Diseases 0.000 description 1
- 206010043866 Tinea capitis Diseases 0.000 description 1
- 201000010618 Tinea cruris Diseases 0.000 description 1
- 206010067197 Tinea manuum Diseases 0.000 description 1
- 206010056131 Tinea versicolour Diseases 0.000 description 1
- HJLSLZFTEKNLFI-UHFFFAOYSA-N Tinidazole Chemical compound CCS(=O)(=O)CCN1C(C)=NC=C1[N+]([O-])=O HJLSLZFTEKNLFI-UHFFFAOYSA-N 0.000 description 1
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 description 1
- 102100030859 Tissue factor Human genes 0.000 description 1
- 206010051526 Tolosa-Hunt syndrome Diseases 0.000 description 1
- UQVNRKBFAXNOGA-IUODEOHRSA-N Tomaymycin Natural products CO[C@H]1Nc2cc(O)c(OC)cc2C(=O)N3CC(=CC)C[C@H]13 UQVNRKBFAXNOGA-IUODEOHRSA-N 0.000 description 1
- 102100026160 Tomoregulin-2 Human genes 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 206010044269 Toxocariasis Diseases 0.000 description 1
- 241000223996 Toxoplasma Species 0.000 description 1
- 241000222354 Trametes Species 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 1
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 1
- 101710170091 Transmembrane glycoprotein NMB Proteins 0.000 description 1
- 101800001690 Transmembrane protein gp41 Proteins 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 241000242541 Trematoda Species 0.000 description 1
- 241000589884 Treponema pallidum Species 0.000 description 1
- 241000243774 Trichinella Species 0.000 description 1
- 241000243777 Trichinella spiralis Species 0.000 description 1
- 206010044608 Trichiniasis Diseases 0.000 description 1
- 208000005448 Trichomonas Infections Diseases 0.000 description 1
- 206010044620 Trichomoniasis Diseases 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- 241001045770 Trichophyton mentagrophytes Species 0.000 description 1
- RTKIYFITIVXBLE-UHFFFAOYSA-N Trichostatin A Natural products ONC(=O)C=CC(C)=CC(C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-UHFFFAOYSA-N 0.000 description 1
- 241001489151 Trichuris Species 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 241000223104 Trypanosoma Species 0.000 description 1
- 241001442397 Trypanosoma brucei rhodesiense Species 0.000 description 1
- 208000034784 Tularaemia Diseases 0.000 description 1
- 102100040115 Tumor necrosis factor receptor superfamily member 10C Human genes 0.000 description 1
- 102100040110 Tumor necrosis factor receptor superfamily member 10D Human genes 0.000 description 1
- 102100032236 Tumor necrosis factor receptor superfamily member 11B Human genes 0.000 description 1
- 102100028786 Tumor necrosis factor receptor superfamily member 12A Human genes 0.000 description 1
- 102100033725 Tumor necrosis factor receptor superfamily member 16 Human genes 0.000 description 1
- 102100022203 Tumor necrosis factor receptor superfamily member 25 Human genes 0.000 description 1
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 1
- 241000287411 Turdidae Species 0.000 description 1
- 208000026928 Turner syndrome Diseases 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 102000003425 Tyrosinase Human genes 0.000 description 1
- 108060008724 Tyrosinase Proteins 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000025851 Undifferentiated connective tissue disease Diseases 0.000 description 1
- 208000017379 Undifferentiated connective tissue syndrome Diseases 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 241000202898 Ureaplasma Species 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 102100024689 Urokinase plasminogen activator surface receptor Human genes 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 201000005969 Uveal melanoma Diseases 0.000 description 1
- QRZVUAAKNRHEOP-GUBZILKMSA-N Val-Ala-Val Chemical compound [H]N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O QRZVUAAKNRHEOP-GUBZILKMSA-N 0.000 description 1
- AEMPCGRFEZTWIF-IHRRRGAJSA-N Val-Leu-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O AEMPCGRFEZTWIF-IHRRRGAJSA-N 0.000 description 1
- JKHXYJKMNSSFFL-IUCAKERBSA-N Val-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN JKHXYJKMNSSFFL-IUCAKERBSA-N 0.000 description 1
- KRNYOVHEKOBTEF-YUMQZZPRSA-N Val-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(O)=O KRNYOVHEKOBTEF-YUMQZZPRSA-N 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 241000710959 Venezuelan equine encephalitis virus Species 0.000 description 1
- 201000009693 Venezuelan hemorrhagic fever Diseases 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 102000013127 Vimentin Human genes 0.000 description 1
- 108010065472 Vimentin Proteins 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 201000006449 West Nile encephalitis Diseases 0.000 description 1
- 206010057293 West Nile viral infection Diseases 0.000 description 1
- 241000710886 West Nile virus Species 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 208000006110 Wiskott-Aldrich syndrome Diseases 0.000 description 1
- 241000244005 Wuchereria bancrofti Species 0.000 description 1
- 238000012452 Xenomouse strains Methods 0.000 description 1
- 208000003152 Yellow Fever Diseases 0.000 description 1
- 241000710772 Yellow fever virus Species 0.000 description 1
- 241000607447 Yersinia enterocolitica Species 0.000 description 1
- 241000607477 Yersinia pseudotuberculosis Species 0.000 description 1
- 208000025087 Yersinia pseudotuberculosis infectious disease Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- LJFFDOBFKICLHN-IXWHRVGISA-N [(1S,2R,3S,5S,6S,16E,18E,20R,21S)-11-chloro-21-hydroxy-12,20-dimethoxy-2,5,9,16-tetramethyl-8,23-dioxo-4,24-dioxa-9,22-diazatetracyclo[19.3.1.110,14.03,5]hexacosa-10,12,14(26),16,18-pentaen-6-yl] (2S)-2-[methyl(4-sulfanylpentanoyl)amino]propanoate Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCC(C)S)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 LJFFDOBFKICLHN-IXWHRVGISA-N 0.000 description 1
- NBLHOLNNKJBEDC-XOGQCRKLSA-N [(2r,3s,4s,5r,6r)-2-[(2r,3s,4s,5s,6s)-2-[(1r,2s)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[[(2r,3s,4s)-5-[[(2s,3r)-1-[2-[4-[4-[4-(diaminomethylideneamino)butylcarbamoyl]-1,3-th Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCCN=C(N)N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C NBLHOLNNKJBEDC-XOGQCRKLSA-N 0.000 description 1
- VORIUEAZEKLUSJ-UHFFFAOYSA-M [(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylidene]-dimethylazanium;trifluoroborane;fluoride Chemical compound [F-].FB(F)F.C1=C(Cl)C=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 VORIUEAZEKLUSJ-UHFFFAOYSA-M 0.000 description 1
- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 241000606834 [Haemophilus] ducreyi Species 0.000 description 1
- ZPCXEXWLOJRITL-UHFFFAOYSA-N [O-][N+](C(CC(N1O)=O)(C1=O)OC1=CC=CC=C1)=O Chemical compound [O-][N+](C(CC(N1O)=O)(C1=O)OC1=CC=CC=C1)=O ZPCXEXWLOJRITL-UHFFFAOYSA-N 0.000 description 1
- DULZJSBFYXKCJG-UHFFFAOYSA-M [OH-].[Si+4].CN(C)CCC[Si](C)(C)[O-].c1ccc2c3nc(nc4[n-]c(nc5nc(nc6[n-]c(n3)c3ccccc63)c3ccccc53)c3ccccc43)c2c1 Chemical compound [OH-].[Si+4].CN(C)CCC[Si](C)(C)[O-].c1ccc2c3nc(nc4[n-]c(nc5nc(nc6[n-]c(n3)c3ccccc63)c3ccccc53)c3ccccc43)c2c1 DULZJSBFYXKCJG-UHFFFAOYSA-M 0.000 description 1
- RKTBAMPZUATMIO-MXZHIVQLSA-N [[(e)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N\OC(N(C)C)=[N+](C)C RKTBAMPZUATMIO-MXZHIVQLSA-N 0.000 description 1
- FPQVGDGSRVMNMR-JCTPKUEWSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N/OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-JCTPKUEWSA-N 0.000 description 1
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 description 1
- AVQQQNCBBIEMEU-UHFFFAOYSA-O [dimethylamino(hydroxy)methylidene]-dimethylazanium Chemical compound CN(C)C(O)=[N+](C)C AVQQQNCBBIEMEU-UHFFFAOYSA-O 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- 229950008805 abexinostat Drugs 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940119059 actemra Drugs 0.000 description 1
- 201000007691 actinomycosis Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000002552 acute disseminated encephalomyelitis Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 229950009084 adecatumumab Drugs 0.000 description 1
- 229960001997 adefovir Drugs 0.000 description 1
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 208000011589 adenoviridae infectious disease Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 201000006966 adult T-cell leukemia Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 108010056243 alanylalanine Proteins 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-STGXQOJASA-N alpha-D-lyxopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-STGXQOJASA-N 0.000 description 1
- SRHNADOZAAWYLV-XLMUYGLTSA-N alpha-L-Fucp-(1->2)-beta-D-Galp-(1->4)-[alpha-L-Fucp-(1->3)]-beta-D-GlcpNAc Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](NC(C)=O)[C@H](O)O[C@@H]2CO)O[C@H]2[C@H]([C@H](O)[C@H](O)[C@H](C)O2)O)O[C@H](CO)[C@H](O)[C@@H]1O SRHNADOZAAWYLV-XLMUYGLTSA-N 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 150000003978 alpha-halocarboxylic acids Chemical class 0.000 description 1
- WUOACPNHFRMFPN-UHFFFAOYSA-N alpha-terpineol Chemical compound CC1=CCC(C(C)(C)O)CC1 WUOACPNHFRMFPN-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229950009106 altumomab Drugs 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 108010014709 amatoxin Proteins 0.000 description 1
- 229960003099 amcinonide Drugs 0.000 description 1
- ILKJAFIWWBXGDU-MOGDOJJUSA-N amcinonide Chemical compound O([C@@]1([C@H](O2)C[C@@H]3[C@@]1(C[C@H](O)[C@]1(F)[C@@]4(C)C=CC(=O)C=C4CC[C@H]13)C)C(=O)COC(=O)C)C12CCCC1 ILKJAFIWWBXGDU-MOGDOJJUSA-N 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960001830 amprenavir Drugs 0.000 description 1
- YMARZQAQMVYCKC-OEMFJLHTSA-N amprenavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 YMARZQAQMVYCKC-OEMFJLHTSA-N 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- 201000007538 anal carcinoma Diseases 0.000 description 1
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 1
- 229950000242 ancitabine Drugs 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 229950005794 anrukinzumab Drugs 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003429 anti-cardiolipin effect Effects 0.000 description 1
- 230000003476 anti-centromere Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000002583 anti-histone Effects 0.000 description 1
- 230000003302 anti-idiotype Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000001064 anti-interferon Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000002001 anti-metastasis Effects 0.000 description 1
- 230000003460 anti-nuclear Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 210000000628 antibody-producing cell Anatomy 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229950003145 apolizumab Drugs 0.000 description 1
- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- 229960005397 arbekacin Drugs 0.000 description 1
- MKKYBZZTJQGVCD-XTCKQBCOSA-N arbekacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)CC[C@H]1N MKKYBZZTJQGVCD-XTCKQBCOSA-N 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- RBFQJDQYXXHULB-UHFFFAOYSA-N arsane Chemical compound [AsH3] RBFQJDQYXXHULB-UHFFFAOYSA-N 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 108010038633 aspartylglutamate Proteins 0.000 description 1
- 108010092854 aspartyllysine Proteins 0.000 description 1
- 229940091771 aspergillus fumigatus Drugs 0.000 description 1
- 229960003277 atazanavir Drugs 0.000 description 1
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 229950000103 atorolimumab Drugs 0.000 description 1
- 201000004984 autoimmune cardiomyopathy Diseases 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 208000027625 autoimmune inner ear disease Diseases 0.000 description 1
- 201000004339 autoimmune neuropathy Diseases 0.000 description 1
- 201000005011 autoimmune peripheral neuropathy Diseases 0.000 description 1
- 206010071572 autoimmune progesterone dermatitis Diseases 0.000 description 1
- 201000004982 autoimmune uveitis Diseases 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 206010064097 avian influenza Diseases 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- JTWOMNBEOCYFNV-NFFDBFGFSA-N azlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCNC1=O JTWOMNBEOCYFNV-NFFDBFGFSA-N 0.000 description 1
- 229960003623 azlocillin Drugs 0.000 description 1
- DMLAVOWQYNRWNQ-UHFFFAOYSA-N azobenzene Chemical compound C1=CC=CC=C1N=NC1=CC=CC=C1 DMLAVOWQYNRWNQ-UHFFFAOYSA-N 0.000 description 1
- 206010003883 azoospermia Diseases 0.000 description 1
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 1
- 229960003644 aztreonam Drugs 0.000 description 1
- PFOLLRNADZZWEX-FFGRCDKISA-N bacampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OC(C)OC(=O)OCC)=CC=CC=C1 PFOLLRNADZZWEX-FFGRCDKISA-N 0.000 description 1
- 229960002699 bacampicillin Drugs 0.000 description 1
- 229960003071 bacitracin Drugs 0.000 description 1
- 229930184125 bacitracin Natural products 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 229950002365 bafetinib Drugs 0.000 description 1
- ZGBAJMQHJDFTQJ-DEOSSOPVSA-N bafetinib Chemical compound C1[C@@H](N(C)C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=NC=3)C(C)=CC=2)C=C1C(F)(F)F ZGBAJMQHJDFTQJ-DEOSSOPVSA-N 0.000 description 1
- 229950000805 balofloxacin Drugs 0.000 description 1
- 229940092524 bartonella henselae Drugs 0.000 description 1
- 229940092705 beclomethasone Drugs 0.000 description 1
- 229950003269 bectumomab Drugs 0.000 description 1
- 229960003270 belimumab Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229950000321 benralizumab Drugs 0.000 description 1
- 229940095744 benzathine phenoxymethylpenicillin Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- YJEJKUQEXFSVCJ-WRFMNRASSA-N bevirimat Chemical compound C1C[C@H](OC(=O)CC(C)(C)C(O)=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C YJEJKUQEXFSVCJ-WRFMNRASSA-N 0.000 description 1
- 229950002892 bevirimat Drugs 0.000 description 1
- MRMBZHPJVKCOMA-YJFSRANCSA-N biapenem Chemical compound C1N2C=NC=[N+]2CC1SC([C@@H]1C)=C(C([O-])=O)N2[C@H]1[C@@H]([C@H](O)C)C2=O MRMBZHPJVKCOMA-YJFSRANCSA-N 0.000 description 1
- 229960003169 biapenem Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 229950001303 biciromab Drugs 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 229950002903 bivatuzumab Drugs 0.000 description 1
- 210000002459 blastocyst Anatomy 0.000 description 1
- NBLHOLNNKJBEDC-UHFFFAOYSA-N bleomycin B2 Natural products N=1C(C=2SC=C(N=2)C(=O)NCCCCN=C(N)N)=CSC=1CCNC(=O)C(C(O)C)NC(=O)C(C)C(O)C(C)NC(=O)C(C(OC1C(C(O)C(O)C(CO)O1)OC1C(C(OC(N)=O)C(O)C(CO)O1)O)C=1NC=NC=1)NC(=O)C1=NC(C(CC(N)=O)NCC(N)C(N)=O)=NC(N)=C1C NBLHOLNNKJBEDC-UHFFFAOYSA-N 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229960000517 boceprevir Drugs 0.000 description 1
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 1
- 238000011243 body radiation therapy Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229960001169 brivudine Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- MBABCNBNDNGODA-LUVUIASKSA-N bullatacin Chemical compound O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-LUVUIASKSA-N 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 230000028956 calcium-mediated signaling Effects 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 201000004927 campylobacteriosis Diseases 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 102000023852 carbohydrate binding proteins Human genes 0.000 description 1
- 108091008400 carbohydrate binding proteins Proteins 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 125000005626 carbonium group Chemical group 0.000 description 1
- VQXINLNPICQTLR-UHFFFAOYSA-N carbonyl diazide Chemical compound [N-]=[N+]=NC(=O)N=[N+]=[N-] VQXINLNPICQTLR-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 208000002458 carcinoid tumor Diseases 0.000 description 1
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 1
- 229930188550 carminomycin Natural products 0.000 description 1
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 150000001749 carotenones Chemical class 0.000 description 1
- 235000005472 carotenones Nutrition 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- CMKFQVZJOWHHDV-DYHNYNMBSA-N catharanthine Chemical compound C([C@@H]1C=C([C@@H]2[C@@]3(C1)C(=O)OC)CC)N2CCC1=C3NC2=CC=CC=C12 CMKFQVZJOWHHDV-DYHNYNMBSA-N 0.000 description 1
- GKWYINOZGDHWRA-UHFFFAOYSA-N catharanthine Natural products C1C(CC)(O)CC(CC2C(=O)OC)CN1CCC1=C2NC2=CC=CC=C12 GKWYINOZGDHWRA-UHFFFAOYSA-N 0.000 description 1
- 229960004841 cefadroxil Drugs 0.000 description 1
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 description 1
- XIURVHNZVLADCM-IUODEOHRSA-N cefalotin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CC1=CC=CS1 XIURVHNZVLADCM-IUODEOHRSA-N 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 1
- 229960003012 cefamandole Drugs 0.000 description 1
- 229960004350 cefapirin Drugs 0.000 description 1
- SMSRCGPDNDCXFR-CYWZMYCQSA-N cefbuperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H]([C@H](C)O)C(=O)N[C@]1(OC)C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 SMSRCGPDNDCXFR-CYWZMYCQSA-N 0.000 description 1
- 229960001817 cefbuperazone Drugs 0.000 description 1
- HJJRIJDTIPFROI-NVKITGPLSA-N cefcapene Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=C/CC)C1=CSC(N)=N1 HJJRIJDTIPFROI-NVKITGPLSA-N 0.000 description 1
- 229960002966 cefcapene Drugs 0.000 description 1
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 description 1
- 229960003719 cefdinir Drugs 0.000 description 1
- KMIPKYQIOVAHOP-YLGJWRNMSA-N cefditoren Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C KMIPKYQIOVAHOP-YLGJWRNMSA-N 0.000 description 1
- 229960004069 cefditoren Drugs 0.000 description 1
- 229960003791 cefmenoxime Drugs 0.000 description 1
- HJJDBAOLQAWBMH-YCRCPZNHSA-N cefmenoxime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NN=NN1C HJJDBAOLQAWBMH-YCRCPZNHSA-N 0.000 description 1
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 description 1
- 229960003585 cefmetazole Drugs 0.000 description 1
- 229960001958 cefodizime Drugs 0.000 description 1
- XDZKBRJLTGRPSS-BGZQYGJUSA-N cefodizime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(C)=C(CC(O)=O)S1 XDZKBRJLTGRPSS-BGZQYGJUSA-N 0.000 description 1
- DYAIAHUQIPBDIP-AXAPSJFSSA-N cefonicid Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](O)C=2C=CC=CC=2)CC=1CSC1=NN=NN1CS(O)(=O)=O DYAIAHUQIPBDIP-AXAPSJFSSA-N 0.000 description 1
- 229960004489 cefonicid Drugs 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- 229960004292 ceforanide Drugs 0.000 description 1
- SLAYUXIURFNXPG-CRAIPNDOSA-N ceforanide Chemical compound NCC1=CC=CC=C1CC(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)CC(O)=O)CS[C@@H]21 SLAYUXIURFNXPG-CRAIPNDOSA-N 0.000 description 1
- SRZNHPXWXCNNDU-RHBCBLIFSA-N cefotetan Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CS[C@@H]21)C(O)=O)=O)C(=O)C1SC(=C(C(N)=O)C(O)=O)S1 SRZNHPXWXCNNDU-RHBCBLIFSA-N 0.000 description 1
- 229960005495 cefotetan Drugs 0.000 description 1
- WZOZEZRFJCJXNZ-ZBFHGGJFSA-N cefoxitin Chemical compound N([C@]1(OC)C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)CC1=CC=CS1 WZOZEZRFJCJXNZ-ZBFHGGJFSA-N 0.000 description 1
- 229960002682 cefoxitin Drugs 0.000 description 1
- QDUIJCOKQCCXQY-WHJQOFBOSA-N cefozopran Chemical compound N([C@@H]1C(N2C(=C(CN3C4=CC=CN=[N+]4C=C3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=NSC(N)=N1 QDUIJCOKQCCXQY-WHJQOFBOSA-N 0.000 description 1
- 229960002642 cefozopran Drugs 0.000 description 1
- PWAUCHMQEXVFJR-PMAPCBKXSA-N cefpiramide Chemical compound C1=NC(C)=CC(O)=C1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 PWAUCHMQEXVFJR-PMAPCBKXSA-N 0.000 description 1
- 229960005446 cefpiramide Drugs 0.000 description 1
- DKOQGJHPHLTOJR-WHRDSVKCSA-N cefpirome Chemical compound N([C@@H]1C(N2C(=C(C[N+]=3C=4CCCC=4C=CC=3)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DKOQGJHPHLTOJR-WHRDSVKCSA-N 0.000 description 1
- 229960000466 cefpirome Drugs 0.000 description 1
- 229950009592 cefquinome Drugs 0.000 description 1
- 229960002588 cefradine Drugs 0.000 description 1
- SYLKGLMBLAAGSC-QLVMHMETSA-N cefsulodin Chemical compound C1=CC(C(=O)N)=CC=[N+]1CC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)[C@@H](C=3C=CC=CC=3)S(O)(=O)=O)[C@H]2SC1 SYLKGLMBLAAGSC-QLVMHMETSA-N 0.000 description 1
- 229960003202 cefsulodin Drugs 0.000 description 1
- 229950000679 cefteram Drugs 0.000 description 1
- DZMVCVMFETWNIU-LDYMZIIASA-N ceftezole Chemical compound O=C([C@@H](NC(=O)CN1N=NN=C1)[C@H]1SC2)N1C(C(=O)O)=C2CSC1=NN=CS1 DZMVCVMFETWNIU-LDYMZIIASA-N 0.000 description 1
- 229960004366 ceftezole Drugs 0.000 description 1
- 229960004755 ceftriaxone Drugs 0.000 description 1
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- DSRNKUZOWRFQFO-UHFFFAOYSA-N cephalotaxine Natural products COC1=CC23CCCN2CCc4cc5OCOc5cc4C3=C1O DSRNKUZOWRFQFO-UHFFFAOYSA-N 0.000 description 1
- UCKZMPLVLCKKMO-LHLIQPBNSA-N cephamycin Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](C)[C@]21OC UCKZMPLVLCKKMO-LHLIQPBNSA-N 0.000 description 1
- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 description 1
- 201000007335 cerebellar astrocytoma Diseases 0.000 description 1
- 208000025434 cerebellar degeneration Diseases 0.000 description 1
- 208000030239 cerebral astrocytoma Diseases 0.000 description 1
- 229960003115 certolizumab pegol Drugs 0.000 description 1
- 235000005513 chalcones Nutrition 0.000 description 1
- 150000001789 chalcones Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- DDTDNCYHLGRFBM-YZEKDTGTSA-N chembl2367892 Chemical compound CC(=O)N[C@H]1[C@@H](O)[C@H](O)[C@H](CO)O[C@H]1O[C@@H]([C@H]1C(N[C@@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(O)C=C(C=4)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@H](CC=4C=C(Cl)C(O5)=CC=4)C(=O)N3)C(=O)N1)C(O)=O)=O)C(C=C1Cl)=CC=C1OC1=C(O[C@H]3[C@H]([C@@H](O)[C@H](O)[C@H](CO)O3)NC(C)=O)C5=CC2=C1 DDTDNCYHLGRFBM-YZEKDTGTSA-N 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 210000003763 chloroplast Anatomy 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 229960004475 chlortetracycline Drugs 0.000 description 1
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 description 1
- 235000019365 chlortetracycline Nutrition 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229940107161 cholesterol Drugs 0.000 description 1
- 208000012601 choreatic disease Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000019069 chronic childhood arthritis Diseases 0.000 description 1
- 201000005795 chronic inflammatory demyelinating polyneuritis Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 201000010002 cicatricial pemphigoid Diseases 0.000 description 1
- 229960000724 cidofovir Drugs 0.000 description 1
- 229940090100 cimzia Drugs 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 229950010905 citatuzumab bogatox Drugs 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 229960003324 clavulanic acid Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229950002334 clenoliximab Drugs 0.000 description 1
- 229960005338 clevudine Drugs 0.000 description 1
- GBBJCSTXCAQSSJ-XQXXSGGOSA-N clevudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1[C@H](F)[C@@H](O)[C@H](CO)O1 GBBJCSTXCAQSSJ-XQXXSGGOSA-N 0.000 description 1
- QGPKADBNRMWEQR-UHFFFAOYSA-N clinafloxacin Chemical compound C1C(N)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl QGPKADBNRMWEQR-UHFFFAOYSA-N 0.000 description 1
- 229950001320 clinafloxacin Drugs 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 229960003326 cloxacillin Drugs 0.000 description 1
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 description 1
- 229940047766 co-trimoxazole Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 201000003486 coccidioidomycosis Diseases 0.000 description 1
- 229960003346 colistin Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940047120 colony stimulating factors Drugs 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 201000003056 complement component 2 deficiency Diseases 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 229950007276 conatumumab Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 201000003278 cryoglobulinemia Diseases 0.000 description 1
- 108010006226 cryptophycin Proteins 0.000 description 1
- 108010089438 cryptophycin 1 Proteins 0.000 description 1
- 108010090203 cryptophycin 8 Proteins 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 125000002993 cycloalkylene group Chemical group 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960003077 cycloserine Drugs 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 201000008167 cystoisosporiasis Diseases 0.000 description 1
- 102000003675 cytokine receptors Human genes 0.000 description 1
- 108010057085 cytokine receptors Proteins 0.000 description 1
- 208000001763 cytomegalovirus retinitis Diseases 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 description 1
- 229960003850 dabigatran Drugs 0.000 description 1
- 229950007409 dacetuzumab Drugs 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 229960002488 dalbavancin Drugs 0.000 description 1
- 108700009376 dalbavancin Proteins 0.000 description 1
- 229960004385 danofloxacin Drugs 0.000 description 1
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 1
- 229960005484 daptomycin Drugs 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960000958 deferoxamine Drugs 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- SQIFACVGCPWBQZ-UHFFFAOYSA-N delta-terpineol Natural products CC(C)(O)C1CCC(=C)CC1 SQIFACVGCPWBQZ-UHFFFAOYSA-N 0.000 description 1
- 229960002398 demeclocycline Drugs 0.000 description 1
- 230000003210 demyelinating effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229950008962 detumomab Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229960003807 dibekacin Drugs 0.000 description 1
- JJCQSGDBDPYCEO-XVZSLQNASA-N dibekacin Chemical compound O1[C@H](CN)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N JJCQSGDBDPYCEO-XVZSLQNASA-N 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- NOCJXYPHIIZEHN-UHFFFAOYSA-N difloxacin Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1 NOCJXYPHIIZEHN-UHFFFAOYSA-N 0.000 description 1
- 229950001733 difloxacin Drugs 0.000 description 1
- FOCAHLGSDWHSAH-UHFFFAOYSA-N difluoromethanethione Chemical compound FC(F)=S FOCAHLGSDWHSAH-UHFFFAOYSA-N 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 208000024558 digestive system cancer Diseases 0.000 description 1
- 108020001096 dihydrofolate reductase Proteins 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 229940042406 direct acting antivirals neuraminidase inhibitors Drugs 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 229960004100 dirithromycin Drugs 0.000 description 1
- WLOHNSSYAXHWNR-NXPDYKKBSA-N dirithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H]2O[C@H](COCCOC)N[C@H]([C@@H]2C)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 WLOHNSSYAXHWNR-NXPDYKKBSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 125000002228 disulfide group Chemical group 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 229960002563 disulfiram Drugs 0.000 description 1
- 125000005883 dithianyl group Chemical group 0.000 description 1
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229960000735 docosanol Drugs 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- 229930188854 dolastatin Natural products 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 1
- 229960000895 doripenem Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229960003722 doxycycline Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 102000013035 dynein heavy chain Human genes 0.000 description 1
- 108060002430 dynein heavy chain Proteins 0.000 description 1
- 229960002224 eculizumab Drugs 0.000 description 1
- 229960000284 efalizumab Drugs 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- 208000000292 ehrlichiosis Diseases 0.000 description 1
- 229920002549 elastin Polymers 0.000 description 1
- 208000006036 elephantiasis Diseases 0.000 description 1
- 229950002507 elsilimomab Drugs 0.000 description 1
- JUZYLCPPVHEVSV-LJQANCHMSA-N elvitegravir Chemical compound COC1=CC=2N([C@H](CO)C(C)C)C=C(C(O)=O)C(=O)C=2C=C1CC1=CC=CC(Cl)=C1F JUZYLCPPVHEVSV-LJQANCHMSA-N 0.000 description 1
- 229960003586 elvitegravir Drugs 0.000 description 1
- 229950006528 elvucitabine Drugs 0.000 description 1
- MLILORUFDVLTSP-UHFFFAOYSA-N emivirine Chemical compound O=C1NC(=O)N(COCC)C(CC=2C=CC=CC=2)=C1C(C)C MLILORUFDVLTSP-UHFFFAOYSA-N 0.000 description 1
- 229950002002 emivirine Drugs 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 201000005901 endemic typhus Diseases 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- RDYMFSUJUZBWLH-SVWSLYAFSA-N endosulfan Chemical compound C([C@@H]12)OS(=O)OC[C@@H]1[C@]1(Cl)C(Cl)=C(Cl)[C@@]2(Cl)C1(Cl)Cl RDYMFSUJUZBWLH-SVWSLYAFSA-N 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 description 1
- 229960002062 enfuvirtide Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229950002798 enlimomab Drugs 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960000740 enrofloxacin Drugs 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- 208000037902 enteropathy Diseases 0.000 description 1
- INVTYAOGFAGBOE-UHFFFAOYSA-N entinostat Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)OCC1=CC=CN=C1 INVTYAOGFAGBOE-UHFFFAOYSA-N 0.000 description 1
- 229950005837 entinostat Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- QGXBDMJGAMFCBF-LUJOEAJASA-N epiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC[C@H]21 QGXBDMJGAMFCBF-LUJOEAJASA-N 0.000 description 1
- 108010087914 epidermal growth factor receptor VIII Proteins 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- 229950001757 epitumomab Drugs 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 229960002061 ergocalciferol Drugs 0.000 description 1
- 229950004292 erlizumab Drugs 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229960002770 ertapenem Drugs 0.000 description 1
- 229950008579 ertumaxomab Drugs 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- WHRIKZCFRVTHJH-UHFFFAOYSA-N ethylhydrazine Chemical compound CCNN WHRIKZCFRVTHJH-UHFFFAOYSA-N 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- 229960002049 etravirine Drugs 0.000 description 1
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 201000008819 extrahepatic bile duct carcinoma Diseases 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 208000002980 facial hemiatrophy Diseases 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 229950001488 faralimomab Drugs 0.000 description 1
- 229950009929 farletuzumab Drugs 0.000 description 1
- 229960000379 faropenem Drugs 0.000 description 1
- 208000006275 fascioliasis Diseases 0.000 description 1
- 201000006061 fatal familial insomnia Diseases 0.000 description 1
- 229950001563 felvizumab Drugs 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229950010512 fezakinumab Drugs 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229960002878 flomoxef Drugs 0.000 description 1
- UHRBTBZOWWGKMK-DOMZBBRYSA-N flomoxef Chemical compound O([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSC(F)F)OC)CC=1CSC1=NN=NN1CCO UHRBTBZOWWGKMK-DOMZBBRYSA-N 0.000 description 1
- 229960003760 florfenicol Drugs 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- XCWFZHPEARLXJI-UHFFFAOYSA-N fomivirsen Chemical compound C1C(N2C3=C(C(NC(N)=N3)=O)N=C2)OC(CO)C1OP(O)(=S)OCC1OC(N(C)C(=O)\N=C(\N)C=C)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C(NC(=O)C(C)=C2)=O)CC1OP(O)(=S)OCC1OC(N2C3=C(C(NC(N)=N3)=O)N=C2)CC1OP(O)(=S)OCC1OC(N2C(N=C(N)C=C2)=O)CC1OP(O)(=S)OCC(C(C1)OP(S)(=O)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C(NC(=O)C(C)=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=S)OCC2C(CC(O2)N2C(N=C(N)C=C2)=O)OP(O)(=S)OCC2C(CC(O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)OC1N1C=C(C)C(=O)NC1=O XCWFZHPEARLXJI-UHFFFAOYSA-N 0.000 description 1
- 229960001447 fomivirsen Drugs 0.000 description 1
- 229950004923 fontolizumab Drugs 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- YVUBWJOBCFNMES-UHFFFAOYSA-N formamide;pyridine Chemical compound NC=O.C1=CC=NC=C1 YVUBWJOBCFNMES-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960003142 fosamprenavir Drugs 0.000 description 1
- MLBVMOWEQCZNCC-OEMFJLHTSA-N fosamprenavir Chemical compound C([C@@H]([C@H](OP(O)(O)=O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1COCC1)C1=CC=CC=C1 MLBVMOWEQCZNCC-OEMFJLHTSA-N 0.000 description 1
- 229960005102 foscarnet Drugs 0.000 description 1
- 229960000308 fosfomycin Drugs 0.000 description 1
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- 229960003704 framycetin Drugs 0.000 description 1
- PGBHMTALBVVCIT-VCIWKGPPSA-N framycetin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO PGBHMTALBVVCIT-VCIWKGPPSA-N 0.000 description 1
- 229950004003 fresolimumab Drugs 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N fumaric acid group Chemical group C(\C=C\C(=O)O)(=O)O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 229960001625 furazolidone Drugs 0.000 description 1
- PLHJDBGFXBMTGZ-WEVVVXLNSA-N furazolidone Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)OCC1 PLHJDBGFXBMTGZ-WEVVVXLNSA-N 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- FNUPUYFWZXZMIE-HUUCEWRRSA-N fustin Chemical compound C1([C@@H]2[C@@H](C(C3=CC=C(O)C=C3O2)=O)O)=CC=C(O)C(O)=C1 FNUPUYFWZXZMIE-HUUCEWRRSA-N 0.000 description 1
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 1
- 229950001109 galiximab Drugs 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- UHBYWPGGCSDKFX-VKHMYHEASA-N gamma-carboxy-L-glutamic acid Chemical compound OC(=O)[C@@H](N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-VKHMYHEASA-N 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- PFJKOHUKELZMLE-VEUXDRLPSA-N ganglioside GM3 Chemical compound O[C@@H]1[C@@H](O)[C@H](OC[C@@H]([C@H](O)/C=C/CCCCCCCCCCCCC)NC(=O)CCCCCCCCCCCCC\C=C/CCCCCCCC)O[C@H](CO)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@]2(O[C@H]([C@H](NC(C)=O)[C@@H](O)C2)[C@H](O)[C@H](O)CO)C(O)=O)[C@@H](O)[C@@H](CO)O1 PFJKOHUKELZMLE-VEUXDRLPSA-N 0.000 description 1
- 150000002270 gangliosides Chemical class 0.000 description 1
- 229950002508 gantenerumab Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- PUBCCFNQJQKCNC-XKNFJVFFSA-N gastrin-releasingpeptide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)C(C)C)[C@@H](C)O)C(C)C)[C@@H](C)O)C(C)C)C1=CNC=N1 PUBCCFNQJQKCNC-XKNFJVFFSA-N 0.000 description 1
- 201000010231 gastrointestinal system cancer Diseases 0.000 description 1
- 229960003923 gatifloxacin Drugs 0.000 description 1
- 229950004792 gavilimomab Drugs 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960003170 gemifloxacin Drugs 0.000 description 1
- ZRCVYEYHRGVLOC-HYARGMPZSA-N gemifloxacin Chemical compound C1C(CN)C(=N/OC)/CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 ZRCVYEYHRGVLOC-HYARGMPZSA-N 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 201000006592 giardiasis Diseases 0.000 description 1
- 229950010415 givinostat Drugs 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 229930182480 glucuronide Natural products 0.000 description 1
- 150000008134 glucuronides Chemical class 0.000 description 1
- 150000002341 glycosylamines Chemical class 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 229960002913 goserelin Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 244000000013 helminth Species 0.000 description 1
- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- MCAHMSDENAOJFZ-BVXDHVRPSA-N herbimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](OC)[C@@H](OC)C[C@H](C)[C@@H](OC)C2=CC(=O)C=C1C2=O MCAHMSDENAOJFZ-BVXDHVRPSA-N 0.000 description 1
- 229930193320 herbimycin Natural products 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 201000010884 herpes simplex virus keratitis Diseases 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 208000002557 hidradenitis Diseases 0.000 description 1
- 201000007162 hidradenitis suppurativa Diseases 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 208000029080 human African trypanosomiasis Diseases 0.000 description 1
- 201000009163 human granulocytic anaplasmosis Diseases 0.000 description 1
- 208000022340 human granulocytic ehrlichiosis Diseases 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 201000009162 human monocytic ehrlichiosis Diseases 0.000 description 1
- 208000021145 human papilloma virus infection Diseases 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 150000002429 hydrazines Chemical group 0.000 description 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- GRRNUXAQVGOGFE-NZSRVPFOSA-N hygromycin B Chemical compound O[C@@H]1[C@@H](NC)C[C@@H](N)[C@H](O)[C@H]1O[C@H]1[C@H]2O[C@@]3([C@@H]([C@@H](O)[C@@H](O)[C@@H](C(N)CO)O3)O)O[C@H]2[C@@H](O)[C@@H](CO)O1 GRRNUXAQVGOGFE-NZSRVPFOSA-N 0.000 description 1
- 229940097277 hygromycin b Drugs 0.000 description 1
- 201000006866 hypopharynx cancer Diseases 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 229950010245 ibalizumab Drugs 0.000 description 1
- 229940015872 ibandronate Drugs 0.000 description 1
- 125000002951 idosyl group Chemical class C1([C@@H](O)[C@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 description 1
- 229960004716 idoxuridine Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 229940071829 ilaris Drugs 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229950007354 imciromab Drugs 0.000 description 1
- LFKYBJLFJOOKAE-UHFFFAOYSA-N imidazol-2-ylidenemethanone Chemical compound O=C=C1N=CC=N1 LFKYBJLFJOOKAE-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 208000015446 immunoglobulin a vasculitis Diseases 0.000 description 1
- 201000008319 inclusion body myositis Diseases 0.000 description 1
- 230000001965 increasing effect Effects 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 201000011422 infant botulism Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000019715 inherited Creutzfeldt-Jakob disease Diseases 0.000 description 1
- 229950002133 iniparib Drugs 0.000 description 1
- 229950007937 inolimomab Drugs 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 239000002348 inosinate dehydrogenase inhibitor Substances 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 108040006858 interleukin-6 receptor activity proteins Proteins 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 229950001014 intetumumab Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229950010939 iratumumab Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- UDIIBEDMEYAVNG-ZKFPOVNWSA-N isepamicin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)O)[C@@H](N)C[C@H]1NC(=O)[C@@H](O)CN UDIIBEDMEYAVNG-ZKFPOVNWSA-N 0.000 description 1
- 229960000798 isepamicin Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229960004144 josamycin Drugs 0.000 description 1
- XJSFLOJWULLJQS-NGVXBBESSA-N josamycin Chemical compound CO[C@H]1[C@H](OC(C)=O)CC(=O)O[C@H](C)C\C=C\C=C\[C@H](O)[C@H](C)C[C@H](CC=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](N(C)C)[C@H](O[C@@H]2O[C@@H](C)[C@H](OC(=O)CC(C)C)[C@](C)(O)C2)[C@@H](C)O1 XJSFLOJWULLJQS-NGVXBBESSA-N 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 239000003835 ketolide antibiotic agent Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 210000000244 kidney pelvis Anatomy 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 206010023497 kuru Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 229950002183 lebrikizumab Drugs 0.000 description 1
- 229940115932 legionella pneumophila Drugs 0.000 description 1
- 229950001275 lemalesomab Drugs 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229960003784 lenvatinib Drugs 0.000 description 1
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 1
- 229950010470 lerdelimumab Drugs 0.000 description 1
- 229940121292 leronlimab Drugs 0.000 description 1
- 206010024378 leukocytosis Diseases 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 229960005535 lidamycin Drugs 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- 229950002950 lintuzumab Drugs 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- KBEMFSMODRNJHE-JFWOZONXSA-N lodenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)C[C@@H]1F KBEMFSMODRNJHE-JFWOZONXSA-N 0.000 description 1
- 229950003557 lodenosine Drugs 0.000 description 1
- 229960002422 lomefloxacin Drugs 0.000 description 1
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 1
- 229960004525 lopinavir Drugs 0.000 description 1
- JAPHQRWPEGVNBT-UTUOFQBUSA-N loracarbef Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CC[C@@H]32)C([O-])=O)=O)[NH3+])=CC=CC=C1 JAPHQRWPEGVNBT-UTUOFQBUSA-N 0.000 description 1
- 229960001977 loracarbef Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 108010038320 lysylphenylalanine Proteins 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000011976 maleic acid Chemical group 0.000 description 1
- 208000030883 malignant astrocytoma Diseases 0.000 description 1
- 208000006178 malignant mesothelioma Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229950001869 mapatumumab Drugs 0.000 description 1
- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 description 1
- 229960004710 maraviroc Drugs 0.000 description 1
- 229960002531 marbofloxacin Drugs 0.000 description 1
- 229950002736 marizomib Drugs 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 229950008001 matuzumab Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 201000004015 melioidosis Diseases 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960005108 mepolizumab Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- ANZJBCHSOXCCRQ-FKUXLPTCSA-N mertansine Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCS)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 ANZJBCHSOXCCRQ-FKUXLPTCSA-N 0.000 description 1
- DWPCPZJAHOETAG-UHFFFAOYSA-N meso-lanthionine Natural products OC(=O)C(N)CSCC(N)C(O)=O DWPCPZJAHOETAG-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 229950005555 metelimumab Drugs 0.000 description 1
- 229940042016 methacycline Drugs 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- QRMNENFZDDYDEF-GOSISDBHSA-N methyl (8s)-8-(bromomethyl)-2-methyl-4-(4-methylpiperazine-1-carbonyl)oxy-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-1-carboxylate Chemical compound C1([C@H](CBr)CN(C1=C1)C(=O)C=2NC3=C(OC)C(OC)=C(OC)C=C3C=2)=C2C(C(=O)OC)=C(C)NC2=C1OC(=O)N1CCN(C)CC1 QRMNENFZDDYDEF-GOSISDBHSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-O methylsulfide anion Chemical compound [SH2+]C LSDPWZHWYPCBBB-UHFFFAOYSA-O 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
- 229960000198 mezlocillin Drugs 0.000 description 1
- 206010063344 microscopic polyangiitis Diseases 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 229960002757 midecamycin Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 229950003734 milatuzumab Drugs 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000008588 molluscum contagiosum Diseases 0.000 description 1
- 229950008814 momelotinib Drugs 0.000 description 1
- ZVHNDZWQTBEVRY-UHFFFAOYSA-N momelotinib Chemical compound C1=CC(C(NCC#N)=O)=CC=C1C1=CC=NC(NC=2C=CC(=CC=2)N2CCOCC2)=N1 ZVHNDZWQTBEVRY-UHFFFAOYSA-N 0.000 description 1
- VYQNWZOUAUKGHI-UHFFFAOYSA-N monobenzone Chemical compound C1=CC(O)=CC=C1OCC1=CC=CC=C1 VYQNWZOUAUKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000001620 monocyclic carbocycle group Chemical group 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N monoethyl amine Natural products CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229950008897 morolimumab Drugs 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 229960001521 motavizumab Drugs 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 229960003702 moxifloxacin Drugs 0.000 description 1
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 1
- ZTFBIUXIQYRUNT-MDWZMJQESA-N mubritinib Chemical compound C1=CC(C(F)(F)F)=CC=C1\C=C\C1=NC(COC=2C=CC(CCCCN3N=NC=C3)=CC=2)=CO1 ZTFBIUXIQYRUNT-MDWZMJQESA-N 0.000 description 1
- 229950002212 mubritinib Drugs 0.000 description 1
- 201000002273 mucopolysaccharidosis II Diseases 0.000 description 1
- 208000022018 mucopolysaccharidosis type 2 Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 229960003128 mupirocin Drugs 0.000 description 1
- 229930187697 mupirocin Natural products 0.000 description 1
- DDHVILIIHBIMQU-YJGQQKNPSA-L mupirocin calcium hydrate Chemical compound O.O.[Ca+2].C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1.C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1 DDHVILIIHBIMQU-YJGQQKNPSA-L 0.000 description 1
- 229960003816 muromonab-cd3 Drugs 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 description 1
- ZOGSYTPLAROSTP-UHFFFAOYSA-N n-[bis(ethylamino)phosphoryl]ethanamine Chemical compound CCNP(=O)(NCC)NCC ZOGSYTPLAROSTP-UHFFFAOYSA-N 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- PPJWMNPSKPESFN-UHFFFAOYSA-N n-benzyl-n'-cyclohexylmethanediimine Chemical compound C=1C=CC=CC=1CN=C=NC1CCCCC1 PPJWMNPSKPESFN-UHFFFAOYSA-N 0.000 description 1
- 125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960003808 nadifloxacin Drugs 0.000 description 1
- JYJTVFIEFKZWCJ-UHFFFAOYSA-N nadifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)CCC3=C1N1CCC(O)CC1 JYJTVFIEFKZWCJ-UHFFFAOYSA-N 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 208000037830 nasal cancer Diseases 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 229960005027 natalizumab Drugs 0.000 description 1
- 229960000513 necitumumab Drugs 0.000 description 1
- 230000002956 necrotizing effect Effects 0.000 description 1
- 229940126662 negative allosteric modulator Drugs 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- QAGYKUNXZHXKMR-HKWSIXNMSA-N nelfinavir Chemical compound CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 QAGYKUNXZHXKMR-HKWSIXNMSA-N 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 229950009675 nerelimomab Drugs 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 230000009223 neuronal apoptosis Effects 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229960000564 nitrofurantoin Drugs 0.000 description 1
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 1
- 230000001293 nucleolytic effect Effects 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- XXUPLYBCNPLTIW-UHFFFAOYSA-N octadec-7-ynoic acid Chemical compound CCCCCCCCCCC#CCCCCCC(O)=O XXUPLYBCNPLTIW-UHFFFAOYSA-N 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 201000002575 ocular melanoma Diseases 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229950008516 olaratumab Drugs 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 208000002042 onchocerciasis Diseases 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 206010030861 ophthalmia neonatorum Diseases 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229950007283 oregovomab Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 201000000901 ornithosis Diseases 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- 229940029358 orthoclone okt3 Drugs 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 description 1
- 229960001019 oxacillin Drugs 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- LDCYZAJDBXYCGN-UHFFFAOYSA-N oxitriptan Natural products C1=C(O)C=C2C(CC(N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-UHFFFAOYSA-N 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 229950010626 pagibaximab Drugs 0.000 description 1
- 201000005580 palindromic rheumatism Diseases 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- VREZDOWOLGNDPW-UHFFFAOYSA-N pancratistatine Natural products C1=C2C3C(O)C(O)C(O)C(O)C3NC(=O)C2=C(O)C2=C1OCO2 VREZDOWOLGNDPW-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229950011346 panipenem Drugs 0.000 description 1
- 229950003570 panobacumab Drugs 0.000 description 1
- 206010033794 paragonimiasis Diseases 0.000 description 1
- 210000003695 paranasal sinus Anatomy 0.000 description 1
- 201000007052 paranasal sinus cancer Diseases 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- UOZODPSAJZTQNH-LSWIJEOBSA-N paromomycin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO UOZODPSAJZTQNH-LSWIJEOBSA-N 0.000 description 1
- 229960001914 paromomycin Drugs 0.000 description 1
- 201000003045 paroxysmal nocturnal hemoglobinuria Diseases 0.000 description 1
- 229960004236 pefloxacin Drugs 0.000 description 1
- FHFYDNQZQSQIAI-UHFFFAOYSA-N pefloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 FHFYDNQZQSQIAI-UHFFFAOYSA-N 0.000 description 1
- 229960003407 pegaptanib Drugs 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 229960005570 pemtumomab Drugs 0.000 description 1
- 229960001179 penciclovir Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 229940056367 penicillin v Drugs 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 description 1
- 229960001084 peramivir Drugs 0.000 description 1
- FWZLYKYJQSQEPN-SKLAJPBESA-N peregrine Chemical compound OC1[C@H]2[C@@H]3C4([C@@H]5C6OC(C)=O)C(OC)CC[C@@]5(C)CN(CC)[C@H]4C6[C@@]2(OC)C[C@H](OC)[C@H]1C3 FWZLYKYJQSQEPN-SKLAJPBESA-N 0.000 description 1
- FWZLYKYJQSQEPN-UHFFFAOYSA-N peregrine Natural products OC1C2C3C4(C5C6OC(C)=O)C(OC)CCC5(C)CN(CC)C4C6C2(OC)CC(OC)C1C3 FWZLYKYJQSQEPN-UHFFFAOYSA-N 0.000 description 1
- 235000011197 perejil Nutrition 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 229950003203 pexelizumab Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- BPLBGHOLXOTWMN-MBNYWOFBSA-N phenoxymethylpenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)COC1=CC=CC=C1 BPLBGHOLXOTWMN-MBNYWOFBSA-N 0.000 description 1
- BBTOYUUSUQNIIY-ANPZCEIESA-N phenoxymethylpenicillin benzathine Chemical compound C=1C=CC=CC=1C[NH2+]CC[NH2+]CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)COC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)COC1=CC=CC=C1 BBTOYUUSUQNIIY-ANPZCEIESA-N 0.000 description 1
- 208000028591 pheochromocytoma Diseases 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- BZQFBWGGLXLEPQ-REOHCLBHSA-N phosphoserine Chemical compound OC(=O)[C@@H](N)COP(O)(O)=O BZQFBWGGLXLEPQ-REOHCLBHSA-N 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000006552 photochemical reaction Methods 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229940126620 pintumomab Drugs 0.000 description 1
- 229960002292 piperacillin Drugs 0.000 description 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- 208000010916 pituitary tumor Diseases 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-M pivalate Chemical class CC(C)(C)C([O-])=O IUGYQRQAERSCNH-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- ZEMIJUDPLILVNQ-ZXFNITATSA-N pivampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)[C@H](C(S3)(C)C)C(=O)OCOC(=O)C(C)(C)C)=CC=CC=C1 ZEMIJUDPLILVNQ-ZXFNITATSA-N 0.000 description 1
- 229960003342 pivampicillin Drugs 0.000 description 1
- 108010031345 placental alkaline phosphatase Proteins 0.000 description 1
- 229940118768 plasmodium malariae Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920001481 poly(stearyl methacrylate) Polymers 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 229930001119 polyketide Natural products 0.000 description 1
- 125000000830 polyketide group Chemical group 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 229920000024 polymyxin B Polymers 0.000 description 1
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 description 1
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 description 1
- 229960005266 polymyxin b Drugs 0.000 description 1
- 208000019629 polyneuritis Diseases 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 description 1
- 229960000688 pomalidomide Drugs 0.000 description 1
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 description 1
- 229960001131 ponatinib Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- JHDKZFFAIZKUCU-ZRDIBKRKSA-N pracinostat Chemical compound ONC(=O)/C=C/C1=CC=C2N(CCN(CC)CC)C(CCCC)=NC2=C1 JHDKZFFAIZKUCU-ZRDIBKRKSA-N 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000013823 prenylation Effects 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 229950003700 priliximab Drugs 0.000 description 1
- 201000010672 primary amebic meningoencephalitis Diseases 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 1
- 229960003961 pristinamycin Drugs 0.000 description 1
- DAIKHDNSXMZDCU-OUDXUNEISA-N pristinamycin-IIA Natural products CC(C)[C@H]1OC(=O)C2=CCCN2C(=O)c3coc(CC(=O)C[C@H](O)C=C(C)C=CCNC(=O)C=C[C@@H]1C)n3 DAIKHDNSXMZDCU-OUDXUNEISA-N 0.000 description 1
- JOOMGSFOCRDAHL-XKCHLWDXSA-N pristinamycin-IIB Natural products CC(C)[C@@H]1OC(=O)[C@H]2CCCN2C(=O)c3coc(CC(=O)C[C@@H](O)C=C(C)C=CCNC(=O)C=C[C@H]1C)n3 JOOMGSFOCRDAHL-XKCHLWDXSA-N 0.000 description 1
- 229950009904 pritumumab Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 229940092597 prolia Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- NSETWVJZUWGCKE-UHFFFAOYSA-N propylphosphonic acid Chemical compound CCCP(O)(O)=O NSETWVJZUWGCKE-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 201000009474 prostate rhabdomyosarcoma Diseases 0.000 description 1
- 108010043671 prostatic acid phosphatase Proteins 0.000 description 1
- 229940034080 provenge Drugs 0.000 description 1
- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- YBBJKCMMCRQZMA-UHFFFAOYSA-N pyrithione Chemical compound ON1C=CC=CC1=S YBBJKCMMCRQZMA-UHFFFAOYSA-N 0.000 description 1
- JFINOWIINSTUNY-UHFFFAOYSA-N pyrrolidin-3-ylmethanesulfonamide Chemical compound NS(=O)(=O)CC1CCNC1 JFINOWIINSTUNY-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 229950011613 racotumomab Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 229950002786 rafivirumab Drugs 0.000 description 1
- 229960004742 raltegravir Drugs 0.000 description 1
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 108010076689 ramoplanin Proteins 0.000 description 1
- 229950003551 ramoplanin Drugs 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 229960004910 raxibacumab Drugs 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 229950005854 regavirumab Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 229940116176 remicade Drugs 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- BXNMTOQRYBFHNZ-UHFFFAOYSA-N resiquimod Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CC(C)(C)O)C3=C(N)N=C21 BXNMTOQRYBFHNZ-UHFFFAOYSA-N 0.000 description 1
- 229960003254 reslizumab Drugs 0.000 description 1
- FECGNJPYVFEKOD-VMPITWQZSA-N resminostat Chemical compound C1=CC(CN(C)C)=CC=C1S(=O)(=O)N1C=C(\C=C\C(=O)NO)C=C1 FECGNJPYVFEKOD-VMPITWQZSA-N 0.000 description 1
- 229950002821 resminostat Drugs 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229960003471 retinol Drugs 0.000 description 1
- 235000020944 retinol Nutrition 0.000 description 1
- 239000011607 retinol Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 229960003485 ribostamycin Drugs 0.000 description 1
- 229930190553 ribostamycin Natural products 0.000 description 1
- NSKGQURZWSPSBC-UHFFFAOYSA-N ribostamycin A Natural products NC1C(O)C(O)C(CN)OC1OC1C(OC2C(C(O)C(CO)O2)O)C(O)C(N)CC1N NSKGQURZWSPSBC-UHFFFAOYSA-N 0.000 description 1
- NSKGQURZWSPSBC-VVPCINPTSA-R ribostamycin(4+) Chemical compound [NH3+][C@@H]1[C@@H](O)[C@H](O)[C@@H](C[NH3+])O[C@@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H]([NH3+])C[C@@H]1[NH3+] NSKGQURZWSPSBC-VVPCINPTSA-R 0.000 description 1
- 229940075118 rickettsia rickettsii Drugs 0.000 description 1
- 229960003292 rifamycin Drugs 0.000 description 1
- HJYYPODYNSCCOU-ODRIEIDWSA-N rifamycin SV Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 description 1
- WDZCUPBHRAEYDL-GZAUEHORSA-N rifapentine Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N(CC1)CCN1C1CCCC1 WDZCUPBHRAEYDL-GZAUEHORSA-N 0.000 description 1
- 229960002599 rifapentine Drugs 0.000 description 1
- 229960001886 rilonacept Drugs 0.000 description 1
- 108010046141 rilonacept Proteins 0.000 description 1
- 229950003238 rilotumumab Drugs 0.000 description 1
- 229960002814 rilpivirine Drugs 0.000 description 1
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- MBABCNBNDNGODA-WPZDJQSSSA-N rolliniastatin 1 Natural products O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@H]1[C@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-WPZDJQSSSA-N 0.000 description 1
- 229950010316 rontalizumab Drugs 0.000 description 1
- 229950009092 rovelizumab Drugs 0.000 description 1
- 229960005224 roxithromycin Drugs 0.000 description 1
- 229950009213 rubitecan Drugs 0.000 description 1
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 1
- 229960000215 ruxolitinib Drugs 0.000 description 1
- NGWSFRIPKNWYAO-SHTIJGAHSA-N salinosporamide A Chemical compound C([C@@H]1[C@H](O)[C@]23C(=O)O[C@]2([C@H](C(=O)N3)CCCl)C)CCC=C1 NGWSFRIPKNWYAO-SHTIJGAHSA-N 0.000 description 1
- NGWSFRIPKNWYAO-UHFFFAOYSA-N salinosporamide A Natural products N1C(=O)C(CCCl)C2(C)OC(=O)C21C(O)C1CCCC=C1 NGWSFRIPKNWYAO-UHFFFAOYSA-N 0.000 description 1
- 206010039447 salmonellosis Diseases 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229930182947 sarcodictyin Natural products 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 229950007308 satumomab Drugs 0.000 description 1
- 208000005687 scabies Diseases 0.000 description 1
- 201000004409 schistosomiasis Diseases 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 229950004951 sevirumab Drugs 0.000 description 1
- 201000005113 shigellosis Diseases 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 229950008684 sibrotuzumab Drugs 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229940068638 simponi Drugs 0.000 description 1
- 229950003804 siplizumab Drugs 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960005456 sisomicin Drugs 0.000 description 1
- URWAJWIAIPFPJE-YFMIWBNJSA-N sisomycin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(CN)O2)N)[C@@H](N)C[C@H]1N URWAJWIAIPFPJE-YFMIWBNJSA-N 0.000 description 1
- 229960003177 sitafloxacin Drugs 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000002612 sleeping sickness Diseases 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 208000014680 small intestine neoplasm Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 108091006284 sodium-phosphate co-transporters Proteins 0.000 description 1
- 229950007874 solanezumab Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940055944 soliris Drugs 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 229950006551 sontuzumab Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960004954 sparfloxacin Drugs 0.000 description 1
- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 229960001294 spiramycin Drugs 0.000 description 1
- 235000019372 spiramycin Nutrition 0.000 description 1
- 229930191512 spiramycin Natural products 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- UQZIYBXSHAGNOE-XNSRJBNMSA-N stachyose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)O2)O)O1 UQZIYBXSHAGNOE-XNSRJBNMSA-N 0.000 description 1
- 229950002549 stamulumab Drugs 0.000 description 1
- 201000002190 staphyloenterotoxemia Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 229940041030 streptogramins Drugs 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 208000008467 subacute bacterial endocarditis Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 229960005256 sulbactam Drugs 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004306 sulfadiazine Drugs 0.000 description 1
- 229960000654 sulfafurazole Drugs 0.000 description 1
- 229960005404 sulfamethoxazole Drugs 0.000 description 1
- IHBMMJGTJFPEQY-UHFFFAOYSA-N sulfanylidene(sulfanylidenestibanylsulfanyl)stibane Chemical compound S=[Sb]S[Sb]=S IHBMMJGTJFPEQY-UHFFFAOYSA-N 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 229960005559 sulforaphane Drugs 0.000 description 1
- 235000015487 sulforaphane Nutrition 0.000 description 1
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 201000008205 supratentorial primitive neuroectodermal tumor Diseases 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 208000006379 syphilis Diseases 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 208000004441 taeniasis Diseases 0.000 description 1
- 101150047061 tag-72 gene Proteins 0.000 description 1
- 229950004218 talizumab Drugs 0.000 description 1
- 229950008160 tanezumab Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940059300 technetium (99mtc) votumumab Drugs 0.000 description 1
- 229960001608 teicoplanin Drugs 0.000 description 1
- ONUMZHGUFYIKPM-MXNFEBESSA-N telavancin Chemical compound O1[C@@H](C)[C@@H](O)[C@](NCCNCCCCCCCCCC)(C)C[C@@H]1O[C@H]1[C@H](OC=2C3=CC=4[C@H](C(N[C@H]5C(=O)N[C@H](C(N[C@@H](C6=CC(O)=C(CNCP(O)(O)=O)C(O)=C6C=6C(O)=CC=C5C=6)C(O)=O)=O)[C@H](O)C5=CC=C(C(=C5)Cl)O3)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](NC(=O)[C@@H](CC(C)C)NC)[C@H](O)C3=CC=C(C(=C3)Cl)OC=2C=4)O[C@H](CO)[C@@H](O)[C@@H]1O ONUMZHGUFYIKPM-MXNFEBESSA-N 0.000 description 1
- 229960005240 telavancin Drugs 0.000 description 1
- 108010089019 telavancin Proteins 0.000 description 1
- 229960005311 telbivudine Drugs 0.000 description 1
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 1
- 229960004576 temafloxacin Drugs 0.000 description 1
- BVCKFLJARNKCSS-DWPRYXJFSA-N temocillin Chemical compound N([C@]1(OC)C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C=1C=CSC=1 BVCKFLJARNKCSS-DWPRYXJFSA-N 0.000 description 1
- 229960001114 temocillin Drugs 0.000 description 1
- 229950001289 tenatumomab Drugs 0.000 description 1
- 229950000301 teneliximab Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 229950010127 teplizumab Drugs 0.000 description 1
- BWMISRWJRUSYEX-SZKNIZGXSA-N terbinafine hydrochloride Chemical compound Cl.C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 BWMISRWJRUSYEX-SZKNIZGXSA-N 0.000 description 1
- 229940116411 terpineol Drugs 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- IXFPJGBNCFXKPI-FSIHEZPISA-N thapsigargin Chemical compound CCCC(=O)O[C@H]1C[C@](C)(OC(C)=O)[C@H]2[C@H](OC(=O)CCCCCCC)[C@@H](OC(=O)C(\C)=C/C)C(C)=C2[C@@H]2OC(=O)[C@@](C)(O)[C@]21O IXFPJGBNCFXKPI-FSIHEZPISA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 229960003053 thiamphenicol Drugs 0.000 description 1
- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CO)NC(=O)C(Cl)Cl)C=C1 OTVAEFIXJLOWRX-NXEZZACHSA-N 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003569 thioglycosides Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000004035 thiopropyl group Chemical group [H]SC([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 208000008732 thymoma Diseases 0.000 description 1
- 229960002175 thyroglobulin Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 description 1
- 229960004659 ticarcillin Drugs 0.000 description 1
- 229950004742 tigatuzumab Drugs 0.000 description 1
- VAMSVIZLXJOLHZ-QWFSEIHXSA-N tigemonam Chemical compound O=C1N(OS(O)(=O)=O)C(C)(C)[C@@H]1NC(=O)C(=N/OCC(O)=O)\C1=CSC(N)=N1 VAMSVIZLXJOLHZ-QWFSEIHXSA-N 0.000 description 1
- 229950010206 tigemonam Drugs 0.000 description 1
- 201000009642 tinea barbae Diseases 0.000 description 1
- 201000003875 tinea corporis Diseases 0.000 description 1
- 229960005053 tinidazole Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960000940 tivozanib Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229950005801 tosedostat Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 229950008187 tosufloxacin Drugs 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Chemical group OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 208000009174 transverse myelitis Diseases 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- LGSAOJLQTXCYHF-UHFFFAOYSA-N tri(propan-2-yl)-tri(propan-2-yl)silyloxysilane Chemical compound CC(C)[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)C(C)C LGSAOJLQTXCYHF-UHFFFAOYSA-N 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940096911 trichinella spiralis Drugs 0.000 description 1
- 208000003982 trichinellosis Diseases 0.000 description 1
- 201000007588 trichinosis Diseases 0.000 description 1
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 1
- LZAJKCZTKKKZNT-PMNGPLLRSA-N trichothecene Chemical compound C12([C@@]3(CC[C@H]2OC2C=C(CCC23C)C)C)CO1 LZAJKCZTKKKZNT-PMNGPLLRSA-N 0.000 description 1
- 229930013292 trichothecene Natural products 0.000 description 1
- 208000009920 trichuriasis Diseases 0.000 description 1
- 229940117957 triethanolamine hydrochloride Drugs 0.000 description 1
- WILBTFWIBAOWLN-UHFFFAOYSA-N triethyl(triethylsilyloxy)silane Chemical compound CC[Si](CC)(CC)O[Si](CC)(CC)CC WILBTFWIBAOWLN-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 229940035722 triiodothyronine Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- XMTVPWPWVYPLDO-UHFFFAOYSA-N trityloxysilane Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O[SiH3])C1=CC=CC=C1 XMTVPWPWVYPLDO-UHFFFAOYSA-N 0.000 description 1
- 230000001573 trophoblastic effect Effects 0.000 description 1
- 201000002311 trypanosomiasis Diseases 0.000 description 1
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229950005082 tuvirumab Drugs 0.000 description 1
- 206010061393 typhus Diseases 0.000 description 1
- 229940079023 tysabri Drugs 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- KCFYEAOKVJSACF-UHFFFAOYSA-N umifenovir Chemical compound CN1C2=CC(Br)=C(O)C(CN(C)C)=C2C(C(=O)OCC)=C1CSC1=CC=CC=C1 KCFYEAOKVJSACF-UHFFFAOYSA-N 0.000 description 1
- 229960004626 umifenovir Drugs 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- DNYWZCXLKNTFFI-UHFFFAOYSA-N uranium Chemical compound [U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U] DNYWZCXLKNTFFI-UHFFFAOYSA-N 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 229960003824 ustekinumab Drugs 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 108010073969 valyllysine Proteins 0.000 description 1
- 108010021889 valylvaline Proteins 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 229950000386 vapaliximab Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229950005208 vepalimomab Drugs 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- 229940118696 vibrio cholerae Drugs 0.000 description 1
- 210000005048 vimentin Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 229950004393 visilizumab Drugs 0.000 description 1
- 210000000239 visual pathway Anatomy 0.000 description 1
- 230000004400 visual pathway Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- 239000011653 vitamin D2 Substances 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 229950001212 volociximab Drugs 0.000 description 1
- 229950003511 votumumab Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- JFCFGYGEYRIEBE-YVLHJLIDSA-N wob38vs2ni Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCC(C)(C)S)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 JFCFGYGEYRIEBE-YVLHJLIDSA-N 0.000 description 1
- 229940051021 yellow-fever virus Drugs 0.000 description 1
- 229940098232 yersinia enterocolitica Drugs 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- 229950009002 zanolimumab Drugs 0.000 description 1
- KGPGQDLTDHGEGT-JCIKCJKQSA-N zeven Chemical compound C=1C([C@@H]2C(=O)N[C@H](C(N[C@H](C3=CC(O)=C4)C(=O)NCCCN(C)C)=O)[C@H](O)C5=CC=C(C(=C5)Cl)OC=5C=C6C=C(C=5O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@H](O5)C(O)=O)NC(=O)CCCCCCCCC(C)C)OC5=CC=C(C=C5)C[C@@H]5C(=O)N[C@H](C(N[C@H]6C(=O)N2)=O)C=2C(Cl)=C(O)C=C(C=2)OC=2C(O)=CC=C(C=2)[C@H](C(N5)=O)NC)=CC=C(O)C=1C3=C4O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O KGPGQDLTDHGEGT-JCIKCJKQSA-N 0.000 description 1
- 229950009083 ziralimumab Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/68035—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a pyrrolobenzodiazepine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6817—Toxins
- A61K47/6829—Bacterial toxins, e.g. diphteria toxins or Pseudomonas exotoxin A
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6817—Toxins
- A61K47/6831—Fungal toxins, e.g. alpha sarcine, mitogillin, zinniol or restrictocin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
- A61K47/6863—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from stomach or intestines cancer cell
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6883—Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Toxicology (AREA)
- Oncology (AREA)
- Cell Biology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Biotechnology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Diabetes (AREA)
- Virology (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明涉及具有一组丙酰基,取代的丙烯酰基或二取代的丙酰基的链接体以及使用这种链接基团偶联化合物,特别是用于细胞毒素分子与细胞结合分子的偶联。
Description
技术领域
本发明涉及一类含有丙炔酰基,取代的丙烯酰基或二取代的丙酰基的连接体,所述的连接体用于化合物偶联,特别是细胞毒性剂与细胞结合分子的偶联。本发明还涉及制备细胞结合剂-药物(细胞毒性剂)偶联物的方法,包括首先用所述的连接体修饰药物,然后与细胞结合剂反应;或者先用所述的连接体修饰细胞结合剂,然后再与药物反应,或者将合成的连接体-药物复合物直接与细胞结合分子偶联。
技术背景
化疗药物的主要问题是其治疗窗口狭窄,原因在于它们通常不能区分正常细胞和恶性癌细胞,由此引起的副作用将药物耐受剂量限制在临床有效剂量以下。相反,免疫治疗,特别是单克隆抗体(mAb)可以与癌细胞的某些蛋白质或分子特异性结合,使正常细胞不受伤害,因而与化学疗法相比具有更少的副作用和更宽的治疗窗口。抗体-药物偶联物(ADC)是一种细胞免疫疗法,它联合了特异性结合肿瘤的单克隆抗体和高效的细胞毒性剂,一起用于癌症靶向治疗。该治疗方法非常具有前景,美国FDA已批准了治疗霍奇金淋巴瘤的药物Adcetris(brentuximab vedotin)和治疗HER-2阳性乳腺癌的药物Kadcyla(ado-trastuzumab emtansine)。在过去的二十年中,学术界和制药行业一直在增加对ADC研发的时间和金钱的投入。有超过50个ADC药物正在进行临床试验,行业的预期是在未来几年内将会有其他8-10个ADC药物可能会获得市场准入(Lambert,J.M.Ther.Deliv.2016,7,279-82;Jerjian,T.V.等Pharmacotherapy 2016,36,99-116;Donaghy,H.MAbs 2016,8,659-71;deGoeij,B.E.和Lambert,J.M.Curr Opin Immunol 2016,40,14-23;Mehrling,T.FutureOncol,2015,11,549)。
影响可临床应用的抗体-药物偶联物研制关键因素包括,在正常细胞上有限表达的肿瘤靶抗原的选择,对靶标具有高选择性的抗体,当经细胞内化和被释放后,细胞毒性分子(有效荷载)需要高效地杀死靶细胞,连接细胞毒性分子和抗体的连接体需要在体循环内保持稳定,但在目标细胞中要能释放细胞毒性剂,以及合适的将细胞毒性分子连接到抗体的偶联方法。虽然目前抗体-药物偶联物的研制已经有很多进展,但是人们对于ADC脱靶毒性背后的机制仍然知之甚少,相当数量的ADCs在临床试验阶段被终止,因为它们在临床上的治疗窗口比临床前模型显示的窄得多,其给药方案受到剂量限制性毒性(DLT)的阻碍,而DLT通常很难根据临床前数据来预测(de Goeij,B.E.和Lambert,J.M.Curr Opin Immunol2016,40,14-23)。目前ADC的研发在扩展连接体-细胞毒性剂和偶联化学的范围,已经超越单一有效的有效荷载,尤其是解决ADC上的连接体-有效负载对靶标/靶标疾病的活性(Lambert,J.M.Ther Deliv 2016,7,279-82;Zhao,R.Y.等,2011,J.Med.Chem.54,3606-23)。如今,许多药物开发者和学术机构都致力于开发新型可靠的定点ADC偶联方法,这种偶联物具有更长的循环半衰期,更高的疗效,可能更低的脱靶毒性,更好的ADC体内药代动力学(PK)特性,以及ADC生产中更好的批次间一致性(Hamblett,K.J.等,Clin.CancerRes.2004,10,7063-70;Adem,Y.T.等,Bioconjugate Chem.2014,25,656-664;Boylan,N.J.Bioconjugate Chem.2013,24,1008–1016;Strop,P.,等Chem.Biol.2013,20,161-67;Wakankar,A.mAbs,2011,3,161–172)。
近些年来也有一些定点的ADC药物制备方法(Panowsky S.,2014,mAbs 6,34)。这些方法包括:在抗体上引入非配对的半胱氨酸,如抗体工程改造的反应活性半胱氨酸,即Genentech的THIOMAB抗体(Junutula,J.R.,等Clin.Cancer Res.2010,16,4769;Junutula,J.R.,等Nat Biotechnol.2008 26,925-32;美国专利8,309,300;7,855,275;7,521,541;7,723,485;WO2008/141044);或引入谷氨酰胺标签,可通过轮枝链霉菌转谷氨酰胺酶(mTG)(Strop,P.,Bioconjugate Chem.,2014,25,855–862;Strop,P.,et al.,Chem.Biol.2013,20,161–167;美国专利8,871,908)或通过细菌来源的谷氨酰胺转胺酶(MTGase)(Dennler,P.,et al,Bioconjug.Chem.2014,25,569–578;美国专利20130189287;7,893,019)而识别;引入巯基-L-岩藻糖(Okeley,N.M.等,Bioconjugate Chem.2013,24,1650);通过诱变引入非天然氨基酸(Axup,J.Y.等,Proc.Natl.Acad.Sci.2012,109,16101–16106;Zimmerman,E.S.等,Bioconjug.Chem.2014,25,351–361;Wu,P.等,Proc.Natl.Acad.Sci.2009,106,3000-3005;Rabuka,D.等,Nat.Protoc.2012,7,1052-67;美国专利8,778,631;20100184135;WO2010/081110;WO2006/069246,2007/059312,美国专利7,332,571,7,696,312;7,638,299;WO2007/130453,美国专利7,632,492;7,829,659);引入硒代半胱氨酸(Hofer,T.等Biochemistry 2009,48,12047–12057;美国专利8,916,159);用甲酰甘氨酸生成酶(FGE)将CXPXR共有序列上的半胱氨酸转化为甲酰甘氨酸(FGly)(Drake,P.M.等,Bioconjug.Chem.2014,25,1331–1341;美国专利7,985,783;8,097,701;8,349,910;美国专利申请20140141025,20100210543);或用半乳糖或唾液酸转移酶通过糖工程引入唾液酸(Zhou,Q.等Bioconjug.Chem.,2014,25,510-520,美国专利申请20140294867)。但是上述的方法都需要抗体工程改造和重新优化细胞培养条件。在实践中可采用简单的均相偶联方法,通过重新桥接天然抗体上的被还原的链间二硫键,例如使用称为下一代马来酰亚胺(NGM)连接体的溴或二溴马来酰亚胺(Schumacher,F.F.等Org.Biomol.Chem.2014,12,7261–69;UCL Cancer Institute),或通过三碳桥使用双烷基化试剂偶联(Badescu,G.等,Bioconjug.Chem.2014,25,1124–36;WO2013/190272,WO2014/064424)。我们已经公开了几种桥联天然抗体上,链间二硫键被还原而产生的一对巯基的偶联方法,例如使用溴代马来酰亚胺和二溴马来酰亚胺连接体(WO2014/009774),2,3-二取代的琥珀酸,2-取代/2,3-二取代的富马酸或马来酸连接体(WO2015/155753,WO20160596228),乙炔二羧酸连接体(WO2015/151080,WO20160596228)或肼连接体(WO2015/151081)。在本专利申请中我们扩展了之前的范围。更重要的是,本专利申请的双硫连接体能够在每个连接体上偶联两种或更多种药物以实现更高的DAR(≥4)或与细胞结合分子上两个或更多个巯基位点偶联,或偶联两个或更多个细胞结合分子。因此,本专利申请免疫偶联物的主要优势包括:在靶向递送期间更长的偶联物半衰期;偶联两种或更多种不同功能分子/药物,使其在细胞周期的不同阶段起作用,以增加暴露于特定药物或效应物的靶细胞的数量;可能偶联两种或多种细胞结合分子,实现对增殖细胞的双重,三重或多重靶向策略;通过偶联功能分子,使药物最小量地暴露于非靶细胞,组织或器官;精确定点控制药物有效负载和药物比例,产生均一的最终产品。
发明内容
本发明申请包括一类含有取代丙烯酰基团或丙炔酰基团的,能与巯基反应的连接体,其中可选地含有磷酰胺,胺,肼,三唑,杂芳基,乙酰胺,糖苷等基团及其类似物,可以与药物和/或功能分子,和/或细胞结合剂(例如抗体)发生偶联。
本发明申请的一个方面,连接体由式(I)和(II)表示
Lv1和Lv2表示相同或不同的,可被巯基取代的离去基团。这些离去基团包括,但不限于卤化物(例如氟化物,氯化物,溴化物和碘化物),甲磺酰基(mesyl),甲苯磺酰基(tosyl),三氟甲基磺酰基(triflate),硝基苯氧基,N-琥珀酰亚胺基氧基(NHS),苯氧基;二硝基苯氧基;五氟苯氧基,四氟苯氧基,三氟苯氧基,二氟苯氧基,单氟苯氧基,五氯苯氧基,1H-咪唑-1-基,氯苯氧基,二氯苯氧基,三氯苯氧基,四氯苯氧基,N-(苯并三唑基)氧基,2-乙基-5-苯基异恶唑-3’-磺酰基,苯基恶二唑-磺酰基(-sulfone-ODA),2-乙基-5-苯基异恶唑-基,苯基恶二唑基(ODA),恶二唑基,或者与Mitsunobu反应缩合试剂作用产生的中间体。
Y是能够与细胞毒性药物反应形成二硫化物,醚,酯,硫醚,硫酯,肽,腙,氨基甲酸酯,碳酸酯,胺(二级,三级或四级),亚胺,环杂烷基,杂芳基,烷基肟或酰胺键的官能团;优选地,Y具有以下结构:
二硫化物;/>卤代乙酰基;/>酰卤;/>N-羟基琥珀酰亚胺酯基;/>马来酰亚胺基;/>单取代马来酰亚胺基;二取代马来酰亚胺基;/>单取代的琥珀酰亚胺基;/>二取代琥珀酰亚胺基;醛基;/>乙烯基磺酰基;/>丙烯酰基;2-(甲苯磺酰氧基)乙酰基;/>2-(甲磺酰氧基)乙酰基;/>2-(硝基苯氧基)乙酰基;/>2-(二硝基苯基)乙酰基;/>2-(氟代苯氧基)-乙酰基;/>2-(二氟苯氧基)-乙酰基;/>2-(((三氟甲基)-磺酰)氧基)乙酰基;酮或醛基;/>2-(五氟苯氧基)乙酰基;甲基砜苯基恶二唑(ODA)苯基;/> 酸酐,/>烷氧基氨基;/>叠氮基,/>炔基,或酰肼。
其中X1’为F,Cl,Br,I或Lv3;X2’是O,NH,N(R1)或CH2;R3和R5独立地为H,R1,芳基,杂芳基或芳香基团,其中一个或几个H原子被-R1,-卤素,-OR1,-SR1,-NR1R2,-NO2,-S(O)R1,-S(O)2R1,或-COOR1取代;Lv3是下列离去基团:硝基苯氧基,N-琥珀酰亚胺基氧基(NHS),苯氧基;二硝基苯氧基;五氟苯氧基,四氟苯氧基,二氟苯氧基,单氟苯氧基,五氯苯氧基,三氟甲基磺酰基,咪唑基,二氯苯氧基,四氯苯氧基,1-羟基苯并三唑基,甲苯磺酸基,甲磺酸基,2-乙基-5-苯基异恶唑-3’-磺酸基,自身形成,或与其它酸酐形成的酸酐,例如乙酸酐,甲酸酐,或与多肽缩合试剂作用产生的或Mitsunobu反应的中间体。
R1可以缺省,或者可以选自C1-C8(1-8个碳原子)烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或含2-8个碳原子的酯,醚或酰胺;或含有1-8个氨基酸的肽;或具有式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p是0至约1000的整数,或其上述基团的组合。
另外,R1是包含C,N,O,S,Si,和P原子的链状结构,最优含0~500个原子,共价连接于Y和L1。R1中的各个原子以所有可能的化学方式结合,比如形成烷基、亚烷基、亚烯基、亚炔基、醚、聚氧烷基、酯、胺、亚胺、聚胺、肼、腙、酰胺、脲、氨基脲、卡巴肼、烷氧胺、聚氨酯、氨基酸、多肽、酰氧胺、异羟肟酸,或这些基团的组合。
T为CH2,NH,NHNH,N(R3),N(R3)N(R3’),O,S,C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;含有1~4氨基酸单位的肽,优选自天冬氨酸,谷氨酸,精氨酸,组氨酸,赖氨酸,丝氨酸,苏氨酸,天冬酰胺,谷氨酰胺,半胱氨酸,硒代半胱氨酸,酪氨酸,苯丙氨酸,甘氨酸,脯氨酸,色氨酸,丙氨酸;或以下结构之一:
X1,X2,X3,X4,X5,X6,X1’,X2’和X3’独立地选自NHNH;N(R3);N(R3)N(R3’);O;S;C1-C6烷基;C2-C6杂烷基,烷基环烷基,杂环烷基的;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或1~8个氨基酸;其中R3和R3’独立地为H;C1-C8烷基;C2-8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或含1-8个碳原子的酯,醚或酰胺;或具有式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p是0至约1000的整数,或其上述基团的组合。
L1和L2是相同或不同的,独立地选自O,NH,S,NHNH,N(R3),N(R3)N(R3’),如式(OCH2CH2)pOR3,或(OCH2CH(CH3))pOR3,或NH(CH2C水)pR3,或NH(CH2CH(CH3)O)pR3,或N[(CH2C水)pR3][(CH2C水)p’R3’],或(OCH2CH2)pCOOR3,或CH2CH2(OCH2CH2)pCOOR3的聚乙烯氧基单元,其中p和p’是独立的选自0至约1000的整数,或它们的组合;C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基的;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;其中,R3和R3’独立地为H;C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基的;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或含1-8个碳原子的酯,醚或酰胺;或1~8个氨基酸;或具有式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p是0至约1000的整数,或其上述基团的组合。
L1或L2可以由一个或多个以下连接体单元构成:6-马来酰亚胺基己酰基(“MC”),马来酰亚胺丙酰基(“MP”),缬氨酸-瓜氨酸(“val-cit”或“vc”),丙氨酸-苯丙氨酸(“ala-phe”或"af”),对氨基苄氧基羰基(“PAB"),4-硫代戊酰基(“SPP”),4-(N-马来酰亚胺甲基)环己烷-1酰基(“MCC“),(4-乙酰基)氨基-苯酰基(“SIAB”),4-硫代丁酰基(SPDB),4-硫代-2-羟基磺酰基-丁酰基(2-sulfo-SPDB),或具有1~8个天然或非天然氨基酸单元的天然或非天然肽。
m1,m2,m3,m4和m5是独立的选自1到10的整数,优选1到4。
此外,L1,L2,X1,X2,X3,X1’,X2’和X3’可以独立地缺省。
另一方面,本发明包括如式(III),(IV),(V),(VI),(VII),(VIII),和(IX)的细胞结合剂-药物偶联物,其中细胞结合剂Cb和药物Drug,分别在连接体两末端反应:
其中Cb,Cb’,Cb”,Cb”’表示相同或不同的细胞结合剂或免疫治疗蛋白,优选为抗体或抗体片段。
式(III),(VII),(VIII)和(IX)的右括号(方括号)内是与细胞结合剂/分子的巯基对偶联的连接体-药物组分。巯基优选为细胞结合剂的链间二硫键被还原剂还原而产生,还原剂选自二硫苏糖醇(DTT)、二硫季戊四醇(DTE)、L-谷胱甘肽(GSH)、三(2-羧基乙基)膦(TCEP)、2-巯基乙胺(β-MEA)或/和β-巯基乙醇(β-ME,2-ME)。
Drug,Drug’,和Drug”表示相同或不同的细胞毒性剂,或治疗药物,或免疫治疗蛋白质,或用于增强细胞结合剂的结合或稳定的功能分子,或者细胞表面受体结合配体,其应用本专利申请的桥接剂,经由R1与细胞结合剂连接,R1含有C1-C8烷基;C2-C8亚烷基,亚烯基,亚炔基,芳基,醚,聚氧亚烷基,酯,胺,亚胺,多胺,肼,腙,酰胺,脲,氨基脲,卡巴肼,烷氧基胺,氨基甲酸,氨基酸,肽,酰氧基胺,异羟肟酸,二硫化物,硫醚,硫酯,氨基甲酸酯,碳酸酯,杂环,杂烷基,杂芳基,烷氧基或上述基团组合。
Drug,Drug’,和Drug”还可以是细胞毒性分子,免疫治疗化合物,化学治疗化合物,抗体或抗体片段,siRNA或DNA分子,或细胞表面结合配体。
方括号内是通过细胞结合分子上的一对硫原子与细胞结合分子偶联的试剂。
m1,m1’,m1”,m2,m2’,m2”,m3,m4,m5,m4’,m5’,m4”,m5”,m4”’,m5”’,m4””和m5””独立地是1到10的整数,优选1到4的整数。
X1,X1’,X1”,X1”’和X2””独立地选自NH;NHNH;N(R3);N(R3)N(R3’);O;S;C1-C6烷基;C2-C6杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或1~8个氨基酸;其中R3和R3’独立地为H;C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、杂芳基;1-8个碳原子的酯、醚或酰胺;或如式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p为从0到1000的整数;或以上的组合。此外,X1,X1’,X1”,X1”’和X2””可以独立地缺省。
R1,R1’,和R1”相同或不同,选自C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、杂芳基;2-8个碳原子的酯、醚或酰胺;或如式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p为从0到1000的整数;或以上的组合。
L1,L1’,L1”,L1”’,L2,L2’,L2”和L2”’的定义与式(I)和(II)中的L1和L2相同,它们也可以各不相同。
n是1~20;T与前式(I)中定义相同。
另一方面,本发明申请还包括如式(X),(XI),(XII),(XIII),(XIV),(XV)和(XVI)的经修饰的细胞结合剂,细胞结合剂Cb通过还原二硫键产生的巯基对与连接体反应,其中含有官能团Y,可以与药物反应:
更进一步的,本发明申请包含如式(XVII)和(XVIII)经修饰的药物,药物“Drug”与式(I)和(II)的连接体反应后,引入可以与巯基反应的取代丙烯酰基团或丙炔酰基团:
本发明申请进一步涉及式(III)–(IX)中细胞结合分子-药物偶联物的制备方法,其中药物“Drug”通过连接体与细胞结合剂连接。
本发明还涉及式(X)–(XVI)中修饰的细胞结合分子的制备方法,其中所述细胞结合分子与式(I)和(II)中的连接体反应。
本发明还涉及式(XVII)和(XVIII)中修饰药物的制备方法,其中药物与式(I)和(II)中的连接体反应。
附图说明
图1显示了本专利申请中含有两个或四个药物的连接体的合成,以及连接体通过一对巯基偶联抗体。
图2显示了本专利申请中含有两种或四种药物的连接体的合成,以及连接体通过一对巯基偶联抗体。
图3显示了本专利申请中含有一个药物和聚乙二醇基团连接体的合成,以及连接体通过一对巯基偶联抗体。
图4显示了本专利申请中含有一个药物的连接体的合成,以及连接体通过一对巯基偶联抗体。
图5显示了本专利申请中含有一个药物,氨基酸和聚乙二醇基团的连接体的合成,以及连接体通过一对巯基偶联抗体。
图6显示了本专利申请中含有一个药物、磷酰胺和聚乙二醇基团的连接体的合成,以及连接体通过一对巯基偶联抗体。
图7显示了本专利申请中含有一个药物和磷酰胺基团的连接体的合成,以及连接体通过一对巯基偶联抗体。
图8显示了本专利申请中含有药物和磷酰胺基团的连接体的合成,以及连接体通过一对巯基偶联抗体。
图9显示了本专利申请中含有一个药物和聚乙二醇基团的连接体的合成,以及连接体通过一对巯基偶联抗体。
图10显示了本专利申请中含有药物和连接体单元L1和L2的连接体的合成,以及连接体通过一对巯基偶联抗体。
图11显示了本专利申请中含有前列腺表面抗原(PSA)结合配体的连接体的合成。
图12显示了本专利申请中含有前列腺表面抗原(PSA)结合配体的连接体的合成,以及连接体通过一对巯基偶联抗体。
图13显示了Tubulysin类似物中间体的合成。
图14显示了可偶联的Tubulysin类似物的合成,以及通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图15显示了通过本专利申请的连接体合成抗体-MMAF类似物的偶联物。
图16显示了通过本专利申请的连接体合成抗体-MMAF类似物的偶联物。
图17显示了通过本专利申请的连接体合成抗体-MMAF类似物的偶联物。
图18显示了通过本专利申请的连接体合成抗体-MMAF类似物的偶联物。
图19显示了可偶联的Tubulysin类似物组分的合成,以及通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图20显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图21显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图22显示了通过本专利申请之连接体合成抗体-Tubulysin类似物的偶联物。
图23显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图24显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图25显示了通过本专利申请的连接体合成含有MMAF类似物和Tubulysin类似物的偶联物。
图26显示了通过本专利申请的连接体合成含有MMAF类似物和PBD二聚体类似物的偶联物。
图27显示了通过本专利申请的连接体合成含有MMAF类似物和PBD二聚体类似物的偶联物。
图28显示了通过本专利申请的连接体合成的包含两个MMAF类似物的偶联物。
图29显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图30显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图31显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图32显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图33显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图34显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物和可偶联的MMAF类似物。
图35显示通过本专利申请的连接体合成抗体-MMAF类似物的偶联物。
图36显示了通过本专利申请的连接体合成抗体-鹅膏毒素类似物的偶联物。
图37显示了通过本专利申请的连接体合成抗体-鹅膏毒素类似物的偶联物。
图38显示了通过本专利申请的连接体合成抗体-鹅膏毒素类似物的偶联物。
图39显示了通过本专利申请的连接体合成抗体-鹅膏毒素类似物的偶联物。
图40显示了通过本专利申请的连接体合成抗体-Tubulysin类似物和抗体-MMAF类似物的偶联物。
图41显示了通过本专利申请的连接体合成抗体-Tubulysin类似物的偶联物。
图42显示通过本专利申请的连接体合成抗体-Tubulysin类似物、抗体-PBD二聚体类似物及抗体-MMAF类似物的偶联物。
图43显示了通过本专利申请的连接体合成包含PMSA结合配体的抗体-Tubulysin类似物,包含PEG链的抗体-Tubulysin类似物的偶联物。
图44显示了含有还原剂DTT的SDS-PAGE谱。泳道1和11是生物标记物,泳道2和泳道16是偶联物232,泳道3和泳道15是偶联物339,泳道4是偶联物234,泳道5是偶联物238,泳道6是偶联物261,泳道7和泳道17是偶联物308,泳道8是偶联物239,泳道9是偶联物476,泳道10是偶联物478,泳道12是偶联物360,泳道14是偶联物238,泳道18为偶联物481,泳道19为偶联物483,泳道20为T-DM1。通过本专利申请的连接体得到的偶联物232、234、238、261、308、339、354和360的条带为75kd,表明单克隆抗体的重链和轻链被连接体交联。偶联物上两条重链之间的连接可以被DTT还原剂取代,导致150kD条带微弱。偶联物476、478、481和483的交联被SDS-PAGE内的DTT所取代(可逆结合),75kD和150kD的带也非常微弱。相比之下,无交联的T-DM1无75kD带,制备时不使用紫外光的偶联物239仅有微弱的75kD条带,表明在偶联条件下可能不存在交联。
图45显示了偶联物232、308、327、339、476、485和500与T-DM1在人胃癌N87细胞模型上抗肿瘤作用的比较,一次静脉注射,偶联物232、308、327、339、476和485的剂量为5mg/kg,偶联物339和500为4mg/kg。测试的7个偶联物显示出比T-DM1更好的抗肿瘤活性。化合物476、483、339和500组的6/6动物在第14天至第52天完全没有肿瘤。与之对照,剂量为5mg/kg的T-DM1不能消除肿瘤,仅能抑制肿瘤生长31天。偶联物232、308和327在剂量为5mg/kg时不能完全去除肿瘤。
发明概要
定义
“烷基”是指在烷烃上除去一个或两个氢原子而产生的脂肪烃基团或单价基团。它可以是直链或是支链的,在链中具有1-8个碳原子(C1-C8)。“支链”是指直链烷基上连接有一个或多个低碳数的烷基,如甲基、乙基或丙基。示例性的烷基包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、3-戊基、辛基、壬基、癸基、环戊基、环己基、2,2-二甲基丁基、2,3-二甲基丁基、2,2-二甲基戊基、2,3-二甲基戊基、3,3-二甲基戊基、2,3,4-三甲基戊基、3-甲基-己基、2,2-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,5-二甲基己基、2,4-二甲基戊基、2-甲基庚基、3-甲基庚基、正庚基、异庚基、正辛基和异辛基。C1-C8烷基可以是未被取代的或被一个或多个基团取代,包括但不限于-C1-C8烷基、-O-(C1-C8烷基)、-芳基、-C(O)R’、-OC(O)R’、-C(O)OR’、-C(O)NH2,-C(O)NHR’、-C(O)N(R’)2、-NHC(O)R’、-SR’、-S(O)2R’、-S(O)R’、-OH、-卤素、-N3、-NH2、-NH(R’)、-N(R’)2和-CN;其中每个R’独立地选自于-C1-C8烷基和芳基。
“杂烷基”指其中1至4个碳原子独立地被选自O、S和N的杂原子所取代的C2-C8烷基。
“碳环”指含有3到8个碳原子的饱和或不饱和单环,或含有7到13个碳原子的饱和或不饱和双环。单环碳环有3到6个环原子,典型的有5或6个环原子。双环碳环有7到12个环原子,构成[4,5]、[5,5]、[5,6]或[6,6]的双环系统,或有9个或10个环原子,构成[5、6]或[6,6]的双环系统。具有代表性的C3-C8的碳环包括但不限于:-环丙基、-环丁基、-环戊基、-环戊二烯基、-环己基、-环己烯基、-1,3-环己二烯基、-1,4-环己二烯基、-环庚基、-1,3-环庚二烯基、-1,3,5-环庚三烯基、-环辛基和-环辛二烯基。
C3-C8碳环可以是未被取代的或被一个或多个基团取代,包括但不限于-C1-C8烷基、-O-(C1-C8烷基)、-芳基、-C(O)R’、-OC(O)R’、-C(O)OR’、-C(O)NH2、-C(O)NHR’、-C(O)N(R’)2、-NHC(O)R’、-SR’、-S(O)R’、-S(O)2R’、-OH、-卤素、-N3、-NH2、-NH(R’)、-N(R’)2及-CN;其中每个R’独立地选自-C1-C8烷基和芳基。
“烯基”指含有碳-碳双键的直链或支链脂肪烃基团,链内含有2-8个碳原子。示例性的烯基包括乙烯基、丙烯基、正丁烯基、异丁烯基、3-甲基丁-2-烯基、正戊烯基、己烯基、庚烯基、辛烯基。
“炔基”指含有碳-碳三键的直链或支链脂肪烃基团,链内含有2-8个碳原子。示例性的炔基包括乙炔基、丙炔基、正丁炔基、2-丁炔基、3-甲基丁炔基、5-戊炔基、正戊炔基、己炔基、庚炔基和辛炔基。
“亚烷基”是指含1-18个碳原子的饱和的支炼或直链或环状烃基,并带有两个通过从母体烷烃的相同或两个不同碳原子上除去两个氢原子而产生的一价自由基。典型的亚烷基包括但不限于:亚甲基(-CH2-)、1,2-乙基(-CH2CH2-)、1,3-丙基(-CH2CH2CH2-)、1,4-丁基(-CH2CH2CH2CH2-)等。
“亚烯基”指含2-18个碳原子的不饱和的支炼或直链或环状烃基,并带有两个通过从母体烯烃的相同或两个不同碳原子上除去两个氢原子而产生的一价自由基。典型的亚烯基包括但不限于:1,2-亚乙基(-CH=CH-)。
“亚炔基”指含2-18个碳原子的不饱和的支炼或直链或环状烃基,并带有两个通过从母体炔的相同或两个不同碳原子上除去两个氢原子而产生的一价自由基。典型的亚炔基包括但不限于:乙炔、炔丙基和4-戊炔基。
“芳基”或“芳香基”指由一个或多个环组成的芳香或杂芳香基团,包含三至十四个碳原子,优选六至十个碳原子。术语“杂芳香基团”是指芳香基团上的一个或几个碳,最优是一个、两个、三个或四个碳原子,被氧(O)、氮(N)、硅(Si)、硒(Se)、磷(P)或(S)所取代,优选被氧、硫和氮所取代而产生的基团。术语“芳基”或“芳香基”也指其中一个或几个氢原子独立地被-R’、卤素、-OR’,-SR’、-NR’R’、-N=NR’、-N=R’、-NR’R’、-NO2、-S(O)R’、-S(O)2R’、-S(O)2OR’、-OS(O)2OR’、-PR’R’、-P(O)R’R’、-P(OR’)(OR’)、-P(O)(OR’)(OR’)或-OP(O)(OR’)(OR’)所取代而产生的芳香基团。其中R’和R’独立地为氢、烷基、烯基、炔基、杂烷基、芳基、芳烷基、羰基或其药用盐。
“杂环”指其中一到四个环碳原子独立地被O、N、S、Se、B、Si或P等杂原子所取代而产生的的环结构。优选的杂原子是O、N和S。在《化学与物理手册》第78版的225-226页(TheHandbook of Chemistry and Physics,78th Edition,CRC Press,Inc.,1997-1998,p.225to 226)上也有杂环化合物的相关描述,在此引作参考。优选的非芳基杂环包括环氧基、氮丙啶基、硫杂丙基、吡咯烷基、吡唑烷基、咪唑烷基、环氧乙烷基、四氢呋喃基、二氧戊环基、四氢吡喃基、二恶烷基、二氧戊环基、呱啶基、呱嗪基、吗啉基、吡喃基、咪唑啉基、吡咯啉基、吡唑啉基、噻唑烷基、四氢噻喃基、二噻烷基、硫代吗啉基、二氢吡喃基、四氢吡喃基、二氢吡喃基、四氢吡啶基、二氢吡啶基、四氢嘧啶基、二氢噻喃基、氮杂环庚烷基,以及上述基团与苯基缩合得到的稠环体系。
术语“杂芳基”或“芳基杂环”是指含3到14,优选5至10个原子的芳香性杂环、包含单环、双环或多环。示例包括吡咯基、吡啶基、吡唑基、噻吩基、嘧啶基、吡嗪基、四唑基、吲哚基、喹啉基、嘌呤基、咪唑基、噻吩基、噻唑基、苯并噻唑基、呋喃基、苯并呋喃基、1,2,4-噻二唑基、异噻唑基、三唑基、四唑基、异喹啉基、苯并噻吩基、异苯并呋喃基、吡唑基、咔唑基、苯并咪唑基、异恶唑基、吡啶基-N-氧化物,以及上述基团与苯基缩合得到的稠环体系。
“烷基”、“环烷基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“杂环”等,也包含各自对应的“亚烷基”、“亚环烷基”、“亚烯基”、“亚炔基”、“亚芳基”、“亚杂芳基”、“亚杂环”等,为论述方便,本专利申请对它们未做完全区分。
“芳烷基”指一类非环烷基,其中一个与碳原子(通常为末端或sp3碳原子)键合的氢原子被芳基取代。典型的芳烷基包括芐基、2-苯基乙-1-基、2-苯基乙烯-1-基、萘基甲基、2-萘基乙-1-基、2-萘基乙-1-基、萘并芐基、2-萘基苯基-1-基等。
“杂芳烷基”指一类非环烷基,其中一个与碳原子(通常为末端或sp3碳原子)键合的氢原子被杂芳基取代。杂芳烷基的实例有2-苯并咪唑基甲基、2-呋喃基乙基。
“羟基保护基”的实例包括甲氧基甲基醚、2-甲氧基乙氧基甲基醚、四氢吡喃基醚、芐基醚、对甲氧基芐基醚、三甲基甲硅醚、三乙基硅醚、三异丙基硅醚、叔丁基二甲基硅醚、三苯基甲基硅醚、乙酸酯、取代乙酸酯、特戊酸酯、苯甲酸酯、甲磺酸酯和对甲苯磺酸酯。
“离去基团”指可以被另一个官能团取代的官能团。这些离去基团是本领域公知的、实例包括卤化物(如氯化物、溴化物和碘化物)、甲磺酰基、对甲苯磺酰基和三氟甲磺酰基。优选的离去基团选自硝基苯氧基;N-羟基琥珀酰亚胺基(NHS);苯氧基;二硝基苯氧基;五氟苯氧基;四氟苯氧基;二氟苯氧基;一氟苯氧基;五氯苯氧基;三氟甲磺酰基;咪唑基;氯酚基;四氯苯氧基;1-羟基苯并三唑基;甲苯磺酰基;甲磺酰基;2-乙基-5-苯基异恶唑-3’-磺酰基,酸酐或与其它酸酐作用形成的酸酐,例如乙酸酐、甲酸酐;或与多肽缩合试剂、Mitsunobu反应试剂作用生成的中间体。
以下缩写为本发明所采用,其定义为:Boc,叔丁氧基羰基;BroP,溴代十四烷基鏻六氟磷酸盐;CDI,1,1’-羰基二咪唑;DCC,二环己基碳二亚胺;DCE,二氯乙烷;二氯甲烷,二氯甲烷;DEAD,偶氮二甲酸二乙酯;DIAD,偶氮二甲酸二异丙基酯;DIBAL-H,二异丁基氢化铝;DIPEA或DEA,二异丙基乙胺;DEPC,二乙基氰基磷酸酯;DMA,N,N-二甲基乙酰胺;DMAP,4-(N,N-二甲基氨基)吡啶;DMF,N,N-二甲基甲酰胺;DMSO,二甲基亚砜;DTPA,二亚乙基三胺五乙酸;DTT,二硫苏糖醇;EDC,1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐;ESI-MS,电喷雾质谱;乙酸乙酯,乙酸乙酯;Fmoc,N-(9-芴基甲氧基羰基);HATU,O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐;HOBt,1-羟基苯并三唑;HPLC,高效液相色谱;NHS,N-羟基琥珀酰亚胺;MeCN,乙腈;MeOH,甲醇;MMP,4-甲基吗啉;PAB,对氨基苯甲酸;PBS,磷酸盐缓冲液(pH 7.0-7.5);Ph,苯基;Phe,L-苯丙氨酸;PyBrop,溴-三-吡咯烷-鏻六氟磷酸盐;PEG,聚乙二醇;SEC,尺寸排阻色谱;TCEP,三(2-羧乙基)膦;TFA,三氟乙酸;四氢呋喃,四氢呋喃;Val,缬氨酸;TLC,薄层色谱;UV是紫外线。
“氨基酸”可以是天然或非天然的,优选α-氨基酸。天然氨基酸可以由遗传密码所编码,它们是丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷氨酸、谷氨酰胺、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、蛋氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、酪氨酸、色氨酸和缬氨酸。非天然氨基酸是蛋白质氨基酸的衍生物,包括羟脯氨酸、羊毛硫氨酸、2-氨基异丁酸、脱氢丙氨酸、γ-氨基丁酸(神经递质)、鸟氨酸、瓜氨酸、β-丙氨酸(3-氨基丙酸)、γ-羧基谷氨酸、硒代半胱氨酸(存在于许多非真核以及大多数真核细胞中、但不是由DNA直接进行编码)、吡咯赖氨酸(仅在一些古细菌和一种细菌中发现)、N-甲酰基甲硫氨酸(通常是细菌、线粒体和叶绿体中蛋白质中最初的氨基酸)、5-羟色氨酸、L-二羟基苯丙氨酸、三碘甲腺原氨酸、L-3,4-二羟基苯丙氨酸(DOPA)和O-磷酸丝氨酸。术语“氨基酸”还包括氨基酸同系物和模拟物。同系物是具有与天然氨基酸相同结构通式H2N(R)CHCO2H的化合物,其中R在天然氨基酸里。同系物的实例包括高丝氨酸、正亮氨酸、甲硫氨酸-亚砜和甲硫氨酸甲基锍。更优的是氨基酸模拟物,它是具有与α-氨基酸的化学结构不同、但是作用方式类似的化合物。天然氨基酸多为“L”立体化学构型,“非天然氨基酸”也用于代表“D”构型的氨基酸。在本专利申请中使用1至8个氨基酸时、其序列优选为蛋白水解酶可识别的序列。许多水解酶识别序列是本领域已知的,可以参见:Matayoshi等.Science 247:954(1990);Dunn等.Meth.Enzymol.241:254(1994);Seidah等.Meth.Enzymol.244:175(1994);Thornberry,Meth.Enzymol.244:615(1994);Weber等.Meth.Enzymol.244:595(1994);Smith等.Meth.Enzymol.244:412(1994);及Bouvier等.Meth.Enzymol.248:614(1995);此处引作参考。特别是选自以下序列:Val-Cit、Ala-Val、Ala-Ala、Val-Val、Val-Ala-Val、Lys-Lys、Ala-Asn-Val、Val-Leu-Lys、Cit-Cit、Val-Lys、Ala-Ala-Asn、Asp-Lys、Asp-Glu、Glu-Lys、Lys、Cit、Ser及Glu。
“糖苷”是糖通过糖苷键在其异头碳上与另一基团键合得到的分子。糖苷可以通过O-(产生O-糖苷)、N-(产生糖基胺)、S-(产生硫代糖苷)或C-(产生C-糖苷)糖苷键连接,其实验式为Cm(水)n(其中m可以不同于n、m、n<36),本发明中的糖苷包括葡萄糖(右旋糖)、果糖(左旋糖)、阿洛糖、阿卓糖、甘露糖、古洛糖、艾杜糖、半乳糖、塔罗糖、半乳糖胺、氨基葡萄糖、唾液酸、N-乙酰氨基葡萄糖、磺基奎诺糖(6-脱氧-6-磺基-D-吡喃葡萄糖)、核糖、阿拉伯糖、木糖、来苏糖、山梨糖醇、甘露醇、蔗糖、乳糖、麦芽糖、海藻糖、麦芽糖糊精、棉子糖、葡萄糖醛酸(葡糖苷酸)和水苏糖。它可以是D或L的构型、5原子环状呋喃糖的形式、6原子环状吡喃糖的形式,或是非环形式、α-异构体(异头碳的-OH在Haworth投影碳原子平面之下)、或β-异构体(异头碳的-OH在Haworth投影碳原子平面之上)。本发明中亦称为单糖、二糖、多元醇或含3-6个糖单元的低聚糖。
“药学上”或“药学上可接受的”是指当分子实体和组合物酌情施用于动物或人时,不会产生不利、过敏或其他不良反应。
“药学上可接受的溶剂化物”或“溶剂化物”是指一种或多种溶剂分子与本发明公开的化合物的结合物。形成药学上可接受的溶剂合物,溶剂的实例包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。
“药学上可接受的赋形剂”包括任何载体、稀释剂、佐剂或其它,例如防腐剂或抗氧化剂、填充剂、崩解剂、润湿剂、乳化剂、悬浮剂、溶剂、分散介质、包衣剂、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。这些介质和药剂用于药物活性物质在本领域内是熟知的。任何传统介质或药剂,除非与活性成分不兼容,也可以考虑将其用于治疗组合物中。补充活性成分也可以加入组合物中,成为合适的治疗组合。
如本文所用,“药用盐”是指所公开化合物的衍生物,通过制备母体化合物的酸盐或碱盐来获得。药学上可接受的盐包括由无毒无机酸或有机酸与母体化合物形成的常规无毒盐或季铵盐。例如,所述常规无毒盐包括衍生自无机酸(例如盐酸、氢溴酸盐、硫酸、氨基磺酸、磷酸、硝酸等)的盐;以及由有机酸(例如乙酸、丙酸、琥珀酸、酒石酸、柠檬酸、甲磺酸、苯磺酸、葡萄糖醛酸、谷氨酸、苯甲酸、水杨酸、甲苯磺酸、草酸、富马酸、马来酸及乳酸等制备的盐。另外的加成盐包括铵盐,如三甲胺、葡甲胺、丙三醇等的盐、金属盐、如钠、钾、钙、锌或镁盐。
本发明的药用盐可由含有碱性或酸性部分的母体化合物,通过常规化学方法合成。通常而言,这些盐可以通过在水或有机溶剂中或两者的混合物中,向母体化合物里,加入等当量的适当碱或酸来制备。一般来说,乙醚、乙酸乙酯、乙醇、异丙醇或乙腈是非水介质的首选。适用盐的列表见于1985年由麦克出版公司出版的《雷明顿药物科学》(Remington’sPharmaceutical Sciences),其公开内容纳入本文作参考。
“施用”或“给药”是指以任何方式向受试者转移、递送、引入或运输药物或其他药剂。这些方式包括口服用药、局部接触、静脉内、腹膜内、肌肉内、病灶内、鼻内、皮下或鞘内给药。本发明还考虑使用装置或器械来施用药剂。这种装置可以使用主动或被动型传输,而且可以是缓释或快速释放递送装置。
本文公开的新型偶联物使用了连接体,一些连接体及其合成的实施例显示在图1至34中。
连接体
图1-20显示了连接体的合成路线以及本发明申请中的细胞结合分子-药物偶联物的制备方法。连接体包含两个元素:a)取代基,一个或两个以上取代的丙烯酰基团或丙炔酰基团,可以与一对巯基反应形成共价硫醚键,和b)一个能够与一种药物发生反应的基团,例如,但不限于二硫化物,马来酰亚胺,卤代乙酰基,醛,酮,叠氮化物,胺,烷氧基胺,酰肼,乙烯磺酰基,酰基卤(酰卤),丙烯酰基和/或酸酐基团。连接体上的取代的丙烯酰基团或丙炔酰与胺,醇或巯基反应生成酰胺,酯或硫酯键。这些桥接连接体的合成及在抗体偶联物上的应用示例于图1-20中。
优选地,桥接连接体是下列式(I)和(II)的化合物:
Lv1和Lv2表示相同或不同的,可被巯基取代的离去基团。这些离去基团包括,但不限于卤化物(例如氟化物,氯化物,溴化物和碘化物),甲磺酰基(mesyl),甲苯磺酰基(tosyl),三氟甲基磺酰基(triflate),硝基苯氧基,N-琥珀酰亚胺基氧基(NHS),苯氧基;二硝基苯氧基;五氟苯氧基,四氟苯氧基,三氟苯氧基,二氟苯氧基,单氟苯氧基,五氯苯氧基,1H-咪唑-1-基,氯苯氧基,二氯苯氧基,三氯苯氧基,四氯苯氧基,N-(苯并三唑基)氧基,2-乙基-5-苯基异恶唑-3’-磺酰基,苯基恶二唑-磺酰基(-sulfone-ODA),2-乙基-5-苯基异恶唑-基,苯基恶二唑基(ODA),恶二唑基,或者与Mitsunobu反应缩合试剂作用产生的中间体。
Y是能够与细胞毒性药物反应形成二硫化物,醚,酯,硫醚,硫酯,肽,腙,氨基甲酸酯,碳酸酯,胺(二级,三级或四级),亚胺,环杂烷基,杂芳基,烷基肟或酰胺键的官能团;优选地,Y具有以下结构:
二硫化物;/>卤代乙酰基;/>酰卤;/>N-羟基琥珀酰亚胺酯基;/>马来酰亚胺基;/>单取代马来酰亚胺基;二取代马来酰亚胺基;/>单取代的琥珀酰亚胺基;/>二取代琥珀酰亚胺基;醛基;/>乙烯基磺酰基;/>丙烯酰基;2-(甲苯磺酰氧基)乙酰基;/>2-(甲磺酰氧基)乙酰基;/>2-(硝基苯氧基)乙酰基;/>2-(二硝基苯基)乙酰基;/>2-(氟代苯氧基)-乙酰基;2-(二氟苯氧基)-乙酰基;/>2-(((三氟甲基)-磺酰)氧基)乙酰基;
其中X1’为F,Cl,Br,I或Lv3;X2’是O,NH,N(R1)或CH2;R3和R5独立地为H,R1,芳基,杂芳基或芳香基团,其中一个或几个H原子被-R1,-卤素,-OR1,-SR1,-NR1R2,-NO2,-S(O)R1,-S(O)2R1,或-COOR1取代;Lv3是下列离去基团:硝基苯氧基,N-琥珀酰亚胺基氧基(NHS),苯氧基;二硝基苯氧基;五氟苯氧基,四氟苯氧基,二氟苯氧基,单氟苯氧基,五氯苯氧基,三氟甲基磺酰基,咪唑基,二氯苯氧基,四氯苯氧基,1-羟基苯并三唑基,甲苯磺酸基,甲磺酸基,2-乙基-5-苯基异恶唑-3’-磺酸基,自身形成,或与其它酸酐形成的酸酐,例如乙酸酐,甲酸酐,或与多肽缩合试剂作用产生的或Mitsunobu反应的中间体。
R1可以缺省,或者可以选自C1-C8(1-8个碳原子)烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或含2-8个碳原子的酯,醚或酰胺;或含有1-8个氨基酸的肽;或具有式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p是0至约1000的整数,或其上述基团的组合。
另外,R1是包含C,N,O,S,Si,和P原子的链状结构,最优含0~500个原子,共价连接于Y和L1。R1中的各个原子以所有可能的化学方式结合,比如形成烷基、亚烷基、亚烯基、亚炔基、醚、聚氧烷基、酯、胺、亚胺、聚胺、肼、腙、酰胺、脲、氨基脲、卡巴肼、烷氧胺、聚氨酯、氨基酸、多肽、酰氧胺、异羟肟酸,或这些基团的组合。
T为CH2,NH,NHNH,N(R3),N(R3)N(R3’),O,S,C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;含有1~4氨基酸单位的肽,优选自天冬氨酸,谷氨酸,精氨酸,组氨酸,赖氨酸,丝氨酸,苏氨酸,天冬酰胺,谷氨酰胺,半胱氨酸,硒代半胱氨酸,酪氨酸,苯丙氨酸,甘氨酸,脯氨酸,色氨酸,丙氨酸;或以下结构之一:
X1,X2,X3,X4,X5,X6,X1’,X2’和X3’独立地选自NHNH;N(R3);N(R3)N(R3’);O;S;C1-C6烷基;C2-C6杂烷基,烷基环烷基,杂环烷基的;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或1~8个氨基酸;其中R3和R3’独立地为H;C1-C8烷基;C2-8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或含1-8个碳原子的酯,醚或酰胺;或具有式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p是0至约1000的整数,或其上述基团的组合。
m1,m2,m3,m4和m5是独立的选自1到10的整数,优选1到4。
L1或L2可以含有自我毁灭或非自我毁灭的组分、肽单元、腙键、二硫化物、酯、肟、酰胺或硫醚键。自我毁灭单元包括但不限于,与对氨基芐基氨甲酰基(PAB)的电子结构相似的芳香化合物,例如2-氨基咪唑-5-甲醇的衍生物、杂环PAB同系物、β-葡糖苷酸、以及邻或对氨基芐基缩醛。
优选的自我毁灭型连接体单元具有以下结构之一:
其中,*标记的是额外的间隔体或可释放的连接体、或细胞毒性剂、和/或结合分子(CBA)的连接点;X1、Y1、Z2和Z3独立地为NH、O或S;Z1为H、NHR1、OR1、SR1、COX1R1,其中X1和R1如前文所定义;v为0或1;U1为H、OH、C1-C6烷基、(OCH2CH2)n、F、Cl、Br、I、OR5、SR5、NR5R5’、N=NR5、N=R5、NO2、SOR5R5’、SO2R5、SO3R5、OSO3R5、PR5R5’、POR5R5’、PO2R5R5’、OPO(OR5)(OR5’)或OCH2PO(OR5(OR5’),其中R5和R5’独立地选自H、C1-C8烷基;C2-C8烯基、炔基、杂烷基或氨基酸;C3-C8芳基、杂环、碳环、环烷基、杂环烷基、杂芳烷基、烷基羰基或糖苷;或药学上的阳离子盐。
非自我毁灭的组分具有以下结构之一:
其中,*标记的是额外的间隔体或可释放的连接体、或细胞毒性剂、和/或结合分子的连接点;X1、Y1、U1、R5、R5’如前文所定义;r为0-100;m和n独立地为0-6;
更优选地,L1或L2可以由下列一个或多个连接体单元组成:
6-马来酰亚胺己酰基(MC),/>马来酰亚胺丙酰基(MP),/>缬氨酸-瓜氨酸(val-cit),丙氨酸-苯丙氨酸(ala-phe),/>赖氨酸-苯丙氨酸(lys-phe),/>对氨基苄氧酰基(PAB),/>4-硫代戊酰基(SPP),/>4-硫代丁酰基(SPDB),/>4-(N-马来酰亚胺甲基)环己烷-1-酰基(MCC),/>马来酰亚胺乙基(ME),/>4-硫代-2-羟基磺酰基-丁酰基(2-Sulfo-SPDB),/>芳基巯基(PySS),/>(4-乙酰基)氨基苯甲酰基(SIAB),/>氧苄硫基,/>氨基苄硫基,/>二氧苄硫基,二氨基苄硫基,/>氨氧基苄硫基,/>烷氧基氨基(AOA),/>亚乙基氧基(EO),/>4-甲基-4-硫代-戊酰基(MPDP),/>三唑,/>二硫,/>烷基磺酰基,/>烷基磺酰胺基,/>砜二磺胺基,/>膦二酰胺,/>烷基膦酰胺,/>膦酸,/>N-甲基烷基膦酰胺,/>N,N’-二甲基磷二酰胺,/>烷基膦二酰胺,/>肼,/>乙脒;肟,/>二乙酰肼,/>氨基乙基胺,氨基乙基-氨基乙基胺,和L-或D-,含有1-20个氨基酸的天然或非天然肽。/>
更为优选的是,L1或L2是可释放的连接体单元。术语“可释放的”是指连接体上包含至少一个可在生理条件下被破坏的键,例如pH、酸、碱、氧化作用、代谢、生化或酶不稳定的键。应当理解,导致键断裂不一定是生物或代谢过程、而可能是一个标准化学反应、例如水解或取代反应,这种生理条件的例子有:pH值比细胞浆内pH低的内涵体,恶性细胞内存在的毫摩尔浓度的大量谷胱甘肽,它能够与细胞内硫醇发生二硫键交换反应。
可释放连接体(L,L1或L2)的实例,包括但不限于:-(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-,-(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t-,-(Aa)r-(CR5R6)m(CR7R8)n(OCH2CH2)t-,-(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t-,-(CR5R6)m-(CR7=CR8)(CR9R10)n(Aa)t(OCH2CH2)r-,-(CR5R6)m(NR11CO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(CO)(Aa)t-(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-(CR5R6)m-(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-(CR5R6)m(CO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-(CR5R6)m-苯基-CO(Aa)t(CR7R8)n-,-(CR5R6)m-呋喃-CO(Aa)t(CR7R8)n-,-(CR5R6)m-恶唑-CO(Aa)t(CR7R8)n-,-(CR5R6)m-噻唑基-CO(Aa)t(CCR7R8)n-,-(CR5R6)t-噻吩-CO(CR7R8)n-,-(CR5R6)t-咪唑-CO-(CR7R8)n-,-(CR5R6)t-吗啉-CO(Aa)t-(CR7R8)n-,-(CR5R6)t哌嗪-CO(Aa)t-(CR7R8)n-,-(CR5R6)t-N-甲基哌嗪-CO(Aa)t-(CR7R8)n-,-(CR5R)m-(Aa)t苯基-,-(CR5R6)m-(Aa)t呋喃-,-(CR5R6)m-恶唑(Aa)t-,-(CR5R6)m-噻唑基(Aa)t-,-(CR5R6)m-噻吩-(Aa)t-,-(CR5R6)m-咪唑(Aa)t-,-(CR5R6)m-吗啉-(Aa)t-,-(CR5R6)m-哌嗪-(Aa)t-,-(CR5R6)m-N-甲基哌嗪-(Aa)t-,-K(CR5R6)m(Aa)r(CR7R8)n(OCH2CH2)t-,-K(CR5R6)m(CR7R8)n(Aa)r(OCH2CH2)t-,-K(Aa)r-(CR5R6)m(CR7R8)n(OCH2CH2)t-,-K(CR5R6)m(CR7R8)n(OCH2CH2)r(Aa)t-,-K(CR5R6)m-(CR7=CR8)(CR9R10)n(Aa)t(OCH2CH2)r-,-K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(Aa)t(NR11CO)(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(OCO)(Aa)t(CR9R10)n-(OCH2CH2)r-,-K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(CO)(Aa)t-(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(NR11CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m-(OCO)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m(OCNR7)(Aa)t(CR9R10)n(OCH2CH2)r-,-K-(CR5R6)m(CO)(Aa)t(CR9R10)n(OCH2CH2)r-,-K(CR5R6)m-苯基-CO(Aa)t(CR7R8)n-,-K-(CR5R6)m-呋喃-CO(Aa)t-(CR7R8)n-,-K(CR5R6)m-恶唑-CO(Aa)t(CR7R8)n-,-K(CR5R6)m-噻唑基-CO(Aa)t-(CR7R8)n-,-K(CR5R6)t-噻吩-CO(CR7R8)n-,-K(CR5R6)t咪唑-CO-(CR7R8)n-,-K(CR5R6)t吗啉-CO(Aa)t(CR7R8)n-,-K(CR5R6)t哌嗪-CO(Aa)t-(CR7R8)n-,-K(CR5R6)t-N-甲基哌嗪CO(Aa)t(CR7R8)n-,-K(CR5R)m(Aa)t苯基,-K-(CR5R6)m-(Aa)t呋喃-,-K(CR5R6)m-恶唑(Aa)t-,-K(CR5R6)m-噻唑基(Aa)t-,-K(CR5R6)m-噻吩-(Aa)t-,-K(CR5R6)m-咪唑(Aa)t-,-K(CR5R6)m-吗啉(Aa)t-,-K(CR5R6)m-哌嗪-(Aa)tG,-K(CR5R6)mN-甲基哌嗪(Aa)t-;其中m,Aa,m,n,R3,R4,和R5已如上所定义;t和r独立地为0-100;R6,R7和R8独立地选自H,卤素,C1-C8烷基、芳基、烯基、炔基、醚、酯、胺或酰胺,这些基团均可以被以下成分所取代:一个或多个卤素、CN、NR1R2、CF3、OR1、芳基、杂环、S(O)R1、SO2R1、-CO2H、-SO3H、-OR1、-CO2R1、-CONR1、-PO2R1R2、-PO3H或P(O)R1R2R3;K是NR1、-SS-、-C(=O)-、-C(=O)NH-、-C(=O)O-、-C=NH-O-、-C=N-NH-、-C(=O)NH-NH-、O、S、Se、B、C3-C8的杂环或杂芳环,或含有1-20个氨基酸的肽。
另外,L1,L2,X1,X2,X3,X1’,X2’和X3’可以独立地缺省。
在式(I)或(II)中,取代的丙烯酰基团或丙炔酰基团能够与巯基反应,优选与细胞结合剂上的一对巯基反应;该优选的巯基是通过还原细胞结合剂链间二硫键所得,还原剂如二硫苏糖醇(DTT),二硫赤藓糖醇(DTE),L-谷胱甘肽(GSH),三(2-羧乙基)膦(TCEP),2-巯基乙胺(β-MEA),和/或β巯基乙醇(β-ME,2-ME)。
能够连接药物或细胞毒性剂的官能团Y的实例,包括能够产生二硫化物,硫醚,硫酯,肽,腙,酯,氨基甲酸酯,碳酸酯,烷氧肟或酰胺键连接的基团。这些官能团包括但不限于巯基,二硫化物,氨基,羧基,醛,酮,马来酰亚胺基,卤代乙酰基,肼,烷氧基氨基和/或羟基。
能够与药物/细胞毒性剂的末端胺反应的官能团Y的实例,包括但不限于N-羟基琥珀酰亚胺酯,对硝基苯酯,二硝基苯酯,五氟苯酯,酰氯或羧酸酐;能与末端巯基反应的官能团,包括但不限于,吡啶基二硫化物,硝基吡啶基二硫化物,马来酰亚胺,卤代乙酸酯,甲基砜苯基恶二唑(ODA),酰氯和羧酸酐;能与末端酮或醛反应的官能团,包括但不限于,胺,烷氧基胺,肼,酰氧基胺或酰肼;能与末端叠氮反应的官能团,包括但不限于炔烃。
在优选的实施例中,R1,L1,或L2独立地为含1-6个碳原子的直链烷基,或如式(OCH2CH2)p的聚乙烯氧基单元,p=1~100,或含有1~4个氨基酸的肽(L或D构型),或以上组合。
在优选的实施例中,Lv1和Lv2相同或独立地为OH,F,Cl,Br,I,硝基苯氧基,N-羟基琥珀酰亚胺(NHS)基,苯氧基,二硝基苯氧基,五氟苯氧基,四氟苯氧基,二氟苯氧基,单氟苯氧基,五氯苯氧基,三氟甲磺酰基,咪唑,二氯苯氧基,四氯苯氧基,1-羟基苯并三唑,甲苯磺酰基,甲磺酰基,2-乙基-5-苯基异恶唑-3’-磺酰基,或多肽缩合反应中间体或Mitsunobu反应中间体;缩合剂的例子包括:1-乙基-(3-二甲基氨基丙基)碳二亚胺(EDC)、二环己基碳二亚胺(DCC)、N,N’-二异丙基碳二亚胺(DIC)、N-环己基-N’-(2-吗啉代-乙基)碳二亚胺甲基对甲苯磺酸盐(CMC或CME-CDI)、1,1’-羰基二咪唑(CDI)、氧-(苯并三唑-1-)基)-N,N,N’,N’-四甲基脲四氟硼酸盐(TBTU)、N,N,N’,N’-四甲基-氧-(1H-苯并三唑-1-基)-六氟磷酸铵(HBTU)、(苯并三唑-1-基氧基)三(二甲基氨基)-六氟磷酸盐(BOP)、(苯并三唑-1-基氧基)三吡咯烷基六氟磷酸盐(PyBOP)、氰基膦酸二乙酯(DEPC)、氯-N,N,N’,N’-四甲基甲脒六氟磷酸盐、1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶3-氧六氟磷酸盐(HATU)、1-[(二甲氨基)(吗啉代)亚甲基]-1H-[1,2,3]三唑并[4,5-b]吡啶-1-鎓3-氧六氟磷酸盐(HDMA)、2-氯-1,3-二甲基-咪唑六氟磷酸盐(CIP)、六氟磷酸氯代吡咯烷酮鎓(PyCloP)、氟-N,N,N’,N’-双(四亚甲基)甲脒六氟磷酸盐(BTFFH)、N,N,N’,N’-四甲基-S-(1-氧代-2-吡啶基)硫脲六氟磷酸盐、氧-(2-氧代-1(2H)吡啶基)-N,N,N’,N’-四甲基脲四氟硼酸盐(TPTU)、S-(1-氧代-2-吡啶基)N,N,N’,N’-四甲基硫脲四氟硼酸盐、氧-[(乙氧基羰基)-氰基甲基氨基]-N,N,N’,N’-六氟磷酸四甲基脲(HOTU)、(1-氰基-2-乙氧基-2-氧代乙基氨基氧基)二甲氨基-吗啉代-六氟磷酸盐(COMU)、氧-(苯并三唑-1-基)-N,N,N’,N’-双(四亚甲基)六氟磷酸盐(HBPyU)、N-芐基-N’-环己基-碳二亚胺(有或没有聚合物结合)、二吡咯烷基(N-琥珀酰亚胺基氧基)碳鎓六氟磷酸盐(HSPyU)、氯二吡咯烷基六氟磷酸盐(PyClU)、2-氯-1,3-二甲基咪唑四氟硼酸盐(CIB)、(苯并三唑-1-基氧基)二呱啶碳六氟磷酸盐(HBPipU)、氧-(6-氯苯并三唑-1-基)-N,N,N’,N’-四甲基脲四氟硼酸盐(TCTU)、溴代(二甲基氨基)-六氟磷酸盐(BroP)、丙基膦酸酐(PPACA、 )、2-吗啉代乙基异氰化物(MEI)、N,N,N’,N’-四甲基-氧-(N-琥珀酰亚胺基)六氟磷酸盐(HSTU)、2-溴-1-乙基-吡啶鎓四氟硼酸盐(BEP)、氧-[(乙氧基羰基)氰基-亚甲基氨基]-N,N,N’,N’-四甲基脲四氟硼酸盐(TOTU)、4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉氯化物(MMTM、DMTMM)、N,N,N’,N’-四甲基-氧-(N-琥珀酰亚胺基)脲四氟硼酸(TSTU)、氧-(3,4-二氢-4-氧代-1,2,3-苯并三嗪-3-基)-N,N,N’,N’-四甲基脲四氟硼酸盐(TDBTU)、1,1’-(偶氮二羰基)-二呱啶(ADD)、二-(4-氯芐基)偶氮二羧酸酯(DCAD)、偶氮二羧酸二叔丁酯(DBAD)、偶氮二羧酸二异丙酯(DIAD)、偶氮二羧酸二乙酯(DEAD)。另外,Lv1和Lv2可以是酸酐,由酸本身形成或与其它C1-C8酸酐形成。
在优选的实施例中,式(I)或(II)具有以下结构:
连接体合成的详细实例如图1~33所示。通常丙炔酰基、取代的丙烯酰基或二取代的丙酰基上的取代基,可以与其它连接体单元反应,该组分含有能够与药物反应的官能团。
细胞结合剂-药物偶联物
本发明的偶联物可由式(III),(IV),(V),(VI),(VII),(VIII)或(IX)表示:
其中:
n是1~20;T与之前式(I)中描述的相同。
Cb,Cb’,Cb”,Cb”’表示相同或不同的细胞结合剂或免疫治疗蛋白,优选为抗体或抗体片段。
式(III),(VII),(VIII)和(IX)的右括号(方括号)内是与细胞结合剂/分子的巯基对偶联的连接体-药物组分。巯基优选为细胞结合剂的链间二硫键被还原剂还原而产生,还原剂选自二硫苏糖醇(DTT)、二硫季戊四醇(DTE)、L-谷胱甘肽(GSH)、三(2-羧基乙基)膦(TCEP)、2-巯基乙胺(β-MEA)或/和β-巯基乙醇(β-ME,2-ME)。
Drug,Drug’,和Drug”表示相同或不同的细胞毒性剂,或治疗药物,或免疫治疗蛋白质,或用于增强细胞结合剂的结合或稳定的功能分子,或者细胞表面受体结合配体,其应用本专利申请的桥接剂,经由R1与细胞结合剂连接,R1含有C1-C8烷基;C2-C8亚烷基,亚烯基,亚炔基,芳基,醚,聚氧亚烷基,酯,胺,亚胺,多胺,肼,腙,酰胺,脲,氨基脲,卡巴肼,烷氧基胺,氨基甲酸,氨基酸,肽,酰氧基胺,异羟肟酸,二硫化物,硫醚,硫酯,氨基甲酸酯,碳酸酯,杂环,杂烷基,杂芳基,烷氧基或上述基团组合。
Drug,Drug’,和Drug”还可以是细胞毒性分子,免疫治疗化合物,化学治疗化合物,抗体或抗体片段,siRNA或DNA分子,或细胞表面结合配体。
方括号内是通过细胞结合分子上的一对硫原子与细胞结合分子偶联的试剂。
m1,m1’,m1”,m2,m2’,m2”,m3,m4,m5,m4’,m5’,m4”,m5”,m4”’,m5”’,m4””和m5””独立地是1到10的整数,优选1到4的整数。
X1,X1’,X1”,X1”’和X2””独立地选自NH;NHNH;N(R3);N(R3)N(R3’);O;S;C1-C6烷基;C2-C6杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基,杂环,碳环,环烷基,杂烷基环烷基,烷基羰基,杂芳基;或1~8个氨基酸;其中R3和R3’独立地为H;C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、杂芳基;1-8个碳原子的酯、醚或酰胺;或如式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p为从0到1000的整数;或以上的组合。此外,X1,X1’,X1”,X1”’和X2””可以独立地缺省。
R1,R1’,和R1”相同或不同,选自C1-C8烷基;C2-C8杂烷基,烷基环烷基,杂环烷基;C3-C8芳基,Ar-烷基、杂环、碳环、环烷基、杂烷基环烷基、烷基羰基、杂芳基;2-8个碳原子的酯、醚或酰胺;或如式(OCH2CH2)p或(OCH2CH(CH3))p的聚乙烯氧基单元,其中p为从0到1000的整数;或以上的组合。
L1,L1’,L1”,L1”’,L2,L2’,L2”和L2”’的定义与式(I)和(II)中的L1和L2相同,它们也可以各不相同。
L1,L1’,L1”,L1”’,L2,L2’,L2”和L2”’可以由一个或者多个连接体单元组成。示例的连接体单元包括6-马来酰亚胺基己酰基(“MC”),马来酰亚胺丙酰基(“MP”),缬氨酸-瓜氨酸(“val-cit”或“vc”),丙氨酸-苯丙氨酸(“ala-phe”或“af”),对氨基苄氧基酰基(“PAB”),4-硫代戊酰基(“SPP”),4-(N-马来酰亚胺甲基)环己烷-1酰基(“MCC”),(4-乙酰基)氨基-苯酰基(“SIAB”),4-硫代丁酰基(“SPDB”),4-硫代-2-羟基磺酰基-丁酰基(“2-磺基-SPDB”),作为一个或多个重复乙烯氧基-CH2C水-单元(“EO”或“PEO”)。其它的连接体单元是本领域公知的,部分示例如下:
包含连接体单元的结构例子:
(ME,含马来酰亚胺基),/>(含缬氨酸瓜氨酸),/>(MCC,含有4-(N-马来酰亚胺基甲基)环己烷-1-酰基),含((4-乙酰基)氨基苯甲酰基)/>(4-硫代-2-羟基磺酰基丁酰基,2-sulfo-SPDB),/>4-硫代戊酰基(SPP),/>4-硫代丁酰基(SPDB),/>4-(N-马来酰亚胺甲基)环己烷-1-酰基(MCC),/>马来酰亚胺乙基(ME),/>4-硫代-2-羟基磺酰基-丁酰基(2-Sulfo-SPDB),/>芳基巯基(PySS),/>(4-乙酰基)氨基苯甲酰基(SIAB),/>氧苄硫基,/>氨基苄硫基,/>二氧苄硫基,/>二氨基苄硫基,氨氧基苄硫基,/>烷氧基氨基(AOA),/>亚乙基氧基(EO),/>4-甲基-4-硫代-戊酰基(MPDP),/>三唑,二硫,/>烷基磺酰基,/>烷基磺酰胺基,/>砜二磺胺基,/>膦二酰胺基,/>烷基膦酰胺基,/>膦酸基,/>N-甲基烷基膦酰胺基,/>N,N’-二甲基磷二酰胺基,烷基膦二酰胺基,/>肼基,/>乙脒基;/>肟基,/>二乙酰肼基,/>氨基乙基胺基,/>氨基乙基-氨基乙基胺基。
见下文更详细的描述,Drug,Drug’和Drug”可以是任何小分子药物,包括但不限于,tubulysin,卡奇霉素、澳瑞他汀,美登素,CC-1065同系物,吗啉代,阿霉素,紫杉烷类,隐藻菌素,鹅膏毒肽(鹅膏毒环肽),埃博霉素,布林,格尔德霉素,多卡霉素,道诺霉素,甲氨蝶呤,长春地辛,长春新碱和苯并二氮卓系列二聚体(例如,吡咯苯并二氮卓(PBD)或托马霉素,吲哚苯并二氮卓,咪唑苯并二氮卓或噁唑苯并二氮卓二聚体)。
通常,式(III),(IV),(V)(VI),(VII),(VIII)和(IX)中的偶联物由式(I)和(II)中的化合物制备,其中“Drug”和“Cb”与式(I)和(II)中的化合物分别或同时反应。当两个以上的巯基和取代的丙烯酰基团或丙炔酰基团加成反应,形成式(III),(IV),(V)或(VI)中的偶联物时,需要使用波长范围为190-390nm的紫外光以辅助反应,优选使用340-380nm,更优选365nm。光化学反应在石英或Pyrex烧瓶或在控温的含有UV灯的浸入式井反应器中进行,优选在连续流的石英管中或Pyrex管中进行,其UV辐射最大且同时可以有效冷却,降低了细胞结合分子因热产生的不稳定。在式(VII)(VIII)或(IX)中偶联物的形成过程中,当两个以上的巯基与式(I)和(II)中两个或更多个取代的丙烯酰基团或丙炔酰基团反应时,可不使用UV光。
合成偶联物时,首先使药物或细胞毒性分子在化学溶剂或水性介质中与式(I)或(II)的连接体反应,生成式(XVII)或(XVIII)。(XVII)或(XVIII)可以被分离,也可以立即或同时或依次地在25-38℃,pH 5~9水性介质中,与细胞结合分子上还原二硫键产生的一对游离巯基反应,反应介质中可添加或不添加0~30%可溶于水(混溶)的有机溶剂,例如DMA,DMF,乙醇,甲醇,丙酮,乙腈,四氢呋喃,异丙醇,二恶烷,丙二醇或乙二醇,生成(III),(IV),(V)或(VI),此时优选需要使用365nm的UV光辅助,或形成(VII),(VIII)或(IX),此时可不使用UV光。
或者,式(III),(IV),(V)(VI),(VII),(VIII)和(IX)中的偶联物也可以首先使式(I)或(II)中的连接体在0-38℃、pH5~9水介质中与细胞结合剂上的一对巯基反应,可加或不加0~30%可溶于水(混溶)的有机溶剂,在365nm的UV光照下,形成如式(X),(XI),(XII)或(XIII)的修饰的细胞结合分子,或可选的,无UV光照下,形成如式(XIV),(XV)或(XVI)的修饰的细胞结合分子。成对的巯基优选为使用还原剂将细胞结合剂的链间二硫键还原所产生,所述还原剂可以选自二硫苏糖醇(DTT),二硫赤藓糖醇(DTE),L-谷胱甘肽(GSH),三(2-羧乙基)膦(TCEP),2-巯基乙胺(β-MEA),或/和β巯基乙醇(β-ME,2-ME),反应在pH4~9水中进行,可加入或不加入0~30%的可溶于水(混溶)的有机溶剂。
式(X),(XI),(XII),(XIII),(XIV),(XV)or(XVI)中的反应性基团Y,可以是二硫化物,马来酰亚胺基,卤代乙酰基,叠氮化物,1-炔,酮,醛,烷氧基氨基,三氟甲磺酸酯,羰基咪唑,甲苯磺酸酯,甲磺酸酯,2-乙基-5-苯基异恶唑-3’-磺酸酯,或硝基苯酚,N-羟基琥珀酰亚胺(NHS),苯酚;二硝基苯酚,五氟苯酚,四氟苯酚,二氟苯酚,单氟苯酚,五氯苯酚,二氯苯酚,四氯苯酚和1-羟基苯并三唑的羧酸酯,酸酐或酰肼基团,或其它酸的衍生物,可以与药物/细胞毒性剂Drug,Drug’或Drug”同时或依次反应,反应在15-38℃,pH 4~9.5水性介质中进行,可加入或不加入另外的0~30%可溶于水(混溶)的有机溶剂,纯化后得到(III),(IV),(V)(VI),(VII),(VIII)和(IX)。
细胞毒性分子的反应基团可以与被修饰的细胞结合剂以不同的方式反应。例如,通过二硫键连接的细胞结合剂-药物偶联物的合成,是通过修饰的细胞结合剂中的二硫键和含有游离巯基的药物之间的二硫键交换来实现的;通过硫醚键结合的细胞结合子-药物偶联物的合成,是通过经马来酰亚胺基或卤乙酰基或乙基砜修饰的细胞结合剂和含游离巯基的药物反应来实现;合成分子内含酸不稳定的腙的偶联物,可由一个连接体中的酰肼基团和羰基反应来实现,其具体方法为本领域内公知(参考P.Hamann et al.,Hinman,L.M.,et al,Cancer Res.1993,53,3336-334;B.Laguzza et al.,J.Med.Chem.,1959,32;548-555;P.Trail et al.,Cancer Res.,1997,57;100-105);合成含三唑基团的偶联物可以通过一个连接体上的1-炔与含叠氮基团的药物以点击化学反应(偶极环加成)来实现(Lutz,J-F.et al,Adv.Drug Del.Rev.2008,60,958–970;Sletten,E.M.et alAcc.Chem.Research 2011,44,666–676);合成含肟偶联物可以通过含有酮或醛的修饰的细胞结合剂和含有氧胺基的药物的反应来实现。
包含巯基的药物可以和(X),(XI),(XII),(XIII),(XIV),(XV)或(XVI)中连接体上的马来酰亚胺、卤乙酰基或乙磺酰基,在pH 5.0-9.0的缓冲液中反应,生成硫醚键连接的共轭偶联物。含巯基的药物可以与(X),(XI),(XII),(XIII),(XIV),(XV)或(XVI)中连接体上的吡啶二硫片段进行二硫键交换,生成二硫键连接的共轭偶联物。含有羟基或巯基的药物可与(X),(XI),(XII),(XIII),(XIV),(XV)或(XVI)中连接体上的卤素,尤其是α卤代羧酸上的卤素,在弱碱条件下,如pH值8.0-9.5,反应得到醚或硫醚键连接的共轭偶联物。含羟基的药物,也可以在EDC或DCC的缩合剂的作用下,和式(I)或(II)中连接体上的羧基缩合成酯。经药物修饰的连接体再与细胞结合分子进行偶联。含有氨基的药物可以和(X),(XI),(XII),(XIII),(XIV),(XV)或(XVI)中连接体上的NHS、咪唑、硝基苯酚、N-羟基丁二酰亚胺、苯酚、二硝基苯酚、五氟苯酚、2,3,5,6-四氟苯酚、二氟苯酚、单氟苯酚、五氯苯酚、三氟甲烷磺酸、二氯苯酚、四氯苯酚、1-羟基苯并三唑、甲苯磺酸、甲磺酸、2-乙基-5-苯基异恶唑-3’-磺酸的羧酸酯反应,得到酰胺键连接的共轭偶联物。
偶联物可以通过标准的生化方法纯化,如用Sephadex G25或Sephacryl S300进行凝胶过滤、吸附层析、离子交换或透析。在某些情形,如小分子细胞结合剂(如叶酸、黑素细胞刺激素、EGF等)与小分子药物结合后,可以通过HPLC、中压柱层析或离子交换色谱等色谱法纯化。
优选的实施例中,(III),(IV),(V),(VI),(VII),(VIII)或(IX)为下列结构:
修饰的细胞结合剂/分子
与本发明中的连接体反应而得到的修饰的细胞结合剂由式(X),(XI),(XII),(XIII),(XIV),(XV)或(XVI)表示:
其中R1,R1’,R1”,R2,X1,X1’,X1”,L1,L1’,L1”,L2,L2’,L2”,Cb,m1,m1’,m1”,m2,m2’,m2”,m3,m4,m5,m4’,m5’,m4”,和m5”的定义与式(III)–(IX)中相同。
其中Y,Y’,和Y”的定义与式(I)和(II)中的Y相同。
在优选的实施例中,Y,Y’和Y”独立地是二硫化物,马来酰亚胺基,卤代乙酰基,烷氧基胺,叠氮基,酮,醛,肼,炔烃,N-羟基琥珀酰亚胺酯,或苯酚,二硝基苯酚,五氟苯酚,四氟苯酚,二氟苯酚,单氟苯酚,五氯苯酚,咪唑,氯酚,四氯苯酚,1-羟基苯并三唑形成的羧基酯;甲苯磺酸酯;甲磺酸酯;三氟甲磺酸酯;2-乙基-5-苯基异恶唑-3’-磺酸酯。Y,Y’和Y”可以独立地与细胞毒性剂反应,形成二硫化物,硫醚,腙,酰胺,烷氧基,氨基甲酸酯,酯,醚键或杂芳环。修饰的细胞结合剂可以通过细胞结合剂与式(I)或(II)的连接体的反应来制备。
为了实现结构式(I)或(II)中连接体上取代丙烯酰或丙炔酰与细胞结合剂,尤其是抗体中游离的一对巯基的高效连接,需要在反应体系中或反应完成后,加入少量有机共溶剂以使得式(III)~(IX)中的结构在水中良好溶解。在修饰细胞结合剂时,首先把结构式(I)或(II)中的交联剂(连接体)溶解在可以与水混溶的极性有机溶剂中,例如:各种醇如甲醇、乙醇和丙醇,丙酮,乙腈,四氢呋喃(THF),1,4-二氧六环,二甲基甲酰胺(DMF),二甲基乙酰胺(DMA)或二甲基亚砜(DMSO);溶液浓度略高,如1-500mM。同时将细胞结合剂,如抗体以1~35mg/mL的浓度溶解在pH 4~9.5,最好6~8.5的缓冲液中,与1~20当量的TCEP或者DTT反应20分钟到48小时。还原后,用SEC色谱柱纯化除去DTT,TCEP可以用SEC色谱柱纯化或者不纯化直接进入下一步。此外,用TCEP还原的抗体或其他细胞结合剂可以在结构式(I)或(II)的连接体存在的情形下进行,此时与细胞结合剂的共轭偶联就和TCEP还原同步进行。如前文所述,式(X),(XI),(XII)或(XIII)的修饰的细胞结合分子的合成需要340-380nm的UV光辅助。但是式(XIV),(XV)或(XVI)的修饰的细胞结合分子的合成可选不用UV光的辅助。
修饰细胞结合剂的反应一般在pH 4至9,优选6.0至7.5的缓冲液里进行,可以是该pH范围内的任何没有亲核性的缓冲盐体系。典型的缓冲液包括磷酸盐、三乙醇胺盐酸盐,HEPES,和MOPS缓冲液,可以包含其它成分,如环糊精,蔗糖和盐,如氯化钠和氯化钾。将结构式(I)或(II)中的连接体溶液加入到被还原的细胞结合剂溶液中,并在4至45℃,最好是15℃-室温孵育,并通过测量溶液在254nm吸光度的下降,或者在280nm吸光度的上升,或者其他合适的波长上吸光度的变化,来监测反应的进程。在反应完成后,可以按照常规方法纯化修饰的细胞结合剂,例如使用凝胶过滤层析或吸附色谱法。
通过测量反应产生的硝基吡啶硫酮、二硝基吡啶二硫酮、吡啶硫酮、甲酰胺吡啶二硫酮和二甲酰胺吡啶二硫酮基团的紫外吸光,可以确定细胞结合剂被修饰的程度。如果偶联物没有发色团,可以用LC-MS或者更优选的UPLC-QTOF质谱,或毛细管电泳质谱(CE-MS)来分析确定。本发明中的连接体上可以含有不同种类的官能团,与各种药物反应,尤其是具有合适的取代官能团的细胞毒性药物。例如,修饰后含氨基或羟基取代基的细胞结合剂能与含N-羟基琥珀酰亚胺(NHS)酯的药物反应,修饰后含巯基的细胞结合剂能与含马来酰亚胺基或卤素乙酰基的药物反应。此外,修改后含羰基(醛或酮基)的细胞结合剂能与含酰肼或烷氧基胺的药物反应。本领域的专业技术人员可以很容易地根据其官能团的反应活性来决定使用怎样的连接体。
修饰的细胞毒性药物
通过与本发明申请的交联连接体反应而得到的修饰的细胞毒性药物,由式(XVII)和(XVIII)表示,“Drug”已与式(I)和(II)中的连接体反应,其中仍然包含取代的丙烯酰基或丙炔酰基,能够与细胞结合剂中的一对巯基反应:
通过药物分子与结构式(I)或(II)中的连接体反应,得到具有结构(XVII)和(XVIII)的修饰的药物,其中含有取代的丙烯酰基或丙炔酰基。但是对于含有巯基的药物,或者通过含硫醚、硫酯或二硫键连接细胞结合分子的药物,药物Drug最好首先通过硫醚、硫酯或二硫键与R1连接,然后将合成的R1-Drug与取代的丙烯酰基或丙炔酰基组装,形成连接体修饰的药物(XVII)和(XVIII)。
例如,含巯基的药物可在中性pH的缓冲液中与R1上的马来酰亚胺反应,形成以硫醚键结合的R1-Drug,然后与连接有取代的丙烯酰基或丙炔酰基的组分缩合,形成如式(XVII)和(XVIII)中包含硫醚键的修饰药物。含羟基的药物,在弱碱条件下,可与含有卤素、对甲苯磺酸或甲磺酸酯的R1反应,得到以醚键结合R1-Drug,然后与连接有取代的丙烯酰基或丙炔酰基的组分缩合,形成如式(XVII)和(XVIII)中包含硫醚键的修饰药物。含有羟基的药物还可与结构(I)中带有羧基的连接体,在脱水剂如EDC或DCC作用下,缩合得到如结构式(XVII)和(XVIII)中含酯键的修饰药物。含巯基的药物可与R1上的马来酰亚胺、乙烯砜基或卤代乙酰基反应,生成以硫醚键结合的R1-Drug,然后与连接有取代的丙烯酰基或丙炔酰基的组分缩合,形成如式(XVII)和(XVIII)中包含硫醚键的修饰药物。类似地,含氨基的药物也可以与连接体(I)或(II)上的羧基进行缩合,得到如式(XVII)和(XVIII)中含酰胺键的修饰药物。修饰的药物可以用标准的方法纯化,如硅胶或氧化铝柱层析、重结晶、制备薄层色谱、离子交换色谱或高效液相色谱。
在优选的实施例中,式(XVII)或(XVIII)中的化合物具有以下结构:
其中Lv1和Lv2与式(I)中定义相同;L1,L2,L3,L4,L5,L6,L7和L8相同或不同,并且与式(I)中的L1的定义相同;Drug1,Drug2,Drug3,Drug4,Drug5,Drug6,Drug7和Drug8相同或不同,并且与式(II)中的Drug1的定义相同。
细胞结合剂
本发明中的细胞结合剂,包括偶联物内和被修饰的细胞结合剂,可以是目前已知的或即将公开的,能够与具有治疗意义或者被生物学修饰的细胞片段结合,复合或反应的任何种类分子。
细胞结合剂包括,但不仅限于大分子量蛋白质,例如完整抗体(多克隆抗体,单克隆抗体,二聚体,多聚体,多特异性抗体,例如双特异性抗体);单链抗体;抗体片段如Fab,Fab’,F(ab’)2,Fv(Parham,J.Immunol.1983,131,2895-2902);由Fab表达库产生的片段,抗独特型(抗-Id)抗体;CDR;双价抗体;三价抗体;四价抗体;微抗体;小分子免疫蛋白(SIP)和免疫特异性结合癌细胞抗原的上述任何抗体的表位结合片段;病毒抗原;微生物抗原或由免疫系统产生的蛋白质,能够识别、结合特定抗原或具有期望的生物学活性(Miller et alJ.of Immunology 2003,170,4854-4861);干扰素(如I,II,III型);多肽;淋巴因子如IL-2,IL-3,IL-4,IL-5,IL-6,IL-10,GM-CSF,干扰素-γ(IFN-γ);激素例如胰岛素,TRH(促甲状腺激素释放激素),MSH(促黑色素细胞激素),类固醇激素如雄激素和雌激素;生长因子和集落刺激因子,如表皮生长因子(EGF),粒细胞巨噬细胞集落刺激因子(GM-CSF),转化生长因子(TGF)如TGFα,TGFβ,胰岛素和胰岛素样生长因子(IGF-I,IGF-II),G-CSF,M-CSF和GM-CSF(Burgess,Immunology Today 1984,5,155-158);牛痘生长因子(VGF);成纤维细胞生长因子(FGF);小分子量的蛋白质;多肽;肽和肽激素,如铃蟾肽,胃泌素,胃泌素释放肽;血小板衍生的生长因子;白细胞介素和细胞因子,例如,白细胞介素-2(IL-2),白细胞介素-6(IL-6),白血病抑制因子,粒细胞巨噬细胞集落刺激因子(GM-CSF);维生素,如叶酸;脱辅基蛋白和糖蛋白,如转铁蛋白(O’Keefe et al,J.Biol.Chem.1985260932-937);糖结合蛋白或脂蛋白,如凝集素;细胞营养传递分子;小分子抑制剂,如前列腺特异性膜抗原(PSMA)抑制剂和小分子酪氨酸激酶抑制剂(TKI),非肽或任何其它细胞结合分子或物质,如生物活性聚合物(Dhar,et al,Proc.Natl.Acad.Sci.2008,105,17356-61),生物活性树枝状大分子(Lee,et al,Nat.Biotechnol.2005,23,1517-26;Almutairi,et al;Proc.Natl.Acad.Sci.2009,106,685-90),纳米粒子(Liong,et al,ACS Nano,2008,19,1309-12;Medarova,et al,Nat.Med.2007,13,372-7;Javier,et al,Bioconjugate Chem.2008,19,1309-12),脂质体(Medinai,et al,Curr.Phar.Des.2004,10,2981-9)和病毒外壳(Flenniken,et al,Viruses Nanotechnol.2009,327,71-93)。
一般而言,如果适当的单克隆抗体是可用的,则优选单克隆抗体作为细胞表面结合剂。抗体可以是鼠源,人源,人源化,嵌合或源于其他物种。
用于本发明中的抗体的生产包括体内或体外方法或其组合。生产多克隆抗受体肽抗体的方法在本领域是公知的,例如美国专利4,493,795中所述。通常是通过将骨髓瘤细胞,与已经用所需抗原免疫的小鼠的脾细胞融合,来制备单克隆抗体(G.;Milstein,C.Nature 1975,256:495-497)。详细的过程在“Antibodies--A Laboratory Manual,Harlow and Lane,eds.,Cold Spring Harbor Laboratory Press,New York(1988)”中有描述,此处引作参考。具体地,可以用目标抗原,如完整的靶细胞,从靶细胞分离的抗原,完整的病毒,灭活的全病毒和病毒蛋白质,免疫小鼠,大鼠,仓鼠或任何其它哺乳动物。通常使用聚乙二醇(PEG)6000将脾细胞与骨髓瘤细胞融合。通过对HAT(次黄嘌呤-氨基蝶呤-胸腺嘧啶)的敏感性来筛选融合细胞。通过它们免疫反应特异性受体的能力或抑制靶细胞上的受体活性的能力,可以确定实施本发明的单克隆抗体的杂交瘤。
用于本发明中的单克隆抗体的生产在单克隆杂交瘤培养物里进行,其中包含营养培养基和能分泌具有合适抗原特异性的抗体分子的杂交瘤。培养物在合适的条件下保持充足的一段时间,以使杂交瘤将抗体分子分泌到培养基。然后收集含有抗体的培养基。使用通过公知的技术进一步分离抗体分子,如蛋白质A亲和层析,阴离子、阳离子、疏水或体积排阻色谱法(特别是通过蛋白质A亲和层析和体积排阻色谱法),离心,差异溶解度或任何其他纯化蛋白质的标准技术。
培养物里的培养基在本领域中是公知的,并且可商业获得,也包括合成培养基。一个合成的培养基的例子是Dulbecco最少必需培养基(DMEM;Dulbecco et al.,Virol.1959,8,396)补充有4.5g/ml葡萄糖,0-20mM谷氨酰胺,0-20%胎牛血清,几个ppm的Cu,Mn,Fe或Zn等重金属或/和重金属盐,以及消泡剂如聚氧乙烯-聚氧丙烯嵌段共聚物。
另外,生产抗体的细胞系也可以通过融合以外的技术来获得,例如将成瘤DNA转化至B淋巴细胞,或成瘤病毒转染,如爱泼斯坦-巴尔病毒(EBV,也称为人类疱疹病毒4(HHV-4))或卡波西肉瘤相关疱疹病毒(KSHV),见于美国专利4,341,761;4,399,121;4,427,783;4,444,887;4,451,570;4,466,917;4,472,500;4,491,632;4,493,890。单克隆抗体也可以通过含末端羧基的抗受体肽或肽制备,这些都为如本领域所公知,可参考文献Niman etal.,Proc.Natl.Acad.Sci.USA,1983,80:4949-4953;Geysen et al.,Proc.Natl.Acad.Sci.USA,1985,82:178-182;Lei et al.Biochemistry 1995,34(20):6675-6688。通常,抗受体肽或肽同系物作为产生抗受体肽单克隆抗体免疫原,可以单独使用或与免疫原性载体连接。
用作本发明中结合分子的单克隆抗体也可以通过其他本领域已知的技术获得。特别有用的是制造完整人源抗体的方法。一种方法是噬菌体显示技术,它使用亲和富集的方式,可用于选择能与抗原特异性结合的人源抗体。噬菌体展示技术在文献中也有详细描述,噬菌体展示库的构建和筛选在本领域也是众所周知的,可参考文献Dente et al,Gene.1994,148(1):7-13;Little et al,Biotechnol Adv.1994,12(3):539-55;Clacksonet al.,Nature 1991,352:264-628;Huse et al.,Science 1989,246:1275-1281。
通过与非人如小鼠细胞融合的杂交瘤产生的单克隆抗体,可以被人源化以避免产生人类抗小鼠抗体。常见的抗体人源化方法是互补决定区移植技术,这些方法也已被详细地描述,如美国专利5,859,205和6,797,492;Liu et al,Immunol Rev.2008,222:9-27;Almagro et al,Front Biosci.2008,13:1619-33;Lazar et al,MolImmunol.2007,44(8):1986-98;Li et al,Proc.Natl.Acad.Sci.U S A.2006,103(10):3557-62,此处引为参考。完整人抗体也可以通过用免疫原免疫携带大部分的人类球蛋白重轻链的转基因小鼠、兔子、猴子或其他哺乳动物来制备。这些老鼠的例子有:Xenomouse(Abgenix/Amgen),HuMAb-Mouse(Medarex/BMS)和VelociMouse(Regeneron),参考美国专利6596541,6207418,6150584,6111166,6075181,5922545,5661016,5545806,5436149和5569825。用于人类治疗时,小鼠的可变区域和人的恒定区域也可以被融合,成为“嵌合抗体”,它在人类身上的免疫原性显著低于小鼠单抗(Kipriyanov et al,MolBiotechnol.2004,26:39-60;Houdebine,CurrOpinBiotechnol.2002,13:625-9)。另外,在抗体可变区域的定点诱变能导致抗体具有较高的亲和性和特异性(Brannigan et al,Nat Rev Mol Cell Biol.2002,3:964-70;Adams et al,J Immunol Methods.1999,231:249-60),抗体恒定区域的改变可以提高其介导结合和细胞毒性的效应功能。
恶性细胞抗原的免疫特异性抗体也可以从商业途径获得或通过任何已知方法生产,例如化学合成或重组表达技术。对恶性细胞抗原具有免疫特异性的抗体的核苷酸序列编码可以商业获得,例如从GenBank数据库或类似数据库,文献出版物获得,或通过常规克隆和测序得到。
除了抗体之外,与目标细胞上的表位或相应受体相互作用(结合、阻断、靶向或其他类型作用)的一种肽或蛋白质也可以作为结合分子。这些肽或蛋白质可能是任何随机的肽或蛋白质,它们对表位或相应的受体有亲和力,不一定非得是免疫球蛋白家族成员。这些肽可以通过类似噬菌体显示抗体的技术分离出来(Szardenings,J Recept SignalTransduct Res.2003;23(4):307-49)。从随机肽库中获得的肽可以与抗体和抗体片段类似地被使用。肽或蛋白质结合分子可以偶联或连接至大分子或其他物质,包括但不限于白蛋白、聚合物、脂质体、纳米粒子、树形分子,只要这样的连接能保留肽或蛋白质的抗原结合特异性。
在用于治疗癌症、自身免疫性疾病和/或传染性疾病的偶联物上,和药物分子通过本专利申请的连接体连接的抗体的例子包括,但不限于3F8(抗GD2),阿巴单抗(抗CA-125),阿昔单抗(抗CD41(整联蛋白α-IIb),阿达木单抗(抗TNF-α),Adecatumumab(抗EpCAM,CD326),阿非莫单抗(抗TNF-α),Afutuzumab(抗CD20),Alacizumab单抗(抗VEGFR2),ALD518(抗IL-6),Alemtuzumab(Campath,MabCampath,抗CD52),Altumomab(抗CEA),Anatumomab(抗TAG-72),Anrukinzumab(IMA-638,抗-IL-13),Apolizumab(抗-HLA-DR),阿奇单抗(抗-CEA),阿塞珠单抗(抗-L-选择蛋白CD62L),Atlizumab(tocilizumab,Actemra,RoActemra,抗-IL-6受体),Atorolimumab(抗-Rhesus因子),Bapineuzumab(抗-β淀粉样蛋白),Basiliximab(Simulect,抗CD25(IL-2受体的α链)),Bavituximab(抗磷脂酰丝氨酸),Bectumomab(LymphoScan,抗-CD22),贝利单抗(Benlysta,LymphoStat-B,抗BAFF),Benralizumab(抗CD125),Bertilimumab(抗CCL11(eotaxin-1)),Besilesomab(Scintimun,抗CEA相关抗原),贝伐单抗(Avastin,抗VEGF-A),Biciromab(FibriScint,抗纤维蛋白IIβ链),Bivatuzumab(抗-CD44v6),Blinatumomab(BiTE,抗CD19),Brentuximab(cAC10,抗-CD30TNRSF8),Briakinumab(抗IL-12,IL-23),Canakinumab(Ilaris,抗IL-1),Cantuzumab(C242,抗CanAg),Capromab,Catumaxomab(Removab,抗EpCAM,抗CD3),CC49(抗TAG-72),Cedelizumab(抗CD4),Certolizumab单抗(Cimzia抗TNF-α),西妥昔单抗(爱必妥,IMC-C225,抗EGFR),Citatuzumab bogatox(抗EpCAM),Cixutumumab(抗IGF-1),Clenoliximab(抗CD4),Clivatuzu-mab(抗MUC1),Conatumumab(抗TRAIL-R2),CR6261(抗流感A血凝素),Dacetuzumab(抗CD40),Daclizumab(Zenapax,抗CD25(IL-2受体α链)),Daratumumab(抗CD38(环ADP核糖水解酶),Denosumab(Prolia,抗RANKL),Detumomab(抗B淋巴瘤细胞),Dorlimomab,Dorlixizumab,Ecromeximab(抗GD3神经节苷脂),Eculizumab(Soliris,抗-C5),Edobacomab(抗内毒素),Edrecolomab(Panorex,MAb17-1A,抗-EpCAM),Efalizumab(Raptiva,抗LFA-1(CD11a)),Efungumab(Mycograb,抗Hsp90),Elotuzumab(抗SLAMF7),Elsilimomab(抗IL-6),Enlimomab单抗(抗ICAM-1(CD54)),Epitumomab(抗episialin),依他珠单抗(抗-CD22),Erlizumab(抗-ITGB2(CD18)),Ertumaxomab(Rexomun,抗HER2/neu,CD3),依他拉单抗(Abegrin,抗整联蛋白αvβ3),Exbivirumab(抗乙肝表面抗原),Fanolesomab(NeutroSpec,抗CD15),Faralimomab(抗干扰素受体),Farletuzumab(抗叶酸受体1),Felvizumab(抗呼吸道合胞病毒),Fezakinumab(抗-IL-22),Figitumumab(抗-IGF-1受体),Fontolizumab(抗-IFN-γ),Foravirumab(抗狂犬病病毒糖蛋白),Fresolimumab(抗TGF-β),Galiximab(抗CD80),Gantenerumab(抗β淀粉样蛋白),Gavilimomab(抗CD147(basigin)),Gemtuzumab(抗CD33),Girentuximab(抗碳酸酐酶9),Glembatumumab(CR011,抗GPNMB),Golimumab(Simponi,抗-TNF-α),Gomiliximab(抗-CD23(IgE受体)),Ibalizumab(抗-CD4),Ibritumomab(抗CD20),Igovomab(Indimacis-125,抗CA-125),Imciromab(Myoscint,抗心肌肌凝蛋白),Infliximab(Remicade,抗TNF-α),Intetumumab(抗CD51),Inolimomab(抗CD25(IL-2受体α链),伊珠单抗(抗-CD22),Ipilimumab(抗CD152),Iratumumab(抗CD30(TNFRSF8)),Keliximab(抗-CD4),Labetuzumab(CEA-Cide,抗CEA),Lebrikizumab(抗IL-13),Lemalesomab(抗NCA-90(粒细胞抗原)),Lerdelimumab(抗TGFβ2),Lexatumumab(抗TRAIL-R2),Libivirumab(抗乙肝表面抗原),Lintuzumab(抗CD33),鲁米木单抗(抗CD40),鲁米单抗(抗CD23(IgE受体),Mapatumumab(抗TRAIL-R1),马西莫单抗(抗T-细胞受体),马妥珠单抗(抗EGFR),Mepolizumab(Bosatria,抗IL-5),Metelimumab(抗TGFβ1),Milatuzumab(抗CD74),Minretumomab(抗TAG-72),Mitumomab(BEC-2,抗GD3神经节苷脂),Morolimumab(抗恒河猴因子),Motavizumab(Numax,抗呼吸道合胞病毒),Muromonab-CD3(Orthoclone OKT3,抗CD3),Nacolomab(抗C242),Naptumomab(抗5T4),那他珠单抗(Tysabri,抗整联蛋白α4),奈巴单抗(抗内毒素),Necitumumab(抗EGFR),Nerelimomab(抗-TNF-α),Nimotuzumab(Theracim,Theraloc,抗-EGFR),Nofetumomab,Ocrelizumab(抗CD20),澳利木单抗(Afolimomab,抗LFA-1(CD11a)),Ofatumumab(Arzerra,抗CD20),Olaratumab(抗PDGF-Rα),Omalizumab(Xolair,抗IgE Fc区)Oportuzumab(抗EpCAM),Oregovomab(OvaRex,抗CA-125),Otelixizumab(抗CD3),Pagibaximab(抗脂磷壁酸),Palivizumab(Synagis,Abbosynagis,抗呼吸道合胞病毒),帕尼单抗(Vectibix,ABX-EGF,抗EGFR),Panobacumab(抗铜绿假单胞菌(Pseudomonas aeruginosa)),帕考珠单抗(抗IL-4),Pemtumomab(Theragyn,抗MUC1),Pertuzumab(Omnitarg,2C4,抗HER2/neu),Pexelizumab(抗C5),Pintumomab(抗腺癌抗原),Priliximab(抗-D4),Pritumumab(抗波形蛋白),PRO140(抗-CCR5),Racotumomab(1E10,抗-N-羟乙酰神经氨酸(NeuGc,NGNA)-神经节苷脂GM3)),Rafivirumab(抗狂犬病病毒糖蛋白),Ramucirumab(抗VEGFR2),Ranibizumab(Lucentis,抗VEGF-A),Raxibacumab(抗炭疽毒素,保护性抗原),Regavirumab(抗巨细胞病毒糖蛋白B),Reslizumab(抗-IL-5),Rilotumumab(抗-HGF),Rituximab(MabThera,Rituxanmab,抗-CD20),Robatumumab(抗-IGF-1受体),Rontalizumab(抗IFN-α),Rovelizumab(LeukAr-rest,抗CD11,CD18),Ruplizumab(Antova,抗CD154(CD40L)),Satumomab(抗TAG-72),Sevirumab(抗巨细胞病毒),Sibrotuzumab(抗FAP),西法木单抗(抗IFN-α),Siltuximab(抗IL-6),Siplizumab(抗CD2),Smart MI95(抗CD33),Solanezumab(抗β淀粉状蛋白),Sonepcizumab(抗鞘氨醇-1-磷酸),Sontuzumab(抗-episialin),Stamulumab(抗-myostatin),Sulesomab(LeukoScan,抗NCA-90(粒细胞抗原)),Tacatuzumab(抗α甲胎蛋白),Tadocizumab(抗整联蛋白αIIbβ3),Talizumab(抗IgE),Tanezumab(anti-NGF),Taplitumomab(抗CD19),Tefibazumab(Aurexis,(抗凝聚因子A)),Telimomab,Tenatumomab(抗腱生蛋白C),Teneliximab(抗CD40),Teplizumab(抗CD3),TGN1412(抗CD28),Ticilimumab(Tremelimumab,抗-CTLA-4),Tigatuzumab(抗TRAIL-R2),TNX-650(抗IL-13),Tocilizumab(Atlizumab,Actemra,RoActemra,IL-6受体),Toralizumab(抗CD154(CD40L)),Tositumomab(抗CD20),曲妥珠单抗(赫赛汀,抗HER2/neu),Tremelimumab(抗CTLA-4),Tucotuzumab celmoleukin(抗EpCAM),Tuvirumab(抗乙型肝炎病毒),Urtoxazumab(抗大肠杆菌),Ustekinumab(Stelara,抗-IL-12,IL-23),Vapaliximab(抗-AOC3(VAP-1)),维多珠单抗(抗整联蛋白α4β7),维妥珠单抗(抗CD20),Vepalimomab(抗AOC3(VAP-1)),Visilizumab(Nuvion,抗CD3),Vitaxin(抗血管整合素avb3),Volociximab(抗整联蛋白α5β1),Votumumab(HumaSPECT,抗肿瘤抗原CTAA16.88),Zalutumumab(HuMax-EGFR,Zanolimumab(HuMax-CD4,抗-CD4),Ziralimumab(抗-CD147(basigin)),Zolimomab(抗-CD5),依那西普Alefacept/> Abatacept/>Rilonacept(Arcalyst),14F7(抗IRP-2(铁调节蛋白2)),14G2a(抗GD2神经节苷脂,源于Nat.Cancer Inst.,治疗黑素瘤和实体瘤),J591(抗-PSMA,源于WeillCornell医学院,治疗前列腺癌),225.28S(抗HMW-MAA(高分子量黑素瘤相关抗原),SorinRadiofarmaci SRL(源于意大利米兰,治疗黑色素瘤),COL-1(抗CEACAM3,CGM1,源于NatCancer Inst.治疗结肠直肠癌和胃癌),CYT-356(/>治疗前列腺癌),HNK20(OraVaxInc.治疗呼吸道合胞病毒感染),ImmuRAIT(源于Immunomedics,治疗NHL),Lym-1(抗HLA-DR10,Peregrine Pharm),MAK-195F(抗TNF(肿瘤坏死因子,TNFA,TNF-α,TNFSF2,源于Abbott/Knoll,治疗脓毒症中毒性休克),MEDI-500(T10B9,抗CD3,TRαβ(T细胞受体α/β),源于MedImmune Inc,用于移植物抗宿主疾病病),RING SCAN(抗TAG 72(肿瘤相关糖蛋白72),源于Neoprobe Corp.,用于乳腺癌,结肠癌和直肠癌),Avicidin(抗EPCAM(上皮细胞粘附分子)),抗-TACSTD1(肿瘤相关钙信号转导1),抗GA733-2(胃肠肿瘤相关蛋白2),抗EGP-2(上皮糖蛋白2),抗KSA,KS1/4抗原,M4S,肿瘤抗原17-1A,CD326(源于NeoRx公司,治疗结肠癌,卵巢癌,前列腺癌和NHL),LymphoCide(源于Immunomedics),Smart ID10(源于ProteinDesign Labs),Oncolym(源于Techniclone Inc),Allomune(源于BioTransplant),抗VEGF(源于Genentech);CEAcide(源于Immunomedics),IMC-1C11(源于ImClone Systems)和Cetuximab(源于ImClone)。
其他可作为细胞结合分子/配体的抗体,包括但不限于,以下抗原的抗体:氨肽酶N(CD13),膜联蛋白A1,B7-H3(CD276,各种癌症),CA125(卵巢癌),CA15-3(各种癌症),CA19-9(各种癌症),L6(各种癌症),路易斯Y(各种癌症),路易斯X(各种癌症),甲胎蛋白(各种癌症),CA242(结直肠癌),胎盘碱性磷酸酶(各种癌症),前列腺特异抗原(前列腺癌),前列腺酸磷酸酶(前列腺癌),表皮生长因子(各种癌症),CD2(霍奇金症,NHL淋巴瘤,多发性骨髓瘤),CD3ε(T细胞淋巴瘤,肺癌,乳腺癌,胃癌,卵巢癌,自身免疫性疾病,恶性腹水),CD19(B细胞恶性肿瘤),CD20(非霍奇金淋巴瘤),CD22(白血病,淋巴瘤,多发性骨髓瘤,SLE),CD30(霍奇金淋巴瘤),CD33(白血病,自身免疫性疾病),CD38(多发性骨髓瘤),CD40(淋巴瘤,多发性骨髓瘤,白血病(CLL)),CD51(转移性黑色素瘤,肉瘤),CD52(白血病),CD56(小细胞肺癌,卵巢癌,梅克细胞癌,以及液体肿瘤,多发性骨髓瘤),CD66e(各种癌症),CD70(转移性肾细胞癌和非霍奇金淋巴瘤),CD74(多发性骨髓瘤),CD80(淋巴瘤),CD98(各种癌症),粘液素(各种癌症),CD221(实体肿瘤)、CD227(乳腺癌、卵巢癌)、CD262(非小细胞肺癌及其他癌症)、CD309(卵巢癌)、CD326(实体肿瘤)、CEACAM3(结肠直肠癌、胃癌)、CEACAM5(癌胚抗原,CEA,CD66e)(乳腺,结直肠癌和肺癌),DLL4,EGFR(表皮生长因子受体,各种癌症),CTLA4(黑色素瘤),CXCR4(CD184,血液肿瘤,实体肿瘤),Endoglin(CD105,实体瘤),EPCAM(上皮细胞粘附分子,膀胱癌,头颈癌,结肠癌,NHL前列腺癌,卵巢癌),ERBB2(表皮生长因子受体2,肺癌,乳腺癌,前列腺癌),FCGR1(自身免疫性疾病),FOLR(叶酸受体,卵巢癌),GD2神经节苷(各种癌症),G-28(细胞表面抗原糖脂质,黑色素瘤),GD3独特型(各自癌症),热休克蛋白(各种癌症),HER1(肺癌,胃癌),HER2(乳腺癌,肺癌和卵巢癌),HLA-DR10(NHL),HLA-DRB(NHL,B细胞白血病),人绒毛膜促性腺激素(各种癌症),IGF1R(类胰岛素生长因子1受体,实体瘤,血癌),IL-2受体(白介素2受体,T细胞白血病和淋巴瘤),IL-6R(白介素6受体,多发性骨髓瘤,风湿性关节炎,Castleman病,白细胞介素6依赖肿瘤),整合蛋白(αvβ3、α5β1、α6β4、αllβ3、α5β5、αvβ5,各种癌症),MAGE-1(各种癌症),MAGE-2(各种癌症),MAGE-3(各种癌症),MAGE 4(各种癌症),抗转铁蛋白受体(各种癌症),p97(黑色素瘤),MS4A1(跨膜4结构域亚家族A成员1,非霍奇金B细胞淋巴瘤,白血病),MUC1或MUC1-KLH(乳腺癌、卵巢癌、子宫颈癌、支气管癌和α胃肠道癌),MUC16(CA125)(卵巢癌),CEA(结直肠癌),gp100(黑色素瘤),MART1(黑色素瘤),MPG(黑素瘤),MS4A1(跨膜4结构域亚家族A成员1,小细胞肺癌,NHL),Nucleolin,Neu癌基因产物(各自癌症),P21(各种癌),抗(N-羟乙酰神经氨酸)抗体结合部位(乳腺癌,黑色素瘤),类PLAP睾丸碱性磷酸酶(卵巢癌、睾丸癌),PSMA(前列腺瘤),PSA(前列腺癌),ROBO4,TAG 72(肿瘤相关糖蛋白72,AML,胃癌、结肠直肠癌、卵巢癌),T细胞跨膜蛋白(各种癌症),Tie(CD202b),TNFRSF10B(肿瘤坏死因子受体超家族成员10B,各种癌症),TNFRSF13B(肿瘤坏死因子受体超家族成员13B,多发性骨髓瘤,NHL,其他癌症,RA和SLE),TPBG(滋养细胞糖蛋白,肾细胞癌),TRAIL-R1(TNF相关坏死诱导配体受体1,淋巴瘤,NHL,结直肠癌,肺癌),VCAM-1(CD106,黑色素瘤),VEGF,VEGF-a,VEGF-2(CD309)(各种癌症)。其它肿瘤相关,可被抗体识别的抗原已被总结和评述(Gerber,et al,mAbs 2009,1:3,247-253;Novellino et al,Cancer ImmunolImmunother.2005,54(3),187-207;Franke,et al,Cancer BiotherRadiopharm.2000,15,459-76)。
细胞结合剂,优选为抗体,可以是任何能够抗肿瘤细胞,病毒感染细胞,微生物感染细胞,寄生虫感染细胞,自身免疫细胞,活化的细胞,骨髓细胞,激活T细胞,B细胞,或黑色素细胞的分子。更具体地,细胞结合剂可以是任何能够抗下列抗原或受体之一的药物/分子:CD3,CD4,CD5,CD6,CD7,CD8,CD9,CD10,CD11a,CD11b,CD11c,CD12w,CD14,CD15,CD16,CDw17,CD18,CD19,CD20,CD21,CD22,CD23,CD24,CD25,CD26,CD27,CD28,CD29,CD30,CD31,CD32,CD33,CD34,CD35,CD36,CD37,CD38,CD39,CD40,CD41,CD42,CD43,CD44,CD45,CD46,CD47,CD48,CD49b,CD49c,CD51,CD52,CD53,CD54,CD55,CD56,CD58,CD59,CD61,CD62E,CD62L,CD62P,CD63,CD66,CD68,CD69,CD70,CD72,CD74,CD79,CD79a,CD79b,CD80,CD81,CD82,CD83,CD86,CD87,CD88,CD89,CD90,CD91,CD95,CD96,CD98,CD100,CD103,CD105,CD106,CD109,CD117,CD120,CD125,CD126,CD127,CD133,CD134,CD135,CD138,CD141,CD142,CD143,CD144,CD147,CD151,CD147,CD152,CD154,CD156,CD158,CD163,CD166,.CD168,CD174,CD180,CD184,CDw186,CD194,CD195,CD200,CD200a,CD200b,CD209,CD221,CD227,CD235a,CD240,CD262,CD271,CD274,CD276(B7-H3),CD303,CD304,CD309,CD326,4-1BB,5AC,5T4(Trophoblast糖蛋白,TPBG,WNT-活化抑制因子1或WAIF1),腺癌抗原,AGS-5,AGS-22M6,激活素受体激酶1,AFP,AKAP-4,ALK,α整合素,αvβ6,氨基肽酶N,淀粉样蛋白β,雄激素受体,促血管新生蛋白因子2,促血管新生蛋白因子3,膜联蛋白A1,炭疽毒素保护性抗原,抗转移蛋白受体,AOC3(VAP-1),B7-H3,炭疽杆菌,BAFF(B细胞激活因子),B淋巴瘤细胞,bcr-abl,蛙皮素,BORIS,C5,C242抗原,CA125(糖抗原125,MUC16),CA-IX(或CAIX,碳酸酐酶9),CALLA,CanAg,犬红斑狼疮IL31,碳酸酐酶IX,心肌肌凝蛋白,CCL11(C-C片段趋化因子11),CCR4(C-C趋化因子受体4,CD194),CCR5,CD3E(ε),CEA(癌胚抗原),CEACAM3,CEACAM5(癌胚抗原),CFD(因子D),Ch4D5,胆囊收缩素2(CCK2R),CLDN18(Claudin-18),丛生因子A,CRIPTO,FCSF1R(集落刺激因子1受体,CD115),CSF2(集落刺激因子2,粒细胞-巨噬细胞集落刺激因子(GM-CSF)),CTLA4(细胞毒性T淋巴细胞相关蛋白4),CTAA16.88肿瘤抗原,CXCR4(CD184),C-X-C趋化因子受体4,环状ADP核糖核酸酶,细胞周期蛋白B1,CYP1B1,巨细胞病毒,巨细胞病毒糖蛋白B,Dabigatran,DLL4(类Δ配体4),DPP4(双肽-肽酶4),DR5(死亡受体5),大肠杆菌shiga毒素类型-1,大肠杆菌shiga毒素类型-2,ED-B,EGFL7(类EGF结构域蛋白7),EGFR,EGFRII,EGFRvIII,内皮因子(CD105),内皮素B受体,内毒素,EpCAM(上皮细胞粘附分子),EphA2,Episialin,ERBB2(表皮生长因子受体2),ERBB3,ERG(TMPRSS2ETS融合基因),大肠杆菌,ETV6-AML,FAP(成纤维细胞活化蛋白α),FCGR1,甲胎蛋白,纤维蛋白IIβ链,纤连蛋白额外结构域-B,FOLR(叶酸受体),叶酸受体α,叶酸水解酶,Fos相关抗原1,呼吸道合胞病毒的F蛋白,卷曲的受体,岩藻糖GM1,GD2神经节苷脂,G-28(细胞表面抗原糖脂),GD3独特型,GloboH,Glypican 3,N-羟乙酰神经氨酸,GM3,GMCSF受体α链,生长分化因子8,GP100,GPNMB(跨膜糖蛋白NMB),GUCY2C(鸟苷酸环化酶2C),鸟苷酸环化酶C(GC-C),肠鸟苷酸环化酶,鸟苷酸环化酶C受体,热稳定肠毒素受体(hSTAR),热休克蛋白,血凝素,乙肝表面抗原,乙型肝炎病毒,HER1(人类表皮生长因子受体1),HER2,HER2/neu,HER3(ERBB-3),IgG4,HGF/SF(肝细胞生长因子/分散因子),HHGFR,HIV-1,组蛋白复合物,HLA-DR(人类白细胞抗原),HLA-DR10,HLA-DRB,HMWMAA,人类绒毛膜促性腺激素,HNGF,人类分散因子受体激酶,HPVE6/E7,Hsp90,hTERT,ICAM-1(细胞间粘附分子1),独特型,IGF1R(IGF–1,类胰岛素生长因子1受体),IGHE,IFN-γ,流感血凝素,IgE,IgE Fc区,IGHE,IL–1,IL-2R(白介素2受体),IL–4,IL-5,IL–6,IL-6R(白介素6受体),IL-9,IL–10,IL–12,IL-13,IL-17,IL-17A,IL-20,IL-22,IL-23,IL31RA,ILGF2(类胰岛素生长因子2),整合蛋白(α4、αIIbβ3、αvβ3、α4β7、α5β1、α6β4、α7β7、αllβ3、α5β5、αvβ5),干扰素γ诱导蛋白质,ITGA2,ITGB2,KIR2D,LCK,Le,Legumain,Lewis-Y抗原,LFA-1(淋巴细胞功能相关抗原1,CD11a),LHRH,LINGO-1,脂磷壁酸,LIV1A,LMP2,LTA,MAD-CT-1,MAD-CT-2,MAGE-1,MAGE-2,MAGE-3,MAGE A1,MAGE A3,MAGE 4,MART1,MCP-1,MIF(巨噬细胞迁移抑制因子,或糖基抑制因子(GIF)),MS4A1(跨膜4结构域亚家族A成员1),MSLN(间皮素),MUC1(粘蛋白1,细胞表面相关(MUC1)或多态性上皮粘蛋白(PEM)),MUC1-KLH,MUC16(CA125),MCP1(单核细胞趋化蛋白1),MelanA/MART1,ML-IAP,MPG,MS4A1,MYCN,髓磷脂相关糖蛋白,Myostatin,NA17,NARP-1,NCA-90(粒细胞抗原),Nectin-4(ASG-22ME),NGF,神经细胞凋亡调控蛋白酶1,NOGO-A,Notch受体,核仁素,Neu致癌基因产物,NY-BR-1,NY-ESO-1,OX-40,OxLDL(氧化低密度脂蛋白),OY-TES1,P21,p53非突变体,P97,PAP,抗(N-羟乙酰神经氨酸)抗体结合部位,PAX3,PAX5,PCSK9,PDCD1(PD-1、程序性细胞死亡蛋白1,CD279),PDGF-Rα(α血小板源生长因子受体),PDGFR-β,PDL-1,PLAC1,类PLAP睾丸碱性磷酸酶,血小板衍生生长因子受体β,磷酸钠联合转运体,PMEL 17,聚唾液酸,蛋白酶3(PR1),前列腺癌,PS(磷脂酰丝氨酸),前列腺癌细胞,铜绿假单胞菌,PSMA,PSA,PSCA,狂犬病病毒糖蛋白,RHD(Rh多肽1(RhPI),CD240),Rhesus因子,RANKL,RhoC,Ras突变,RGS5,ROBO4,呼吸道合胞病毒,RON,肉瘤易位断点,SART3,Sclerostin,SLAMF7(SLAM成员7),Selectin P,SDC1(多配体蛋白聚糖1),系统性红斑狼疮(a),生长调节素C,SIP(1-磷酸鞘氨醇),生长激素抑制素,精子蛋白17,SSX2,STEAP1(6-跨膜上皮前列腺抗原1),STEAP2,STn,TAG-72(肿瘤相关糖蛋白),存活素,T细胞受体,T细胞跨膜蛋白,TEM1(肿瘤血管内皮标记1),TENB2,Tenascin C(TN-C),TGF-α,TGF-β(转化生长因子β),TGF-β1,TGF-β2(转化生长因子2),Tie(CD202b),Tie2,TIM-1(CDX-014),Tn,TNF,TNF-α,TNFRSF8,TNFRSF10B(肿瘤坏死因子受体超家族成员10B),TNFRSF13B(肿瘤坏死因子受体超家族成员13B),TPBG(滋养细胞糖蛋白),TRAIL-R1(TNF相关坏死诱导配体受体1),TRAILR2(死亡受体5(DR5)),肿瘤相关的钙信号传感器2,肿瘤特异糖基化的MUC1,TWEAK受体,TYRP1(糖蛋白75),TRP-2,酪氨酸酶,VCAM-1(CD106),VEGF,VEGF-A,VEGF-2(CD309),VEGFR-1,VEGFR2,vimentin,WT1,XAGE 1,表达任何胰岛素生长因子受体的细胞,或任何表皮生长因子受体。
在另一个具体的实施例中,通过本专利申请的连接体连接的细胞结合剂-药物偶联物,可用于癌症靶向治疗。目标癌症包括但不限于,肾上腺皮质癌、肛门癌、膀胱癌、大脑肿瘤(脑干神经胶质瘤、小脑星形细胞瘤、脑星形细胞瘤、室管膜瘤、成神经管细胞瘤、幕上原始神经外胚层和松果体肿瘤、视觉通路和下丘脑胶质瘤)、乳腺癌、类癌肿瘤、胃肠道癌症、未知小细胞癌、宫颈癌、结肠癌、子宫内膜癌、食道癌、肝外胆管癌、尤因家族肿瘤(PNET)、颅内生殖细胞肿瘤、眼癌、眼内黑色素瘤、胆囊癌、胃癌(胃癌)、性腺外生殖细胞瘤、孕周滋养细胞瘤、头颈癌、下咽癌、胰岛细胞癌、肾癌(肾细胞癌)、喉癌、白血病(急性淋巴细胞,急性髓系,慢性淋巴细胞,慢性粒细胞,毛细胞)、嘴唇和口腔癌症、肝癌、肺癌(非小细胞,小细胞)、淋巴瘤(艾滋病相关,中枢神经系统,皮肤T细胞,霍奇金病,非霍奇金病)、恶性间皮瘤、黑色素瘤、梅克尔细胞癌、转移性鳞状颈癌与隐匿性原发性癌、多发性骨髓瘤和其他浆细胞肿瘤、蕈样肉芽肿、骨髓增生异常综合征、骨髓增生异常、鼻咽癌、神经母细胞瘤、口腔癌、口咽癌、骨肉瘤、卵巢癌(上皮、生殖细胞瘤、低恶性肿瘤)、胰腺癌(外分泌,胰岛细胞癌)、副鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、嗜铬细胞瘤、垂体肿瘤、浆细胞肿瘤、前列腺癌横纹肌肉瘤、直肠癌、肾细胞癌(肾癌)、肾盂和输尿管(移行细胞)、唾腺癌、赛塞里综合症、皮肤癌(皮肤T细胞淋巴瘤,卡波西氏肉瘤,黑色素瘤)、小肠肿瘤、软组织肉瘤、胃癌、睾丸癌、胸腺瘤(恶性)、甲状腺癌、尿道癌症、子宫癌、不寻常的少年癌症、阴道肿瘤、外阴肿瘤和维尔姆斯瘤。
在另一个具体的实施例中,通过本专利申请的连接体连接的细胞结合剂-药物偶联物,可用作治疗或预防自身免疫疾病的成分和方法。自身免疫性疾病包括但不限于,Achlorhydra自身免疫性活动性慢性肝炎,急性播散性脑脊髓炎,急性出血性脑白质炎,艾迪生病,无精症,斑秃,肌萎缩侧索硬化症,强直性脊柱炎,抗GBM/TBM肾炎,抗磷脂综合征,抗异常酶综合征,关节炎,特应性过敏,特应性皮炎,自身免疫性再生障碍性贫血,自身免疫性心肌病,自身免疫性溶血性贫血,自身免疫性肝炎,自身免疫性内耳疾病,自身免疫性淋巴组织增生综合征,自身免疫性周围神经病,自身免疫性胰腺炎,自身免疫性多内分泌综合征I,II和III型,自身免疫性黄体酮皮炎,自身免疫性血小板减少性紫癜,自身免疫性葡萄膜炎,Balo病/Balo同心硬化症,Bechets综合征,Berger氏病,Bickerstaff脑炎,Blau综合征,大疱性类天疱疮,Castleman病,Chagas病,慢性疲劳免疫功能障碍综合征,慢性炎性脱髓鞘性多发性神经病,慢性复发性多灶性骨髓炎,慢性莱姆病,慢性阻塞性肺病,Churg-Strauss综合征,瘢痕性类天疱疮,乳糜泄,Cogan综合征,冷凝集素病,补体成分2缺乏症,颅骨动脉炎,CREST综合征,Crohns病(特发性炎症性肠病),库欣综合征,皮肤白细胞增多性血管炎,德戈氏病,Dercum氏病,疱疹样皮炎,皮肌炎,1型糖尿病,弥漫性皮肤系统性硬化症,Dressler综合征,盘状红斑狼疮,湿疹,子宫内膜异位症,附着点炎相关的关节炎,Eosinophilic筋膜炎,大疱性表皮松解症,结节性红斑,特发性混合性冷球蛋白血症,伊文氏综合征,纤维发育不良性骨化症,纤维肌痛,纤维化性肌炎,纤维性肺泡炎,胃炎,胃肠类天疱疮,巨细胞动脉炎,肾小球肾炎,古德帕斯丘尔综合征,格雷夫斯病,格林-巴利综合征,桥本氏脑炎,桥本氏甲状腺炎,溶血性贫血,过敏性紫癜,妊娠性肝炎,化脓性汗腺炎,休斯综合征(抗磷脂综合征),低丙球蛋白血症,特发性炎性脱髓鞘疾病,特发性肺纤维化,特发性血小板减少性紫癜(自身免疫性血小板减少性紫癜),IgA肾病(伯杰氏病),包涵体肌炎,炎性脱髓鞘性多神经炎,间质性膀胱炎,过敏性肠综合征,少年特发性关节炎,青少年类风湿性关节炎,川崎氏病,朗伯-伊顿重症肌无力综合征,白细胞碎屑性血管炎,扁平苔癣,硬化性硬化症,线状IgA疾病(LAD),Lou Gehrig病(也称肌萎缩侧索硬化症),狼疮性肝炎,红斑狼疮,Majeed综合征,美尼尔氏病,显微镜下多动脉炎,米勒-费希尔综合征,混合性结缔组织病,硬斑病,穆罕默德-哈贝曼病,麦考利综合征,多发性骨髓瘤,多发性硬化症,重症肌无力,肌炎,嗜睡症,视神经脊髓炎(Devic病),神经性肌强直,眼睑瘢痕性类天疱疮,Opsoclonus myoclonus综合征,Ord甲状腺炎,回文风湿病,PANDAS(与链球菌相关的小儿自身免疫性神经精神病),Paraneoplastic小脑变性,阵发性睡眠性血红蛋白尿症,ParryRomberg综合征,Parsonnage-Turner综合征,睫状体平部炎,天疱疮,寻常型天疱疮,贫血,周围脑脊髓炎,POEMS综合征,结节性多动脉炎,风湿性多肌痛,多发性肌炎,原发性胆汁性肝硬化,原发性硬化性胆管炎,进行性炎症性神经病变,牛皮癣,牛皮癣性关节炎,坏疽性皮肤炎,纯红细胞再生障碍,Rasmussen脑炎,雷诺现象,复发性多软骨炎,赖特综合征,不宁腿综合症,后神经纤维化,类风湿性关节炎,类风湿热,结节病,精神分裂症,施密特综合征,Schnitzler综合征,施尼茨勒综合征,巩膜炎,硬皮病,干燥综合征,脊椎关节病,粘稠血症,Still病,僵人综合征,亚急性细菌性心内膜炎,苏萨克综合征,Sweet综合征,小舞蹈病,交感神经性贫血,Takayasu动脉炎,颞动脉炎(巨细胞动脉炎),Tolosa-Hunt综合征,横贯性脊髓炎,溃疡性结肠炎(特发性炎性肠病),未分化结缔组织病,未分化脊柱关节病,血管炎,白癜风,韦格纳肉芽肿病,威尔逊氏综合征,威斯科特-澳尔德里奇综合征。
在另一个具体的实施例中,在用于治疗或预防自身免疫性疾病的偶联物上,和药物分子通过本发明的连接体连接的结合分子,包括但不限于,抗弹性蛋白抗体,Abys抗上皮细胞抗体,抗地下室膜IV型胶原蛋白抗体,抗核抗体,抗ds DNA,抗ss DNA,抗心磷脂抗体IgM,IgG,抗乳糜泻抗体,抗磷脂抗体IgK,IgG,抗SM抗体,抗线粒体抗体,甲状腺抗体,微粒体抗体,T细胞抗体,甲状腺球蛋白抗体,抗SCL-70,抗Jo,抗U.sub.1RNP,抗La/SSB,抗SSA,抗SSB,抗壁细胞抗体,抗组蛋白,抗RNP,C-ANCA,P-ANCA,抗着丝粒,抗纤维蛋白原,抗GBM抗体,抗神经节苷脂抗体,抗Desmogein 3抗体,抗p62抗体,抗sp100抗体,抗线粒体(M2)抗体,类风湿因子抗体,抗MCV抗体,抗拓扑异构酶抗体,抗中性粒细胞胞质(cANCA)抗体。
在某些优选的实施例中,本专利申请中偶联物上的结合分子,可以与自身免疫性疾病相关的激活淋巴细胞上表达的受体或受体复合物相结合。受体或受体复合物包含,免疫球蛋白基因超家族成员(例如CD2,CD3,CD4,CD8,CD19,CD20,CD22,CD28,CD30,CD33,CD37,CD38,CD56,CD70,CD79,CD79b,CD90,CD125,CD147,CD152/CTLA-4,PD-1或ICOS),TNF受体超家族成员(例如CD27,CD40,CD95/Fas,CD134/OX40,CD137/4-1BB,INF-R1,TNFR-2,RANK,TACI,BCMA,骨保护素,Apo2/TRAIL-R1,TRAIL-R2,TRAIL-R3,TRAIL-R4和APO-3),整合蛋白,细胞因子受体,趋化因子受体,主要组织相容性蛋白,凝集素(C型,S型或I型)或补体控制蛋白。
在另一个具体实施例中,可用的对病毒或微生物抗原具有免疫特异性的细胞结合配体是人源化或人单克隆抗体。“病毒抗原”包括但不限于,任何能够引发免疫应答的病毒肽,多肽蛋白(例如HIV gp120,HIV nef,RSV F糖蛋白,流感病毒神经氨酸苷酶,流感病毒血凝素,HTLV Tax,疱疹单纯疱疹病毒糖蛋白(例如gB,gC,gD和gE)和乙型肝炎表面抗原)。“微生物抗原”包括但不限于,任何能够引发免疫应答的微生物肽,多肽,蛋白质,糖,多糖或脂质分子(例如细菌,真菌,致病原生动物或酵母多肽,包括如LPS和荚膜多糖)。可用于治疗病毒或微生物感染的抗体的实例,包括但不限于:帕利珠单抗,它是用于治疗RSV感染的,人源化抗呼吸道合胞病毒单克隆抗体;PRO542,是一种CD4融合抗体,用于治疗HIV感染;澳斯他韦,是一种用于治疗乙型肝炎病毒的人抗体;PROTVIR,是一种人源化IgG1抗体,用于治疗巨细胞病毒,和抗LPS抗体。
通过本专利申请的连接体制得的细胞结合分子-药物偶联物可用于治疗感染性疾病。这些感染性疾病包括但不限于,不动杆菌属感染,放线菌病,非洲昏睡病(非洲锥虫病),艾滋病(获得性免疫缺陷综合症),阿米巴病,无形体病,炭疽,溶血性耶尔森菌感染,阿根廷出血热,蛔虫病,曲霉病,星状病毒感染,巴贝斯虫病,蜡状芽孢杆菌感染,细菌性肺炎,细菌性阴道炎,类杆菌感染,小袋虫病,蛔虫感染,BK病毒感染,黑色发结节病,人芽囊原虫感染,芽生菌病,玻利维亚出血热,疏螺旋体感染,肉毒中毒(和婴儿肉毒中毒),巴西出血热,布鲁氏杆菌病,伯克霍尔德氏菌感染,布鲁里溃疡,杯状病毒感染(诺如病毒和沙波病毒),弯曲杆菌病,念珠菌病(念珠菌病,鹅口疮),猫抓病,蜂窝组织炎,Chagas病(美洲锥虫病),子囊,水痘,衣原体,肺炎衣原体感染,霍乱,色素母细胞瘤,华支睾吸虫,艰难梭状芽孢杆菌感染,球孢子菌病,科罗拉多蜱热病,普通感冒(急性病毒性鼻咽炎,急性鼻炎),克雅氏病,克里米亚-刚果出血热,隐球菌病,隐孢子虫病,皮肤幼虫迁徙,环孢子虫病,肠杆菌感染,肠道病毒感染,流行性斑疹伤寒,传染性红斑(第五种疾病),急疹,姜片虫病,肝片吸虫病,致命性家族性失眠,丝虫病,产气荚膜梭菌食物中毒,自由活体阿米巴感染,梭杆菌感染,气性坏疽(梭菌性肌坏死),地丝菌病,格斯特曼-斯特拉斯勒-谢克尔病综合征,贾第鞭毛虫病,马鼻疽,淋病,肉芽肿性腹泻(第五性病),A群链球菌感染,B群链球菌感染,流感嗜血杆菌感染,手足口病(HFMD),汉坦病毒肺综合征,幽门螺杆菌感染,溶血性尿毒综合征,肾综合征出血热,甲型肝炎,乙型肝炎,丙型肝炎,丁型肝炎,戊型肝炎,单纯性疱疹,组织胞浆菌病,钩虫感染,人类博卡病毒感染,人类ewingii埃里希体病,人类粒细胞无形体病,人类偏肺病毒感染,人类单核细胞埃里希体病,人乳头瘤病毒感染,人副流感病毒感染,膜壳绦虫病,艾巴氏病毒传染性单核细胞增多症(单),流行性感冒,等孢子虫病,川崎病,角膜炎,金格杆菌感染,库鲁病,拉沙热,军团病(退伍军人症),军团病(庞蒂亚克热),利什曼病,莱姆病,淋巴丝虫病(象皮病),淋巴细胞性脉络丛脑膜炎,疟疾,马尔堡出血热,麻疹,类鼻疽病(惠氏病),脑膜炎,脑膜炎球菌病,后殖吸虫病,微孢子虫病,传染性软疣,腮腺炎,小鼠斑疹伤寒(地方性斑疹伤寒),支原体肺炎,足菌肿,蝇蛆病,新生儿结膜炎(新生儿眼病),变异型克雅氏病(vCJD,nvCJD),诺卡氏菌病,盘尾丝虫病(河盲症),副球孢子菌病(南美芽生菌病),肺吸虫病,巴斯德氏菌病,头虱,体虱,阴虱,盆腔炎,百日咳,鼠疫,肺炎球菌感染,肺孢子虫肺炎,肺炎,脊髓灰质炎,普氏菌感染,原发性阿米巴脑膜脑炎,进行性多灶性白质脑病,鹦鹉热,Q热,狂犬病,鼠咬热,呼吸道合胞病毒感染,鼻孢子虫病,鼻病毒感染,立克次体感染,立克次体痘,裂谷热,落基山斑疹热,轮状病毒感染,风疹,沙门氏菌病,SARS(严重急性呼吸综合征),疥疮,血吸虫病,败血症,志贺氏菌病(Bacillary痢疾),带状疱疹(带状疱疹),天花(天花),孢子丝菌,葡萄球菌食物中毒,感染金黄色葡萄球菌,粪类圆线虫病,梅毒,绦虫病,破伤风,须癣(Barber痒),头皮癣,体癣,股癣,手癣,掌黑癣,足癣(香港脚),甲癣(灰指甲),花斑癣,弓蛔虫病(眼幼虫移行症),弓蛔虫病(内脏幼虫移行症),弓形体病,旋毛虫病,滴虫病,鞭虫病(鞭虫感染),肺结核,兔热病,解脲脲原体感染,委内瑞拉马脑炎,委内瑞拉出血热,病毒性肺炎,西尼罗河热,白毛结节病(白癣),假结核耶尔森氏菌,耶尔森氏鼠疫杆菌肠道病,黄热病,接合菌病。
本发明的细胞结合剂,更优选为抗体,抗的病原菌株包括但不限于,鲍氏不动杆菌,以色列放线菌,放线菌和丙酸杆菌,布氏锥虫,HIV(人免疫缺陷病毒病毒),溶组织内阿米巴,无形体属,炭疽芽孢杆菌,溶血弧菌,胡宁病毒,蛔虫属,曲霉属,星状病毒科,巴贝虫属,蜡状芽孢杆菌,多种细菌,拟杆菌属,大肠杆菌,蛔虫属,BK病毒,结节菌,人芽囊原虫,皮炎芽生菌,马丘波病毒,疏螺旋体属,肉毒梭菌,清风藤属,布鲁氏菌属,通常为洋葱伯克霍尔德菌和其他伯克霍尔德氏菌种,溃疡分枝杆菌,杯状病毒科,弯曲杆菌属,通常为白色假丝酵母和其他假丝酵母属,汉赛巴尔通体,A群链球菌和葡萄球菌,克氏锥虫,杜克雷嗜血杆菌,VZV,沙眼衣原体,科罗拉多蜱热病毒,鼻病毒,冠状病毒,CJD朊病毒,克里米亚-刚果出血热病毒,新型隐球菌,隐孢子虫属,巴西钩虫,多种寄生虫,环孢子虫,带状绦虫,巨细胞病毒,登革热病毒(DEN-1,DEN-2,DEN-3和DEN-4)-黄病毒,脆弱双歧杆菌,白喉棒状杆菌,裂头绦虫,麦地那龙线虫,埃博拉病毒,棘球绦虫属,埃立克体肠球菌属,肠道病毒属,普氏立克次体,细小病毒B19,人疱疹病毒6和人疱疹病毒7,布氏姜片虫,肝片吸虫和巨大片吸虫,FFI朊病毒,丝虫目超家族,产气荚膜梭菌,梭杆菌属,其他梭状芽孢杆菌,白地霉,GSS朊病毒,肠道贾第虫,伯克霍尔德氏菌,刺孢小芽孢杆菌和革兰氏假丝酵母,淋球菌,肉芽肿克雷伯氏菌,化脓性链球菌,无乳链球菌,流感嗜血杆菌,肠道病毒,主要是柯萨奇A病毒和肠道病毒71,无名病毒,幽门螺旋杆菌,大肠杆菌O157:H7,布尼亚病毒科,甲型肝炎病毒,乙型肝炎病毒,丙型肝炎病毒,丁型肝炎病毒,戊型肝炎病毒,单纯疱疹病毒1,单纯疱疹病毒2,荚膜组织胞浆菌,十二指肠腺瘤和壶腹癌流感嗜血杆菌,人博卡病毒,埃里希体,嗜吞噬细胞无嗜血杆菌,人偏肺病毒,查菲埃里希体,人乳头瘤病毒,人副流感病毒,微小膜壳绦虫和缩小膜壳绦虫,艾巴氏病毒,正粘病毒科家族,贝氏等孢球虫,金格杆菌,肺炎克雷伯菌,克雷伯氏菌,嗜肺军团菌,嗜肺军团菌,嗜肺军团菌,利什曼原虫属,麻风分枝杆菌和结核分枝杆菌,钩端螺旋体属,单核细胞增多性李斯特氏菌,伯氏疏螺旋体和其他疏螺旋体属物种,班氏旋毛虫和马来丝虫,淋巴细胞脉络丛脑膜炎病毒(LCMV)疟原虫属,马尔堡病毒,麻疹病毒,类鼻疽伯克霍尔德氏菌,脑膜炎奈瑟氏球菌,横川后殖吸虫,小孢子虫目门,传染性软疣病毒(MCV),腮腺炎病毒,伤寒立克次氏体,肺炎支原体,多种细菌和真菌寄生双翅蝇幼虫,沙眼衣原体和淋病奈瑟菌,vCJD朊病毒,诺卡氏菌和其他诺卡氏菌属,盘尾丝虫属,盘鲍拟亚科,副龙属西马尼和其他副属,巴斯德氏菌属,头虱,人体虱,百日咳博德特氏菌鼠疫耶尔森氏菌,肺炎链球菌,肺炎球菌,脊髓灰质炎病毒,普雷沃氏菌属,奈氏格氏杆菌,JC病毒,鹦鹉热衣原体,伯氏考克斯体,狂犬病病毒,单链球菌和螺旋菌,呼吸道合胞病毒,鼻孢子菌,鼻病毒,立克次体属,由小株立克次体,裂谷热病毒,立克次体立克次体,轮状病毒,风疹,沙门氏菌属,SARS冠状病毒,人疥螨,血吸虫属,体细胞属,志贺菌属,水痘带状疱疹病毒,天花少校或天花小,申克孢子丝菌,金黄色葡萄球菌属,金黄色葡萄球菌,链球菌化脓,圆线虫,梅毒螺旋体,绦虫属,破伤风,癣属癣音铀,癣属,絮状表皮癣菌,红色毛癣菌,须毛癣菌,红色毛癣菌,威尼克外瓶黴,毛癣菌属属,细胞死亡属,弓箭毒或弓箭毒,刚地弓形虫、旋毛虫,阴道毛滴虫,三丘里三种,结核分枝杆菌,弗朗西拉图拉菌,尿素和马脑炎病毒,委内瑞拉马脑炎病毒,霍乱弧菌,瓜纳里托病毒,西尼罗河病毒,beigelii丝孢,假结核耶尔森氏菌,小肠结肠炎耶尔森氏菌,黄热病病毒,毛霉菌目阶(毛霉菌病)和虫霉目阶(虫霉属真菌病),毛霉菌目绿脓杆菌,弯曲杆菌(弧菌),气单胞菌,艾氏菌,耶尔森氏菌,志贺痢疾杆菌,志贺氏杆菌,志贺氏菌,沙门氏菌,伤寒沙门氏菌,雅司螺旋体,奋森氏螺旋体,伯氏疏螺旋体,细螺旋体,卡氏肺孢子虫,流产布鲁氏菌,布鲁杆菌,布鲁氏菌,支原体属,普氏立克次体,恙虫病立克次氏体,衣原体属,致病性真菌(烟曲霉,白色念珠菌,荚膜组织胞浆菌),原生动物(溶组织内阿米巴,Tenas毛滴虫,Hominis毛滴虫,冈比亚锥虫,罗得西亚锥虫,罗氏利什曼原虫,热带利什曼原虫,巴西利什曼原虫,肺孢子虫肺炎,间日疟原虫,恶性疟原虫,疟原虫疟疾)或Helminiths(日本血吸虫,曼氏血吸虫,埃及血吸虫和钩虫)。
其他用作本专利申请细胞结合剂,治疗病毒性疾病的抗体,包括但不限于,对下列致病性病毒抗原的抗体:痘病毒;疱疹病毒;腺病毒;小黄病毒;肠病毒;小核糖核酸病毒;细小病毒;呼肠病毒;逆转录病毒;流感病毒;副流感病毒;腮腺炎;麻疹;呼吸道合胞病毒;风疹;虫媒病毒;弹状病毒;沙门氏菌;非a/非b型肝炎病毒;鼻病毒;冠状病毒;罗托病毒;致癌病毒,如HBV(肝细胞癌),人乳头状瘤病毒(宫颈癌,肛门癌),卡波济氏肉瘤相关的疱疹病毒(卡波济氏肉瘤肉瘤)、人类疱疹病毒第四型(鼻咽癌、伯基特淋巴瘤、原发性中枢神经系统淋巴瘤)、瘤病毒(默克尔细胞癌)、SV40(猿猴病毒40)、HCV(肝细胞癌),HTLV-1(成人T细胞白血病/淋巴瘤);免疫紊乱导致病毒,如人类免疫缺陷病毒(艾滋病);中枢神经系统病毒,如JCV(进行性多灶性脑白质病),丙型肝炎病毒(亚急性硬化性全脑炎),LCV(淋巴细胞性脉络丛脑膜炎),亚博病毒脑炎,正粘病毒(脑炎性脑炎),RV(狂犬病),长鼻病毒,疱疹病毒脑膜炎,拉姆齐亨特综合征II型,脊髓灰质炎病毒(脊髓灰质炎病毒,后脊髓灰质炎综合征),HTLV-1(热带麻痹性麻痹));巨细胞病毒(巨细胞病毒视网膜炎,HSV(疱疹性角膜炎);心血管病毒,如CBV(心包炎,心肌炎);呼吸系统/急性病毒性鼻内炎/病毒性肺炎,如爱泼斯坦-巴尔病毒(EBV感染/传染性单核病),巨细胞病毒,非典冠状病毒(严重急性呼吸综合征)或正黏液病毒,流感病毒a/b/c(流感/禽流感),副粘病毒,人类副流感病毒,RSV(人类呼吸道合胞病毒),hMPV;消化系统病毒(腮腺炎病毒,巨细胞病毒(巨细胞病毒食管炎),腺病毒(腺病毒感染),轮状病毒,诺瓦克病毒,星状病毒,冠状病毒,乙型肝炎病毒,CBV,甲型肝炎病毒,丙型肝炎病毒,丁型肝炎病毒,戊型肝炎病毒,HGV);泌尿生殖病毒,如BK病毒,MuV(腮腺炎)。
更进一步,本发明也包括用桥接体连接的共轭偶联物和可接受的载体,稀释剂或辅料构成的组合物,以治疗癌症、感染或自身免疫性疾病。治疗癌症、感染和自身免疫性疾病的方法可以在体外,体内或离体实施。体外用途的实例包括用它处理细胞培养物,以杀死除了不表达靶抗原的变体以外的所有细胞;或者杀死表达不需要的抗原的变体。离体使用的例子包括在进行移植(HSCT)之前对造血干细胞(HSC)进行处理,以杀死患病或恶性细胞。例如,在癌症治疗中的自体移植之前或在自身免疫性疾病的治疗中从骨髓中去除肿瘤细胞或淋巴细胞,或在移植之前为了防止移植物抗宿主疾病从同种异体骨髓或组织中除去T细胞和其他淋巴细胞。这样的临床离体治疗可以按如下步骤进行:从患者或其他个体收获骨髓,然后在含有血清的培养基中约37℃下孵育约30分钟至约48小时,在该培养基中加入本发明的偶联物,浓度范围从约1pM至0.1mM。具体的药物浓度和孵育时间应当由专业临床医师决定。孵育后,用含血清的培养基洗涤骨髓细胞,并按照已知的方法通过静脉注射给患者。若患者在骨髓采集和再输注治疗细胞之间,还接受其它治疗(例如消融化疗或全身辐射疗程)的情况下,应使用标准医疗设备将处理后的骨髓细胞在液氮中冷冻储存。
在临床体内的使用中,可将本专利申请连接体连接的偶联物作为溶液或冻干固体供应,固体可以被重新溶解在注射用无菌水中。偶联物施用方案的实例如下:偶联物每周一次性静脉注射,连续给予8至20周。在50-500ml生理盐水中给予推注剂量,可以向其中加入人血清白蛋白(例如0.5至1mL的人血清白蛋白的浓缩溶液,100mg/mL)。静脉注射剂量将是约50μg至200mg/kg(体重)每周(每次注射10μg至200mg/kg)。治疗后周,患者可以接受第二疗程治疗。有关施用途径,赋形剂,稀释剂,剂量,次数等的具体临床方案可以由专业临床医生确定。
可用体内或离体方法治疗的医学病症的实例,包括任何类型癌症的恶性肿瘤,自身免疫疾病,移植物排斥和感染(病毒,细菌或寄生虫)。
为达到期望的生物效应所需的偶联物的量将随多种因素而变化,所述因素包括偶联物的化学特性,效力和生物利用度,疾病的类型,患者种族,患者的疾病发展状态,给药途径,所有因素决定了所需剂量、给药方式和给药方案。
一般而言,可将本发明的偶联物配制成含有0.1至10%w/v偶联物的水性生理缓冲溶液中,供注射使用。典型的剂量范围是从1μg/kg至0.1g/kg(体重),每天1次。优选的剂量范围是0.01mg/kg至20mg/kg体重/每天或每周,或幼儿等效剂量。待施用的药物的优选剂量可能取决于诸如疾病或病症的进展的类型和程度,特定患者的总体健康状况,所选化合物的相对生物功效,药物的配方,给药途径(静脉内,肌肉内或其他),药物指定运送途径的药代动力学性质,以及给药速度(推注或连续输注)和给药方案(给定时间内的重复次数)。
本发明的偶联物还能够以单位剂量形式给药,其中术语“单位剂量”是指能够给予患者的单次剂量,并且可以很容易地处置和包装,保持物理和化学上稳定的剂量,它含有活性偶联物本身或如下文所述的药学上可接受的组合物。典型的每日/周/双周/月总剂量范围是从0.01至100mg/kg(体重)。作为一般指导原则,人的单位剂量其范围为每天,每周,每两周,每三周或者每月1mg到3000mg。单位剂量范围优选1至500mg,一周一次至四次,更优选为1mg至100mg,一周一次,两周一次,三周一次或每月一次。本文提供的偶联物可以通过与一种或多种药学上可接受的赋形剂混合而配制成药物组合物。这样的单位剂量组合物可以通过口服给药,如片剂,简单胶囊或软凝胶胶囊的形式的药物;或鼻内给药,如粉剂,滴鼻剂或气雾剂的药物;或皮肤给药,如使用局部用软膏,乳膏,乳液,凝胶或喷雾剂或通过透皮贴剂给药。
药物/细胞毒素分子
可以与本发明中的细胞结合分子偶联的药物是包括细胞毒性剂在内的小分子药物,它们可以被连接到,或者被修饰后连接到细胞结合剂上。这里的“小分子药物”在本文中广泛用于指有机,无机或有机金属化合物,其可具有例如100至2500,更合适地为120至1500的分子量。这些小分子药物在本领域文献中已被充分描述,如WO05058367A2和美国专利4,956,303等,此处引作参考。小分子药物包括已知的药物和即将被公开的药物。
已知的药物包括,但不限于:
1)化疗剂:a)烷基化剂,如氮芥:氯苯那普,氯普那嗪,环磷酰胺,达卡巴嗪,雌二醇氮芥,异环磷酰胺,氮芥,盐酸二甲氧胺,氧化二氮芥,盐酸氨氯地平,麦考酚酸,卫矛醇,哌泊溴烷,新氮芥,苯芥胆甾醇,松龙苯芥,噻替哌,曲磷胺对,尿嘧啶;CC-1065(包括其阿多来新,卡折来新和比折来新合成类似物);多卡霉素(包括合成类似物KW-2189和CBI-TMI);苯并二氮卓二聚体(例如吡咯并苯二氮卓(PBD)或托美霉素,吲哚并苯并二氮卓,咪唑并苯并噻二氮卓或恶唑烷并苯并二氮卓的二聚体);亚硝基脲(卡莫司汀,洛莫司汀,氯化梭菌素,福莫司汀,尼莫司汀,拉莫司汀);烷基磺酸盐(白消安,硫丹,硫丹和硫磺);三氮烯(达卡巴嗪);含铂化合物(卡铂,顺铂,澳沙利铂);吖丙啶类,如苯并二氢吡喃酮,卡洛酮,美妥替派和乌雷多巴;乙烯亚胺和甲基三聚氰胺,包括六甲蜜胺,三亚乙基三胺,三乙基磷酰胺,三亚乙基硫代磷酰胺和三羟甲基甲基胺;b)植物生物碱:如长春花生物碱(长春新碱,长春碱,长春地辛,长春瑞滨,去甲长春碱);紫杉烷(紫杉醇,多西紫杉醇)及其类似物;美登素(DM1,DM2,DM3,DM4,美登素和安沙霉素)及其类似物;cryptophycin(特别是cryptophycin 1和cryptophycin 8);埃博霉素,软珊瑚醇,迪莫利德,草苔虫内酯,海兔毒素,澳瑞他汀,tubulysin,cephalostatin,pancratistatin,sarcodictyin,海绵抑制素;c)DNA拓扑异构酶抑制剂,例如依托泊苷替尼(9-氨基喜树碱,喜树碱,克立那托,道诺霉素,依托泊苷,磷酸依托泊苷,伊立替康,米托蒽醌,诺消灵,视黄酸(视黄醇),替尼泊苷,拓扑替康,9-硝基喜树碱(RFS 2000));丝裂霉素(丝裂霉素C);d)抗代谢物,例如抗叶酸剂,DHFR抑制剂(甲氨蝶呤,曲麦克特,二甲叶酸,蝶罗呤,氨喋呤(4-氨基苯甲酸)或其他叶酸类似物);IMP脱氢酶抑制剂(麦考酚酸,噻唑呋林,利巴韦林,EICAR);核糖核苷酸还原酶抑制剂(羟基脲,去铁胺);嘧啶类似物,尿嘧啶类似物(安西他滨,阿扎胞苷,6-氮尿嘧啶,卡培他滨(希罗达),卡莫氟,阿糖胞苷,双脱氧尿苷,去氧氟尿苷,依诺他滨,5-氟尿嘧啶,氟尿苷,ratitrexed(Tomudex);胞嘧啶类似物(阿糖胞苷,胞嘧啶阿拉伯糖苷,氟达拉滨);嘌呤类似物(硫唑嘌呤,氟达拉滨,巯嘌呤,硫胺素,硫鸟嘌呤);叶酸补充剂,如弗洛林酸;e)激素疗法剂,如受体拮抗剂,抗雌激素(甲地孕酮,雷洛昔芬,他莫昔芬),LHRH兴奋剂(戈斯他林,醋酸亮丙瑞林);抗雄激素药(比卡鲁胺,氟他胺,卡鲁司酮,丙酸倍他雄酮,表雄甾醇,戈舍瑞林,亮丙瑞林,美替利定,尼鲁米特,睾内酯,曲洛司坦及其他雄激素抑制剂);维甲类化合物,维生素D3类似物(CB1093,EB1089KH1060,胆钙化醇,麦角钙化甾醇);光动力疗法剂(维替泊芬,酞菁,光敏剂Pc4,去甲氧基-竹红菌素A);细胞因子(干扰素-α,干扰素-γ,肿瘤坏死因子(TNF),含TNF的人蛋白);f)激酶抑制剂,如BIBW 2992(抗-EGFR/Erb2),伊马替尼,吉非替尼,哌加他尼,索拉非尼,达沙替尼,舒尼替尼,厄洛替尼,尼洛替尼,拉帕替尼,阿西替尼,帕唑帕尼,凡德他尼,E7080(抗VEGFR2),mubritinib,普纳替尼(AP24534),bafetinib(INNO-406),bosutinib(SKI-606),卡博替尼,维莫德吉,iniparib,鲁索利替尼,CYT387,阿西替尼,tivozanib,索拉非尼,贝伐单抗,西妥昔单抗,曲妥珠单抗,雷珠单抗,帕尼单抗,伊斯平斯;g)聚(ADP核糖)聚合酶(PARP)抑制剂,如澳拉帕里、尼拉帕里、尼帕里、他拉唑帕里、维利帕里、维利帕里、CEP 9722(Cephalon)、E7016(Eisai)、BGB-290(BeiGene)、3-氨基苯甲酰胺。h)抗生素,如烯二炔类抗生素(加利车霉素,特别是加利车霉素γ1,δ1,α1和β1(参考J.Med.Chem.1996,39(11),2103-2117;Angew Chem Intl.Ed.Engl.1994,33:183-186),达因霉素,包括达因霉素A和脱氧米霉素,埃斯培拉霉素,卡达霉素,C-1027,maduropeptin以及新制癌菌素发色团和相关色蛋白烯二炔抗生素发色团),aclacinomysins,放线菌素,安曲霉素,重氮丝氨酸,博来霉素,卡诺霉素,卡拉霉素,洋红霉素,嗜癌素,阿霉素,阿霉素,吗啉代阿霉素,2-吡咯啉阿霉素和脱氧柔红霉素,表柔比星,阿柔比星,伊达比星,马可霉素,霉素,霉酚酸,洛匹霉素,培洛霉素,培洛霉素,嘌呤霉素,三铁阿霉素,阿霉素,链脲霉素,链脲佐菌素,杀结核菌素,乌苯美司,净司他丁,佐柔比星;i)其他,如聚酮化合物(番荔素),特别是bullatacin和bullatacinone,吉西他滨,环氧酶素(如卡菲偌米布),硼替佐米,沙利度胺,来那度胺,pomalidomide,tosedostat,zybrestat,PLX4032,STA-9090,Stimuvax,allovectin-7,Xegeva,Provenge,Yervoy,异戊二烯化抑制剂(如洛伐他汀),多巴胺能神经毒素(如星形孢菌素),放线菌素(如放线菌素D,更生霉素),博莱霉素(如博来霉素A2,博莱霉素B2,培洛霉素),蒽环类抗生素(如柔红霉素),阿霉素(亚德里亚霉素),伊达比星,表柔比星,吡柔比星,佐柔比星,米托蒽醌,MDR抑制剂(如维拉帕米),Ca2+ATP酶抑制剂(如毒胡萝卜素),组蛋白去乙酰酶抑制剂(伏立诺他,罗米地辛,帕比司他,丙戊酸,Mocetinostat(MGCD0103),Belinostat,PCI-24781,恩替诺特,SB939,Resminostat,Givinostat,AR-42,CUDC-101,萝卜硫素,曲古抑菌素A);塞来昔布,格列酮类,表没食子儿茶素没食子酸酯,双硫仑,Salinosporamide A;抗肾上腺药物,如氨鲁米特,米托坦,曲洛司坦,醋葡醛内酯,醛磷酰胺,氨基乙酰丙酸,安吖啶,阿拉伯糖苷,bestrabucil,比生群,edatraxate,defofamine,美可辛,地吖醌,依氟鸟氨酸(DFMO),elfomithine,依利醋铵,乙基葡糖酸,硝酸镓,胞嘧啶,羟基脲,伊班膦酸盐,香菇多糖,氯尼达明,米托胍腙,米托蒽醌,莫哌达醇,二胺硝吖啶,喷司他丁,蛋氨氮芥,吡柔比星,鬼臼酸,2-乙肼,甲基苄肼,哌嗪二酮丙烷,根霉素,西佐,螺环锗,细格孢氮杂酸,三亚胺醌,三氯三乙胺,单端孢霉烯(特别是T-2毒素,疣孢菌素A,杆孢菌素A和anguidine),聚氨酯,siRNA,反义药物和核酸分解酶。
2)自身免疫疾病药物,包括但不限于环孢菌素,环孢菌素A,氨基己酸,硫唑嘌呤,溴隐亭,苯丁酸氮芥,氯喹,环磷酰胺,皮质类固醇(例如安西奈德,地塞米松,曲安奈德,丙酸倍氯米松,DHEA,依那西普,羟基氯喹,英夫利昔单抗,美洛昔康,甲氨蝶呤,麦考酚酸酯,泼尼松,西罗莫司,他克莫司。
3)抗感染性疾病药物,包括但不限于a)氨基糖苷类:阿米卡星,阿司米星,庆大霉素(奈替米星,西索米星,异帕米星),潮霉素B,卡那霉素(阿米卡星,阿贝卡星,氨基去氧卡那霉素,地贝卡星,妥布霉素),新霉素(framycetin,巴龙霉素,核糖霉素),奈替米星,壮观霉素,链霉素,妥布霉素,甲基姿苏霉素;b)酰胺醇类:叠氮氯霉素,氯霉素,氟苯尼考,甲砜霉素;c)安沙霉素:格尔德霉素,除莠霉素;d)碳青霉烯类:比阿培南,多利培南,厄他培南,亚胺培南/西司他丁,美罗培南,帕尼培南;e)头孢烯:碳头孢烯(洛拉卡比),头孢乙腈,氯氨苄青霉素,头孢拉定,头孢羟氨,头孢洛宁,头孢噻啶,头孢噻吩或头孢金素,头孢氨苄,头孢来星,头孢孟多,头孢匹林,羟胺唑头孢菌素,氟唑头孢菌素,孢西酮,唑啉头孢菌素,头孢拉宗,头孢卡品,头孢达肟,头孢吡,头孢克肟,头孢西丁,头孢罗齐,头孢甲氧环烯胺,头孢替唑,头孢呋辛,头孢克肟,头孢地尼,头孢托仑,头孢吡,头孢他美,头孢甲肟,头孢地嗪,头孢尼西,头孢哌酮,头孢雷特,头孢噻肟,噻乙胺唑头孢菌素,头孢唑兰,头孢氨苄,头孢咪唑,头孢匹胺,头孢匹罗,头孢泊肟,头孢罗齐,头孢喹诺,头孢磺啶,头孢他啶,头孢特仑,头孢布腾,头孢噻林,头孢唑肟,头孢吡普,头孢曲松,头孢呋辛,头孢唑南,头霉素(头孢西丁,头孢替坦,头孢氰唑),氧(碳)头孢烯(氟氧头孢,头孢);f)糖肽:博来霉素,万古霉素(澳利万星,特拉万星),替考拉宁(达巴万星),雷莫拉宁,g)甘氨酰环素:如替加环素,h)β-内酰胺酶抑制剂:青霉烷(舒巴坦,他唑巴坦),氧青霉烷(克拉维酸);i)林可酰胺:克林霉素,林可霉素;j)脂肽:达托霉素,A54145,钙依赖性抗生素(CDA);k)大环内酯类:阿奇霉素,克霉素,克拉霉素,地红霉素,红霉素,氟雷霉素,交沙霉素,酮内酯(泰利霉素,塞红霉素),麦迪霉素,米卡霉素,竹桃霉素,利福霉素(异烟肼、利福平,利福布丁,利福喷汀),罗匹霉素,罗红霉素,大观霉素,螺旋霉素,他克莫司(FK506),醋竹桃霉素,泰利霉素;l)单环胺:氨曲南,替吉莫南;m)恶唑烷酮类:利奈唑胺;n)青霉素类:阿莫西林,氨苄青霉素(匹氨西林,海洛西林,巴氨西林,氨苄青霉素,阿霉素),阿替代西林,阿洛西林,苄青霉素,苄星青霉素苄青霉素,苄星青霉素苯氧甲基青霉素,克洛西林,普鲁卡因青霉素(美替西林),美洛西林,甲氧西林,萘夫西林,苯唑西林,醋甲西林,青霉素,非奈西林,苯氧基甲基青霉素,哌拉西林,氨苄西林,磺苯西林,替莫西林,替卡西林;o)多肽:杆菌肽,粘菌素,多粘菌素B,p)喹诺酮类:阿拉曲沙星,巴洛沙星,环丙沙星,克林沙,达氟沙星,二氟沙星,依诺沙星,恩诺沙星,加雷沙星,加替沙星,吉米沙星,格帕沙星,卡诺曲伐沙星,左氧氟沙星,洛美沙星,麻保沙星,莫西沙星,那氟沙星,诺氟沙星,澳比沙星,氧氟沙星,培氟沙星,曲伐沙星,格帕沙星,西他沙星,司帕沙星,替马沙星,托沙星,曲伐沙星;q)链阳性菌素:普那霉素,奎奴普丁/达福普汀,r)磺胺类药物:磺胺类药物:磺胺类药物,磺胺嘧啶,磺胺嘧啶,磺胺嘧啶,柳氮磺胺吡啶,磺胺异恶唑,三苯氧胺,甲氧苄氨嘧啶-磺胺甲恶唑(复方新诺明);s)类固醇抗菌药物:如夫西地酸;t)四环素类:强力霉素,金霉素,氯米西环素,地美环素,雷莫昔林,美西环素,美他环素,米诺环素,土霉素,青霉素V钾哌四环素,吡咯烷甲基四环素,四环素,甘氨酰环素(如替加环素):u)其他类型的抗生素:番荔枝素,胂凡纳明,细菌萜醇抑制剂(杆菌),DANAL/AR抑制剂(环丝氨酸),dictyostatin,圆皮海绵内酯,软珊瑚醇,埃博霉素,乙胺丁醇,依托泊苷,法罗培南,夫西地酸,呋喃唑酮,异烟肼,laulimalide,甲硝唑,莫匹罗星,NAM合成抑制剂(例如磷霉素),呋喃妥因,紫杉醇,普兰西霉素,吡嗪酰胺,奎奴普丁/达福普汀,利福平(利福平),他唑巴坦替硝唑,乌菊花素。
4)抗病毒药物:a)进入/融合抑制剂:阿帕韦洛,马拉韦罗,vicriviroc,gp41(恩夫韦肽),PRO 140,CD4(艾巴利珠单抗);b)整合酶抑制剂:雷特格韦,elvitegravir,globoidnan A;c)成熟抑制剂:bevirimat,vivecon;d)神经氨酸酶抑制剂:澳司他韦,扎那米韦,帕拉米韦;e)核苷和核苷酸:阿巴卡韦,阿昔单韦,阿德福韦,阿莫西韦,阿昔单抗,溴夫定,西多福韦,克拉夫定,地塞米松,去羟肌苷(ddI),elvucitabine,恩曲他滨(FTC),恩替卡韦,泛昔洛韦,氟拉西林(5-FU),3’-氟取代的2’,3’-脱氧核苷类似物(如3,3’-氟-2′,3′-双脱氧胸苷(FLT)和3’-氟-2’,3’-双脱氧鸟苷(FLG),福米韦生,9-鸟嘌呤,碘苷,拉米夫定(3TC),1-核苷(例如β-1-胸苷和β-1-2’-脱氧胞苷),喷昔洛韦,racivir,利巴韦林,迪替丁,司他夫定(d4T),塔利巴韦林(viramidine),替比夫定,替诺福韦,三氟尿苷伐昔洛韦,缬更昔洛韦,扎西他滨(ddC),齐多夫定(AZT);f)非核苷类:金刚烷胺,阿替吡啶,卡普韦林,二芳基嘧啶(依曲韦林,rilpivirine),地拉夫定,二十二烷醇,乙米韦林,依法韦仑,膦甲酸(磷酰基甲酸),咪喹莫特,聚乙二醇干扰素,洛韦胺,洛德腺苷,甲吲噻腙,奈韦拉平,NOV-205,长效干扰素α,鬼臼毒素,利福平,金刚乙胺,瑞喹莫德(R-848),醋胺金刚烷;g)蛋白酶抑制剂:安普那韦阿扎那韦,boceprevir,darunavir,福沙那韦,印地那韦,洛匹那韦,奈非那韦,普来可那立,利托那韦,沙奎那韦,telaprevir(VX-950),替拉那韦;h)其它类型的抗病毒药物:抗氧化酶,阿比朵尔,卡拉诺莱德,ceragenin,氰维林-n,二芳基嘧啶,表没食子儿茶素没食子酸酯(EGCG),膦甲酸,格里菲辛,taribavirin(viramidine),羟基脲,KP-1461,米替福新,普来可那立,混成抑制剂,利巴韦林,seliciclib。
5)通过本发明的连接体连接的药物也包括放射性同位素。放射性同位素(放射性核素)的实例有3H,11C,14C,18F,32P,35S,64Cu,68Ga,86Y,99Tc,111In,123I,124I,125I,131I,133Xe,177Lu,211At或213Bi。放射性同位素标记的抗体可用于受体靶向成像实验,或者可用于如本发明的抗体-药物偶联物的靶向治疗(Wu等Nature Biotechnology2005,23(9):1137-1146)。细胞结合分子,例如抗体可以通过本专利申请的连接体连接配体试剂,进行标记。配体可以用文献(Current Protocols in Immunology,Volumes1和2,Coligen等,Ed.Wiley-Interscience,New York,N.Y.,Pubs.(1991))所述的方法与放射性金属结合、螯合或生成复合物。可以络合金属离子的螯合配体包括DOTA,DOTP,DOTMA,DTPA和TETA(Macrocyclics,Dallas,TX)等。
6)上述任何药物的药学上可接受的盐,酸或衍生物。
在另一个实施例中,结构式(II)和(IV)中的药物可以是发色分子,偶联物可用于检测,监测或研究细胞结合分子与靶细胞的相互作用。发色分子可以吸收一种光,如紫外光,荧光,红外光,近红外光或可见光;发色分子包括黄色素,红细胞,虹彩色素,白细胞,黑色素和蓝绿色素的一类或一个亚类,荧光分子(吸收光后再发光的荧光化学物质)的一类或一个亚类,视觉光转导分子的一类或一个亚类,光子分子的一类或一个亚类,冷光分子的一类或一个亚类和荧光素化合物的一类或一个亚类。
发色分子可选自但不限于,非蛋白质有机荧光团,例如氧杂蒽衍生物(荧光素,罗丹明,俄勒冈绿,伊红和德克萨斯红);花青衍生物(花青,吲哚羰花青,氧杂花青,硫代花青和部花青);方酸衍生物和环取代的方酸,包括Seta,SeTau和Square染料;萘衍生物(丹酰和氟硅酸钠衍生物);香豆素衍生物;恶二唑衍生物(吡啶基恶唑,硝基苯并恶唑和苯并恶二唑);蒽衍生物(蒽醌类,包括DRAQ5,DRAQ7和CyTRAK橙);芘衍生物(级联蓝等);恶嗪衍生物(尼罗红,尼罗蓝,甲酚紫,恶嗪170等);吖啶衍生物(黄醇黄素,吖啶橙,吖啶黄等);芳基甲胺衍生物(金胺,结晶紫,孔雀石绿)和四吡咯衍生物(卟吩,酞菁,胆红素)。
生色分子选自以下荧光化合物的任何类似物和衍生物:CF染料(Biotium),DRAQ和CyTRAK探针(BioS-tatus),BODIPY(Invitrogen),Alexa Fluor(Invitrogen),DyLightFluor(Thermo Scientific,Pierce),Atto和Tracy(Sigma Aldrich),FluoProbes(Interchim),Abberior染料(Abberior),DY和MegaStokes染料(Dyomics),Sulfo Cy染料(Cyandye),HiLyte Fluor(AnaSpec),Seta,SeTau和Square染料(BiosearchTechnologies),SureLight染料(APC,RPEPerCP,Phycobilisomes)(ColumbiaBiosciences),APC,APCXL,RPE,BPE(Phyco-Biotech)。
广泛使用的可与本发明连接体反应或偶联的荧光化合物的实例有:别藻蓝蛋白(APC),氨基胭脂蛋白,APC-Cy7偶联物,BODIPY-FL,Cascade Blue,Cy2,Cy3,Cy3.5,Cy3B,Cy5,Cy5.5,Cy7,荧光素,FluorX,羟基香豆素,丽丝胺罗丹明B,萤光黄,Me-甲氧基香豆素,NBD,Pacific Blue,Pacific Orange,PE-Cy5偶联物,PE-R-藻红蛋白(PE),Red 613,Seta-555-Azide,Seta-555-DBCO,Seta-555-NHS,Seta-580-NHS,Seta-680-NHS,Seta-APC-780,Seta-PerCP-680,Seta-R-PE-670,SeTau-380-NHS,SeTau-405-马来酰亚胺,SeTau-405-NHS,SeTau-425-NHS,SeTau-647-NHS,Texas Red,TRITC,TruRed,X-Rhodamine。
可以与本发明的连接体相连,用于研究核酸或蛋白质的荧光化合物,选自下列化合物或其衍生物:7-AAD(7-氨基放线菌素D,CG-选择性的),吖啶橙,色霉素A3,CyTRAK橙(Biostatus),DAPI,DRAQ5,DRAQ7,溴化乙锭,Hoechst33258,Hoechst33342,LDS 751,光辉霉素,碘化丙啶(PI),SYTOX蓝,SYTOX绿,SYTOX橙,噻唑橙,TO-PRO,菁染料单体,TOTO-1,TO-PRO-1,TOTO-3,TO-PRO-3,YOSeta-1,YOYO-1。可以与本发明的连接体相连,用于研究细胞的荧光化合物,选自下列化合物或其衍生物:DCFH(2’,7’-二氯二氢荧光素,氧化形式),DHR(二氢罗丹明123,氧化形式,光催化氧化),Fluo-3(AM酯,pH>6),Fluo-4(AM酯,pH7.2),Indo-1(AM酯,低/高钙(Ca 2+)),SNARF(pH 6/9)。优选的荧光化合物选自:别藻蓝蛋白(APC),AmCyan1(四聚体,Clontech),AsRed2(四聚体,Clontech),蓟绿(单体,MBL),Azurite,B-藻红蛋白(BPE),Cerulean,CyPet,DsRed单体(Clontech),DsRed2(RFP,Clontech),EBFP,EBFP2,ECFP,EGFP(弱二聚体,Clontech),Emerald(弱二聚体,Invitrogen),EYFP(弱二聚体,Clontech),GFP(S65A突变),GFP(S65C突变),GFP(S65L突变)GFP(Y66H突变),GFP(Y66W突变),GFPuv,HcRed1,J-Red,Katusha,Kusabira Orange(单聚体,MBL),mCFP,mCherry(单体,MBL),mKate(TagFP635,单体,Evrogen),mKeima-Red(单体,MBL),mKO,mOrange,mPlum,mRaspberry,mRFP1(单体,Tsien实验室),mStrawberry,mTFP1,mTurquoise2,P3(藻胆体复合物),多甲藻黄素-叶绿素-蛋白质复合物(PerCP),R-phycoerythrin(RPE),T-Sapphire,TagCFP(二聚体,Evrogen),TagGFP(二聚体,Evrogen),TagRFP(二聚体,Evrogen),TagYFP(二聚体,Evrogen),tdTomato(串联二聚体),Topaz,TurboFP602(二聚体,Evrogen),TurboFPP635(二聚体,Evrogen),TurboGFP(二聚体,Evrogen),TurboRFP(二聚体,Evrogen),TurboYFP(二聚体,Evrogen),Venus,野生型GFP型,YPet,ZsGreen1(四聚体,Clontech),ZsYellow1(四聚体,Clontech)。
通过本发明的连接体连接的抗体-发色团分子偶联物的实例如Ac01,Ac02,Ac03,Ac04,Ac05,Ac06,和Ac07所示:
(FNIR-774偶联物)
Ac08(IR800CW偶联物)
在另一个实施例中,式(I)和(II)中的药物分子是聚乙烯二醇类分子,可用于哺乳动物给药时,延长细胞结合分子半衰期。聚乙烯二醇类分子包括但不限于聚(乙二醇)(PEG),聚(丙二醇)以及环氧乙烷和环氧丙烷的共聚物;特别优选的是PEG,更优选的是单官能活化的羟基PEG(例如,在单个末端活化的羟基PEGs,包括羟基PEG-单羧酸的活性酯,羟基PEG-单醛,羟基PEG-单胺,羟基PEG-单酰肼,羟基PEG-单肼基甲酸酯,羟基PEG-单碘乙酰胺,羟基PEG-单马来酰亚胺,羟基PEG-单原甲基吡啶基二硫化物,羟基PEG-单肟,羟基PEG-单苯基碳酸酯,羟基PEG-单苯基乙二醛,羟基PEG-单噻唑烷-2-硫酮,羟基PEG-单硫代酯,羟基PEG-单巯基,羟基PEG-单三嗪和羟基PEG-单乙烯基砜)。
在某些这样的实施例中,聚乙烯二醇分子量为约10Da至约200kDa,优选约88Da至约40kDa的;两个分支,每个分子具有约88Da至约40kDa的分子量;更优选两个分支,每个分支约88Da至约20kDa。在一个具体的实施例中,聚乙烯二醇类分子是聚乙二醇并且具有约10kDa的分子量;约20kDa,或约40kDa。在具体的实施方案中,PEG是PEG 10kDa(线性或分支),PEG 20kDa(线性或分支)或PEG 40kDa(线性或分支)。许多美国专利公公布了直链或支链“非抗原性”PEG聚合物及其衍生物或其偶联物的制备,例如,美国专利5428128;5621039;5622986;5643575;5728560;5730990;5738846;5811076;5824701;5840900;5880131;5900402;5902588;5919455;5951974;5965119;5965566;5969040;5981709;6011042;6042822;6113906;6127355;6132713;6177087和6180095.通过连接体连接的抗体-聚乙烯二醇偶联物的结构如Pg01,Pg02和Pg03所示:
其中mAb是抗体;R’是H或CH3;m3是1至5000的整数;R3是OH,H或R1;表示单键或双键;m1,m2,n,L1,L2,X1,X2,R1,R2,和R与式(I)和(II)中定义的相同。另外,R1和R3可以独立地为H,OH,OCH3或OC2H5;p是1-2000;Drug1与式(III)中定义相同。
在另一个实施方案中,通过本专利申请的连接体连接至细胞结合分子的优选细胞毒性剂是tubulysin类,美登木素生物碱类,紫杉烷类(taxanes),CC-1065类似物,柔红霉素或多柔比星化合物,鹅膏毒肽,苯并二氮卓类二聚体(例如吡咯并苯二氮卓(PBD)的二聚体,托美霉素,氨茴霉素,吲哚并苯并二氮杂二聚体,咪唑并苯并二氮杂二聚体,或者恶唑烷苯并二氮杂卓),加利车霉素或烯二炔抗生素,放线菌素,重氮丝氨酸,博来霉素,表柔比星,艾日布林,他莫昔芬,伊达比星,多拉司他汀,澳瑞他汀衍生物(例如MMAE,MMAF,澳瑞他汀PYE,澳瑞他汀TP,澳瑞他汀2-AQ,6-AQ,EB(AEB)和EFP(AEFP))及其类似物,多卡霉素,格尔德霉素,甲氨喋呤,噻替派,长春地辛,长春新碱,半米塔林,nazumamides,microginin,放射敏素,链霉素,SN38或喜树碱的其他类似物或代谢物,alterobactins,microsclerodermins,theonellamides,esperamicin,PNU-159682,和它们的类似物及其衍生物。
Tubulysin化合物优选用于本发明中偶联物,它是本领域公知的,并且可以根据已知方法从天然来源分离,或者根据已知方法合成制备,如Balasubramanian,R.,等J.Med.Chem.,2009,52,238–40;Wipf,P.,等Org.Lett.,2004,6,4057–60;Pando,O.,等J.Am.Chem.Soc.,2011,133,7692–5;Reddy,J.A.,等Mol.Pharmaceutics,2009,6,1518–25;Raghavan,B.,等J.Med.Chem.,2008,51,1530–33;Patterson,A.W.,等J.Org.Chem.,2008,73,4362–9;Pando,O.,等Org.Lett.,2009,11(24),5567–9;Wipf,P.,等Org.Lett.,2007,9(8),1605–7;Friestad,G.K.,Org.Lett.,2004,6,3249–52;Peltier,H.M.,等J.Am.Chem.Soc.,2006,128,16018–9;Chandrasekhar,S.,等J.Org.Chem.,2009,74,9531–4;Liu,Y.,等Mol.Pharmaceutics,2012,9,168–75;Friestad,G.K.,等Org.Lett.,2009,11,1095–8;Kubicek,K.,等,Angew Chem Int Ed Engl,2010.49:4809-12;Chai,Y.,等,ChemBiol,2010,17:296-309;Ullrich,A.,等,Angew Chem Int Ed Engl,2009,48,4422-5;Sani,M.,等Angew Chem Int Ed Engl,2007,46,3526-9;Domling,A.,等,Angew Chem IntEd Engl,2006,45,7235-9;专利申请:Zanda,M.,等,Can.Pat.Appl.CA 2710693(2011);Chai,Y.,等Eur.Pat.Appl.2174947(2010),WO 2010034724;Leamon,C.等,WO2010033733,WO 2009002993;Ellman,J.,等,PCT WO2009134279;WO 2009012958,USappl.20110263650,20110021568;Matschiner,G.,等,WO2009095447;Vlahov,I.,等,WO2009055562,WO 2008112873;Low,P.,等,WO2009026177;Richter,W.,WO2008138561;Kjems,J.,等,WO 2008125116;Davis,M.;等,WO2008076333;Diener,J.;等,U.S.Pat.Appl.20070041901,WO2006096754;Matschiner,G.,等,WO2006056464;Vaghefi,F.,等,WO2006033913;Doemling,A.,德国专利DE102004030227,WO2004005327,WO2004005326,WO2004005269;Stanton,M.,等,美国专利20040249130;Hoefle,G.,等,德国专利DE10254439,DE10241152,DE10008089;Leung,D.,等,WO2002077036;Reichenbach,H.,等,德国专利DE19638870;Wolfgang,R.,US20120129779;Chen,H.,美国专利20110027274等。专利申请PCT/IB2012/053554中描述了用于与细胞结合分子偶联的tubulysin化合物的优选结构。
通过本发明的连接体连接的抗体-tubulysin类似物的偶联物的结构示例如T01,T02,T03,T04,T05,T06T07,T08,T09,T10和T11:
其中mAb是抗体或细胞结合分子;n,m1,m2,Drug1,X1,X2,L1,L2,L3,R1,R2,R3,R4和R5与式(I)和(II)中的定义相同;优选地,R1,R2,R3,和R4独立地为H,C1-C8直链或支链烷基,芳基,杂芳基,杂烷基,烷基环烷基,酯,醚,酰胺,胺,杂环烷基或酰氧基胺;或含有1-8个氨基酸的肽或如式(OCH2CH2)p或(OCH2CH(CH3))p的聚氧乙烯单元,其中p是1至约2000的整数。两个R,R1R2,R2R3,R1R3或R3R4可以形成3~8元环烷基,芳基,杂芳基,杂烷基或烷基环烷基;X3为H,CH3或X1’R1’,其中X1’为NH,N(CH3),NHNH,O或S,R1’为H,C1-C8直链或支链烷基,芳基,杂芳基,杂烷基,烷基环烷基,酰氧基胺;R3’是H,C1-C6直链或支链烷基;p为0-2000;Z3为H,OH,OP(O)(OM1)(OM2),OCH2OP(O)(OM1)(OM2),OSO3M1,R1,或O-糖苷(葡萄糖苷,半乳糖苷,甘露糖苷,葡萄糖醛酸苷/葡糖苷酸,异香糖苷,果糖苷等),NH-糖苷,S-糖苷或CH2-糖苷;表示单键或双键;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3;此外,R1’可以是在本专利申请中所描述的细胞毒性剂。
加利车霉素及其相关的烯二炔抗生素优选用于本专利申请中细胞结合分子-药物偶联物,相关文献包括Nicolaou,K.C.等,Science 1992,256,1172-1178;Proc.Natl.Acad.Sci USA.1993,90,5881-8),美国专利4970198;5053394;5108912;5264586;5384412;5606040;5712374;5714586;5739116;5770701;5770710;5773001;5877296;6015562;6124310;8153768。通过连接体连接的抗体-加利车霉素类似物偶联物的结构示例如C01和C02:
其中mAb是抗体或细胞结合分子;n,m1,X1,L1,L2,和R1与式(I)和(II)中定义相同;R1’和R3’独立地为H或C1-C6直链或支链烷基;p是0-2000。此外,R1’可以是本发明中描述的细胞毒性剂。
美登木素生物碱包括美登醇及其类似物优选用于本发明,相关描述见于美国专利4256746,4361650,4307016,4294757,4294757,4371533,4424219,4331598,4450254,4364866,4313946,4315929 4362663,4322348,4371533,4424219,5208020,5416064,5208020,5416064,6333410,6441163,6716821,7276497,7301019,7303749,7368565,7411063,7851432和8163888。通过本专利申请的连接体连接的抗体-美登木素生物碱偶联物结构示例如My01,My02和My03:
其中mAb是抗体或细胞结合分子;n,m1,X1,L1,L2,和R1与式(I)和(II)中定义相同;R1’和R3’独立地为H或C1-C6直链或支链烷基;p是0-2000。此外,R1’可以是本发明中描述的细胞毒性剂。
紫杉烷,包括紫杉醇(Taxol),一种细胞毒性天然产物,和多西紫杉醇(Taxotere),一种半合成衍生物,以及它们的类似物优选用于以本专利申请的连接体连接的偶联物,其描述可见于K C.Nicolaou等,J.Am.Chem.Soc.117,2409-20,(1995);Ojima等,J.Med.Chem.39:3889-3896(1996);40:267-78(1997);45,5620-3(2002);Ojima等,Proc.Natl.Acad.Sci.,96:4256-61(1999);Kim等,Bull.Korean Chem.Soc.,20,1389-90(1999);Miller,等J.Med.Chem.,47,4802-5(2004);美国专利5475011;5728849;5811452;6340701;6372738;6391913,6436931;6589979;6596757;6706708;7008942;7186851;7217819;7276499;7598290和7667054。通过本专利申请的连接体连接的抗体-紫杉烷偶联物的结构示例如Tx01,Tx02和Tx03:
其中mAb是抗体或细胞结合分子;表示单键或双键;n,m1,X1,L1,L2,和R1与式(I)和(II)中定义的相同;R1’和R3’独立地为H或C1-C6直链或支链烷基;p为0-2000;此外,R1’可以是本专利申请中描述的细胞毒性剂。
CC-1065类似物和多卡霉素类似物也优选用于以本专利申请的连接体连接的偶联物。CC-1065类似物和多卡霉素类似物的实例及其合成记载于Warpehoski,等,J.Med.Chem.31:590-603(1988);D.Boger等,J.Org.Chem;66;6654-61,2001;美国专利4169888,4391904,4671958,4816567,4912227,4923990,4952394,4975278,4978757,4994578,5037993,5070092,5084468,5101038,5117006,5137877,5138059,5147786,5187186,5223409,5225539,5288514,5324483,5332740,5332837,5334528,5403484,5427908,5475092,5495009,5530101,5545806,5547667,5569825,5571698,5573922,5580717,5585089,5585499,5587161,5595499,5606017,5622929,5625126,5629430,5633425,5641780,5660829,5661016,5686237,5693762,5703080,5712374,5714586,5739116,5739350,5770429,5773001,5773435,5786377 5786486,5789650,5814318,5846545,5874299,5877296,5877397,5885793,5939598,5962216,5969108,5985908,6060608,6066742,6075181,6103236,6114598,6130237,6132722,6143901,6150584,6162963,6172197,6180370,6194612,6214345,6262271,6281354,6310209,6329497,6342480,6486326,6512101,6521404,6534660,6544731,6548530,6555313,6555693,6566336,6,586,618,6593081,6630579,6756397,6759509,6762179,6884869,6897034,6946455,7049316,7087600,7091186,7115573,7129261,7214663,7223837,7304032,7329507,7329760,7388026,7655660,7655661,7906545,和8012978。通过本专利申请的连接体连接的抗体-CC-1065类似物的偶联物的结构示例如CC01,CC02和CC03:
其中mAb是抗体;Z3为H,PO(OM1)(OM2),SO3M1,CH2PO(OM1)(OM2),CH3N(CH2CH2)2NC(O)-,O(CH2CH2)2NC(O)-,R1,或糖苷;X3为O,NH,NHC(O),OC(O),-C(O)O,R1或缺省;表示单键或双键;n,m1,m2,“——,”X1,X2,R1,R2与式(I)和(II)中的定义相同;R1’和R3’独立地为H或C1-C6直链或支链烷基;p是0-2000。此外,R1’可以是在本专利申请中描述的细胞毒性剂。
柔红霉素/多柔比星类似物也优选用于以本专利申请的连接体连接的偶联物。优选化合物的结构及其合成可见于Hurwitz,E.,等,Cancer Res.35,1175-81(1975).Yang,H.M.,和Reisfeld,R.A.,Proc.Natl.Acad.Sci.85,1189-93(1988);Pietersz,C.A.,E.,等,Cancer Res.48,926-311(1988);Trouet,等,79,626-29(1982);Z.Brich等,J.ControlledRelease,19,245-58(1992);Chen等,Syn.Comm.,33,2377-90,2003;King等,Bioconj.Chem.,10,279-88,1999;King等,J.Med.Chem.,45,4336-43,2002;Kratz等,J MedChem.45,5523-33,2002;Kratz等,Biol Pharm Bull.Jan.21,56-61,1998;Lau等,Bioorg.Med.Chem.3,1305-12,1995;Scott等,Bioorg.Med.Chem.Lett.6,1491-6,1996;Watanabe等,Tokai J.ExperimentalClin.Med.15,327-34,1990;Zhou等,J.Am.Chem.Soc.126,15656-7,2004;WO 01/38318;美国专利5106951;5122368;5146064;5177016;5208323;5824805;6146658;6214345;7569358;7803903;8084586;8053205.通过本专利申请的连接体连接的抗体-CC-1065类似物的偶联物结构示例如Da01,Da02,Da03和Da04:
其中mAb是抗体或细胞结合分子;表示单键或双键;n,m1,X1,X2,L1,L2,和R1与式(I)和(II)中的定义相同;R1’和R3’独立地为H或C1-C6直链或支链烷基;p是0-2000。此外,R1’可以是本专利申请中描述的细胞毒性剂。
澳瑞他汀和多拉司他汀优选用于以本专利申请的连接体连接的偶联物。澳瑞他汀(如多澳瑞他汀E(AE),澳瑞他汀EB(AEB),澳瑞他汀EFP(AEFP),单甲基澳瑞他汀E(MMAE),单甲基澳瑞他汀F(MMAF),澳瑞他汀F苯二胺(AFP)和MMAE的苯丙氨酸变体)是多拉司他汀的类似物,在如下文献中有描述:Int.J.Oncol.15:367-72(1999);Molecular CancerTherapeutics,vol.3,No.8,pp.921-32(2004);美国专利11134826,20060074008,2006022925,4414205,4753894,4764368,4816444,4879278,4943628,4978744,5122368,5165923,5169774,5286637,5410024,5521284,5530097,5554725,5585089,5599902,5629197,5635483,5654399,5663149,5665860,5708146,5714586,5741892,5767236,5767237,5780588,5821337,5840699,5965537,6004934,6033876,6034065,6048720,6054297,6054561,6124431,6143721,6162930,6214345,6239104,6323315,6342219,6342221,6407213,6569834,6620911,6639055,6884869,6913748,7090843,7091186,7097840,7098305,7098308,7498298,7375078,7462352,7553816,7659241,7662387,7745394,7754681,7829531,7837980,7837995,7902338,7964566,7964567,7851437,7994135。通过桥连接体连接的抗体-澳瑞他汀偶联物结构的实例如Au01,Au02,Au03,Au04,Au05,Au06,Au07,Au08,Au09,Au10,Au11,Au12和Au13:
其中n,m1,m2,X1,X2,R1,R2,R3,R4和R5与式(I)或(II)或(III)中的定义相同;mAb是抗体或细胞结合分子;L1,L2,L3,L4,和L5定义同式(I)中L1;Z3’是H,OP(O)(OM1)(OM2),OOCCH3,OC水P(O)(OM1)(OM2),OSO3M1,R1,或O-糖苷(葡萄糖苷,半乳糖苷,甘露糖苷,葡萄糖醛酸苷,异香糖苷,果糖苷等),NH-糖苷,S-糖苷或CH2-糖苷;另外,两个R,R1R2,R2R3,R1R3或R3R4可以形成3~8元环状烷基,芳基,杂芳基,杂烷基或烷基环烷基;X3为H,CH3或X1’R1’,其中X1’为NH,N(CH3),NHNH,O或S,R1’为H或C1-C8的直链或支链烷基,芳基,杂芳基,杂烷基,烷基环烷基,酰氧基胺;R3’是H或C1-C6直链或支链烷基;p为0-2000;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3;此外,R1’,Drug1和Drug2可以是本专利申请中描述的细胞毒性剂。
苯并二氮卓二聚体(例如吡咯并苯二氮卓(PBD),托美霉素,吲哚并苯并二氮卓,咪唑并苯并噻二氮卓或恶唑烷并苯并二氮卓的二聚体)是本发明中优选的细胞毒性分子,在本领域的文献中也有描述:美国专利8163736;8153627;8034808;7834005;7741319;7704924;7691848;7678787;7612062;7608615;7557099;7528128;7528126;7511032;7429658;7407951;7326700;7312210;7265105;7202239;7189710;7173026;7109193;7067511;7064120;7056913;7049311;7022699;7015215;6979684;6951853;6884799;6800622;6747144;6660856;6608192;6562806;6977254;6951853;6909006;6344451;5880122;4935362;4764616;4761412;4723007;4723003;4683230;4663453;4508647;4464467;4427587;4000304;美国专利申请20100203007,20100316656,20030195196。通过本发明连接体连接的的抗体-苯并二氮杂二聚体偶联物的结构示例如PB01,PB02,PB03,PB04,PB05,PB06,PB07,PB08,PB09,PB10和PB11:
其中mAb是抗体;X3是CH2,O,NH,NHC(O),NHC(O)NH,C(O),OC(O),OC(O)(NR3),R1,NHR1,NR1,C(O)R1或缺省;X4为CH2,C(O),C(O)NH,C(O)N(R1),R1,NHR1,NR1,C(O)R1or C(O)O;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3;表示单键或双键;n,m1,m2,X1,X2,L1,L2,R1,R2和R3与式(I)和(II)中的定义相同。R1’和R3’独立地为H或C1-C6直链或支链烷基;p是0-2000。此外,R1’可以是本专利申请中描述的细胞毒性剂。
鹅膏毒肽是至少十种最初在几种有毒蘑菇属中,最著名的是毒鹅膏和几种其他蘑菇种类,发现的有毒化合物,也优选用于以本专利申请的连接体连接的偶联物。目前,十种已知的鹅膏毒肽,α-鹅膏蕈碱,β-鹅膏蕈碱,γ-鹅膏蕈碱,ε-鹅膏蕈碱,鹅膏无毒环肽,一羟鹅膏毒肽羧酸,鹅膏毒肽酰胺,三羟鹅膏毒肽和鹅膏毒肽酰胺原为刚性双环多肽,其合成始于35个氨基酸的前蛋白,最终的八个氨基酸由脯氨酰寡肽酶切割而产生(Litten,W.1975Scientific American 232(3):90–101;H.E.Hallen,等2007Proc.Nat.Aca.Sci.USA104,19097–101;.K.Baumann,等,1993Biochemistry 32(15):4043–50;Karlson-Stiber C,Persson H.2003,Toxicon 42(4):339–49;Horgen,P.A.等1978Arch.Microbio.118(3):317-9)。鹅膏毒肽通过抑制RNA聚合酶II(Pol II)和关闭基因转录和蛋白质生物合成来杀死细胞(Brodner,O.G.和Wieland,T.1976Biochemistry,15(16):3480–4;Fiume,L.,CurrProbl Clin Biochem,1977,7:23-8;Karlson-Stiber C,Persson H.2003,Toxicon 42(4):339–49;Chafin,D.R.,Guo,H.&Price,D.H.1995J.Biol.Chem.270(32):19114–19;Wieland(1983)Int.J.Pept.Protein Res.22(3):257-76.)。鹅膏毒肽可以从采集的毒鹅膏蘑菇中获得(Yocum,R.R.1978Biochemistry 17(18):3786-9;Zhang,P.等,2005,FEMSMicrobiol.Lett.252(2),223-8),或用担子菌发酵(Muraoka,S.和Shinozawa T.,2000J.BiosciBioeng.89(1):73-6,美国专利申请20100267019)或用A.fissa进行发酵,或通过培养盔孢伞束状带或黄褐盔孢伞而生成(WO/1990/009799,JP11137291)。然而,这些分离和发酵的方式的产量非常低(低于5mg/L培养物)。在过去的三十年中,也有鹅膏毒肽类和它们的类似物的化学合成方法的报道(W.E.Savige,A.Fontana,Chem.Commun.1976,600–1;Zanotti,G.,等,Int J Pept Protein Res,1981.18(2):162-8;Wieland,T.,等,Eur.J.Biochem.1981,117,161–4;P.A.Bartlett,等,Tetrahedron Lett.1982,23,619–22;Zanotti,G.,等,Biochim Biophys Acta,1986.870(3):454-62;Zanotti,G.,等,Int.J.Peptide Protein Res.1987,30,323–9;Zanotti,G.,等,Int.J.Peptide ProteinRes.1987,30,450–9;Zanotti,G.,等,Int J Pept Protein Res,1988.32(1):9-20;G.Zanotti,T.等,Int.J.Peptide Protein Res.1989,34,222–8;Zanotti,G.,等,Int JPept Protein Res,1990.35(3):263-70;Mullersman,J.E.和J.F.Preston,3rd,Int JPept Protein Res,1991.37(6):544-51;Mullersman,J.E.,等,Int J PeptProtein Res,1991.38(5):409-16;Zanotti,G.,等,Int J Pept Protein Res,1992.40(6):551-8;Schmitt,W.等,J.Am.Chem.Soc.1996,118,4380–7;Anderson,M.O.,等,J.Org.Chem.,2005,70(12):4578-84;J.P.May,等,J.Org.Chem.2005,70,8424–30;F.Brueckner,P.Cramer,Nat.Struct.Mol.Biol.2008,15,811–8;J.P.May,D.M.Perrin,Chem.Eur.J.2008,14,3404–9;J.P.May,等,Chem.Eur.J.2008,14,3410–17;Q.Wang,等,Eur.J.Org.Chem.2002,834–9;May,J.P.和D.M.Perrin,Biopolymers,2007.88(5):714-24;May,J.P.,等,Chemistry,2008.14(11):3410-7;S.De Lamo Marin,等,Eur.J.Org.Chem.2010,3985–9;Pousse,G.,等,Org Lett,2010.12(16):3582-5;Luo,H.,等,Chem Biol,2014.21(12):1610-7;Zhao,L.,等,Chembiochem,2015.16(10):1420-5),并且这些大部分是通过部分合成实现的。由于其极高的效力和独特的细胞毒性机制,鹅膏毒肽已被用作偶联物的有效载荷(Fiume,L.,Lancet,1969.2(7625):853-4;Barbanti-Brodano,G.和L.Fiume,Nat New Biol,1973.243(130):281-3;Bonetti,E.,M.等,Arch Toxicol,1976.35(1):p.69-73;Davis,M.T.,Preston,J.F.Science 1981,213,1385–1388;Preston,J.F.,等,Arch Biochem Biophys,1981.209(1):63-71;H.Faulstich,等,Biochemistry 1981,20,6498–504;Barak,L.S.,等,Proc Natl Acad Sci U S A,1981.78(5):3034-8;Faulstich,H.和L.Fiume,MethodsEnzymol,1985.112:225-37;Zhelev,Z.,A.等,Toxicon,1987.25(9):981-7;Khalacheva,K.,等,Eksp MedMorfol,1990.29(3):26-30;U.Bermbach,H.Faulstich,Biochemistry1990,29,6839–45;Mullersman,J.E.和J.F.Preston,Int.J.Peptide Protein Res.1991,37,544–51;Mullersman,J.E.和J.F.Preston,Biochem Cell Biol,1991.69(7):418-27;J.Anderl,H.Echner,H.Faulstich,Beilstein J.Org.Chem.2012,8,2072–84;Moldenhauer,G.,等,J.Natl.Cancer Inst.2012,104,622–34;A.Moshnikova,等;Biochemistry 2013,52,1171–8;Zhao,L.,等,Chembiochem,2015.16(10):1420-5;Zhou,B.,等,Biosens Bioelectron,2015.68:189-96;WO2014/043403,US20150218220,EP1661584)。我们也一直在研究鹅膏毒肽的偶联。通过本发明中的连接体连接的抗体-鹅膏毒肽偶联物结构的实例如Am01,Am02,Am03,Am0和Am05:
其中mAb是抗体;X3为CH2,O,NH,NHC(O),NHC(O)NH,C(O),OC(O),OC(O)(NR3),R1,NHR1,NR1,C(O)R1或缺省;R7,R8,R9,R10和R11独立地为H,OH,OR1,NH2,NHR1,C1-C6烷基或缺省;Y1为O,O2,S,NH或缺省;表示单键或双键;n,m1,m2,X1,X2,L1,L2,R1,R2和R3与式(I)和(II)中的定义相同。R1’和R3’独立地为H或C1-C6直链或支链烷基;p是0-2000。此外,R1’可以是本专利申请中描述的细胞毒性剂。/>
在另一个实施方案中,优选两个或更多细胞毒性剂通过本专利申请的连接体偶联至细胞结合分子。两个或更多细胞毒性剂可以选自下列分子的任意组合:tubulysin,美登木素生物碱类,紫杉烷类,CC-1065类似物,柔红霉素或多柔比星化合物,苯并二氮卓二聚体(例如吡咯并苯二氮卓(PBD),托美霉素,吲哚并苯并二氮卓,咪唑并苯并噻二氮卓或恶唑烷并苯并二氮卓的二聚体),加利车霉素或烯二炔抗生素,放线菌素,重氮丝氨酸,博来霉素,表柔比星,艾日布林,他莫昔芬,伊达比星,多拉司他汀,澳瑞他汀衍生物(例如MMAE,MMAF,澳瑞他汀PYE,澳瑞他汀TP,澳瑞他汀2-AQ,6-AQ,EB(AEB)和EFP(AEFP)),多卡霉素,格尔德霉素,甲氨喋呤,噻替派,长春地辛,长春新碱,半米塔林,nazumamide,microginin,放射敏素,alterobactins,microsclerodermins,theonellamides,esperamicins,PNU-159682,及其上述化合物的类似物和衍生物。通过连接体连接两种或更多种不同细胞毒性剂的偶联物结构的实例Z01,Z02,Z02,Z04,Z05,Z06,Z07,Z08,Z09,Z10,Z12,Z13,Z14,Z15,Z16,Z17和Z18:
其中mAb是抗体;X3和X3’独立地为CH2,O,NH,NHC(O),NHC(O)NH,C(O),OC(O),OC(O)(NR3),R1,NHR1,NR1,C(O)R1或缺省;X4和X4’独立地为H,CH2,OH,O,C(O),C(O)NH,C(O)N(R1),R1,NHR1,NR1,C(O)R1或C(O)O;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3;n,m1,m2,“——”,X1,X2,R1,R2和R3与式(I)和(II)中的定义相同。另外,R1和/或R2可以独立地缺省。
在另一个实施例中,免疫毒素可以通过本专利申请的连接体与细胞结合分子偶联。本专利申请中的免疫毒素是大分子药物,通常是源自细菌或植物蛋白的细胞毒性蛋白,例如白喉毒素(DT),霍乱毒素(CT),天花粉蛋白(TCS),Dianthin,假单胞菌外毒素A(ETA’),红细胞毒素,白喉毒素,AB毒素,TypeIII型外毒素等。它也可能是一种剧毒的细菌成孔原毒素,需要蛋白水解加工才能被激活。这种原毒素的一个例子是proaerolysin及它被基因改造的分子topsalysin。Topsalysin是一种经过改造的重组蛋白,经过改造后可以被前列腺中的酶选择性激活,导致局部细胞死亡和组织破坏,而不会损伤邻近的组织和神经。
在另一个实施例中,细胞结合配体或细胞受体激动剂可以通过本专利申请的连接体与细胞结合分子偶联。这些偶联的细胞结合配体或细胞受体激动剂,特别是抗体-受体偶联物,不仅可以作为靶向导体/导向剂将偶联物递送至恶性细胞,还可以用于调节或共刺激期望的免疫反应或改变信号传导途径。
在免疫疗法中,细胞结合配体或受体激动剂优选与TCR(T细胞受体)T细胞,或CAR(嵌合抗原受体)T细胞或B细胞受体(BCR),自然杀伤(NK)细胞或细胞毒性细胞的抗体偶联。抗体优选为抗CD3,CD4,CD8,CD16(FcγRIII),CD27,CD40,CD40L,CD45RA,CD45RO,CD56,CD57,CD57bright,TNFβ,Fas配体,MHC I类分子(HLA-A,B,C)或NKR-P1。细胞结合配体或受体激动剂选自,但不限于:叶酸衍生物(与叶酸受体结合,卵巢癌和其他恶性肿瘤中过表达的蛋白质)(Low,P.S.等2008,Acc.Chem.Res.41,120-9);谷氨酸脲衍生物(与前列腺特异性膜抗原结合,前列腺癌细胞的表面标记物)(Hillier,S.M.等,2009,Cancer Res.69,6932-40);生长抑素(也称为生长激素抑制激素(GHIH)或生长激素释放抑制因子(SRIF))或生长激素释放抑制激素)及其类似物,如澳曲肽(Sandostatin)和兰瑞肽(Somatuline)(特别用于神经内分泌肿瘤,分泌GH垂体腺瘤,副神经节瘤,无功能性垂体腺瘤,嗜铬细胞瘤)(Ginj,M.,等,2006,Proc.Natl.Acad.Sci.U.S.A.103,16436-41);一般而言,生长抑素及其受体亚型(sst1,sst2,sst3,sst4和sst5)已在许多类型的肿瘤中被发现,如神经内分泌肿瘤,特别是在分泌GH的垂体腺瘤(Reubi J.C.,Landolt,A.M.1984J.Clin.Endocrinol Metab 59:1148–51;Reubi J.C.,Landolt A.M.1987J Clin Endocrinol Metab 65:65–73;Moyse E,等,J Clin Endocrinol Metab 61:98–103),胃肠胰腺肿瘤(Reubi J.C.,等,1987J ClinEndocrinol Metab 65:1127–34;Reubi,J.C,等,1990Cancer Res 50:5969–77),嗜铬细胞瘤(Epel-baum J,等1995J ClinEndocrinol Metab 80:1837–44;Reubi J.C.,等,1992JClin Endocrinol Metab 74:1082–9),成神经细胞瘤(Prevost G,1996Neuroendocrinology 63:188–197;Moertel,C.L,等1994Am J Clin Path 102:752–756),甲状腺髓样癌(Reubi,J.C,等1991Lab Invest 64:567–573),小细胞肺癌(Sagman U,等,1990Cancer 66:2129–2133),非神经内分泌肿瘤包括脑肿瘤如脑膜瘤,成神经管细胞瘤或神经胶质瘤(Reubi J.C.,等1986J Clin Endocrinol Metab 63:433–8;Reubi J.C.,等1987Cancer Res 47:5758–64;Fruhwald,M.C,等1999Pediatr Res 45:697–708),乳腺癌(Reubi J.C.,等1990Int J Cancer 46:416–20;Srkalovic G,等1990J Clin EndocrinolMetab 70:661–669),淋巴瘤(Reubi J.C.,等1992,Int J Cancer50:895–900),肾细胞癌(Reubi J.C.,等1992,Cancer Res 52:6074–6078),间叶组织肿瘤(Reubi J.C.,等1996Cancer Res 56:1922–31),前列腺癌(Reubi J.C.,等1995,J.Clin.EndocrinolMetab80:2806–14;等1989,Prostate 14:191–208;Halmos G,等J.Clin.Endo-crinol Metab 85:2564–71),卵巢癌(Halmos,G,等,2000J Clin Endocrinol Metab 85:3509–12;ReubiJ.C.,等1991Am J Pathol 138:1267–72),胃癌(Reubi J.C.,等1999,Int J Cancer 81:376–86;Miller,G.V,1992Br J Cancer 66:391–95),肝细胞癌(Kouroumalis E,等1998Gut42:442–7;Reubi J.C.,等1999Gut 45:66–774)和鼻咽癌(Loh K.S,等,2002 VirchowsArch 441:444–8);某些芳香磺酰胺类化合物,尤其是碳酸酐酶IX特异性的(缺氧和肾细胞癌标志物)(Neri,D.,等,Nat.Rev.Drug Discov.2011,10,767-7);垂体腺苷酸环化酶激活肽(PACAP)(PAC1),用于嗜铬细胞瘤和副神经节瘤;血管活性肠肽(VIP)及其受体亚型(VPAC1,VPAC2),用于肺癌,胃癌,结肠癌,直肠癌,乳腺癌,前列腺癌,胰腺导管癌,肝癌,膀胱癌和上皮肿瘤的癌症;各种肿瘤的α-黑素细胞刺激激素(α-MSH)受体;胆囊收缩素(CCK)/胃泌素受体及其受体亚型(CCK1(以前称为CCK-A)和CCK2),用于小细胞肺癌,甲状腺髓样癌,星形细胞瘤,胰岛素瘤和卵巢癌;蛙皮素(Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2)/胃泌素释放肽(GRP)及其受体亚型(BB1,GRP受体亚型(BB2),BB3和BB4),用于肾细胞癌,乳腺癌,肺癌,胃癌和前列腺癌以及神经母细胞瘤和神经母细胞瘤(Ohlsson,B.,等,1999,Scand.J.Gastroenterology 34(12):1224–9;Weber,H.C.,2009,Cur.Opin.Endocri.Diab.Obesity 16(1):66–71,Gonzalez N,等,2008,Cur.Opin.Endocri.Diab.Obesity 15(1),58-64);神经降压素受体及其受体亚型(NTR1,NTR2,NTR3),用于小细胞肺癌,成神经细胞瘤,胰腺癌,结肠癌和尤因肉瘤;物质P受体及其受体亚型(例如神经胶质肿瘤的NK1受体,Hennig I.M.,等1995Int.J.Cancer 61,786–792);神经肽Y(NPY)受体及其受体亚型(Y1-Y6),用于乳腺癌;归巢肽包括RGD(Arg-Gly-Asp),NGR(Asn-Gly-Arg),二聚和多聚环状RGD肽(如cRGDfV),可识别肿瘤表面上的受体(整联蛋白)(Laakkonen P,Vuorinen K.Integr Biol(Camb)),2010,2(7–8):326–337;Chen K,Chen X.Theranostics.2011,1:189–200;Garanger E,等,Anti-Cancer Agents MedChem.7(5):552–558;Kerr,J.S.等,Anticancer Research,19(2A),959-968;Thumshirn,G,等,Chem.Eur.J.2003,9,2717-2725),和TAASGVRSMH或LTLRWVGLMS(硫酸软骨素蛋白多糖NG2受体)和F3肽(结合细胞表面表达的核素受体的31个氨基酸的肽)(Zitzmann,S.,CancerRes.,2002,62,18,pp.5139–5143,Temminga,K.,Drug Resistance Updates,2005,8,381–402;P.Laakkonen和K.Vuorinen,Integrative Biol,2010,2(7-8),326–337;M.A.Burg,Cancer Res.,1999,59(12),2869–2874;K.Porkka,等Proc.Nat.Acad.Sci.USA 2002,99(11),7444-9);细胞穿透肽(Nakase I,等,J.Control Release.2012,159(2),181–188);肽激素,如促黄体激素释放激素(LHRH)激动剂和拮抗剂,和促性腺激素释放激素(GnRH)激动剂,通过靶向卵泡刺激素(FSH)和黄体生成素(LH)以及睾酮生成起作用,例如布舍瑞林(Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-NHEt),戈那瑞林(Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2),戈舍瑞林(Pyr-His-Trp-Ser-Tyr-D-Ser(OtBu)-Leu-Arg-Pro-AzGly-NH2),组氨瑞林(Pyr-His-Trp-Ser-Tyr-D-His(N-benzyl)-Leu-Arg-Pro-NHEt),醋酸亮丙瑞林(Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt),那法瑞林(Pyr-His-Trp-Ser-Tyr-2Nal-Leu-Arg-Pro-Gly-NH2),曲普瑞林(Pyr-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2),那法瑞林,德舍瑞林,阿巴瑞克(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-(N-Me)Tyr-D-Asn-Leu-isopropylLys-Pro-DAla-NH2),西曲瑞克(Ac-D-2Nal-D-4-chloro-Phe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2),加瑞克(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-4-aminoPhe(L-hydroorotyl)-D-4-aminoPhe(carba-moyl)-Leu-isopropylLys-Pro-D-Ala-NH2)和加尼瑞克(Ac-D-2Nal-D-4-chloroPhe-D-3-(3-pyridyl)Ala-Ser-Tyr-D-(N9,N10-diethyl)-homoArg-Leu-(N9,N10-diethyl)-homoArg-Pro-D-Ala-NH2)(Thundimadathil,J.,J.AminoAcids,2012,967347,doi:10.1155/2012/967347;Boccon-Gibod,L.;等,TherapeuticAdvances in Urology 2011,3(3):127–140;Debruyne,F.,Future Oncology,2006,2(6),677–696;Schally A.V;Nagy,A.Eur JEndocrinol 1999,141:1–14;Koppan M,等Prostate1999,38:151–158);和模式识别受体(PRR),如Toll样受体(TLR),C型凝集素和Nodlike受体(NLRs)(Fukata,M.,等,Semin.Immunol.2009,21,242–253;Maisonneuve,C.,等,Proc.Natl.Acad.Sci.U.S.A.2014,111,1–6;Botos,I.,等,Structure 2011,19,447–459;Means,T.K.,等,Life Sci.2000,68,241–258),其范围从小分子(咪喹莫特,鸟嘌呤和腺苷类似物)到大而复杂的生物大分子如脂多糖(LPS),核酸(CpG DNA,polyI:C)和脂肽(Pam3CSK4)(Kasturi,S.P.,等,2011,Nature 470,543–547;Lane,T.,2001,J.R.Soc.Med.94,316;Hotz,C.,和Bourquin,C.,2012,Oncoimmunology 1,227-228;Dudek,A.Z.,等,2007,Clin.Cancer Res.13,7119–25);降钙素受体,一种32-氨基酸神经肽,在很大程度上通过其对破骨细胞和肾脏的作用来调节钙水平(Zaidi M,等,1990Crit Rev ClinLab Sci 28,109–174;Gorn,A.H.,等1995J Clin Invest 95:2680–91);整合素受体及其受体亚型(例如αVβ1,αVβ3,αVβ5,αVβ6,α6β4,α7β1,αLβ2,αIIbβ3等),其通常在血管发生中起重要作用,在各种细胞的表面上表达,特别是破骨细胞,内皮细胞和肿瘤细胞(Ruoslahti,E.等,1994Cell 77,477-8;Albelda,S.M.等,1990Cancer Res.,50,6757-64);短肽,GRGDSPK和环状RGD五肽,如环(RGDfV)(L1)及其衍生物[cyclo(-N(Me)R-GDfV),cyclo(R-Sar-DfV),cyclo-(RG-N(Me)D-fV),cyclo(RGD-N(Me)f-V),cyclo(RGDf-N(Me)V-)(西仑吉肽)]已显示与整合素受体的高结合亲和力(Dechantsreiter,M.A.等,J.Med.Chem.1999,42,3033-40,Goodman,S.L.,等,J.Med.Chem.2002,45,1045-51)。
细胞结合分子或配体或细胞受体激动剂可以是基于Ig和非基于Ig的蛋白质支架分子。基于Ig的支架可以选自,但不限于,纳米抗体(VHH的衍生物(骆驼科动物Ig))(Muyldermans S.,2013Annu Rev Biochem.82,775–97);结构域抗体(dAb,VH或VL结构域的衍生物)(Holt,L.J,等,2003,Trends Biotechnol.21,484–90);双特异性T细胞接头(BiTE、双特异性双抗体)(Baeuerle,P.A等,2009,Curr.Opin.Mol.Ther.11,22–30);双重亲和力重定向剂(DART,双特异性双抗体)(Moore PA P等.2011,Blood 117(17),4542–51);四价串联抗体(T和Ab,、二聚双特异性双抗体)(Cochlovius,B等.2000,Cancer Res.60(16):4336–4341)。非Ig支架可以选自,但不限于,Anticalin(Lipocalins的衍生物)(Skerra A.2008,FEBS J.,275(11):2677–83;Beste G等,1999Proc.Nat.Acad.USA.96(5):1898–903;Skerra,A.2000BiochimBiophys Acta,1482(1-2):337–50;Skerra,A.2007,Curr OpinBiotechnol.18(4):295–304;Skerra,A.2008,FEBS J.275(11):2677–83);Adnectin(第10个FN3(纤连蛋白))(Koide,A等,1998J.Mol.Biol.,284(4):1141–51;Batori V,2002,Protein Eng.15(12):1015–20;Tolcher,A.W,2011,Clin.Cancer Res.17(2):363–71;Hackel,B.J,2010,Protein Eng.Des.Sel.23(4):211–19);设计的锚蛋白重复蛋白(DARPins)(锚蛋白重复(AR)蛋白的衍生物)(Boersma,Y L等,2011Curr OpinBiotechnol.22(6):849–57),例如DARPin C9、DARPin Ec4及DARPinE69_LZ3_E01(WinklerJ等,2009Mol Cancer Ther.8(9),2674–83;Patricia MK.M.等,Clin Cancer Res.2011;17(1):100–10;Boersma Y.L等,2011J.Biol.Chem.286(48),41273–85);高亲和性多聚体(域A/低密度脂蛋白(LDL)受体)(Boersma Y.L,2011J.Biol.Chem.286(48):41273–41285;Silverman J等,2005Nat.Biotechnol.,23(12):1556–61)。
通过本专利申请的连接体连接的抗体-细胞结合配体或抗体-细胞受体激动剂的偶联物示例如下:LB01(叶酸偶联物),LB02(PMSA配体偶联物),LB03(PMSA配体偶联物),LB04(生长抑素偶联物),LB05(澳曲肽,生长抑素类似物偶联物),LB06(兰瑞肽,生长抑素类似物偶联物),LB07(Vapreotide(Sanvar),生长抑素类似物偶联物),LB08(CAIX配体偶联物),LB09(CAIX配体偶联物),LB10(胃泌素释放肽受体(GRPr),MBA偶联物),LB11(促黄体激素释放激素(LH-RH)和GnRH配体偶联物),LB12(促黄体激素释放激素(LH-RH)和GnRH配体偶联物),LB13(GnRH拮抗剂,Abarelix偶联物),LB14(钴胺素,维生素B12类似物偶联物),LB15(钴胺素,维生素B12类似物)偶联物),LB16(αvβ3整联蛋白受体的环状RGD五肽偶联物),LB17(VEGF受体的异二价肽配体偶联物),LB18(神经介素B偶联物),LB19(G蛋白偶联受体的铃蟾肽偶联物),LB20(类Toll受体的TLR2偶联物),L B21(雄激素受体偶联物),LB22(αv整合素受体的西仑吉肽/环(RGDfV)偶联物,LB23(氟氢可的松偶联物),LB24(丙酸氟替卡松偶联物),LB25(丙酸倍氯米松偶联物),LB26(二丙酸倍氯米松偶联物),LB27(曲安奈德偶联物),LB28(泼尼松偶联物),LB29(泼尼松龙偶联物),LB30(甲泼尼松龙偶联物),LB32(伊立替康类似物偶联物),LB33(克唑替尼类似物偶联物),LB34(硼替佐米类似物偶联物),LB35(Carfilzomib类似物偶联物),LB36(Carfilzomib类似物偶联物),LB37(Leuprolide类似物偶联物),LB38(Triptorelin类似物偶联物),LB39(Liraglutide类似物偶联物),LB40(Semaglutide类似物偶联物)和LB41(Lixisenatide类似物偶联物),其结构示例如下:
LB34(硼替佐米类似物偶联物),其中Y1,Y2独立的为N,CH,C(Cl),C(CH3),C(COOR1),R1为H,C1-C6烷基,芳基C3-C8,
其中mAb为抗体;X3为CH2,O,NH,NHC(O),NHC(O)NH,C(O),OC(O),OC(O)(NR3),R1,NHR1,NR1,C(O)R1或缺省;X4为H,CH2,OH,O,C(O),C(O)NH,C(O)N(R1),R1,NHR1,NR1,C(O)R1orC(O)O;X5为H,CH3,F,或Cl;M1和M2独立地为H,Na,K,Ca,Mg,NH4,NR1R2R3;R6为5’-脱氧腺苷,Me,OH,或CN;为单间或者双键;m1,m2,n,“——,”X1,X2,R1和R2与式(I)中定义相同。此外,R1可缺省,R2可为H。
在另一个实施例中,一种,两种或多种DNA,RNA,mRNA,小干扰RNA(siRNA),微RNA(miRNA)和PIWI相互作用RNA(piRNA)是本发明中优选的分子,通过本专利申请的连接体与细胞结合分子偶联。已知小RNA(siRNA,miRNA,piRNA)和长的非编码反义RNA负责细胞内的表观遗传变化(Goodchild,J(2011),Methods in molecular biology(Clifton,N.J.),764:1–15)。本文中的DNA,RNA,mRNA,siRNA,miRNA或piRNA可以是单链或双链,核苷酸单元为3至1百万,其中一些核苷酸可以是非天然(合成)形式,例如具有硫代磷酸酯键的寡核苷酸,例如Fomivirsen,或核苷酸通过硫代磷酸酯键连接而不是天然RNA和DNA的磷酸二酯键,分子中间的糖是脱氧核糖,在两端是2’-O-甲氧基乙基修饰的核糖,例如Mipomersen,或由肽核酸(PNA),吗啉代,硫代磷酸酯,硫代氨基磷酸酯,或2’-O-甲氧基乙基(MOE),2’-O-甲基,2’-氟,锁核酸(LNA),或核糖的双环核酸(BNA)产生的寡核苷酸,或核酸被修饰以去除糖环中的2’-3’碳键(Whitehead,K.A.;等(2011),Annual Review of Chemical andBiomolecular Engineering 2:77–96;Bennett,C.F.;Swayze,E.E.(2010),Annu.Rev.Pharmacol.Toxicol.50:259–29)。优选地,寡核苷酸的长度范围为约8至超过100个核苷酸。偶联物结构的例子如下所示:
其中mAb,m1,m2,n,X1,X2,X3,X4,R1’,R2’,L1,L2,L3,L4,“——”,与式(I)或前文中的定义相同;/>是单链或双链的DNA,RNA,mRNA,siRNA,miRNA,或piRNA;X5的定义与X1相同;Y和Y’是O,S,NH或CH2.
在另一个实施例中,一种,两种或多种不同功能的分子或药物与IgG抗体偶联,优选在轻链和重链之间的一对巯基(通过还原二硫键),两条重链之间的上部巯基和两条重链之间的下部巯基特异性偶联,如以下结构ST1,ST2,ST3,ST4,ST5,ST6,ST7或ST8所示:
其中X1,X1’,X2,X2’,X3,X3’,X4,X4’,L1,L1’,L2,L2’,L3,L3’,L4,L4’,和T的定义与式(I)中X1相同;另外,X1,X1’,X2,X2’,X3,X3’,X4和X4’可以缺省。
在另一个实施方案中,包含治疗有效量的式(II)的偶联物或本专利申请描述的任何偶联物的药物组合物可以与其他治疗剂,如有效治疗或预防癌症或自身免疫疾病或传染病的化学治疗剂,放射疗法,免疫治疗剂,自身免疫病症剂,抗感染剂或其他偶联物协同给药。协同剂优选自以下一种或几种药物:阿巴西普(Orencia),醋酸阿比特龙 对乙酰氨基酚/氢可酮,阿达木单抗,阿法替尼二马来酸盐/>Alectinib(Alecensa),alemtuzumab/>阿维A酸/>曲妥珠单抗emtansine(KadcylaTM),安非他命混合盐(苯丙胺/右旋安非他命或Adderall XR),阿那曲唑/>阿立哌唑,阿扎那韦,Atezolizumab(Tecentriq,MPDL3280A),阿托伐他汀,阿昔替尼/>AZD9291,Belinostat(BeleodaqTM),贝伐单抗/> Bortezomib(PS-341;Velcade,Neomib,Bortecad),Cabazitaxel/>Cabozantinib(Come-triqTM),贝沙罗汀/>Blinatumomab(BlincytoTM),Bortezomib/>波舒替尼/>brentuximabvedotin/>布地奈德,布地奈德/福莫特罗,丁丙诺啡,卡培他滨,carfilzomib塞来昔布,赛替尼(LDK378/Zykadia),西妥昔单抗/>Ciclosporin,Cinacalcet,Crizotinib(Xalkori),Cobimetinib(Cotellic),达比加群,达拉菲尼/>Daratumumab(Darzalex),Darbepoetin alfa,Darunavir,甲磺酸伊马替尼/>达沙替尼/>Denileukin,Diftitox/>Denosumab/>Depakote,Dexamethasone,右兰索拉唑,右旋哌甲酯,Dinutuximab(UnituxinTM),多西环素,度洛西汀,Durvalumab(MEDI4736),Elotuzumab(Empliciti),Emtricitabine/Rilpivirine/Tenofovir地索普西富马酸盐,Emtricitbine/替诺福韦/依法韦仑,依诺肝素,Enzalutamide/>依泊汀α,厄洛替尼/>埃索美拉唑,艾司佐匹克隆,依那西普,依维莫司/>依西美坦/>依维莫司/>依泽替米贝,依泽替米贝/辛伐他汀,非诺贝特,非格司亭,芬戈莫德,丙酸氟替卡松,氟替卡松/沙美特罗,氟维司群/>吉非替尼/>格拉替雷,醋酸戈舍瑞林(Zoladex),伊替替尼,伊马替尼(格列卫),伊布替莫单抗tiuxetan/>Ibrutinib(ImbruvicaTM),Idelalisib/>英夫利西单抗,Iniparib,门冬胰岛素,地特胰岛素,甘精胰岛素,赖脯胰岛素,干扰素β1a,干扰素β1b,拉帕替尼/>伊匹单抗/>异丙托溴铵沙丁胺醇,Ixazomib(Ninlaro),醋酸兰瑞肽(Som/>Depot),Ixazomi/>Kanuma,醋酸兰瑞肽(Somatuline Depot),来那度胺/>Lenvatinib(LenvimaTM),来曲唑/>左旋甲状腺素,利多卡因,利奈唑胺,利拉鲁肽,Lisdexamfetamine,MEDI4736(AstraZeneca,Celgene),美金刚,哌醋甲酯,美托洛尔,莫达非尼,莫米松,Necitumumab(Portrazza),Nilotinib/>Niraparib,Nivolumab澳法木单抗/>Obinutuzumab(GazyvaTM),澳拉帕尼(LynparzaTM),澳美沙坦,澳美沙坦/氢氯噻嗪,澳马珠单抗,澳米加-3脂肪酸乙酯,澳司他韦,Osimertinib(或Mereletinib,Tagrisso),羟考酮,Palbociclib/>帕利珠单抗,帕尼单抗Panobinostat/>帕唑帕尼/>派姆单抗/>培美曲塞(Alimta),帕妥珠单抗(PerjetaTM),肺炎球菌结合疫苗,Pomalidomide/>普瑞巴林,普萘洛尔,喹硫平,雷贝拉唑,镭223氯化物/>雷洛昔芬,拉替拉韦,雷莫芦单抗/>Ranibizumab,瑞格菲尼/>利妥昔单抗/> 利伐沙班,罗米地辛/>罗苏伐他汀,鲁索替尼磷酸盐(JakafiTM),沙丁胺醇,司维拉姆,西地那非,Siltuximab(SylvantTM),西他列汀,西他列汀/二甲双胍,索利那新,Sonidegib(LDE225,Odomzo),索拉非尼/>舒尼替尼/>他达拉非,他莫昔芬,Telaprevir,Talazoparib,Temsirolimus/> 替诺福韦/恩曲他滨,睾酮凝胶,沙利度胺(Immunoprin,Talidex),噻托溴铵,托瑞米芬/>Trametinib曲妥珠单抗,Trabectedin(Ecteinascidin 743,Yondelis),Trifluridinetipiracil(Lonsurf,TAS-102),维甲酸/>优特克单抗,缬沙坦,凡德他尼/>威罗菲尼/>Venetoclax(Venclexta),伏立诺他/>阿柏西普Zostavax以及它们的类似物、衍生物、药学上可接受的盐、载体、稀释剂或赋形剂,或其组合。
通过本专利申请的连接体偶联的药物/细胞毒性剂,可以是本专利申请中描述的药物/分子的任何类似物和/或衍生物。药物/细胞毒剂领域的专业技术人员可以理解,本发明所述的药物/细胞毒剂均可以被修饰,只要获得的化合物仍保留起始化合物的特异性和/或活性。本领域技术人员还会知道,可以使用这些化合物来代替本文所述的药物/细胞毒性剂。因此,本发明的药物/细胞毒性剂包括本文所述化合物的类似物和衍生物。
所有引用的参考文献以及下面的实施例中的全部参考文献都完整明确地并入了本文。
实施例
在以下实施例中对本发明进行了进一步描述,这些实施例并不旨在限制本发明的保护范围。本发明申请的中的细胞系,除非另有说明,都是根据美国典型培养物保藏中心(ATCC)或Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH,Braunschweig,Germany(DMSZ)或中国上海细胞培养研究所规定的条件,保存在培养物中。除非另有说明,否则细胞培养基是从Invitrogen Corp.获得的。商业途径获得所有无水溶剂在氮气下储存在Sure-seal瓶中。所有其他试剂和溶剂均以最高等级购买,无需进一步纯化即可使用。用Varain PreStar HPLC进行制备型HPLC分离。在Varian Mercury 400MHz仪器上记录NMR光谱。化学位移(δ)以百万分之一(ppm)为单位,以四甲基硅烷为基准,以0.00表示,偶联常数(J)以Hz表示。质谱数据在配备Waters Acquity UPLC分离模块和AcquityTUV检测器的Waters Xevo QTOF质谱仪上获得。
实施例1. 1,2-双(2-(叔丁氧基)-2-氧代乙基)肼-1,2-二甲酸二叔丁酯(38)的合成
向二叔丁基肼-1,2-二甲酸酯(37)(8.01g,34,4mmol)的DMF(150mL)溶液中加入NaH(60%在矿物油中,2.76g,68.8mmol)。在室温下搅拌30分钟后,加入2-溴乙酸叔丁酯(14.01g,72.1mmol)。将混合物搅拌过夜,加入甲醇(3mL)淬灭,浓缩,用乙酸乙酯(100mL)和水(100mL)稀释,分层,水层用乙酸乙酯(2×50mL)萃取。合并有机层,用硫酸镁干燥,过滤,浓缩,并通过硅胶柱层析(乙酸乙酯/己烷1:5至1:3)纯化,得到标题化合物(12.98g,82%收率),为无色油状物。MS ESI m/z C22H41N2O8[M+H]+计算值461.28,实测值461.40。
实施例2. 2,2’-(肼-1,2-二基)二乙酸(39)的合成。
向1,2-双(2-(叔丁氧基)-2-氧代乙基)肼-1,2-二甲酸二叔丁酯(6.51g,14.14mmol)的1,4-二恶烷(40mL)溶液中加入盐酸(12M,10mL)。将混合物搅拌30分钟,用二恶烷(20mL)和甲苯(40mL)稀释,浓缩并与二恶烷(20mL)和甲苯(40mL)共浓缩至干,得到用于下一步的粗品,无需进一步纯化(2.15g,103%收率,~93%纯度)。MS ESI m/z C4H9N2O4[M+H]+计算值149.05,实测值149.40。
实施例3. 2,2’-(1,2-双((E)-3-溴丙烯酰基)肼-1,2-二基)二乙酸(36)的合成
向2,2’-(肼-1,2-二基)二乙酸(1.10g,7.43mmol)的四氢呋喃(50mL)和NaH2PO4(0.1M,80mL,pH 6.0)溶液中加入(E)-3-溴丙烯酰溴(5.01g,23.60mmol)。将混合物搅拌6小时,浓缩并在硅胶柱上纯化,用含有3%甲酸的水/乙腈(1:9)洗脱,得到标题化合物(2.35g,77%收率,~93%纯度)。MS ESI m/z C10H11Br2N2O6[M+H]+计算值412.89,实测值413.50。
实施例4. 2,2’-(1,2-双((E)-3-溴丙烯酰基)肼-1,2-二基)二乙酰氯(41)的合成
向2,2’-(1,2-双((E)-3-溴丙烯酰基)肼-1,2-二基)二乙酸(210mg,0.509mmol)的二氯乙烷(15mL)溶液中加入(COCl)2(505mg,4.01mmol),然后加入0.040mL DMF。在室温下搅拌2小时后,将混合物浓缩并与二氯乙烷(2×20mL)和甲苯(2×15mL)共浓缩至干,得到标题粗产物(不稳定)(245mg,107%收率),无需进一步纯化,直接用于下一步骤。MS ESI m/zC10H9Br2Cl2N2O4[M+H]+计算值448.82,450.82,452.82,454.82,测定值448.60,450.60,452.60,454.60.。
实施例5. 2,8-二氧代-1,5-氧杂环辛烷-5-羧酸叔丁酯(47)的合成
在4℃下,1小时内,向3,3’-氮杂二苯基丙酸(42)(10.00g,62.08mmol)的氢氧化钠(1.0M,300mL)溶液中加入二碳酸二叔丁酯(22.10g,101.3mmol)的四氢呋喃(200mL)溶液。添加后,将混合物在4℃下搅拌2小时。用0.2M H3PO4小心地将混合物酸化至pH~4,真空浓缩,用二氯甲烷萃取,用无水硫酸钠干燥,浓缩并用快速硅胶色谱法纯化,用AcOH/MeOH/二氯甲烷(0.01:1:5)洗脱,得到3 3’-((叔丁氧基羰基)氮杂二基)二丙酸(46)(13.62g,84%收率)。ESI MS m/z C11H19NO6[M+H]+,实测值262.27,实测值262.40。
在0℃下,向3,3’-((叔丁氧基羰基)氮杂二基)二丙酸(8.0g,30.6mmol)的二氯甲烷(500mL)溶液中加入五氧化二磷(8.70g,61.30mmol)。将混合物在0℃下搅拌2小时,然后在室温下搅拌1小时,通过短硅胶柱过滤,并用乙酸乙酯/二氯甲烷(1:6)冲洗柱。浓缩滤液,用乙酸乙酯/正己烷打浆,得到标题化合物(47)(5.64g,74%收率)。ESI MS m/z C11H17NO5[M+H]+计算值244.11,实测值244.30。
实施例6. 2,5-二氧代吡咯烷-1-基丙酸酯(61)的合成
将丙酸(5.00g,71.4mmol),NHS(9.01g,78.3mmol)和EDC(20.0g,104.1mmol)加入二氯甲烷(150mL),然后和DIPEA(5mL,28.7mmol)搅拌过夜,浓缩并通过硅胶柱层析(乙酸乙酯/正己烷1:4)纯化,得到标题化合物(9.30g,79%产率),为无色油状物。1H-NMR(500MHz,CDCl3)δ2.68(s,1H),2.61(s,4H).MS ESI m/z C7H5NaNO4[M+Na]+计算值190.02,实测值190.20。
实施例7. 2-丙醇酰肼羧酸叔丁酯的合成(88)
将丙炔酸(5.00g,71.4mmol),肼基羧酸叔丁酯(9.45g,71.5mmol)和EDC(20.0g,104.1mmol)加入二氯甲烷(150mL)和DIPEA(5mL,28.7mmol)并搅拌过夜,浓缩并通过硅胶柱层析法(乙酸乙酯/正己烷1:5)纯化,得到标题化合物(7.92g,84%产率),为无色油状物。1H-NMR(500MHz,CDCl3)δ8.76(m,2H),2.68(s,1H),1.39(s,9H).MS ESI m/z C5H12NaN2O2[M+Na]+计算值为155.09,实测值155.26。
实施例8.丙炔酰肼盐酸盐(89)的合成
将2-丙醇酰肼羧酸叔丁酯(4.01g,30.35mmol)溶解于1,4-二恶烷(12mL)中并与4mL浓盐酸在4℃搅拌30分钟,用二恶烷(30mL)和甲苯(30mL)稀释,并在真空下浓缩。将粗品在硅胶柱上使用含甲醇(5%至10%)和1%甲酸的二氯甲烷溶液作为洗脱液纯化,得到标题化合物(2.11g,83%收率),ESI MS m/z C3H5N2O[M+H]+,计算值85.03,实测值85.30。
实施例9.(S,E)-2-甲基-N-(3-甲基丁-2-基)丙烷-2-磺酰胺(186)的合成
在室温,N2下,向(S)-2-甲基丙烷-2-亚磺酰胺(100g,0.825mol,1.0eq.)的四氢呋喃(1L)溶液中加入Ti(OEt)4(345mL,1.82mol,2.2eq.)和甲基-2-丁酮(81mL,0.825mol,1.0eq.)。将反应混合物回流16小时,然后冷却至室温并倒在冰水中。过滤混合物,之后用乙酸乙酯洗涤滤饼。分离有机层,用无水硫酸钠干燥并浓缩,得到残余物,将其通过真空蒸馏(15-20torr,95℃)纯化,得到标题产物(141g,90%收率),为黄色油状物。1H-NMR(500MHz,CDCl3)δ2.54–2.44(m,1H),2.25(s,3H),1.17(s,9H),1.06(dd,J=6.9,5.1Hz,6H).MS ESIm/z C9H19NaNOS[M+Na]+计算值212.12;实测值212.11。
实施例10.(2S,3S)-2-叠氮基-3-甲基戊酸(177)的合成
在0℃,向NaN3(20.0g,308mmol)的水(50mL)和二氯甲烷(80mL)的混合物中缓慢加入Tf2O(10mL,59.2mmol,2.0eq.)。然后在0℃下搅拌2小时,之后分出有机相,水相用二氯甲烷(2×40mL)萃取。将合并的有机相用饱和碳酸氢钠溶液洗涤并留用。将三氟甲磺酸叠氮化物的二氯甲烷溶液加入(L)-异亮氨酸(4.04g,30.8mmol,1.0eq.),K2CO3(6.39g,46.2mmol,1.5eq.),CuSO4.5H2O(77.4mg,0.31mmol,0.01eq.)的水(100mL)和甲醇(200mL)混合物中。将混合物在室温下搅拌16小时后减压除去有机溶剂,水相用水(250mL)稀释,用浓盐酸酸化至pH6,用磷酸盐缓冲液(0.25M,pH6.2,250mL)稀释。将水层用乙酸乙酯(5×100mL)洗涤以除去磺酰胺副产物,然后用浓盐酸酸化至pH 2,用乙酸乙酯(3×150mL)萃取。将合并的有机层用无水硫酸钠干燥,过滤并浓缩,得到标题产物(4.90g,99%收率),为无色油状物。1H-NMR(500MHz,CDCl3)δ12.01(s,1H),3.82(d,J=5.9Hz,1H),2.00(ddd,J=10.6,8.6,5.5Hz,1H),1.54(dqd,J=14.8,7.5,4.4Hz,1H),1.36–1.24(m,1H),1.08–0.99(m,3H),0.97–0.87(m,3H).
实施例11.D-N-甲基哌啶酸的合成
向D-哌啶酸(10.0g,77.4mmol,1.0eq.)的甲醇(100mL)溶液中加入甲醛(37%水溶液,30.8mL,154.8mmol,2.0eq.),然后加入Pd/C(10wt%,1.0g)。将反应混合物在H2(1atm)下搅拌过夜,然后通过硅藻土过滤,用甲醇洗涤滤垫。减压浓缩滤液,得到标题化合物(10.0g,90%收率),为白色固体。
实施例12.(R)-1-甲基哌啶-2-羧基五氟苯基酯的合成
将D-N-甲基哌啶酸(2.65g,18.5mmol)溶于乙酸乙酯(50mL)中,然后加入五氟苯酚(3.75g,20.4mmol)和DCC(4.21g,20.4mmol)。将反应混合物在室温下搅拌16小时,然后通过Celite过滤。将滤垫用10mL乙酸乙酯洗涤。滤液可立即使用而无需进一步纯化或浓缩。
实施例13. 2,2-二乙氧基乙硫基酰胺(180)的合成
在室温下将2,2-二乙氧基乙腈(100g,0.774mol,1.0eq.)与(NH4)2S水溶液(48%,143mL,1.05mol,1.36eq.)在甲醇(1.5L)中混合。搅拌16小时后,浓缩反应混合物,将残余物溶于二氯甲烷中,用饱和NaHCO 3溶液和盐水洗涤,用无水硫酸钠干燥并浓缩。将残余物用石油醚和二氯甲烷的溶剂混合物打浆。过滤后,收集所需的标题产物,为白色固体(100g,79%收率)。1H-NMR(500MHz,CDCl3)δ7.81(d,J=71.1Hz,2H),5.03(s,1H),3.73(dq,J=9.4,7.1Hz,2H),3.64(dq,J=9.4,7.0Hz,2H),1.25(t,J=7.1Hz,6H).
实施例14. 2-(二乙氧基甲基)噻唑-4-羧酸乙酯(182)的合成
向2,2-二乙氧基乙硫基酰胺(100g,0.61mol,1.0eq.)和溴丙酮酸乙酯(142mL,1.1mol,1.8eq.)的EtOH(1L)溶液中加入90g分子筛将混合物回流1小时(内部温度约60℃),然后在旋转浓缩仪上除去乙醇,将残余物溶于二氯甲烷。滤出固体,浓缩滤液,并通过柱层析(石油醚/乙酸乙酯5:1-3:1)纯化,得到标题化合物(130g,82%产率),为黄色油状物。
实施例15. 2-甲酰基噻唑-4-羧酸乙酯(183)的合成
向2-(二乙氧基甲基)噻唑-4-羧酸酯(130g,0.50mol)的丙酮(1.3L)溶液中加入2N盐酸(85mL,0.165mol,0.33eq.)。将反应混合物回流(内部温度约60℃),TLC分析反应液,直至原料完全耗尽(约1-2小时)。减压除去丙酮,将残余物溶于二氯甲烷(1.3L)中,用饱和碳酸氢钠溶液,水和盐水洗涤,然后经无水硫酸钠干燥。过滤溶液并减压浓缩。用石油醚和乙醚重结晶纯化粗产物,得到标题化合物,为白色固体(40g,43%收率)。1H-NMR(500MHz,CDCl3)δ10.08–10.06(m,1H),8.53–8.50(m,1H),4.49(q,J=7.1Hz,2H),1.44(t,J=7.1Hz,3H).MS ESI m/z C7H8NO3S[M+H]+实测值186.01;计算值186.01。
实施例16. 2-((R,E)-3-(((S)-叔丁基亚磺酰基)亚氨基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯(187)的合成
在-78℃,N2下,向二异丙胺(121mL,0.86mol,4.0eq.)的无水四氢呋喃(300mL)溶液中加入正丁基锂(2.5M,302mL,0.76mol,3.5eq.)。将反应混合物在30分钟内升温至0℃,然后冷却回-78°。加入含(S,E)-2-甲基-N-(3-甲基丁-2-基)丙烷-2-磺酰胺(57g,0.3mol,1.4eq.)的四氢呋喃(200mL)溶液。将反应混合物搅拌1小时,然后逐滴加入含有ClTi(OiPr)3(168.5g,0.645mol,3.0eq.)的四氢呋喃(350mL)溶液。搅拌1小时后,滴加溶解在四氢呋喃(175mL)中的2-甲酰基噻唑-4-羧酸乙酯(40g,0.215mol,1.0eq.),并将所得反应混合物搅拌2小时。TLC分析显示反应完成。用乙酸和四氢呋喃(v/v1:4,200mL)的混合物淬灭反应,然后倒入冰水中,用乙酸乙酯(4×500mL)萃取。将有机相用水和盐水洗涤,用无水硫酸钠干燥,过滤并浓缩。通过柱层析(二氯甲烷/乙酸乙酯/石油醚2:1:2)纯化残余物,得到标题化合物(60g,74%产率),为无色油状物。1H-NMR(500MHz,CDCl3)δ8.13(s,1H),6.63(d,J=8.2Hz,1H),5.20–5.11(m,1H),4.43(q,J=7.0Hz,2H),3.42–3.28(m,2H),2.89(dt,J=13.1,6.5Hz,1H),1.42(t,J=7.1Hz,3H),1.33(s,9H),1.25–1.22(m,6H).MS ESI m/zC16H26NaN2O4S2[M+Na]+的计算值397.13,实测值397.11.
实施例17. 2-((1R,3R)-3-((S)-1,1-二甲基乙基亚磺酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯(188)的合成
将2-((R,E)-3-(((S)-叔丁基亚磺酰基)亚氨基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯(23.5g,62.7mmol)溶于四氢呋喃(200mL)中,冷却至-45℃。缓慢加入Ti(OEt)4(42.9mL,188mmol,3.0eq.)。添加完成后,将混合物搅拌1小时,然后分批加入NaBH4(4.75g,126mmol,2.0eq.)。将反应混合物在-45℃下搅拌3小时。TLC分析显示仍有一些起始原料。用乙酸/四氢呋喃(v/v 1:4,25mL)淬灭反应,然后加入EtOH(25mL)。将反应混合物倒入冰(100g)中并升温至室温。用硅藻土过滤后,分层有机相,用水和盐水洗涤,用无水硫酸钠干燥,过滤并浓缩。通过柱层析(乙酸乙酯/石油醚1:1)纯化残余物,得到标题产物(16.7g,71%产率),为白色固体。1H-NMR(500MHz,CDCl3)δ8.10(s,1H),5.51(d,J=5.8Hz,1H),5.23–5.15(m,1H),4.41(q,J=7.0Hz,2H),3.48–3.40(m,1H),3.37(d,J=8.3Hz,1H),2.29(t,J=13.0Hz,1H),1.95–1.87(m,1H),1.73–1.67(m,1H),1.40(t,J=7.1Hz,3H),1.29(s,9H),0.93(d,J=7.3Hz,3H),0.90(d,J=7.2Hz,3H).MS ESI m/z C16H28NaN2O4S2[M+Na]+计算值为399.15,实测值为399.14。
Example 18. 2-((1R,3R)-3-氨基-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯盐酸盐(189)的合成
在0℃下,向2-((1R,3R)-3-((S)-1,1-二甲基乙基亚磺酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯(6.00g,16.0mmol,1.0eq.)的乙醇(40mL)溶液中缓慢加入4N盐酸的二恶烷溶液(40mL)。使反应升温至室温。搅拌2.5小时,然后浓缩,用石油醚打浆。收集白色固体标题化合物(4.54g,92%收率)。
实施例19. 2-((1R,3R)-3-((2S,3S)-2-叠氮基-3-甲基戊酰氨基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯(190)的合成
将(2S,3S)-2-叠氮基-3-甲基戊酸(5.03g,28.8mmol,2.0eq.)溶解在四氢呋喃(120mL)中并冷却至0℃,向其中依次加入NMM(6.2mL,56.0mmol,4.0)和氯甲酸异丁酯(3.7mL,28.8mmol,2.0eq.)。在0℃下搅拌30分钟并在室温下搅拌1.0小时,然后冷却回0℃。分批加入2-((1R,3R)-3-氨基-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯盐酸盐(4.54g,14.7mmol,1.0eq.)。在0℃下搅拌30分钟后,将反应升温至室温。并搅拌2小时。在0℃加入水以淬灭反应,并将所得混合物用乙酸乙酯萃取三次。将合并的有机层用1N盐酸,饱和碳酸氢钠和盐水洗涤,经无水硫酸钠干燥,过滤并浓缩。通过柱层析(0-30%乙酸乙酯/石油醚)纯化残余物,得到白色固体(4.55g,74%收率)。
实施例20. 2-((1R,3R)-3-((2S,3S)-2-叠氮基-3-甲基戊酰氨基)-4-甲基-1-((三乙基甲硅烷基)氧基)戊基)噻唑-4的合成-羧酸盐(191)
在0℃下,向2-((1R,3R)-3-((2S,3S)-2-叠氮基-3-甲基戊酰氨基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯(5.30g,12.8mmol,1.0eq.)的二氯甲烷(50mL)溶液中加入咪唑(1.75g,25.6mmol,2.0eq.),然后加入三乙基氯硅烷(4.3mL,25.6mmol,2.0eq.)。将反应混合物在一小时内升温至室温,再搅拌一小时。将盐水加入反应混合物中,分离有机层,水层用乙酸乙酯萃取。将合并的有机相干燥,过滤,减压浓缩,并通过柱层析法纯化,用15-35%乙酸乙酯/石油醚溶液梯度洗脱,得到标题产物(6.70g,99%收率),为白色固体。1H-NMR(500MHz,CDCl3)δ8.12(s,1H),6.75(d,J=8.0Hz,1H),5.20–5.12(m,1H),4.44(q,J=7.0Hz,2H),4.06–3.97(m,1H),3.87(d,J=3.8Hz,1H),2.14(d,J=3.8Hz,1H),2.01–1.91(m,3H),1.42(t,J=7.1Hz,3H),1.34–1.25(m,2H),1.06(d,J=6.8Hz,3H),1.00–0.93(m,18H),0.88(dd,J=19.1,6.8Hz,6H).MS ESI m/z C24H44N5O4SSi[M+H]+计算值526.28,实测值526.28。
实施例21. 2-((1R,3R)-3-((2S,3S)-2-叠氮基-N,3-二甲基戊酰氨基)-4-甲基-1-((三乙基甲硅烷基)氧基)戊基)的合成噻唑-4-羧酸酯(192)的合成
将2-((1R,3R)-3-((2S,3S)-2-叠氮基-3-甲基戊酰氨基)-4-甲基-1-((三乙基甲硅烷基)氧基)戊基)噻唑-4-羧酸乙酯(5.20g,9.9mmol,1.0eq.)的四氢呋喃(50mL)的溶液冷却至-45℃并加入KHMDS(1M甲苯溶液,23.8mL,23.8mmol,2.4eq.)。将所得混合物在-45℃下搅拌20分钟。然后加入碘甲烷(1.85mL,29.7mmol,3.0eq.),并将反应混合物在4.5小时内升温至室温,此时用EtOH(10mL)淬灭反应。将粗产物用乙酸乙酯(250mL)稀释,并用盐水(100mL)洗涤。用乙酸乙酯(3×50mL)萃取水层。将有机层干燥,过滤,浓缩并通过柱层析法纯化,用15-35%乙酸乙酯/石油醚溶液梯度洗脱,得到标题产物(3.33g,63%收率),为浅黄色油状物。1H-NMR(500MHz,CDCl3)δ8.09(s,1H),4.95(d,J=6.6Hz,1H),4.41(q,J=7.1Hz,2H),3.56(d,J=9.5Hz,1H),2.98(s,3H),2.27–2.06(m,4H),1.83–1.70(m,2H),1.41(t,J=7.2Hz,3H),1.29(ddd,J=8.9,6.8,1.6Hz,3H),1.01(d,J=6.6Hz,3H),0.96(dt,J=8.0,2.9Hz,15H),0.92(d,J=6.6Hz,3H),0.90(d,J=6.7Hz,3H).MS ESI m/z C25H46N5O4SSi[M+H]+计算值540.30,,实测值540.30。
实施例22. 2-((3S,6R,8R)-3-((S)-仲丁基)-10,10-二乙基-6-异丙基-5-甲基-1-((R)-乙酯的合成1-甲基吡啶-2-基)-1,4-二氧代-9-氧杂-2,5-二氮杂-10-硅十二烷-8-基)噻唑-4-羧酸乙酯的合成
将干燥的Pd/C(10wt%,300mg)和2-((1R,3R)-3-((2S,3S)-2-叠氮基-N,3-二甲基戊酰胺基)-4-甲基-1-乙基将((三乙基甲硅烷基)氧基)戊基)噻唑-4-羧酸酯(3.33g,6.61mmol)加入(R)-全氟苯基1-甲基哌啶-2-羧酸酯的乙酸乙酯溶液中。将反应混合物在氢气环境下搅拌27小时,然后通过硅藻土塞过滤,用乙酸乙酯洗涤滤垫。浓缩合并的有机部分,并通过柱层析法纯化,用0-5%甲醇的乙酸乙酯溶液梯度洗脱,得到标题产物(3.90g,86%收率)。MS ESI m/z C32H59N4O5SSi[M+H]+计算值639.39,实测值639.39。
实施例23. 2-((1R,3R)-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸乙酯的合成
将2-((3S,6R,8R)-3-((S)-仲丁基)-10,10-二乙基-6-异丙基-5-甲基-1-((R)-1-甲基哌啶-2)-1,4-二氧代-9-氧杂-2,5-二氮杂-10-硅杂十八碳-8-基)噻唑-4-羧酸酯(3.90g,6.1mmol)溶于脱氧的乙酸/水/四氢呋喃(v/v/v 3:1:1,100mL)中,并在室温下持续搅拌48小时。然后浓缩反应物并通过柱层析((2:98至15:85甲醇/乙酸乙酯)纯化,得到标题化合物(2.50g,两步收率72%)。C26H45N4O5S[M+H]+的计算值525.30,实测值525.33。
实施例24. 2-((1R,3R)-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸的合成
在0℃,将LiOH水溶液(0.4N,47.7mL,19.1mmol,4.0eq.)加入2-((1R,3R)-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)-戊酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸酯(2.50g,4.76mmol,1.0eq.)的二恶烷溶液(47.7mL)中。将反应混合物在室温下搅拌2小时后浓缩。柱层析纯化(100%二氯甲烷然后二氯甲烷/甲醇/NH4OH 80:20:1洗脱),得到标题化合物(2.36g,99%收率),为无定形固体。MS ESI m/z C24H41N4O5S[M+H]+计算值497.27,实测值497.28。
实施例25. 2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰胺基)-4-甲基戊基)噻唑-4-羧酸的合成
在0℃下,向2-((1R,3R)-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸(2.36g,4.75mmol)的吡啶(50mL)溶液中缓慢加入乙酸酐(2.25mL,24mmol)。将反应混合物在2小时升温至室温并在室温下持续搅拌24小时。浓缩反应物,并通过反相HPLC(C18柱,10-90%乙腈/水)纯化残余物,得到标题化合物(2.25g,88%产率),为无定形白色固体。MS ESI m/z C26H43N4O6S[M+H]+计算值539.28,实测值539.28.
实施例26.(1R,3R)-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰胺基)-4-甲基-1-(4-(全氟苯甲酰基)噻唑-2-基)乙酸戊酯(294)的合成
在0℃下,向2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基-哌啶-2-甲酰胺基)戊酰胺的溶液)4-甲基戊基)噻唑-4-羧酸(86mg,0.16mmol,1.0eq.)的二氯甲烷(2mL)溶液中加入五氟苯酚(44mg,0.24mmol,1.5eq.)和N,N’-二异丙基碳二亚胺(0mg,22mg,0.175mmol,1.1eq.)。将反应混合物升温至室温并搅拌过夜。在减压下除去溶剂后,将反应混合物用乙酸乙酯(2mL)稀释,然后经硅藻土过滤。浓缩滤液,得到标题化合物,不经进一步纯化直接使用。
实施例27. 3-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
向2,2’-(乙烷-1,2-二基双(氧基))二乙醇(55.0mL,410.75mmol,3.0eq.)的无水四氢呋喃(200mL)溶液中加入钠(0.1g)。搅拌混合物直至钠块消失,然后滴加丙烯酸叔丁酯(20.0mL,137.79mmol,1.0eq.)。将混合物搅拌过夜,然后在0℃下用盐酸溶液(20.0mL,1N)淬灭。通过旋转浓缩除去四氢呋喃,加入盐水(300mL)并将所得混合物用乙酸乙酯(3×100mL)萃取。将有机层用盐水(3×300mL)洗涤,经无水硫酸钠干燥,过滤并浓缩,得到无色油状物(30.20g,79.0%产率),其不经进一步纯化而直接使用。MS ESI m/z C13H27O6[M+H]+计算值278.1729,实测值278.1730.
实施例28. 3-(2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
在0℃下,向3-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)丙酸叔丁酯(30.20g,108.5mmol,1.0eq.)和TsCl(41.37g,217.0mmol,2.0eq.)的无水二氯甲烷(220mL)溶液中加入TEA(30.0mL,217.0mmol,2.0eq.)。将混合物在室温下搅拌过夜,然后用水(3×300mL)和盐水(300mL)洗涤,经无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(3:1正己烷/乙酸乙酯)纯化得到无色油状物(39.4g,收率84.0%)。MS ESI m/z C20H33O8S[M+H]+计算值433.1818,实测值433.2838.
实施例29. 3-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
将3-(2-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)乙氧基)丙酸叔丁酯(39.4g,91.1mmol,1.0eq.)溶解于无水DMF(100mL),接着加入NaN3(20.67g,316.6mmol,3.5eq.)。将混合物在室温下搅拌过夜。加入水(500mL)并用乙酸乙酯(3×300mL)萃取。将合并的有机层用水(3×900mL)和盐水(900mL)洗涤,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(5:1正己烷/乙酸乙酯)纯化,得到浅黄色油状物(23.8g,85.53%收率)。MS ESI m/zC13H25O3N5Na[M+Na]+计算值326.2,实际值326.2.
实施例30. 3-(2-(2-(2-氨基乙氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
将Raney-Ni(7.5g,悬浮在水中)用水(三次)和异丙醇(三次)洗涤,并与化合物147(5.0g,16.5mmol)在异丙醇中混合。将混合物在室温下H2气球环境中持续搅拌16小时,然后用硅藻土垫过滤,用异丙醇洗涤垫。浓缩滤液并通过柱层析(5-25%甲醇/二氯甲烷)纯化,得到浅黄色油状物(2.60g,57%收率)。MS ESI m/z C18H23NO2Na[M+Na]+计算值309.1729,实测值309.1967。
实施例31. 2-(2-(二苄基氨基)乙氧基)乙醇(298)的合成
将2-(2-氨基乙氧基)乙醇(21.00g,200mmol,1.0eq.)和K2CO3(83.00g,600mmol,3.0eq.)混合于乙腈(350mL),接着加入苄溴(57.0mL,480mmol,2.4eq.))。将混合物回流过夜。加入水(1L)并用乙酸乙酯(3×300mL)萃取。将合并的有机层用盐水(1000mL)洗涤,经无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(4:1正己烷/乙酸乙酯)纯化,得到无色油状物(50.97g,89.2%产率)。MS ESI m/z C18H23NO2Na[M+Na]+计算值为309.1729,,实测值309.1967。
实施例32. 3-(2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸叔丁酯(300)的合成
向2-(2-(二苄基氨基)乙氧基)乙醇(47.17g,165.3mmol,1.0eq.),丙烯酸叔丁酯(72.0mL,495.9mmol,3.0eq.)和n-Bu4NI(6.10g,16.53mmol,0.1eq.)和二氯甲烷(560mL)的混合物中加入氢氧化钠溶液(300mL,50%)。将混合物搅拌过夜。分离有机层,水层用乙酸乙酯(3×100mL)萃取。将有机层用水(3×300mL)和盐水(300mL)洗涤,经无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(7:1正己烷/乙酸乙酯)纯化,得到无色油状物(61.08g,89.4%收益率)。MS ESI m/z C25H36NO4[M+H]+计算值414.2566,实测值414.2384.
实施例33. 3-(2-(2-氨基乙氧基)乙氧基)丙酸叔丁酯(301)的合成
在氢化瓶中,向3-(2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸叔丁酯(20.00g,48.36mmol,1.0eq.)的四氢呋喃(30mL)和甲醇(60mL)溶液中加入Pd/C(2.00g,10wt%,50%水)。将混合物振荡过夜,通过Celite过滤(助滤剂),浓缩滤液,得到无色油状物(10.58g,93.8%收率)。MS ESI m/z C11H24NO4[M+H]+计算值234.1627,实测值234.1810。
实施例34. 3-(2-(2-羟基乙氧基)乙氧基)丙酸叔丁酯的合成
向2,2’-氧代二乙醇(19.7mL,206.7mmol,3.0eq.)的无水四氢呋喃(100mL)溶液中加入钠(0.1g)。搅拌混合物直至钠块消失,然后滴加丙烯酸叔丁酯(10.0mL,68.9mmol,1.0eq.)。将混合物搅拌过夜,加入盐水(200mL)并用乙酸乙酯(3×100mL)萃取。将有机层用盐水(3×300mL)洗涤,经无水硫酸钠干燥,过滤,浓缩并通过SiO2柱层析(1:1正己烷/乙酸乙酯)纯化,得到无色油状物(8.10g,49.4%收率)。MS ESI m/z C11H23O5[M+H]+的计算值235.1467,实测值235.1667。
实施例35. 3-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)丙酸叔丁酯的合成
在0℃下,向3-(2-(2-羟基乙氧基)乙氧基)丙酸叔丁酯(6.24g,26.63mmol,1.0eq.)和TsCl(10.15g,53.27mmol,2.0eq.)的无水二氯甲烷(50mL)溶液中加入吡啶(4.3mL,53.27mmol,2.0eq.)。将混合物在室温下搅拌过夜,然后用水(100mL)洗涤,水层用二氯甲烷(3×50mL)萃取。将合并的有机层用盐水(300mL)洗涤,经无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(5:1正己烷/乙酸乙酯)纯化,得到无色油状物(6.33g,61.3%产率)。MS ESI m/z C18H27O7S[M+H]+计算值389.1556,实测值389.2809。
实施例36. 3-(2-(2-叠氮基乙氧基)乙氧基)丙酸叔丁酯的合成
向3-(2-(2-(甲苯磺酰氧基)乙氧基)乙氧基)丙酸叔丁酯(5.80g,14.93mmol,1.0eq.)的无水DMF(20mL)溶液中加入NaN3(5.02g,77.22mmol),5.0eq.)。将混合物在室温下搅拌过夜,加入水(120mL)并用乙酸乙酯(3×50mL)萃取。将合并的有机层用水(3×150mL)和盐水(150mL)洗涤,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(5:1正己烷/乙酸乙酯)纯化,得到无色油状物(3.73g,产率69.6%)。MS ESI m/z C11H22O3N4Na[M+H]+计算值260.1532,实测值260.2259。
实施例37. 3-(2-(2-氨基乙氧基)乙氧基)丙酸叔丁酯的合成
将3-(2-(2-叠氮基乙氧基)乙氧基)丙酸叔丁酯(0.18g,0.69mmol)溶于甲醇(3.0mL,含60μL浓盐酸)中并与Pd/C(10wt%,20mg)氢化30分钟。将催化剂通过硅藻土垫过滤,用甲醇洗涤硅藻土垫。浓缩滤液,得到无色油状物(0.15g,93%收率)。ESIm/z C11H24NO4[M+H]+的计算值234.16,实测值234.14。
实施例38. 3-(2-(2-叠氮基乙氧基)乙氧基)丙酸
将3-(2-(2-叠氮基乙氧基)乙氧基)丙酸叔丁酯(2.51g,9.68mmol)溶解于1,4-二恶烷(30mL)中并与10mL浓盐酸在室温下搅拌35分钟,用EtOH(30mL)和甲苯(30mL)稀释,并在真空下浓缩。将粗品在硅胶上使用甲醇/二氯甲烷(5%至10%)(含1%甲酸)纯化,得到标题化合物(1.63g,83%收率),ESI MS m/z C7H12N3O4[M-H]-计算值202.06,实测值202.30。
实施例39. 2,5-二氧代吡咯烷-1-基3-(2-(2-叠氮基乙氧基)乙氧基)丙酸酯的合成
向3-(2-(2-叠氮基乙氧基)乙氧基)丙酸(1.60g,7.87mmol)的30mL的二氯甲烷溶液中边搅拌边加入NHS(1.08g,9.39mmol)和EDC(3.60g,18.75mmol)。8小时后,TLC分析显示反应完成,将反应混合物浓缩并在硅胶上使用乙酸乙酯(5%至10%)在二氯甲烷中的混合物作为洗脱液纯化,得到标题化合物(1.93g,产率82%)。ESI MSm/z C11H17N4O6[M+H]+,计算值301.11,实际值301.20.
实施例40.(S)-15-叠氮基-5-异丙基-4,7-二氧代-10,13-二氧杂-3,6-二氮杂十五烷-1-酸的合成
向(S)-2-(2-氨基-3-甲基丁酰胺基)乙酸(Val-Gly)(1.01g,5.80mmol)的DMA(50mL)和NaH2PO4(50mL,pH 7.5)溶液中加入2,5-二氧代吡咯烷-1-基3-(2-(2-叠氮基乙氧基)乙氧基)丙酸酯(1.90g,6.33)。将混合物搅拌4小时,真空浓缩,在硅胶上使用甲醇/二氯甲烷(5%至15%,含有0.5%乙酸)混合物作为洗脱液纯化,得到标题化合物(1.52g,73%)。ESI MS m/z C14H26N5O6[M+H]+,计算值360.18,实测值360.40。
实施例41.(S)-2,5-二氧代吡咯烷-1-基15-叠氮基-5-异丙基-4,7-二氧代-10,13-二氧杂-3,6-二氮杂十五烷-1-酸的合成
向(S)-15-叠氮基-5-异丙基-4,7-二氧代-10,13-二氧杂-3,6-二氮杂十五烷-1-酸(1.50g,4.17mmol)的二氯甲烷(40mL)溶液中加入NHS(0.88g,7.65mmol)和EDC(2.60g,13.54mmol)。搅拌8小时后,TLC分析显示反应完成,将反应混合物浓缩并在硅胶上使用乙酸乙酯/二氯甲烷(5%-20%)作为洗脱液纯化,得到标题化合物(1.48g,产率78%)。ESI MSm/z C18H29N6O8[M+H]+,计算值457.20,实测值457.50。
实施例42. 4-(((苄氧基)羰基)氨基)丁酸的合成
将4-氨基丁酸(7.5g,75mmol)和氢氧化钠(6g,150mmol)的水(40mL)溶液冷却至0℃,并滴加CbzCl(16.1g,95mmol)的四氢呋喃(32mL)溶液。滴加1小时后,将反应物升温至室温并搅拌3小时。真空除去四氢呋喃,通过加入6N盐酸将水溶液的pH调节至1.5。用乙酸乙酯萃取,有机层用盐水洗涤,干燥并浓缩,得到标题化合物(16.4g,92%收率)。MS ESI m/zC12H16NO5[M+H]+计算值238.10,实测值238.08。
实施例43. 4-(((苄氧基)羰基)氨基)丁酸叔丁酯的合成
向4-(((苄氧基)羰基)氨基)丁酸(16.4g,69.2mmol)和t-BuOH(15.4g,208mmol)的二氯甲烷(100mL)溶液中加入DMAP(0.8g,6.56mmol)和DCC(17.1g,83mmol)。在室温下搅拌过夜,过滤反应物并浓缩滤液。将残余物溶于乙酸乙酯中,用1N盐酸,盐水洗涤,用无水硫酸钠干燥。浓缩并通过柱层析法纯化(10至50%乙酸乙酯/正己烷),得到标题化合物(7.5g,37%收率).MS ESI m/z C16H23NO4Na[M+Na]+计算值316.16,实测值316.13。
实施例44. 4-氨基丁酸叔丁酯的合成
将4-(((苄氧基)羰基)氨基)丁酸叔丁酯(560mg,1.91mmol)溶解在甲醇(50mL)中,并与Pd/C催化剂(10wt%,100mg)混合,然后氢化(1atm)并在室温下保持3小时。滤除催化剂,真空除去所有挥发物,得到标题化合物(272mg,90%收率)。MS ESI m/z C8H18NO2[M+H]+计算值160.13,实际值160.13.。
实施例45. 2-(三苯基亚正膦基)丙酸叔丁酯(206)的合成
将2-溴丙酸叔丁酯(15.5g,74.1mmol,1.0eq.)和三苯基膦(19.4g,74.1mmol,1.0eq.)在无水乙腈(45mL)中混合并在室温下搅拌18小时。减压除去乙腈,加入甲苯,使白色沉淀物析出。然后倒出甲苯,将白色固体溶解在二氯甲烷(100mL)中,并转移到分液漏斗中。向漏斗中加入10%氢氧化钠(100mL),震荡后有机层立即变黄。分离有机层,水层用二氯甲烷(30mL)萃取一次。合并二氯甲烷层并用盐水(50mL)洗涤一次,然后经无水硫酸钠干燥,过滤并浓缩,得到内鎓盐,为黄色固体(16.8g,58%)。
实施例46.(S)-3-(4-(苄氧基)苯基)-2-((叔丁氧基羰基)氨基)丙酸甲酯(203)的合成
向Boc-L-Tyr-OMe(20.0g,67.7mmol,1.0eq.),K2CO3(14.0g,101.6mmol,1.5eq.)和KI(1.12g,6.77mmol,0.1eq.)的丙酮(100mL)混合物中缓慢加入苄溴(10.5mL,81.3mmol,1.2eq.)。然后将混合物回流过夜。加入水(250mL)并将反应混合物用乙酸乙酯(3×100mL)萃取。将合并的有机层用盐水(300mL)洗涤,经无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(4:1正己烷/乙酸乙酯)纯化,得到标题化合物,为白色固体(26.12g,99%收率)。1H-NMR(500MHz,CDCl3)δ7.44–7.41(m,2H),7.41–7.36(m,2H),7.35–7.30(m,1H),7.04(d,J=8.5Hz,2H),6.93–6.89(m,2H),5.04(s,2H),4.97(d,J=7.7Hz,1H),4.55(d,J=6.9Hz,1H),3.71(s,3H),3.03(dd,J=14.4,5.7Hz,2H),1.44(d,J=18.6Hz,10H).MS ESI m/zC22H27NO5Na[M+Na]+计算值408.18,实测值408.11.
实施例47.(S)-(1-(4-(苄氧基)苯基)-3-氧代丙烷-2-基)氨基甲酸叔丁酯(204)的合成
在1小时内,在-78℃下,向(S)-3-(4-(苄氧基)苯基)-2-((叔丁氧基羰基)氨基)-丙酸甲酯(26.1g,67.8mmol,1.0eq.)的无水二氯甲烷(450mL)中加入DIBAL(1.0M正己烷溶液,163mL,2.2eq.)。将混合物在-78℃下搅拌3小时,然后用50mL乙醇猝灭。逐滴加入1N盐酸直至达到pH4。将所得混合物升温至0℃。进行分层,水层进一步用乙酸乙酯(3×100mL)萃取。将合并的有机溶液用盐水洗涤,用无水硫酸钠干燥并浓缩。用石油醚/乙酸乙酯打浆并过滤,得到标题化合物,为白色固体(18.3g,76%收率)。MS ESI m/z C22H27NO5Na[M+Na]+计算值378.11,实际值378.11.
实施例48.(S,Z)-5-(4-(苄氧基)苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸叔丁酯(207)的合成
向(S)-(1-(4-(苄氧基)苯基)-3-氧代丙烷-2-基)氨基甲酸叔丁酯(0.84g,2mmol,1.0eq.)的无水二氯甲烷(50mL)溶液中加入2-(三苯基-亚膦基)丙酸叔丁酯(1.6g,4mmol,2.0eq.),在室温下搅拌1.5小时,TLC分析显示反应完成。通过柱层析(10-50%乙酸乙酯/正己烷)纯化,得到标题化合物(1.16g,98%收率)。
实施例49.(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基苯基)-2-甲基戊酸叔丁酯的合成
将(S,Z)-5-(4-(苄氧基)苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊-2-烯酸叔丁酯(467mg,1mmol)溶解在甲醇(30mL)中并在室温下和Pd/C催化剂(10wt%,250mg)混合并氢化反应(1atm)过夜。滤除催化剂,减压浓缩滤液,得到标题化合物(379mg,99%收率)。
实施例50.(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基-3-硝基苯基)-2-甲基戊酸叔丁酯的合成
将(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基苯基)-2-甲基戊酸叔丁酯(379mg,1mmol,1.0eq.)溶于四氢呋喃(20mL)中,加入亚硝酸叔丁酯(315mg,3mmol,3.0eq.)的四氢呋喃(2mL)溶液。在室温下搅拌3小时,然后倒入水中,用乙酸乙酯(2×50mL)萃取,合并的有机相用盐水(50mL)洗涤,用无水硫酸钠干燥,过滤并浓缩。通过柱层析(10-50%乙酸乙酯/正己烷)纯化,得到标题化合物(300mg,71%收率)。
实施例51.(4R)-5-(3-氨基-4-羟基苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸叔丁酯(210)的合成
将(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基-3-硝基苯基)-2-甲基-戊酸叔丁酯(200mg,0.47mmol)溶于乙酸乙酯(30mL)中并与Pd/C催化剂(10wt%,100mg)混合,然后在室温下氢化(1atm)2小时,滤除催化剂并在真空下除去所有挥发物,得到标题化合物(185mg,99%)。
或者,将(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基-3-硝基苯基)-2-甲基戊酸叔丁酯(56mg,0.132mmol)溶于乙酸乙酯(20mL)中。在室温下与Pd/C催化剂(10wt%,50mg)混合并氢化(1atm)3小时。滤除催化剂,真空除去所有挥发物,得到标题化合物(52mg,99%收率)。MS ESI m/z C21H35N2O5[M+H]+计算值395.25,实际值395.26.
实施例52.(4R)-4-((叔丁氧基羰基)氨基)-5-(4-((叔丁基二甲基甲硅烷基)氧基)-3-硝基苯基)-2-甲基戊酸叔丁酯的合成
向(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基-3-硝基苯基)-2-甲基戊酸叔丁酯(424mg,1mmol)的二氯甲烷(20mL)溶液中加入咪唑(408mg,6mmol)和叔丁基氯二甲基硅烷(602mg,4mmol)。将所得溶液在室温下搅拌3小时。然后,将反应混合物用盐水(50mL)洗涤,经无水硫酸钠干燥,浓缩并通过柱层析(10%至30%乙酸乙酯/正己烷)纯化,得到标题化合物(344mg,64%收率)。
实施例53.(4R)-5-(3-氨基-4-((叔丁基二甲基甲硅烷基)氧基)苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸叔丁酯(215)的合成
将(4R)-4-((叔丁氧基羰基)氨基)-5-(4-((叔丁基二甲基甲硅烷基)氧基)-3-硝基苯基)-2-甲基戊酸叔丁酯(200mg,0.37mmol)溶解于乙酸乙酯(30mL),与Pd/C催化剂(10wt%,100mg)混合并在室温下氢化(1atm)2小时滤除催化剂,真空除去所有挥发物,得到标题化合物(187mg,99%收率)。
实施例54.(S)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯的合成
将溶解在50mL四氢呋喃中的Boc-L-脯氨酸(10.0g,46.4mmol)冷却至0℃,小心地加入BH3的四氢呋喃溶液(1.0M,46.4mL)。将混合物在0℃下搅拌1.5小时,然后倒入冰水中并用乙酸乙酯萃取。将有机层用盐水(50mL)洗涤,经无水硫酸钠干燥,并在减压下浓缩,得到标题化合物(8.50g,91%产率),为白色固体。1H-NMR(500MHz,CDCl3)δ3.94(dd,J=4.9,2.7Hz,2H),3.60(ddd,J=18.7,11.9,9.3Hz,2H),3.49–3.37(m,1H),3.34–3.23(m,1H),2.06–1.91(m,1H),1.89–1.69(m,2H),1.65–1.51(m,1H),1.49–.40(m,9H).
实施例55.(S)-2-甲酰基吡咯烷-1-羧酸叔丁酯的合成
向(S)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(13.0g,64.6mmol)的二甲基亚砜(90mL)的溶液中加入三乙胺(40mL),搅拌15分钟。将混合物在冰浴上冷却,并在40分钟内分批加入三氧化硫-吡啶络合物(35.98g,226mmol)。将反应升温至室温并搅拌2.5小时。加入冰(250g)后,将混合物用二氯甲烷(150mL×3)萃取。将有机相用50%柠檬酸溶液(150mL),水(150mL),饱和碳酸氢钠溶液(150mL)和盐水(150mL)洗涤,经无水硫酸钠干燥。在真空中除去溶剂,得到标题醛(10.4g,81%收率),为稠油状物,且不经进一步纯化而使用。1H-NMR(500MHz,CDCl3)δ9.45(s,1H),4.04(s,1H),3.53(dd,J=14.4,8.0Hz,2H),2.00–1.82(m,4H),1.44(d,J=22.6Hz,9H).
实施例56.(4R,5S)-4-甲基-5-苯基-3-丙酰基恶唑烷-2-酮的合成
在-78℃,N2条件下,向正丁基锂的正己烷(21.6mL,2.2M,47.43mmol)溶液中滴加4-甲基-5-苯基恶唑烷-2-酮(8.0g,45.17mmol)的四氢呋喃(100mL)溶液。将溶液在-78℃保持1小时,然后缓慢加入丙酰氯(4.4mL,50.59mmol)。将反应混合物升温至-50℃,搅拌2小时,然后加入饱和氯化铵溶液(100mL)淬灭。真空除去有机溶剂,用乙酸乙酯(3×100mL)萃取所得溶液。用饱和碳酸氢钠溶液(100mL)和盐水(100mL)洗涤有机层,用无水硫酸钠干燥,过滤并真空浓缩。通过柱层析(20%乙酸乙酯/正己烷)纯化残余物,得到标题化合物,为稠油状物(10.5g,98%收率)。1H-NMR(500MHz,CDCl3)δ7.45–7.34(m,3H),7.30(d,J=7.0Hz,2H),5.67(d,J=7.3Hz,1H),4.82–4.70(m,1H),2.97(dd,J=19.0,7.4Hz,2H),1.19(t,J=7.4Hz,3H),0.90(d,J=6.6Hz,3H).
实施例57.(S)-叔丁基2-((1R,2R)-1-羟基-2-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基恶唑烷-3-基)-3-氧代丙基)吡咯烷-1-羧酸叔丁酯的合成
在0℃下,向(4R,5S)-4-甲基-5-苯基-3-丙酰基恶唑烷-2-酮(9.40g,40.4mmol)的二氯甲烷(60mL)溶液中加入三乙胺(6.45mL,46.64mmol),然后加入1M二丁基硼三氟甲磺酸酯的二氯甲烷(42mL,42mmol)溶液。将混合物在0℃下搅拌45分钟,冷却至-70℃,然后在30分钟内缓慢加入(S)-2-甲酰基吡咯烷-1-羧酸叔丁酯(4.58g,22.97mmol)的二氯甲烷(40mL)溶液。将反应混合物在-70℃下搅拌2小时,0℃下搅拌1小时,并在室温下搅拌15分钟,然后用磷酸盐缓冲溶液(pH 7,38mL)淬灭。在低于10℃下加入甲醇-30%H2O2溶液(2:1,100mL),搅拌20分钟后,加入水(100mL)并将混合物真空浓缩。向残余物中加入更多的水(200mL),用乙酸乙酯(3×100mL)萃取混合物。用1N KHSO4(100mL),碳酸氢钠溶液(100mL)和盐水(100mL)洗涤有机层,用无水硫酸钠干燥并真空浓缩。通过快速柱层析(10%-50%乙酸乙酯/正己烷)纯化残余物,得到标题化合物,为白色固体(7.10g,71%收率).1H-NMR(500MHz,CDCl3)δ7.39(dt,J=23.4,7.1Hz,3H),7.30(d,J=7.5Hz,2H),5.67(d,J=7.1Hz,1H),4.84–4.67(m,1H),4.08–3.93(m,3H),3.92–3.84(m,1H),3.50(d,J=9.0Hz,1H),3.24(d,J=6.7Hz,1H),2.15(s,1H),1.89(dd,J=22.4,14.8Hz,3H),1.48(d,J=21.5Hz,9H),1.33(d,J=6.9Hz,3H),0.88(d,J=6.4Hz,3H).
实施例58.(S)叔丁基2-(-(1R,2R)-1-甲氧基-2-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基恶唑烷-吡啶-3-基)-3-氧代丙基)吡咯烷-1-羧酸叔丁酯的合成
在N2下,向(S)-叔丁基2-((1R,2R)-1-羟基-2-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基恶唑烷-3-基)-3-氧代丙基)吡咯烷-1-甲酸(5.1g,11.9mmol)和分子筛( 5g)的混合物中加入无水二氯乙烷(30mL)。将混合物在室温下搅拌20分钟并冷却至0℃,加入质子海绵(6.62g,30.9mmol),然后加入三甲基氧鎓四氟硼酸盐(4.40g,29.7mmol)。在0℃下继续搅拌2小时,在室温下搅拌48小时。过滤反应混合物,浓缩滤液,并通过柱层析(20-70%乙酸乙酯/正己烷)纯化,得到标题化合物,为白色固体(1.80g,35%收率)。1H-NMR(500MHz,CDCl3)δ7.46–7.27(m,5H),5.65(s,1H),4.69(s,1H),3.92(s,1H),3.83(s,1H),3.48(s,3H),3.17(s,2H),2.02–1.68(m,5H),1.48(d,J=22.3Hz,9H),1.32(t,J=6.0Hz,3H),0.91–0.84(m,3H).
实施例59.(S)-叔丁基(2R,3R)-3-((S)-1-(叔丁氧基羰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酸的合成
在0℃下,在5分钟内向(S)-叔丁基2-((1R,2R)-1-甲氧基-2-甲基-3-((4R,5S)-4-甲基-2-氧代-5-苯基恶唑烷-3-基)-3-氧代丙基)吡咯烷-1-甲酸-(3)-氧代丙基)吡咯烷-1-甲酸酯(1.80g,4.03mmol)的四氢呋喃(30mL)和水(7.5mL)溶液中加入30%H2O2(1.44mL,14.4mmol)。然后加入LiOH(0.27g,6.45mmol)的水溶液(5mL)。在0℃下搅拌3小时后,加入1N亚硫酸钠(15.7mL)并将混合物升温至室温且搅拌过夜。真空除去四氢呋喃,水相用二氯甲烷(3×50mL)洗涤,除去恶唑烷酮助剂。用1N盐酸将水相酸化至pH 3并用乙酸乙酯(3×50mL)萃取。用盐水(50mL)洗涤有机层,用无水硫酸钠干燥,过滤并真空浓缩,得到标题化合物,为无色油状物(1.15g,98%收率)。1H-NMR(500MHz,CDCl3)δ3.99–3.74(m,2H),3.44(d,J=2.6Hz,3H),3.23(s,1H),2.60–2.45(m,1H),1.92(tt,J=56.0,31.5Hz,3H),1.79–1.69(m,1H),1.58–1.39(m,9H),1.30–1.24(m,3H).
实施例60.(4S,5S)-乙基4-((叔丁氧基羰基)氨基)-5-甲基-3-氧代庚酸乙酯的合成
向用冰冷却的N-Boc-L-异亮氨酸(4.55g,19.67mmol)的四氢呋喃(20mL)溶液中加入1,1’-羰基二咪唑(3.51g,21.63mmol)。待气体停止产生后,将所得混合物升温至室温,搅拌3.5小时。
5℃下,向新制备的异丙基溴化镁的四氢呋喃(123mmol,30mL)溶液中滴加预冷至(0℃)的丙二酸单乙酯(6.50g,49.2mmol)溶液。然后将混合物在室温下搅拌1.5小时。将该烯醇镁溶液在冰水浴上冷却,并在1小时内通过双头针向其中加入咪唑化物溶液。将所得混合物在0℃下搅拌30分钟,然后在室温下搅拌64小时。通过加入10%柠檬酸水溶液(5mL)淬灭反应混合物,并用另外的10%柠檬酸水溶液(110mL)酸化至pH 3。用乙酸乙酯(3×150mL)萃取混合物。将有机萃取液用水(50mL),饱和碳酸氢钠水溶液(50mL)和饱和氯化钠水溶液(50mL)洗涤,用无水硫酸钠干燥,并真空浓缩。残留物通过硅胶柱层析纯化,用乙酸乙酯/正己烷(1:4)作为洗脱液,得到标题化合物(5.50g,93%收率)。1H-NMR(500MHz,CDCl3)δ5.04(d,J=7.8Hz,1H),4.20(p,J=7.0Hz,3H),3.52(t,J=10.7Hz,2H),1.96(d,J=3.7Hz,1H),1.69(s,2H),1.44(s,9H),1.28(dd,J=7.1,2.9Hz,3H),0.98(t,J=6.9Hz,3H),0.92–0.86(m,3H).
实施例61.(3R,4S,5S)-4-((叔丁氧基羰基)氨基)-3-羟基-5-甲基庚酸乙酯的合成
在-60℃下向(4S,5S)-4-((叔丁氧基羰基)氨基)-5-甲基-3-氧代庚酸乙酯(5.90g,19.83mmol)的乙醇(6mL)溶液中一次性加入硼氢化钠(3.77g,99.2mmol)。将反应混合物在-55℃下搅拌5.5小时,然后用10%柠檬酸水溶液(100mL)淬灭。用另外的10%柠檬酸水溶液将所得溶液酸化至pH 2,然后用乙酸乙酯(3×100mL)萃取。用饱和氯化钠水溶液(100mL)洗涤有机物,用无水硫酸钠干燥,并真空浓缩。通过柱层析(10-50%乙酸乙酯/正己烷)纯化残余物,得到标题化合物,为非对映异构体(2.20g,37%收率)和两种非对映异构体的混合物(2.0g,34%收率,约9:1比率)。1H-NMR(500MHz,CDCl3)δ4.41(d,J=9.3Hz,1H),4.17(tt,J=7.1,3.6Hz,2H),4.00(t,J=6.9Hz,1H),3.55(dd,J=11.7,9.3Hz,1H),2.56–2.51(m,2H),2.44(dd,J=16.4,9.0Hz,1H),1.79(d,J=3.8Hz,1H),1.60–1.53(m,1H),1.43(s,9H),1.27(dd,J=9.3,5.0Hz,3H),1.03–0.91(m,7H).
实施例62.(3R,4S,5S)-4-((叔丁氧基羰基)氨基)-3-羟基-5-甲基庚酸的合成
向(3R,4S,5S)-4-((叔丁氧基羰基)氨基)-3-羟基-5-甲基庚酸乙酯(2.20g,7.20mmol)的乙醇(22mL)溶液中加入1N氢氧化钠(7.57mL,7.57mmol)。将混合物在0℃下搅拌30分钟,然后在室温下搅拌2小时,通过加入1N盐酸水溶液将所得溶液酸化至pH4,然后用乙酸乙酯(3×50mL)萃取。将有机萃取液用1N硫酸氢钾水溶液(50mL)和饱和氯化钠水溶液(50mL)洗涤,用无水硫酸钠干燥,并真空浓缩,得到化合物(1.90g,95%收率)。1H-NMR(500MHz,CDCl3)δ4.50(d,J=8.7Hz,1H),4.07(d,J=5.5Hz,1H),3.59(d,J=8.3Hz,1H),2.56–2.45(m,2H),1.76–1.65(m,1H),1.56(d,J=7.1Hz,1H),1.45(s,9H),1.26(t,J=7.1Hz,3H),0.93(dd,J=14.4,7.1Hz,6H).。
实施例63.(3R,4S,5S)-4-((叔丁氧基羰基)(甲基)氨基)-3-甲氧基-5-甲基庚酸的合成
向(3R,4S,5S)-4-((叔丁氧基羰基)氨基)-3-羟基-5-甲基庚酸(1.90g,6.9mmol)的四氢呋喃(40mL)溶液中加入氢化钠(在0℃下,60%矿物油中,1.93g,48.3mmol)。搅拌1小时后,加入碘甲烷(6.6mL,103.5mmol)。在0℃下继续搅拌40小时,然后加入饱和碳酸氢钠水溶液(50mL),接着加入水(100mL)。将混合物用乙醚(2×50mL)洗涤,并将水层用1N硫酸氢钾水溶液酸化至pH 3,然后用乙酸乙酯(3×50mL)萃取。将合并的有机萃取液用5%硫代硫酸钠水溶液(50mL)和饱和氯化钠水溶液(50mL)洗涤,用无水硫酸钠干燥,真空浓缩,得到标题化合物(1.00g,48%收率)。1H-NMR(500MHz,CDCl3)δ3.95(d,J=75.4Hz,2H),3.42(d,J=4.4Hz,3H),2.71(s,3H),2.62(s,1H),2.56–2.47(m,2H),1.79(s,1H),1.47(s,1H),1.45(d,J=3.3Hz,9H),1.13–1.05(m,1H),0.96(d,J=6.7Hz,3H),0.89(td,J=7.2,2.5Hz,3H).
实施例64.Boc-N-Me-L-Val-OH的合成
在0℃下,向BOC-L-缬氨酸-OH(2.00克,9.2mmol)和碘甲烷(5.74mL,92mmol)的无水四氢呋喃(40mL)溶液中加入氢化钠(3.68克,92mmol)。将反应混合物在0℃下搅拌1.5小时,然后升温至室温并搅拌24小时。用冰水(50mL)淬灭反应,加入水(100mL)后,将反应混合物用乙酸乙酯(3×50mL))洗涤,将水溶液酸化至pH 3,然后用乙酸乙酯(3×50mL)萃取。将合并的有机相用无水硫酸钠干燥并浓缩,得到白色固体Boc-N-Me-Val-OH(2.00g,94%产量).1H-NMR(500MHz,CDCl3)δ4.10(d,J=10.0Hz,1H),2.87(s,3H),2.37–2.13(m,1H),1.44(d,J=26.7Hz,9H),1.02(d,J=6.5Hz,3H),0.90(t,J=8.6Hz,3H).
实施例65.(S)-2-((1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙烷-2-基)氨基叔丁酯的合成甲基)-2-甲基-3-氧代丙基)吡咯烷-1-羧酸叔丁酯的合成
在0℃下,向(2R,3R)-3-((S)-1-(叔丁氧基羰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酸(100mg,0.347mmol)和L-苯丙氨酸甲酯盐酸盐(107.8mg,0.500mmol)的DMF(5mL)溶液中加入氰基膦酸二乙酯(75.6μL,0.451mmol),然后加入三乙胺(131μL,0.94mmol)。将反应混合物在0℃下搅拌2小时,然后升温至室温并搅拌过夜。然后将反应混合物用乙酸乙酯(80mL)稀释,用1N硫酸氢钾水溶液(40mL),水(40mL),饱和碳酸氢钠水溶液(40mL)和饱和氯化钠水溶液(40)洗涤。用无水硫酸钠干燥,真空浓缩。通过柱层析(15-75%乙酸乙酯/正己烷)纯化残余物,得到标题化合物(130mg,83%产率),为白色固体。1H-NMR(500MHz,CDCl3)δ7.28(dd,J=7.9,6.5Hz,2H),7.23(t,J=7.3Hz,1H),7.16(s,2H),4.81(s,1H),3.98–3.56(m,5H),3.50(s,1H),3.37(d,J=2.9Hz,3H),3.17(dd,J=13.9,5.4Hz,2H),3.04(dd,J=14.0,7.7Hz,1H),2.34(s,1H),1.81–1.69(m,2H),1.65(s,3H),1.51–1.40(m,9H),1.16(d,J=7.0Hz,3H).
实施例66.用三氟乙酸除去Boc官能团的一般步骤
向N-Boc氨基酸(1.0mmol)的二氯甲烷(2.5mL)溶液中加入三氟乙酸(1.0mL)。在室温下搅拌1-3小时后,将反应混合物真空浓缩。与甲苯共浓缩得到脱保护的产物,其不经任何进一步纯化即可使用。
实施例67.(S)-甲基-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((叔丁氧基羰基)(甲基)氨基)-3-甲氧基-5-甲基庚基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸乙酯的合成
在0℃下,向(S)(叔丁基-2-((1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙烷-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-羧酸乙酯(0.29mmol)的Boc-去保护产物和(3R,4S,5S)-4-((叔丁氧基羰基)(甲基)氨基)-3-甲氧基-5-甲基庚酸(96.6mg,0.318mmol)的DMF(5mL)溶液中加入氰基膦酸二乙酯(58μL,0.347mmol),然后加入Et3N(109μL,0.78mmol)。将反应混合物在0℃下搅拌2小时,然后升温至室温并搅拌过夜。将反应混合物用乙酸乙酯(80mL)稀释,用1N硫酸氢钾水溶液(40mL),水(40mL),饱和碳酸氢钠水溶液(40mL)和饱和氯化钠水溶液(40mL)洗涤。用无水硫酸钠干燥并真空浓缩。通过柱层析(15-75%乙酸乙酯/正己烷)纯化残余物,得到标题化合物(150mg,81%产率),为白色固体。LC-MS(ESI)m/z C34H55N3O8[M+H]+计算值634.40,实测值634.40。
实施例68.(S)-2-甲基-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((叔丁氧基羰基)氨基)-N,3-二甲基丁酰胺)-3-甲氧基-5-甲基庚基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸乙酯的合成
在0℃下,向(S)-甲基2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((叔丁氧基羰基))(甲基)氨基)-3-甲氧基-5-甲基庚酰基)-吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯的去Boc保护的产物(0.118mmol)和Boc-Val-OH(51.8mg,0.236mmol))的二氯甲烷(5mL)溶液中加入BroP(70.1mg,0.184mmol),然后加入二异丙基乙胺(70μL,0.425mmol)。将混合物置于避光处并在0℃下搅拌30分钟,然后在室温下搅拌2天,将反应混合物用乙酸乙酯(80mL)稀释,用1N硫酸氢钾水溶液(40mL),水(40mL),饱和碳酸氢钠水溶液(40mL)和饱和氯化钠水溶液(40mL)洗涤。用无水硫酸钠干燥并真空浓缩,通过柱层析(20-100%乙酸乙酯/正己烷)纯化残余物,得到标题化合物为白色固体(67mg,77%产率)。LC-MS(ESI)m/zC39H64N4O9[M+H]+计算值733.47,实测值733.46.
实施例69.(S)-甲基2-((2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-仲丁基)-6,9-二异丙基-13-甲氧基2,2,5,11四甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮十五烷-15酰基)吡咯烷-2-基))-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(221)的合成
在0℃下,向(S)-甲基2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2)-((叔丁氧基羰基)氨基)-N,3-二甲基丁酰胺基)-3-甲氧基-5-甲基庚酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯的去Boc产物(0.091mmol)和Boc-N-Me-Val-OH(127mg,0.548mmol)的DMF(5mL)溶液中加入氰基膦酸二乙酯(18.2μL,0.114mmol),然后加入N-甲基吗啉(59μL,0.548mmol)。将反应混合物在0℃下搅拌2小时,然后升温至室温并搅拌过夜。将反应混合物用乙酸乙酯(80mL)稀释,用1N硫酸氢钾水溶液(40mL),水(40mL),饱和碳酸氢钠水溶液(40mL)和饱和氯化钠水溶液(40mL)洗涤。用硫酸钠干燥,真空浓缩。通过柱层析(20-100%乙酸乙酯/正己烷)纯化残余物,得到标题化合物为白色固体(30mg,39%产率)。LC-MS(ESI)m/z C45H75N5O10[M+H]+计算值846.55,实际值:846.56.
实施例70.(S)-甲基2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-二甲基-2-((S)-3-甲基-2-(甲基氨基)丁酰氨基)丁酰氨基)-3-甲氧基-5-甲基-庚基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙(222)的合成
在室温下,向(S)甲基-(2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-仲丁基)-6,9-二异丙基-13-甲氧基-2,2,5,11-四甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十五烷-15酰基)吡咯烷-2-基)3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(75.0mg,0.0886mmol)的二氯甲烷溶液(5mL)中加入三氟乙酸(2mL)。在室温下搅拌1小时,将反应混合物真空浓缩并与甲苯共浓缩得到去保护的标题产物,其无需进一步纯化即可使用。
实施例71. 3,3’-(苄基氮杂二基)二丙酸二叔丁酯(227)的合成
将苯基甲胺(2.0mL,18.29mmol,1.0eq.)和丙烯酸叔丁酯(13.3mL,91.46mmol,5.0eq.)的混合物在80℃下回流过夜,然后浓缩。通过硅胶柱层析(20:1正己烷/乙酸乙酯)纯化粗产物,得到标题化合物,为无色油状物(5.10g,77%收率)。ESI MS m/z C21H34NO4[M+H]+计算值364.2,实际值364.2.1H-NMR(400MHz,CDCl3)δ7.38–7.21(m,5H),3.58(s,2H),2.76(t,J=7.0Hz,4H),2.38(t,J=7.0Hz,4H),1.43(s,17H).
实施例72. 3,3’-氮杂二基丙酸二叔丁酯(228)的合成
在氢化瓶中,向3,3’-(苄基氮杂二基)二丙酸二叔丁酯(1.37g,3.77mmol,1.0eq.)的甲醇(10mL)溶液中加入Pd/C(0.20g,10wt%,50%水)。将混合物在H2下振荡过夜,然后通过硅藻土垫过滤。浓缩滤液,得到标题化合物,为无色油状物(1.22g,89%收率)。ESI MS m/z C14H28NO4[M+H]+计算值274.19,实际值274.20.
实施例73. 3,3’-(丙酰基偶氮二基)二丙酸二叔丁酯(229)的合成
在0℃下,向3,3’-氮杂二丙基丙酸二叔丁酯(1.22g,4.45mmol,1.0eq.)和丙炔酸(0.468g,6.68mmol,1.5eq.)的无水DMF(100mL)溶液中加入PyBrop(2.49g,5.34mmol,1.2eq.)和DIPEA(2.32mL,13.4mmol,3.0eq.)。将反应在0℃下搅拌10分钟,然后升温至室温并搅拌1.5小时。加入水(500mL)并将混合物用乙酸乙酯(6×200mL)萃取。将合并的有机层用水(4×600mL)和盐水(600mL)洗涤,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(4:1石油醚/乙酸乙酯)纯化,得到标题化合物,为淡黄色油状物(1.00克,产率82%)。ESI MSm/z C17H28NO5[M+H]+计算值326.18,实际值326.208.。
实施例74. 3,3’-(丙酰基氮杂二基)二丙酸(230)的合成
在室温下向3,3’-(丙酰基偶氮二基)二丙酸二叔丁酯(0.078g,0.240mmol,1.0eq.)的二氯甲烷(3mL)溶液中加入TFA(1mL)并搅拌反应物30分钟,然后用无水甲苯稀释,浓缩,重复该操作3次,得到淡黄色油状的标题化合物(0.051g,>100%收率)。ESI MS m/z C9H12NO5[M+H]+214.06,计算值214.06,实测值214.06。
实施例75.(3R,4S,7S,10S,13S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R),2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,13-三甲基-6,9,12,15-四氧代-18-丙二酰基-2-氧杂-5,8,11,14,18-五氮杂苯甲酸-21-酸(231)的合成
在0℃下,向3,3’-(丙酰基氮杂二基)二丙酸(0.051g,0.240mmol,6.5eq.)和(S)-甲基2-((2R,3R)-3-((S)-1-(3R,4S,5S)-4-((S)-2-((S)-2-((S)-2-氨基-N-甲基-丙酰胺基)-3-甲基丁酰胺基)-N,3-二甲基丁酰胺基)-3-甲氧基-5-甲基-庚酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(0.030g,0.0368mmol,1.0eq.)的无水DMF(3mL)溶液中加入PyBrop(0.021g,0.0442mmol,1.2eq.)和DIPEA(0.019mL,0.110mmol,3.0eq.)。将反应在0℃下搅拌10分钟,然后升温至室温并搅拌1.0小时。加入两滴水,浓缩混合物,并用制备HPLC(C18柱,流动相A:水,流动相B:乙腈,从20%B至80%B,50分钟)纯化。合并组分并冻干,得到无色油状物标题化合物(21mg,57%收率)。ESI MS m/z C55H89N8O13[M+H]+计算值1069.64,实测值1069.66.
实施例76.(S)-甲基2-((2R,3R)-3-((S)-1-((14S,17S,20S,23S,24R)-23-((S)-仲丁基)-17,20二异丙基24甲氧基14,16,22三甲基6,12,15,18,21-五氧代-9-丙炔酰基-2-氧杂5,9,13,16,19,22-六氮杂二十六烷-26-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(233)的合成
在0℃下,向(3R,4S,7S,10S,13S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-(1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,13-三甲基-6,9,12,15-四氧代-18-丙烯酰基-2-氧杂-5,8,11,14,18-五氮杂二十一烷-21-酸(0.008g,0.00791mmol,1.0eq.)和2-甲氧基乙胺(0.006g,0.0791mmol,10.0eq.)的无水DMF(2mL)溶液中加入PyBrop(0.004g,0.00870mmol,1.1eq.)和DIPEA(0.004mL,0.00267mmol,3.0eq.)。将反应物在0℃下搅拌10分钟,然后升温至室温并搅拌1.0h。滴加两滴水,将混合物用制备型HPLC纯化(C18柱,流动相A:水,流动相B:乙腈,50分钟内从20%B到80%B)。合并组分并冻干,得到无色油状标题化合物(7.0mg,83%产率)。ESI MS m/z C55H89N8O13[M+H]+计算值1069.64,实测值1069.66.
实施例77.(S)-甲基2-((2R,3R)-3-((S)-1-((81S,84S,87S,90S,91R)-90-((S)-仲丁基)-1-羟基84,87二异丙基91甲氧基81,83,89三甲基73,79,82,85,88-五氧唑-76丙炔酰基-3,6,9,12,15-18,21,24,27,30,33,36,39,42,45,48,51,54,57,60,63,66,69-二十三氧-72,76,80,83,86,89-六氮杂九十三-93-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(237)的合成
在0℃下,向(3R,4S,7S,10S,13S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-(1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧乙基)-5,11,13-三甲基-6,9,12,15-四氧-18-丙烯酰基-2-氧杂-5,8,11,14,18-五氮杂二十一-21-酸(0.021g,在0.0208mmol,1.0eq.)和HO-PEG24-NH2(0.027g,0.0250mmol,1.2eq.)的无水DMF(3mL)溶液中加入PyBrop(0.010g,0.0218mmol,1.05eq。)和DIPEA(0.011mL,0.0624mmol,3.0eq.)。将反应在0℃下搅拌10分钟,然后升温至室温并搅拌1.0小时。加入两滴水,用制备HPLC(C18柱,流动相A:水,流动相B:乙腈,从20%B至80%B,50分钟)纯化。合并组分并冻干,得到标题化合物,为无色油状物(35mg,81%收率),ESI MS m/z C100H179N8O36[M+H]+计算值2068.23,实测值2068.25。
实施例78. 4-(2-(((苄氧基)羰基)氨基)丙烷酰胺基丁酸叔丁酯(251)的合成
在0℃下,向4-氨基丁酸叔丁酯(1.00g,6.28mmol,1.0eq.)和Z-L-丙氨酸(2.10g,9.42mmol,1.5eq.的无水二氯甲烷(50mL)溶液中加入HATU(3.10g,8.164mmol,1.3eq.)和TEA(2.6mL,18.8mmol,3.0eq.)。将反应在0℃下搅拌10分钟,然后升温至室温并搅拌过夜。将混合物用二氯甲烷稀释,然后用水和盐水洗涤,经无水硫酸钠干燥,浓缩,并通过硅胶柱层析(10:3石油醚/乙酸乙酯)纯化,得到标题化合物,为无色油状物(1.39g,61%产率)。ESIMS m/z C19H29N2O5Na[M+H]+计算值387.2,实测值387.2。
实施例79. 4-(2-氨基丙酰胺基)丁酸叔丁酯(252)的合成
在氢化瓶中,向4-(2-(((苄氧基)羰基)氨基)丙酰胺基)丁酸叔丁酯(1.39g,3.808mmol,1.0eq.)的甲醇(12mL)溶液中加入Pd/C(0.20g,10wt%,10%水)。将混合物振荡2小时,然后通过硅藻土(助滤剂)过滤,浓缩,得到标题化合物,为浅黄色油状物(0.838g,95%收率)。ESI MS m/z C11H23N2O3[M+H]+计算值231.16,实测值231.15。
实施例80. 3-(2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸(254)的合成
在室温下,向3-(2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸叔丁酯(2.3g,5.59mmol,1.0eq.)的二氯甲烷(10mL)溶液中加入TFA(5mL)。搅拌90分钟后,将反应混合物用无水甲苯稀释并浓缩,重复该操作三次,得到标题化合物,为浅黄色油状物(2.0g,理论收率),直接用于下一步。ESI MS m/z C21H28NO4[M+H]+计算值358.19,实测值358.19。
实施例81.五氟苯基3-(2-(2-(二苄基氨基)乙氧基)乙氧基)-丙酸酯(255)的合成
在0℃下,向3-(2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸(2.00g,5.59mmol,1.0eq.)的无水二氯甲烷(30mL)溶液中加入DIPEA直至pH为中性,然后加入五氟苯酚(1.54g,8.38mmol,1.5eq.)和DIC(1.04mL,6.70mmol,1.2eq.)。10分钟后,将反应升温至室温并搅拌过夜。将混合物过滤,浓缩并通过SiO2柱层析(15:1石油醚/乙酸乙酯)纯化,得到标题化合物,为无色油状物(2.10g,72%收率)。ESI MS m/z C27H27F5NO4[M+H]+计算值524.2,实测值524.2。
实施例82. 2-苄基-13-甲基-11,14-二氧代-1-苯基-5,8-二氧杂-2,12,15-三氮杂十九烷-19-酸叔丁酯的合成(256)
在0℃下,向4-(2-氨基丙酰胺基)丁酸叔丁酯(0.736g,3.2mmol,1.0eq.)和五氟苯基3-2-(2-(二苄基氨基)乙氧基)乙氧基)丙酸酯(2.01g,3.84mmol,1.2eq.)的无水DMA(20mL)溶液中加入DIPEA(1.7mL,9.6mmol,3.0eq.)。在0℃下搅拌10分钟。将反应升温至室温并搅拌过夜。加入水(100mL)并将混合物用乙酸乙酯(3×100mL)萃取。将合并的有机层用水(3×200mL)和盐水(200mL)洗涤,用无水硫酸钠干燥,过滤,浓缩并通过硅胶柱层析(25:2二氯甲烷/甲醇)纯化,得到标题化合物,为无色油(1.46克,80%产率)。ESI MS m/zC32H48N3O6[M+H]+计算值570.34,实测值570.33。
实施例83. 2-苄基-13-甲基-11,14-二氧代-1-苯基-5,8-二氧杂-2,12,15-三氮杂十九烷-19-酸(257)的合成
在室温下,向2-苄基-13-甲基-11,14-二氧代-1-苯基-5,8-二氧杂-2,12,15-三氮杂十九烷-19-酸叔丁酯(0.057g,0.101mmol)的二氯甲烷(3mL)溶液中加入TFA(1mL)并搅拌40分钟。用无水甲苯稀释反应物,然后浓缩。重复该操作三次,得到标题化合物,为无色油状物(0.052g,理论产量),将其直接用于下一步骤。ESI MS m/z C28H40N3O6[M+H]+计算值514.28,实测值514.28。
实施例84.(2S)-2-((2R,3R)-3-((2S)-1-((21S,24S,27S,28R)-2-苄基-27-((S)-仲丁基)-21,24-二异丙基-28甲氧基13,20,26-三甲基-11,14,19,22,25-五氧唑-1-苯基-5,8-二氧杂-2,12,15,20,23,26-六氮杂三十-30-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(258)的合成
在0℃下,向2-苄基-13-甲基-11,14-二氧代-1-苯基-5,8-二氧杂-2,12,15-三氮杂十九烷-19-酸(0.052g,0.101mmol,1.5eq.)和已合成的(S)-甲基2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-二甲基-2)-((S)-3-甲基-2-(甲基氨基)-丁酰氨基)丁酰氨基)-3-甲氧基-5-甲基-庚基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯丙酸盐(0.050g,0.0671mmol,1.0eq.)的无水二氯甲烷(5mL)溶液中加入BrOP(0.034g,0.0872mmol,1.3eq.)和DIPEA(0.035mL,0.201mmol,3.0eq.)。搅拌10分钟后。在0℃下,将反应升温至室温并搅拌过夜。加入两滴水,浓缩混合物,并在HPLC(C18柱,流动相A:水,流动相B:乙腈,20%B至80%B,50分钟)上纯化。合并组分并冻干,得到标题化合物,为无色油状物(60mg,72%收率)。ESIMS m/z C68H105N8O13[M+H]+计算值1241.77,实测值1241.77。
实施例85.(2S)-2-((2R,3R)-3-((2S)-1-((19S,22S,25S,26R)-1-氨基-25-((S)-仲丁基)-19,22-二异丙基-26-甲氧基-11,18,24-三甲基-9,12,17,20,23-五杂氧-3,6-二氧杂-10,13,18,21,24-五氮二十八烷-28-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(259)的合成
在氢化瓶中,向(2S)-甲基2-((2R,3R)-3-((2S)-1-((21S,24S,27S,28R)-2-苄基-27-((S)-仲丁基)-21,24-二异丙基-28-甲氧-13,20,26-三甲基-11,14,19,22,25-五杂氧-1-苯基-5,8-二氧杂-2,12,15,20,23,26-六氮杂三十烷-30-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(0.030g,0.0288mmol,1.0eq.)的甲醇(3mL)溶液加入Pd/C(0.050g,10wt%,10%水)和一滴6N盐酸。将混合物振荡2小时,然后通过硅藻土(助滤剂)过滤,浓缩,得到标题化合物,为浅黄色油状物(0.030g,>100%收率)。ESI MS m/zC54H93N8O13[M+1]+计算值1061.67,实测值1061.69。
实施例86. 4-丙氨基丁酸叔丁酯的合成
在室温下,向4-氨基丁酸叔丁酯(0.500g,3.14mmol,1.0eq.)和丙炔酸(0.330g,4.71mmol,1.5eq.)的无水二氯甲烷(60mL)中溶液中加入DCC(0.972g,4.71mmol,1.5eq.)。将反应物搅拌3小时,然后过滤,浓缩并通过硅胶柱层析(15:1二氯甲烷/甲醇)纯化,得到标题化合物,为黄色油状物(0.489g,74%收率)。ESI MS m/z C11H18NO3Na[M+H]+计算值234.1,实测值234.1。
实施例87. 4-丙氨基丁酸的合成
在室温下,向4-丙基氨基丁酸叔丁酯(0.498g,2.32mmol,1.0eq.)的二氯甲烷(3mL)溶液中加入TFA(1mL)并将反应物搅拌2小时,然后用无水甲苯稀释并且浓缩。重复该操作三次,得到标题化合物,为浅黄色油状物(0.051g,>100%收率),将其直接用于下一步骤。ESI MS m/z C7H10NO3[M+H]+计算值156.1,实测值156.1。
实施例88. 3,3’-((4-丙酰基氨基丁酰基)氮杂二基)二丙酸二叔丁酯的合成
在0℃下,向4-丙酰基氨基丁酸(0.360g,2.32mmol,1.2eq.)和3,3’-氮杂二羟基丙酸二叔丁酯(0.528g,1.93mmol,1.0eq.)的无水二氯甲烷(15mL)溶液中,加入PyBrop(0.990g,2.22mmol,1.1eq.)和DIPEA(1.0mL,5.80mmol,3.0eq.)。10分钟后,将反应升温至室温并搅拌过夜。然后将混合物用二氯甲烷稀释,用水和盐水洗涤,经无水硫酸钠干燥,浓缩,并通过硅胶柱层析(5:2石油醚/乙酸乙酯)纯化,得到标题化合物,为黄色油状物(0.367g,46%产量)。ESI MS m/z C21H35N2O6[M+H]+计算值411.2,实测值411.3。
实施例89. 3,3’-((4-丙酰胺基丁酰基)氮杂二基)二丙酸的合成
在室温下,向3,3’-((4-丙酰胺丁醇)氮杂环己基)二丙酸二叔丁基酯(0.367g,0.895mmol,1.0eq.)的二氯甲烷(3mL)溶液中加入TFA(1mL)。将反应物搅拌3小时,然后用无水甲苯稀释并浓缩。重复该操作三次,得到标题化合物,为浅黄色油状物(0.266g,>100%收率),将其直接用于下一步骤。ESI MS m/z C13H19N2O6[M+H]+计算值299.1,实测值299.1。
实施例90.(3R,4S,7S,10S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R,2R))-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,1-三甲基-6,9,12,17,20,30-六氧-33-(4-丙二醇酰胺丁醇)-2,23,26-三氧杂-5,8,11,16,19,29,33-七氮杂三十六烷-36-酸(260)的合成
在0℃下,向(2S)-甲基2-((2R,3R)-3-((2S)-1-((19S,22S,25S,26R)-1-氨基-25-((S)-仲丁基)-19,2-二异丙-26-甲氧基-11,18,24-三甲基-9,12,17,20,23-五氧-3,6-二氧杂-10,13,18,21,24-五氮杂二十八烷-28-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(0.030g,0.0288mmol,1.0eq.)和3,3’-((4-丙酰胺基丁酰基)氮杂二基)二丙酸(0.026g,0.0865mmol,3.0eq.)的无水DMF(3mL)溶液中的中加入PyBrop(0.017g,0.0374mmol,1.3eq.)和DIPEA(0.035mL,0.064mmol,3.0eq.)。在0℃下搅拌10分钟。将反应升温至室温并搅拌1小时,加入两滴水,浓缩混合物,并用HPLC(C18柱,流动相A:水,流动相B:乙腈,20%B至80%B,50分钟)纯化。合并组分并冻干,得到标题化合物,为无色油状物(18.1mg,47%收率)。ESI MS m/z C67H109N10O18[M+H]+计算值1341.784,实测值1341.81。
实施例91.(S)-2-((2R,3R)-3-((S)-1-((5S,8S,11S,14S,15R)-14-((S)-仲丁基)-8,11-二异丙基-15-甲氧-5,7,1-三甲基-3,6,9,12-四氧-1-苯基-2-氧杂-4,7,10,13-四氮杂十七烷-17-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸甲基酯(263)的合成
在0℃下,向MMAF-OMe(0.132g,0.178mmol,1.0eq.)和Z-L-丙氨酸(0.119g,0.533mmol,3.0eq.)的无水二氯甲烷(10mL)溶液中加入HATU(0.135g,依次加入0.356mmol,2.0eq.)和NMM(0.12mL,1.07mmol,6.0eq.)。将反应在0℃下搅拌10分钟,然后升温至室温并搅拌过夜。将混合物用二氯甲烷稀释,用水和盐水洗涤,经无水硫酸钠干燥,浓缩,并通过硅胶柱层析(20:1二氯甲烷/甲醇)纯化,得到标题化合物,为白色泡沫状固体(0.148g,88%收率))。ESI MS m/z C51H79N6O11[M+H]+的计算值951.6,实测值951.6。
实施例92.(S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S))-2-((S)-2-氨基-N-甲基丙酰胺基)-3-甲基丁酰胺基)-N,3-二甲基丁酰胺)-3-甲氧基-5-甲基庚基)吡咯烷-2-基)-3-甲氧基-2-(甲基丙酰胺基)-3-苯基丙酸甲基酯(264)的合成
在氢化瓶中,向(S)-2-((2R,3R)-3-((S)-1-((5S,8S,11S,14S,15R)-14-((S)-仲丁基)-8,11-二异丙-甲氧基-5,7,13-三甲基-3,6,9,12-四氧-1-苯基-2-氧杂-4,7,10,13-四氮杂十七烷-17-将酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基-丙酸甲基酯(0.148g,0.156mmol,1.0eq.)的甲醇(5mL)溶液加入Pd/C(0.100g,10wt%,50%水)。将混合物振荡5小时,然后通过硅藻土垫过滤。浓缩滤液,得到标题化合物,为白色泡沫状固体(0.122g,96%收率)。ESI MS m/z C43H73N6O9[M+H]+817.5,计算值817.5,实测值817.5。
实施例93.(E)-3-(2-(2-(3-溴丙烯酰胺基)乙氧基)乙氧基)丙酸叔丁酯(302)的合成
在0℃下,向(E)-3-溴丙烯酸(0.15g,1mmol),DMAP(0.15g,1.2mmol)和DCC(0.21g,1mmol)的二氯甲烷(10mL)溶液中加入3-(2-(2-氨基乙氧基)乙氧基)丙酸叔丁基酯(0.23g,1mmol)。将反应混合物升温至室温并搅拌过夜。浓缩粗产物,并通过硅胶柱层析法用乙酸乙酯/二氯甲烷梯度纯化,得到标题产物(0.31g,85%收率)。ESI MS m/z C14H25BrNO5[M+H]+:计算值366.08,实测值366.08。
实施例94.(E)-3-(2-(2-(3-溴丙烯酰氨基)乙氧基)乙氧基)丙酸(303)的合成
在0℃下,将(E)-3-(2-(3-溴丙烯酰胺基)乙氧基)乙氧基)丙酸叔丁酯(0.31g,0.84mmol)溶解在甲酸(4mL)中,然后加入水(2mL)。将反应混合物升温至室温并搅拌过夜。浓缩粗产物,不经进一步纯化直接用于下一步。ESI MS m/z C10H17BrNO5[M+H]+:计算值310.02,实测值310.03。
实施例95.(E)-2,5-二氧代吡咯烷-1-基3-(2-(2-(3-溴丙烯酰氨基)乙氧基)乙氧基)丙酸酯(304)的合成
将(E)-3-(2-(2-(3-溴丙烯酰胺基)乙氧基)乙氧基)丙酸(0.12g,0.39mmol),NHS(0.067g,0.58mmol)和EDC(0.11g,0.58mmol)溶解在二氯甲烷(10mL)中并将混合物在室温下搅拌过夜,浓缩并通过硅胶柱层析法纯化,得到标题产物(0.13g,82%收率)。ESI MS m/zC14H20BrN2O7[M+H]+:计算值407.04,实测值407.04。
实施例96.(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶)-2-甲酰氨基)戊基)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-(3-(2-(2-((E)-3-溴丙烯氨基)乙氧基)乙氧基)丙酰氨基)-4-羟基苯基)-2-甲基戊酸(306)的合成
向(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰氨基)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-氨基-4-羟基苯基)-2-甲基戊酸(305)(Huang Y.等,Med Chem.#44,249th ACS National Meeting,Denver,CO,Mar.22~26,2015;WO2014009774)(50mg,0.066mmol),(E)-2,5-二氧代吡咯烷-1-基3-(2-(2-(3-溴代丙烯酰胺(乙氧基)丙酸酯(60mg,0.148mmol)的DMA(3mL)溶液中加入NaH2PO4(17.8mg,0.15mmol)。将混合物在室温下搅拌过夜,浓缩并通过反相HPLC纯化,用乙腈/水梯度洗脱,得到标题产物(22.6mg,33%收率)。ESI MS m/z C48H73BrN7O12S[M+H]+:计算值1052.41,实测值1052.40。
实施例97. 3-(2-(2-丙酰胺基乙氧基)乙氧基)丙酸叔丁酯(320)的合成
将3-(2-(2-氨基乙氧基)乙氧基)丙酸叔丁酯(466mg,2mmol)和丙炔酸(210mg,3mmol)溶解在二氯甲烷(50mL)中,加入DCC(618mg,3mmol)。将所得溶液在室温下搅拌3小时后浓缩。通过柱层析(10%至100%乙酸乙酯/正己烷)纯化,得到标题化合物(400mg,70%)。ESI MS m/z 286.17([M+H]+)。
实施例98. 3-(2-(2-丙酰氨基乙氧基)乙氧基)丙酸(321)的合成
将3-(2-(2-丙酰胺基乙氧基)乙氧基)丙酸叔丁酯(200mg,0.7mmol)溶于二氯甲烷(5mL)中,向其中加入甲酸(7mL)。将所得溶液在38℃下搅拌过夜。真空除去所有挥发物,得到标题化合物(160mg,>100%收率)。ESI MS m/z 230.11([M+H]+)。
实施例99. 2,5-二氧代吡咯烷-1-基3-(2-(2-丙酰胺基乙氧基)-乙氧基)丙酸酯的合成(322)
将NHS(115mg,1mmol)和EDC(192mg,1mmol)加入到3-(2-(2-丙酰胺基乙氧基)乙氧基)丙酸(149mg,0.65mmol)的二氯甲烷(15mL)溶液中。在室温下搅拌过夜,浓缩反应物并通过柱层析(0%至10%甲醇/二氯甲烷)纯化,得到标题化合物(180mg,85%)。ESI MS m/z327.11([M+H]+)。
实施例100.(4R)-4-((叔丁氧基羰基)氨基)-5-(4-羟基-3-(3-(2-(2-丙酰氨基乙氧基)乙氧基)丙酰胺基)苯基)-2-甲基戊酸酯(323)的合成
向2,5-二氧代吡咯烷-1-基3-(2-(2-丙酰胺基乙氧基)乙氧基)丙酸酯(90mg,0.276mmol)和5-(3-氨基-4-羟基苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸丁酯(109mg,0.276mmol)的乙醇(7.5mL)溶液中加入NaH2PO4(0.1M,1.5mL)。在室温下搅拌所得溶液24小时。真空除去所有挥发物,并通过柱层析(30%至100%乙酸乙酯/正己烷)纯化残余物,得到标题化合物(160mg,96%)。ESI MS m/z 606.34([M+H]+)。
实施例101.(4R)-4-氨基-5-(4-羟基-3-(3-(2-(2-丙酰胺基乙氧基)-乙氧基)丙酰胺基)苯基)-2-甲基戊酸(324)的合成
将(4R)-4-(叔丁氧基羰基)氨基)-5-(4-羟基-3-(3-(2-(2-丙酰胺基-乙氧基)乙氧基)丙酰胺基)苯基)-2-甲基戊酸叔丁酯(40mg,0.066mmol)溶解在二氯甲烷(3mL)中并与TFA(3mL)在室温下搅拌2小时。真空除去所有挥发物,得到标题化合物(29mg,99%)。ESI MSm/z 450.23([M+H]+)。
实施例102.(4R)-4-(2-((6S,9R,11R)-6-((S)-仲丁基)-9-异丙基-2,3,3,8-四甲基-4,7,13-三氧-12-氧-2,5,8-三氮十四烷-11-基)噻唑-4-甲酰氨基)-5-(4-羟基-3-(3-(2-(2-丙酰胺乙氧基)乙氧基)丙酰胺基)苯基)-2-甲基戊酸(325)的合成
将(4R)-4-氨基-5-(4-羟基-3-(3-(2-(2-丙酰胺基乙氧基)-乙氧基)丙酰胺基)-苯基)-2-甲基戊酸(30mg,0.066mmol)和五氟苯基2-((6S,9R,11R)-6-((S)-仲丁基)-9-异丙基-2,3,3,8-四甲基-4,7,13-三氧-12-氧杂-2,5,8-三氮杂十四烷-11-基)噻唑-4-羧酸酯(46mg,0.066mmol)溶解在DMA(3mL)中。然后加入DIPEA(10mg,0.078mmol)并在室温下搅拌1.5小时。真空除去溶剂,并将残余物在制备型HPLC(C18柱,10-90%乙腈/水)上纯化,得到标题化合物(15mg,24%)。ESI MS m/z 958.47([M+H]+)。
实施例103.(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶)-2-甲酰胺基)戊酰氨基)-4-甲基戊基)噻唑-4-甲酰胺基)-5-(3-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰胺基)-4-羟基苯基)-2-甲基戊酸(335)的合成
在2小时内分四次向(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰氨基)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-氨基-4-羟基苯基)-2-甲基戊酸(100mg,0.131mmol)的DMA(10mL)和NaH2PO4缓冲溶液(pH 7.5,1.0M,0.7mL)的混合物中加入2,5-二氧代吡咯烷-1-基3-(2-(2-叠氮基乙氧基)乙氧基)丙酸酯(80.0mg,0.266mmol)。将混合物搅拌过夜,浓缩并在C18制备HPLC上纯化,用80%水/甲醇至10%水/甲醇洗脱45分钟,得到标题化合物(101.5mg,82%收率)。LC-MS(ESI)m/zC45H70N9O11S[M+H]+:计算值944.48,实测值944.70。
实施例104.(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基)-哌啶-2-甲酰氨基)戊基)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-(3-(2-(2-氨基乙氧基)乙氧基)丙酰氨基)-4-羟基苯基)-2-甲基戊酸(336)的合成
在氢化瓶中,向(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶-2-甲酰胺基)戊酰氨基)-4-甲基戊基)噻唑-4-甲酰胺基)-5-(3-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰胺基)-4-羟基苯基)-2-甲基戊酸(100.0mg,0.106mmol)含有0.1%盐酸的甲醇(25mL)溶液中加入Pd/C(25mg,10wt%,50%水)。将空气抽空并导入35psi H2后,将混合物振荡4小时。通过硅藻土过滤,浓缩滤液,在制备HPLC(C18,3.0×25cm,25mL/min)上纯化,用85%水/甲醇至15%水/甲醇洗脱45分钟,得到标题化合物(77.5mg,79%)。LC-MS(ESI)m/z C45H72N7O11S[M+H]+计算值918.49,实测值918.60。
实施例105.(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶)-2-甲酰氨基)戊基)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-((3R,4S,7S,10S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,18-三甲基6,9,12,17,20,30,36-七氧-33-(5-氧代庚-6-炔基)-2,23,26,40,43-五氧杂-5,8,11,16,19,29,33,37-八氮杂四十六酰胺基)-4-羟基苯基)-2-甲基戊酸(338)的合成
向3R,4S,7S,10S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R,2R))-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,18-三甲基-6,9,12,17,20,30-六氧代-33-(4-丙烯酰胺丁酰基-2,23,26-三氧杂5,8,11,16,19,29,33-七氮杂六氮杂三十六烷-36-酸(0.018g,0.0134mmol)的二氯甲烷(5mL)悬浮液中加入五氟苯酚(3.7mg,0.0201mmol)和DIC(2.0mg,0.0161mmol)。在室温下搅拌4小时,用硅藻土过滤。浓缩滤液并溶于DMF(1mL)中,之后加入(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基-哌啶-2-甲酰氨基)戊胺酰胺)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(3-(3-(2-(2-氨基乙氧基)乙氧基)丙酰氨)-4-羟基苯基)-2-甲基戊酸(13.5mg,0.0147mmol)的无水DMF(2mL)溶液。在0℃下搅拌2小时,将混合物浓缩并在HPLC上纯化(C18柱,流动相A:水,流动相B:乙腈,50%时从20%B至80%B)。合并组分并冻干,得到标题化合物,为无色油状物(8.9mg,30%收率)。ESI MS m/zC112H176N16O28S[M+H]+计算值2226.26,实测值2226.48。
实施例106.(2S,4R)-甲基-4-羟基吡咯烷-2-羧酸甲酯盐酸的合成
在0至4℃下,向反式-4-羟基-L-脯氨酸(15.0g,114.3mmol)的无水甲醇(250mL)溶液中滴加氯化亚砜(17mL,231mmol)。将所得混合物在室温下过夜搅拌。浓缩,用乙醇/正己烷重结晶,得到标题化合物(18.0g,87%收率)。ESI MS m/z 168.2([M+Na]+)。
实施例107.(2S,4R)-1-叔丁基2-甲基-4-羟基吡咯烷-1,2-二羧酸酯的合成
向反式-4-羟基-L-脯氨酸甲酯(18.0g,107.0mmol)的甲醇(150mL)和碳酸氢钠溶液(2.0M,350mL)的混合物中加入Boc2O(30.0g,137.6mmol)在4小时内分为三份。再搅拌4小时后,将反应混合物浓缩至约350mL并用乙酸乙酯(4×80mL)萃取。将合并的有机层用盐水(100mL)洗涤,干燥的(硫酸镁),过滤,浓缩并通过硅胶柱层析(1:1正己烷/乙酸乙酯)纯化,得到标题化合物(22.54g,86%收率)。ESI MS m/z 268.2([M+Na]+)。
实施例108.(S)-1-叔丁基2-甲基4-氧代吡咯烷-1,2-二羧酸酯的合成
通过Dess-Martin氧化制备标题化合物可参考:Franco Manfre等J.Org.Chem.1992,57,2060-2065。此外,也可使用Swern的氧化,操作步骤如下:将(COCl)2(13.0mL,74.38mmol)的二氯甲烷(350mL)溶液冷却至-78℃,加入无水DMSO(26.0mL)。将溶液在-78℃下搅拌15分钟,然后将(2S,4R)-1-叔丁基2-甲基-4-羟基吡咯烷-1,2-二甲酰基酯(8.0g,32.63mmol)的二氯甲烷(100mL)溶液加入。在-78℃下搅拌2小时后,滴加三乙胺(50mL,180.3mmol),将反应溶液升温至室温。将混合物用NaH2PO4溶液稀释(1.0M,400mL),分层,用二氯甲烷(2×60mL)萃取水层,合并有机层,用硫酸镁干燥,过滤,浓缩并通过硅胶柱层析(7:3正己烷/乙酸乙酯)纯化,得到标题化合物(6.73g,85%收率)。ESI MS m/z 266.2([M+Na]+)。
实施例109.(S)-1-叔丁基2-甲基-4-亚甲基吡咯烷-1,2-二羧酸酯的合成
在0℃下,向溴化甲基三苯基鏻(19.62g,55.11mmol)的四氢呋喃(150mL)悬浮液中加入叔丁醇钾(6.20g,55.30mmol)的无水四氢呋喃(80mL)溶液。在0℃下搅拌2小时后,将得到的黄色叶立德加入到(S)-1-叔丁基2-甲基4-氧代吡咯烷-1,2-二甲酸酯(6.70g,27.55mmol)的四氢呋喃(40mL)溶液中。在室温下搅拌1小时,浓缩反应混合物,用乙酸乙酯(200mL)稀释,用水(150mL),盐水(150mL)洗涤,经硫酸镁干燥,浓缩并在硅胶柱层析上纯化(9:1正己烷/乙酸乙酯),得到标题化合物(5.77g,87%收率)。EI MS m/z 264([M+Na]+)。
实施例110.(S)-甲基4-亚甲基吡咯烷-2-羧酸甲酯盐酸盐的合成
在4℃下,向(S)-1-甲基-4-亚甲基吡咯烷-1,2-二甲酸叔丁酯(5.70g,23.63mmol)的乙酸乙酯(40mL)溶液中加入盐酸(12M,10mL)。将混合物搅拌1小时,用甲苯(50mL)稀释,浓缩,之后用乙醇/正己烷重结晶,得到标题化合物,为盐酸盐形式(3.85g,92%收率)。EIMS m/z 142.2([M+H]+)。
实施例111. 4-(苄氧基)-3-甲氧基苯甲酸的合成
向4-羟基-3-甲氧基苯甲酸(50.0g,297.5mmol)的乙醇(350mL)和氢氧化钠溶液(2.0M,350mL)的混合物中加入苄溴(140.0g,823.5mmol)。将混合物在65℃下搅拌8小时,浓缩,与水(2×400mL)共浓缩至约400mL,用6N盐酸酸化至pH 3.0。过滤收集固体,用乙醇重结晶,在45℃下真空干燥,得到标题化合物(63.6g,83%收率)。ESIMS m/z 281.2([M+Na]+)。
实施例112.4-(苄氧基)-5-甲氧基-2-硝基苯甲酸的合成
向4-(苄氧基)-3-甲氧基苯甲酸(63.5g,246.0mmol)二氯甲烷(400mL)和乙酸(100mL)溶液中加入发烟硝酸(25.0mL,528.5mmol)。将混合物搅拌6小时,浓缩,用乙醇结晶,在40℃下真空干燥,得到标题化合物(63.3g,85%收率)。ESI MS m/z 326.1([M+Na]+)。
实施例113.(S)-甲基1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)-4-亚甲基吡咯烷-2-羧酸甲酯的合成
将催化量的DMF(30μl)加入到4-(苄氧基)-5-甲氧基-2-硝基苯甲酸(2.70g,8.91mmol)和草酰氯(2.0mL,22.50mmol)的无水二氯甲烷溶液中,将所得混合物在室温下搅拌2小时。用旋转浓缩仪除去过量的二氯甲烷和草酰氯。在N2条件下,0℃将乙酰氯重新悬浮在新鲜的二氯甲烷(70mL)中,并缓慢加入到预混合的(S)-4-亚甲基吡咯烷-2-羧酸甲酯盐酸盐(1.58g,8.91mmol)和Et3N(6mL)的二氯甲烷溶液中。将反应混合物升温至室温,继续搅拌8小时。除去二氯甲烷和Et3N后,将残余物在水和乙酸乙酯(70/70mL)之间分配。用乙酸乙酯(2×60mL)进一步萃取水层。将合并的有机层用盐水(40mL)洗涤,干燥(硫酸镁)并浓缩。用快速硅胶柱层析(2:8正己烷/乙酸乙酯)纯化残余物,得到标题化合物(2.88g,76%收率)。EI MS m/z 449.1([M+Na]+)。
实施例114.(S)-1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)-4-亚甲基吡咯烷-2-甲醛的合成
在-78℃和N2条件下,剧烈搅拌(S)-1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)-4-亚甲基吡咯烷-2-羧酸甲酯(2.80g,6.57mmol)的无水二氯甲烷(60mL)溶液并滴加DIBAL-H(在二氯甲烷中的1N,10mL)。将混合物再搅拌90分钟后,加入2mL甲醇和5%盐酸(10mL)淬灭反应。将所得混合物升温至0℃,分离各层,水层进一步用二氯甲烷(3×50mL)萃取。将合并的有机层用盐水洗涤,干燥(硫酸镁)并浓缩。用快速硅胶柱层析(95:5CHCl3/甲醇)纯化残余物,得到标题化合物(2.19g,84%收率)。EIMSm/z 419.1([M+Na]+)。
实施例115.(S)-8-(苄氧基)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]-吡咯并[1,2-a]氮杂卓-5(11aH)-酮的合成
将(S)-1-(4-(苄氧基)-5-甲氧基-2-硝基苯甲酰基)-4-亚甲基吡咯烷-2-甲醛(2.18g,5.50mmol)和Na2S2O4(8.0g,45.97mmol)的四氢呋喃(60mL)和水(40mL)的混合物在室温下搅拌20小时。在高真空下除去溶剂。将残余物重新悬浮在甲醇(60mL)中,逐滴加入盐酸(6M)直至达到pH~2。将所得混合物在室温下搅拌1小时,去除甲醇后用乙酸乙酯(100mL)稀释。用饱和NaHCO3水溶液和盐水洗涤乙酸乙酯溶液,干燥(硫酸镁)并浓缩。用快速硅胶柱层析(97:3CHCl3/甲醇)纯化残余物,得到标题化合物(1.52g,80%)。EIMS m/z 372.1([M+Na]+)。
实施例116.(S)-8-羟基-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]-吡咯并[1,2-a]氮杂卓-5(11aH)-酮的合成
在0℃下,向(S)-8-(苄氧基)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]-吡咯并[1,2-a]氮杂卓-5(11aH)-酮(1.50g,4.32mmol)的二氯甲烷(70mL)溶液中加入25mL的CH3SO3H。将混合物在0℃下搅拌10分钟,然后在室温下搅拌2小时。用二氯甲烷稀释,用冷的1.0N碳酸氢钠调节pH至4并过滤。用二氯甲烷(3×60mL)萃取水层。合并有机层,用无水硫酸钠干燥,过滤,浓缩并在硅胶柱层析(甲醇/二氯甲烷1:15)上纯化,得到811mg(73%收率)标题产物。EI-MS m/z 281.1([M+Na]+)。
实施例117.(11aS,11a’S)-8,8’-(戊烷-1,5-二基双(氧))双(7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]的合成吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮)的合成
向搅拌的Cs2CO3(0.761g,2.33mmol)的丁酮(8mL)悬浮液中加入(S)-8-羟基-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯[1,2-a]氮杂-5(11aH)-酮(401mg,1.55mmol)和1,5-二碘戊烷(240mg,0.740mmol)。将混合物在室温下搅拌过夜,浓缩,并在硅胶柱上纯化(乙酸乙酯/二氯甲烷1:10),得到337mg(78%收率)标题产物。EIMS m/z 607.2([M+Na]+)。
实施例118.(S)-7-甲氧基-8-((5-(((S)-7-甲氧-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢)-1H-苯并[e]吡咯并[1,2-α][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮杂-5(11aH)-酮(340)的合成。
在0℃下,向(11aS,11a’S)-8,8’-(戊烷-1,5-二基双(氧))双(7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯烷[1,2-a][1,4]二氮杂-5(11aH)-酮)(150mg,0.256mmol)的无水二氯甲烷(1mL)和无水乙醇(1.5mL)的溶液中加入硼氢化钠的甲氧基乙醚(85μl,0.5M,0.042mmol)混合物。5分钟后除去冰浴,将混合物在室温下搅拌3小时,然后冷却至0℃,用饱和氯化铵淬灭,用二氯甲烷稀释,并分层。将有机层用盐水洗涤,用无水硫酸钠干燥,通过硅藻土过滤并浓缩。通过反相HPLC(C18,乙腈/水)纯化残余物。用二氯甲烷萃取相应的组分并浓缩,得到标题化合物(64.7mg,43%),MSm/z 609.2([M+Na]+),625.3([M+K]+)和627.2([M+Na+H2O]+);得到完全还原的化合物(16.5mg,11%),MS m/z 611.2([M+Na]+),627.2([M+K]+),629.2([M+Na+H2O]+);回收未反应的原料(10.2mg,7%),MS m/z 607.2([M+Na]+),625.2([M+Na+H2O]+)。
实施例119.(S)-8-((5-(((S)-10-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰基)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(341)的合成
向(S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢)-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(60.0mg,0.102mmol)和2,5-二氧代吡咯烷-1-基3-(2-(2-叠氮基乙氧基)乙氧基)丙酸酯(40.5mg,0.134mmol)的二氯甲烷(5mL)的混合物中加入EDC(100.5mg,0.520mmol)。将混合物在室温下搅拌过夜,浓缩并在硅胶柱上纯化(乙酸乙酯/二氯甲烷,1:6),得到63.1mg(81%收率)标题产物。ESI MS m/zC40H50N7O9[M+H]+计算值772.36,实测值772.30。
实施例120.(S)-8-((5-(((S)-10-(3-(2-(2-氨基乙氧基)乙氧基)丙酰基)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(342)的合成
向(S)-8-((5-(((S)-10-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰基)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a六氢-1H-苯并[e]吡咯并[1,2-α][1,4]二氮杂-8-基)氧基)戊基)氧基)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(60mg,0.078mmol)的四氢呋喃(5mL)和Na2HSO4缓冲溶液(pH 7.5,1.0M,0.7mL)的混合物中加入PPh3(70mg,0.267mmol)。将混合物在室温下搅拌过夜,浓缩并在C18制备HPLC上纯化,用水/乙腈(在35分钟内从90%水至35%水)洗脱,在高真空下干燥后得到45.1mg(79%收率)标题产物。ESI MS m/z C40H52N5O9[M+H]+计算值746.37,实测值746.50。
实施例121.(2S)-甲基2-((2R,3R)-3-((2S)-1-((37S,40S,43S,44R)-43-((S)-仲丁基)-37,40二异丙基44甲氧基-1-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-1,2,3,4-5,11a四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代-2,3,4-11,11A-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-29,36,42-三甲基-1,11,17,27,30,35,38,41-八氧代-14-(4-丙酰胺丁酰基)-4,7,21,24-四氧杂-10,14,18,28,31,36,39,42-八氮杂四十六烷-46-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(343)的合成
向(3R,4S,7S,10S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,18三甲基6,9,12,17,20,30-八氧代-33-(4-丙酰胺丁酰基)-2,23,26-三氧杂5,8,11,16,19,29,33-七氮杂三十六烷-36-酸(0.018g,0.0134mmol)和(S)-8-((5-(((S)-10-(3-(2-(2-氨基乙氧基)乙氧基)丙酰基)基)-7-甲氧基-2-亚甲基-5-氧代2,3,5,10,11,11a六氢-1H-苯并[e]吡咯并[1,2-α][1,4]二氮杂-8-基)氧基)戊基)氧)-7-甲氧基-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-α][1,4]二氮杂-5(11aH)酮(11.0mg,0.0145mmol)的无水DMF(3mL)溶液中加入EDC(0.020g,0.104mmol)。在室温下搅拌4小时后,将混合物浓缩并在HPLC上纯化(C18柱,流动相A:水,流动相B:乙腈,50分钟内从20%B至80%B)。合并组分并冻干,得到标题化合物,为无色油状物(15.2mg,55%收率)。ESI MS m/zC107H157N15O26[M+H]+计算值2069.14,实测值2069.42。
实施例122.(S)-2-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰胺基)-N-(2-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-3-甲基丁酰胺(351)
向(S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,10,11,11a-六氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-2,3-二氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-5(11aH)-酮(60.0mg,0.102mmol)和(S)-15-叠氮基-5-异丙基-4,7-二氧代-10,13-二氧杂-3,6-二氮杂十五烷-1-甲酸(45.1mg,0.125mmol)的二氯甲烷(7mL)溶液中加入BrOP(120.1mg,0.309mmol)。将混合物在室温下搅拌过夜,浓缩并在硅胶柱上纯化(乙酸乙酯/二氯甲烷,1:6),得到71.4mg(77%收率)标题产物。ESI MS m/z C47H62N9O11[M+H]+计算值928.45,实测值928.60。
实施例123.(S)-2-(3-(2-(2-氨基乙氧基)乙氧基)丙酰胺基)-N-(2-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-3-甲基丁酰胺(352)
向(S)-2-(3-(2-(2-叠氮基乙氧基)乙氧基)丙酰胺基)-N-(2-((S)-7-甲氧基-8-((5-(((S-7-甲氧基-2-亚甲基-5-氧代2,3,5,11a-四氢-1H-苯并[e]吡咯[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-3-甲基丁酰胺(63mg,0.068mmol)的四氢呋喃(5mL)和NaH2PO4缓冲溶液(pH 7.5,1.0M,0.7mL)的混合物中加入PPh3(70mg,0.267mmol)。将混合物在室温下搅拌过夜,浓缩并在C18制备HPLC上纯化,用水/乙腈(从90%水至35%水,35分钟)洗脱,在高真空下干燥后得到46.5mg(76%收率)标题产物。ESI MS m/z C47H64N7O11[M+H]+,902.46,实测值902.60。
实施例124.(2S)-2-((2R,3R)-3-((2S)-1-((5S,43S,46S,49S,50R)-49-((S)-仲丁基)-5,43,46-三异丙基-50-甲氧基-1-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)-戊基)氧基)-2-亚甲基-5-氧代-2,3,11,11a四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-35,42,48-三甲基-1,4,7,17,23,33,36,41,44,47-十二氧-20-(4-丙酸酰胺-丁酰基)-10,13,27,30-四氧-3,6,16,20,24,34,37,42,45,48-十氮杂五十二烷-52-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(353)
向(3R,4S,7S,10S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)-吡咯烷-1-基)-2-氧代乙基)-5,11,18三甲-6,9,12,17,20,30-六氧代-33-(4-丙酸酰胺-丁酰基)-2,23,26-三氧杂-5,8,11,16,19,29,33-七氮杂三十六烷-36-酸(18.0mg,0.0134mmol)和(S)-2-(3-(2-(2-氨基乙氧基)乙氧基)丙酰胺基)-N-(2-(2-)(S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a四氢-1H-苯并[e]-吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]将吡咯并-[1,2-a][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-3-甲基丁酰胺(13.0mg,0.0144mmol)的无水DMF(3mL)溶液中加入EDC(0.020克,0.104mmol)。在室温下搅拌4小时后,将混合物浓缩并在HPLC上纯化(C18柱,流动相A:水,流动相B:乙腈,50分钟内从20%B至80%B)。合并组分并冻干,得到标题化合物,为无色油状物(18.1mg,47%收率)。ESI MS m/z C114H170N17O28[M+H]+计算值2225.23,实测值2226.22。
实施例125.(2S)-2-((2R,3R)-3-((2S)-1-((5S,37S,40S,43S,44R)-43-((S)-仲丁基)-5,37,40-三异丙基-44-甲氧基-1-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-29,36,42-三甲基-1,4,7,14,20,27,30,35,38,41-十二氧-17-(4-丙醇酰氨基丁酰基)-10,24二氧杂-3,6,13,17,21,28,31,36,39,42-十氮杂四十六烷-46-酰基))吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(354)
在石英管里,向pH 7.5的1.0mL 20mg/mL赫赛汀中,加入1.0mL 100mM NaH2PO4,pH7.5缓冲液和TCEP(25μL,20mM水溶液)。在25℃下搅拌孵育30分钟后,加入(2S)-甲基2-((2R,3R)-3-((2S)-1-((5S,37S,40S,43S,44R)-43-((S)-仲丁基)-5,37,40-三异丙基-44-甲氧基-1-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代-2,3,11,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-10(5H)-基)-29,36,42-三甲基-1,4,7,14,20,27,30,35,38,41-十二氧-17-(4-丙醇酰氨基丁酰基)-10,24二氧杂3,6,13,17,21,28,31,36,39,42-十氮杂四十六烷-46-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯353(27μL,20mM DMA溶液)。将混合物在15℃冷却,并在UV365nm(100W,光通量为~20W/m2,用邻硝基苯甲醛测量,Willett,K.和Hites,R.,J.Chem.Educ.,2000,77,900)照射4~6小时,然后加入DHAA(135μL,50mM)。从冷却器中取出石英管后,将混合物在室温下培养过夜,然后在G-25柱上纯化,用100mM NaH2PO4,50mM NaCl pH 6.0-7.5缓冲液洗脱,得到14.8mg偶联物(在2.73mL缓冲液中,74%产率)。药物/抗体比(DAR)通过UPLC-QTOF质谱确定为2.60(双药)或5.18(分别计算MMAF和PBD时)。SEC HPLC分析(TosohBioscience,Tskgel G3000SW,7.8mm ID×30cm,0.5mL/min,100分钟)单体含量94~99%和SDS-PAGE显示为单一条带。
实施例126.(S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-二甲基-2)-((S)-3-甲基-2-(甲氨基)丁酰氨基)丁酰胺基)-3-甲氧基-5-甲基庚酰基)-吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(356)的合成
将(S)-甲基2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-二甲基-2-((S)-3-甲基-2-(甲基氨基)丁酰氨基)丁酰胺基)-3-甲氧基-5-甲基-庚酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(25mg,0.030mmol)与浓盐酸(0.3mL)的1,4-二恶烷(0.9mL)混合物在室温下搅拌35分钟。将混合物用乙醇(1.0mL)和甲苯(1.0mL)稀释,浓缩并与乙醇/甲苯(2:1)共浓缩,得到标题化合物,为白色固体(22mg,~100%收率),其不经进一步纯化即用于下一步。LC-MS(ESI)m/z C39H66N5O8[M+H]+计算值732.48,实测值732.60。
实施例127.(2S)-2-((2R,3R)-3-((2S)-1-((11S,14S,17S)-1-叠氮基-17-((R)-仲丁基))-11,1-二异丙基-18-甲氧基-10,16-二甲基-9,12,15-三氧代-3,6-二氧杂-10,13,16-三氮杂二十烷-20-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(357)的合成
在两小时内,分四份向(S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-二甲基-2-((S)-3-甲基-2-(甲氨基)丁酰氨基)丁酰氨基)-3-甲氧基-5-甲基庚酰基)-吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸粗品(22毫克,0.030mmol)的DMA(0.8mL)和NaH2PO4缓冲溶液(pH 7.5,1.0M,0.7mL)的混合物中加入2,5-二氧代吡咯烷-1-基3-(2-(2-叠氮基乙氧基)乙氧基)丙酸盐(18.0mg,0.060mmol)。将混合物搅拌过夜,浓缩并在硅胶柱(CH3OH/二氯甲烷/HOAc 1:8:0.01)上纯化,得到标题化合物(22.5mg,82%收率)。LC-MS(ESI)m/z C46H77N8O11[M+H]+计算值917.56,实测值917.60。
实施例128.(2S)-2-((2R,3R)-3-((2S)-1-((11S,14S,17S)-1-氨基-17-((R)-仲丁基))-11,14二异丙基-18-甲氧基-10,16-二甲基-9,12,15-三氧代-3,6-二氧杂-10,13,16-三氮杂二十烷-20-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(358)的合成
在氢化瓶里,向(2S)-2-((2R,3R)-3-((2S)-1-((11S,14S,17S)-1-叠氮基-17-((R)-仲丁基)-11,14二异丙基-18-甲氧基-10,16-二甲基-9,12,15-三氧代-3,6-二氧杂-10,13,16-三氮杂环氧乙烷-20-酰基)吡咯烷-2-基)-3-的甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(22.0mg,0.024mmol)的甲醇(5mL)溶液中加入Pd/C(5mg,10wt%,50%水)。将空气抽空并充入25psi H2,将混合物振荡4小时,通过硅藻土过滤。浓缩滤液,得到标题产物(~20mg,92%收率),其不经进一步纯化直接用于下一步。ESI MSm/z C46H79N6O11[M+H]+计算值891.57,实测值891.60。
实施例129.(2S)-2-((2R,3R)-3-((2S)-1-((3R,4S,7S,10S,48S,51S,54S,55R)-4,54-二((S)-仲丁基)-7,10,48,51-四异丙基-55-甲氧基-3-(2-((S)-2-((1R,2R)-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,18,47,53-五甲基-6,9,12,17,20,30,36,46,49,52-六氧代-33-(4-丙酰胺丁酰基)-2,23,26,40,43-五氧杂-5,8,11,16,19,29,33,37,47,50,53-十一氮杂五十七烷-57-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(359)的合成
向(3R,4S,7S,10S)-4-((S)-仲丁基)-7,10-二异丙基-3-(2-((S)-2-((1R,2R))-1-甲氧基-3-(((S)-1-甲氧基-1-氧代-3-苯基丙-2-基)氨基)-2-甲基-3-氧代丙基)吡咯烷-1-基)-2-氧代乙基)-5,11,18-三甲基-6,9,12,17,20,30-六氧代-33-(4-丙醇酰氨基丁酰基)-2,23,26-三氧杂-5,8,11,16,19,29,33-七氮杂三十六烷-36-甲酸(0.018g,0.0134mmol)的二氯甲烷(5mL)的悬浮液中加入五氟苯酚(3.7mg,0.0201mmol)和DIC(2.0mg,0.0161mmol)。在室温下搅拌4小时,用硅藻土过滤。浓缩滤液并溶于DMF(1mL)中,之后加入(2S)-2-((2R,3R)-3-((2S)-1-((11S,14S,17S)-1-氨基-17-((R)-仲丁基)-11,14二异丙基-18-甲氧基-10,16-二甲基-9,12,15-三氧代-3,6-二氧杂-10,13,16-三氮杂二十-20-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(13.1mg,0.0147mmol)的无水DMF(2mL)溶液。在室温下搅拌2小时后,将混合物浓缩并在HPLC上纯化(C18柱,流动相A:水,流动相B:乙腈,从20%B至80%B在50分中内)。合并组分并冻干,得到标题化合物,为无色油状物(17.8mg,60%收率)。ESI MS m/z C113H184N16O28[M+H]+计算值2214.35,实测值2214.36。
实施例130.(S)-2-((2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-仲丁基)-6,9-二异丙基-13-甲氧基-2,2,5,11-四甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十五烷-15-酰基)吡咯烷-2基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸的合成
向(S)-(2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-仲丁基)-(S)-6,9-二异丙基-13-甲氧基2,2,5,1-1四甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十五烷-15酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸酯(30mg,0.035mmol)的四氢呋喃(1.0mL)溶液中加入LiOH水溶液(1.0M,0.8mL)。将混合物在室温下搅拌35分钟,用0.5MH3PO4中和至pH 6,浓缩并在硅胶柱上纯化(CH3OH/二氯甲烷/HOAc 1:10:0.01),得到标题化合物(25.0mg,85%收率)。LC-MS(ESI)m/z C44H74N5O10[M+H]+计算值832.54,实测值832.60。
实施例131.(S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-N,3-二甲基-2)-((S)-3-甲基-2-(甲氨基)丁酰氨基)丁酰胺基)-3-甲氧基-5-甲基庚酰基)-吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(356)的合成
向(S)-2-((2R,3R)-3-((S)-1-((6S,9S,12S,13R)-12-((S)-仲丁基)-6,9二异丙基-13-甲氧基-2,2,5,11-四甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十五烷-15-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(25mg,0.030mmol)的二恶烷(2.0mL)溶液中加入盐酸(12.0M,0.6mL)。将混合物在室温下搅拌30分钟,用二恶烷(4mL)和甲苯(4mL)稀释,浓缩并用C18HPLC纯化,用甲醇和水洗脱(200mm×Φ20mm,9mL/min,40分钟从5%甲醇至40%甲醇),得到标题化合物(20.0mg,90%收率)。LC-MS(ESI)m/z C39H66N5O8[M+H]+计算值732.48,实测值732.90。
实施例132. 4-(((苄氧基)羰基)氨基)丁酸的合成
将4-氨基丁酸(7.5g,75mmol)和氢氧化钠(6g,150mmol)的水(40mL)溶液冷却至0℃并滴加CbzCl(16.1g,95mmol)的四氢呋喃(32mL)溶液。搅拌1小时后,使反应升温至室温,搅拌3小时。真空除去四氢呋喃,通过加入6N盐酸将水溶液的pH调节至1.5。用乙酸乙酯萃取,有机层用盐水洗涤,干燥并浓缩,得到标题化合物(16.4g,92%收率)。MS ESI m/zC12H16NO5[M+H]+计算值238.10,实测值238.08。
实施例133. 4-(((苄氧基)羰基)氨基)丁酸叔丁酯的合成
向4-(((苄氧基)羰基)氨基)丁酸(16.4g,69.2mmol)和t-BuOH(15.4g,208mmol)的二氯甲烷(100mL)溶液中加入DMAP(0.8g,6.56mmol)和DCC(17.1g,83mmol)。在室温下搅拌过夜,过滤反应物并浓缩滤液。将残余物溶于乙酸乙酯中,用1N盐酸,盐水洗涤,用无水硫酸钠干燥。浓缩并通过柱层析法纯化(10至50%乙酸乙酯/正己烷),得到标题化合物(7.5g,37%收率)。MS ESI m/z C16H23NO4Na[M+Na]+计算值316.16,实测值316.13。
实施例134. 4-氨基丁酸叔丁酯的合成
将4-(((苄氧基)羰基)氨基)丁酸叔丁酯(560mg,1.91mmol)溶解在甲醇(50mL)中,并与Pd/C催化剂(10wt%,100mg)混合,然后在室温下氢化(1atm)3小时。滤除催化剂,真空除去所有挥发物,得到标题化合物(272mg,90%收率)。MS ESI m/z C8H18NO2[M+H]+计算值160.13,实测值160.13。
实施例135. 2,2-二丙酰氨基乙酸(373)的合成。
向2,2-二氨基乙酸(2.0g,22.2mmol)的乙醇(15mL)和50mM NaH2PO4缓冲液(25mL,pH 7.5)的混合物中加入2,5-二氧代吡咯烷-1-基丙酸酯(9.0g,53.8mmol)。将混合物搅拌8小时,浓缩,用0.1M盐酸酸化至pH 3.0,用乙酸乙酯(3×30mL)萃取。合并有机层,用无水硫酸钠干燥,过滤,浓缩并在硅胶柱上纯化,用甲醇/二氯甲烷(1:10to 1:6)洗脱,得到标题化合物(3.27g,76%收率)。1H-NMR(CDCl3)11.8(br,1H),8.12(d,2H),6.66(m,1H),2.66(s,2H)。ESI MS m/z C8H6N2O4[M+H]+计算值195.03,实测值195.20。
实施例136. 2,2-二丙基氨基乙酸全氟苯酯(421)的合成
在室温下,将2,2-二丙基氨基乙酸(2.01g,10.31mmol),五氟苯酚(2.08g,11.30mmol),DIPEA(1.00mL,5.73mmol)和EDC(4.01g,20.88mmol)的二氯甲烷(100mL)溶液搅拌过夜,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1:15to 1:8)洗脱,得到标题化合物(3.08g,83%收率)。1H-NMR(CDCl3)8.10(d,2H),6.61(m,1H),2.67(s,2H)。ESI MS m/zC14H6F5N2O4[M+H]+计算值361.02,实测值361.20。
实施例137.(S)-2-((S)-2-(2,2-二丙酰氨基乙酰氨基)丙酰氨基)-丙酸(423)的合成
向(S)-2-((S)-2-氨基丙酰胺基)丙酸(422)(1.10g,6.87mmol)的DMA(18mL)和50mM NaH2PO4缓冲液(pH 7.5,30mL)的混合物中加入2,2-二丙酰氨基乙酸五氟苯基酯(3.00g,8.33mmol)。将混合物搅拌14小时,浓缩,用0.1M盐酸酸化至pH 3.0,用乙酸乙酯(3×40mL)萃取。合并有机层,用无水硫酸钠干燥,过滤,浓缩并在硅胶柱上纯化,用甲醇/二氯甲烷(1:10to 1:5)洗脱,得到标题化合物(1.80g,78%收率)。ESI MS m/z C14H17N4O6[M+H]+计算值337.11,实测值337.30。
实施例138.(S)-2,5-二氧代吡咯烷-1-基2-((S)-2-(2,2-二丙酰氨基-乙酰氨基)丙酰胺基)丙酸酯(424)的合成
将(S)-2-((S)-2-(2,2-二丙酰氨基乙酰胺基)丙酰胺基)-丙酸(1.01g,3.00mmol),NHS(0.41g,3.56mmol),DIPEA(0.40mL,2.29mmol)和EDC(1.51g,7.86mmol)的二氯甲烷(50mL)溶液在室温下搅拌过夜,浓缩并在硅胶柱上纯化,用乙酸乙酯/二氯甲烷(1:15to1:7)洗脱,得到标题化合物(1.05g,81%收率)。ESI MSm/z C18H20N5O8[M+H]+计算值434.12,实测值434.40。
实施例139.(4R)-5-(4-乙酰氧基-3-硝基苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸叔丁酯的合成
在0℃下,向化合物190(107.1mg,0.252mmol)的二氯甲烷(4.0mL)溶液中依次加入乙酸酐(0.11mL,1.17mmol)和三乙胺(0.16mL)。然后将反应升温至室温,搅拌1小时,用二氯甲烷稀释,之后用水和盐水洗涤,用无水硫酸钠干燥,过滤并浓缩。通过柱层析(0-15%乙酸乙酯/石油醚)纯化残余物,得到无色油状物(120.3mg,>100%收率)。MS ESI m/z C23H35N2O8[M+H]+计算值467.23,实测值467.23。
实施例140.(4R)-5-(4-乙酰氧基-3-氨基苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸叔丁酯的合成
将苯基腈348(120.3mg,0.258mmol)溶于乙酸乙酯(5mL)和乙酸(0.5mL)中。向其中加入Pd/C(10wt%,10mg)并将混合物在氢气中室温下搅拌30分钟。然后通过硅藻土垫过滤,用乙酸乙酯洗涤垫。浓缩滤液,并通过柱层析(0-25%乙酸乙酯/石油醚)纯化,得到黄色油状物(120.9mg,>100%产率)。MS ESI m/z C23H37N2O6[M+H]+4计算值437.26,实测值437.28。
实施例141.(4R)-5-(3-(4-(((苄氧基)羰基)氨基)丁酰氨基)-4-((叔丁基二甲基甲硅烷基)氧基)苯基)-4-((叔丁氧基羰基)乙酯的合成基)氨基)-2-甲基戊酸乙酯
将2,5-二氧代吡咯烷-1-基4-(((苄氧基)羰基)氨基)丁酸酯(0.396克,1.2mmol)和(4R)-乙基-5-(3-氨基-4-羟基苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸酯(0.44g,1.2mmol)溶解在乙醇(10mL)中,并加入磷酸盐缓冲溶液(pH=7.5,0.1M,2mL)。将反应混合物在室温下搅拌过夜,然后减压除去溶剂,残余物用硅胶柱层析纯化,得到标题产物(0.485g,70%)。ESI MS m/z C31H44N3O8[M+H]+计算值586.31,实测值586.31。
实施例142.(4R)-5-(3-(4-氨基丁酰氨基)-4-((叔丁基二甲基甲硅烷基)氧基)苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸乙酯的合成
将(4R)-5-(3-(4-(((苄氧基)羰基)氨基)丁酰氨基)-4-((叔丁基二甲基-甲硅烷基)氧基)苯基)-4-((叔丁氧基羰基)氨基)-2-甲基戊酸酯(0.35g,0.5mmol)溶解在甲醇(5mL)中,然后加入Pd/C(10wt%,35mg)。将反应混合物在室温H2气球下搅拌过夜,然后通过硅藻土过滤,将滤液减压浓缩,得到标题产物(0.22g,79%收率)。ESI MS m/z C29H52N3O6Si[M+H]+计算值566.35,实测值566.35。
实施例143. 2-((6S,9S,12R,14R)-9-((S)-仲丁基)-14-羟基-6,12-二异丙基-2,2,5,11-四甲基-4,7,10-三氧-3-氧杂-5,8,11-三氮杂十四烷-14-基)噻唑-4-羧酸(381)的合成
向Boc-N-Me-L-Val-OH(33mg,0.14mmol)的乙酸乙酯溶液中加入五氟苯酚(39mg,0.21mmol)和DCC(32mg,0.154mmol)。将反应混合物在室温下搅拌16小时,然后通过硅藻土垫过滤,用乙酸乙酯洗涤滤垫。浓缩滤液并重新溶解在DMA(2mL)中,然后加入2-((1R,3R)-3-((2S,3S)-2-氨基-N,3-二甲基戊酰胺基)-1-羟基-4-甲基戊基)噻唑-4-羧酸(52mg,0.14mmol)和DIPEA(48.5μL,0.28mmol)。将反应混合物在室温下搅拌24小时,然后浓缩并通过反相HPLC(C18柱,10-100%乙腈/水)纯化,得到标题化合物(40.2mg,49%收率)。ESI MSm/z C28H49N4O7S[M+H]+585.32,实测值585.32。
实施例144. 2-((6S,9S,12R,14R)-9-((S)-仲丁基)-6,12-二-异丙基-2,2,5,11-四甲基-4,7,10,16-四氧代-3,15-二氧杂-5,8,11-三氮杂十七烷-14-基)噻唑-4-羧酸的合成
在0℃下,将2-((6S,9S,12R,14R)-9-((S)-仲丁基)-14-羟基-6,12-二异丙基-2,2,5,11-四甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十七烷-14-基)噻唑-4-羧酸(40mg,0.069mmol)溶于吡啶(8mL)中,向其中加入乙酸酐(20.4mg,0.2%)mmol)并将反应混合物升温至室温并搅拌过夜。浓缩混合物并通过硅胶柱层析纯化,用二氯甲烷/甲醇梯度洗脱,得到标题产物(48.1mg,~100%产率)。ESI MS m/z C30H51N4O8S[M+H]+计算值627.33,实测值627.33。
实施例145.(4R)-4-(2-((6S,9S,12R,14R)-9-((S)-仲丁基)-6,12-二异丙基-2,2,5,11-四甲基-4,7,10,16-四氧代-3,15-二氧杂-5,8,11-三氮杂十七烷-14-基)噻唑-4-甲酰胺基)-2-甲基-5-苯基戊酸的合成
向2-((6S,9S,12R,14R)-9-((S)-仲丁基)-6,12-二-异丙基-2,2,5,11-四甲基-4,7的10,16-四氧代-3,15-二氧杂-5,8,11-三氮杂十七烷-14-基)噻唑-4-羧酸(48.1mg,0.077mmol)的乙酸乙酯溶液中加入五氟苯酚(21.2mg,0.115mmol)和DCC(17.4mg,0.085mmol)。将反应混合物在室温下搅拌16小时,然后通过硅藻土垫过滤,用乙酸乙酯洗涤滤垫。浓缩滤液并重新溶解在DMA(4mL)中,然后加入(4R)-4-氨基-2-甲基-5-苯基戊酸(20.7mg,0.1mmol)和DIPEA(26.8μL,0.154mmol)。将反应混合物在室温下搅拌24小时,然后浓缩并通过反相HPLC(C18柱,10-100%乙腈/水)纯化,得到标题化合物(63mg,~100%产率)。ESI MS m/z C42H66N5O9S[M+H]+计算值816.45,实测值816.45。
例146(4R)-4-(2-((3S,6S,9R,11R)-6-((S)-仲丁基)-3,9-二异丙基-8-甲基-4,7,13-三氧-12-氧杂-2,5,8-三氮杂十四烷-11-基)噻唑-4-甲酰胺基)-2-甲基-5-苯基戊酸盐酸盐(474)的合成
将(4R)-4-(2-((6S,9S,12R,14R)-9-((S)-仲丁基)-6,12-二异丙基-2,2,5,11-四甲基-4,7,10,16-四氧代-3,15-二氧杂-5,8,11-三氮杂十七烷-14-基)噻唑-4-甲酰胺基)-2-甲基-5-苯基戊酸(60mg,0.073mmol)的乙酸乙酯(3mL)溶液和HCl(0.8mL,12M)搅拌30分钟,并用甲苯(5mL)和二恶烷(5mL)稀释。浓缩混合物,与二恶烷(5mL)和甲苯(5mL)共浓缩至干,得到标题产物(57.1mg,103%产率),不经进一步纯化用于下一步。ESI MS m/zC37H58N5O7S[M+H]+计算值716.40,实测值716.60。
实施例147.(4R)-4-(2-((4R,6R,9S,12S,15S,18S)-9-((S)-仲丁基)-6,12-二异丙-7,13,15,18-四甲基-2,8,11,14,17,20,23-七氧杂-21-丙炔酰胺基-3-氧杂-7,10,13,16,19,22-六氮杂二十五烷-24-炔-4-基)噻唑-4-甲酰胺基)-2-甲基-5-苯基戊酸(475)的合成
向化合物474(25mg,0.034mmol)的DMA(2mL)和0.1M Na2HPO4(pH8.0,1mL)的混合物中,在3小时内分三批加入化合物424(23.1mg,0.053mmol),然后再搅拌12小时。浓缩混合物,并通过反相HPLC(200mm×10mm,C18柱,10-100%乙腈/水,40分钟,8mL/min)纯化,得到标题化合物(30.0mg,85%收率)。ESI MS m/z C51H71N9O12S[M+H]+计算值1034.49,实测值1034.90。
实施例148.(S)-2-((2R,3R)-3-((S)-1-((8S,11S,14S,17S,20S,21R)-20-((S)-仲丁基)-14,17-二异丙基-21-甲氧基-8,11,13,19-四甲基-3,6,9,12,15,18-六氧杂-5-丙炔酰胺基-4,7,10,13,16,19-六氮杂二十三烷-1-炔-23-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(477)的合成
向化合物356(20mg,0.027mmol)的DMA(2mL)和0.1M Na2HPO4的混合物(pH 8.0,1mL)中,在3小时内分3次加入化合物424(20.1mg,0.046mmol)。然后将混合物再搅拌12小时。浓缩混合物,并通过反相HPLC(200mm×10mm,C18柱,10-100%乙腈/水,40分钟,8mL/min)纯化,得到标题化合物(22.1mg,78%收率)。ESI MS m/z C53H80N9O13[M+H]+计算值1050.58,实测值1050.96。
实施例149.(4R)-4-(2-((1R,3R)-1-乙酰氧基-3-((2S,3S)-N,3-二甲基-2-((R)-1-甲基哌啶)-2-甲酰氨基)戊酰胺)-4-甲基戊基)噻唑-4-甲酰氨基)-5-(4-羟基-3-(3-(2-(2-((双(2-丙炔酰肼基)磷酰基)氨基)乙氧基)乙氧基)-丙酰胺基)苯基)-2-甲基戊酸(480)的合成
在0℃下,向化合物89(16.1mg,0.132mmol)的四氢呋喃(5mL)和DIPEA(10μl,0.057mmol)的混合物中加入POCl3(10.1mg,0.0665mmol)。在0℃下搅拌20分钟后,将混合物升温至室温并继续搅拌4小时。然后向混合物中加入化合物336(60mg,0.065mmol)和DIPEA(20μl,0.114mmol)。将混合物在50℃搅拌过夜,浓缩,并通过反相HPLC(200mm×10mm,C18柱,10-100%乙腈/水,40分钟,8mL/min)纯化,得到标题化合物(23.1mg,32%收率)。ESI MS m/z C51H76N11O14PS[M+H]+1130.50,计算值1130.50,实测值1131.20。
实施例150.(2S)-2-((2R,3R)-3-((2S)-1-((11S,14S,17S,18R)-17-((S)-仲丁基)-11,14-二异丙基-18-甲氧基-10,16-二甲-9,12,15-三氧代-1-((双(2-丙炔酰肼基)磷酰基)氨基)-3,6-二氧杂-10,13,16-三氮杂二十烷-20-酰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酰胺基)-3-苯基丙酸(482)的合成
在0℃下,向化合物89(16.1mg,0.132mmol)的四氢呋喃(5mL)和DIPEA(10μl,0.057mmol)的混合物中加入POCl3(10.1mg,0.0665mmol)。在0℃下搅拌20分钟后,将混合物升温至室温并继续搅拌小时。然后向混合物中加入化合物358(60mg,0.067mmol)和DIPEA(20μl,0.114mmol)。将混合物在50℃搅拌过夜,浓缩,并通过反相HPLC(200mm×10mm,C18柱,10-100%乙腈/水,40分钟,8mL/min)纯化,得到标题化合物(25.6mg,34%收率)。ESI MS m/z C52H84N10O14P[M+H]+计算值1103.58,实测值1104.10。
实施例151.(2S,2’S)-2,2’-((13,14-双((E)-3-溴丙烯酰基)-11,16-二氧代-4,7,20,23-四氧杂-10,13,14,17-四氮杂二十六烷-1,26-二酰基)双(氮烷二基))双(N-(2-((S)-7-甲氧基-8-((5-(((S)-7-甲氧基-2-亚甲基-5-氧代-2,3,5,11a-四氢-1H-苯并[e]吡咯并[1,2-a][1,4]二氮杂-8-基)氧基)戊基)氧基)-2-亚甲基-5-氧代2,3,11,11a四氢-1H-苯并[e]吡咯并[1,2-α][1,4]二氮杂-10(5H)-基)-2-氧代乙基)-3-甲基丁酰胺)(497)的合成
将化合物352(25.1mg,0.0278mmol),化合物36(11.50mg,0.0279mmol)和EDC(15mg,0.078mmol)的DMA(2mL)溶液搅拌过夜,浓缩,并通过反相HPLC纯化(200mm×10mm,C18柱,10-100%乙腈/水,40分钟,8mL/min),得到标题化合物(23.8mg,39%收率)。ESI MS m/zC104H133Br2N16O26[M+H]+计算值2179.79,实测值2180.50[M+H]+,219780[M+H2O+H]+,2215.81[M+2H2O+H]+。
实施例152.化合物499的合成
将化合物259(26.1mg,0.0246mmol),化合物36(10.20mg,0.0247mmol)和EDC(15mg,0.078mmol)的DMA(2mL)溶液搅拌过夜,浓缩,并通过反相HPLC纯化(200mm×10mm,C18柱,10-100%乙腈/水,40分钟,8mL/min),得到标题化合物(27.6mg,45%收率)。ESI MS m/zC118H190Br2N18O30[M+H]+计算值2498.23,实测值2499.50。
实施例153.偶联物232,234,238,261,307,326,339,344或360的制备。
从化合物物231,233,237,260,306,325,338,343或359分别制备偶联物232,234,238,261,308,327,339,344或360的方法,类似于实施例125中所描述的从化合物353制备偶联物354的方法。
实施例154.制备偶联物235,239,307,327,339,345,355,361,476,478,481,483,498或500的一般方法
向赫赛汀(pH 6.0~8.0,10mg/mL,2.0mL)中分别加入NaH2PO4(pH 6.5~8.5,100mM,0.70~2.0mL)缓冲液,TCEP(14-35μL,20mM水溶液)和化合物231,233,237,306,325,343,353,359,475,477,480,482,497或499(14-28μL,20mMDMA溶液,化合物497和498加入14-18μL)。将混合物在室温下孵育4-18小时,然后加入DHAA(135μL,50mM)。在室温下孵育过夜后,将混合物在G-25柱上纯化,用100mM NaH2PO4,50mM NaCl pH 6.0~7.5缓冲液洗脱,得到在13.4~15.8mL缓冲液中的12.8~18.1mg偶联化合物235,239,307,327,339,345,355,361,476,478,481,483,498或500(60%~91%产率)。偶联物235,239,307,327,339,345,355,361,476,478,481或483的药物/抗体比(DAR)为2.1~4.2,偶联物498或者500的DAR为2.6~5.3,DAR通过UPLC-QTOF质谱确定。通过SEC HPLC(Tosoh Bioscience,TskgelG3000SW,7.8mm ID×30cm,0.5mL/min,100min)分析单体含量为94%至99%,SDS-PAGE显示为单一条带。
实施例155.与T-DM1相比,偶联物232,234,235,238,239,261,307,308,326,327,339,344,345,354,355,360,361,476,478,481,483,498或500的体外细胞毒性评价:
用于细胞毒性测定的细胞系是NCI-N87,一种人胃癌细胞系;细胞在含有10%FBS的RPMI-1640中生长。为了进行测定,将细胞(180μL,6000个细胞)加入到96孔板中的每个孔中,并在37℃,5%CO2下温育24小时。之后在合适的细胞培养基(总体积0.2mL)中用各种浓度的测试化合物(20μL)处理细胞。对照孔含有细胞和培养基但无测试化合物。在37℃,5%CO2下,将板孵育120小时。然后将MTT(5mg/mL)加入孔中(20μL),在37℃下,将板温育1.5小时。小心地除去培养基,然后加入DMSO(180μL)。振荡15分钟后,在490nm和570nm处测量吸光度(参比滤光片620nm)。根据下式计算抑制率:抑制率%=[1-(样品-空白)/(对照-空白)]×100。
细胞毒性结果(IC50):
实施例156.体内抗肿瘤活性(携带NCI-N87异种移植肿瘤的BALB/c裸鼠)
在人体胃癌N-87细胞系肿瘤异种移植模型上评价偶联物232,308,327,339,476,483和500以及T-DM1的体内活性。在5周龄雌性BALB/c裸鼠(54只动物)右肩下区域皮下接种0.1mL无血清培养基中的N-87癌细胞(5×106细胞/小鼠)。使肿瘤生长8天至平均尺寸135mm3。然后将动物随机分成9组(每组6只动物)。第一组小鼠作为对照组,并注射磷酸盐缓冲盐水(PBS)。6组以5mg/kg的剂量分别静脉注射偶联物232,308,327,476,483和T-DM1。剩余的2组以4mg/Kg的剂量分别静脉注射偶联物339和500。每4天测量肿瘤的三个维度,并使用公式“肿瘤体积=1/2(长×宽×高)”计算肿瘤体积。同时还测量动物的体重。当满足以下任何一个标准时,处死小鼠:(1)体重减轻超过治疗前体重的20%,(2)肿瘤体积大于2000mm3,(3)病得太重,不能进食和饮水,或(4)皮肤坏死。如果没有可感知的肿瘤,则认为小鼠无肿瘤。
结果绘制在图45中。所有8个偶联物均未引起动物体重减轻。对照组的动物由于肿瘤体积大于2200mm3且病重在第56天被杀死。测试的7种偶联物表现出比T-DM1更好的抗肿瘤活性。偶联物476,483,339和500组中的所有动物(6/6)在第14天至第52天完全没有可测量的肿瘤。相比之下,5mg/kg剂量的T-DM1不能消除肿瘤,仅抑制肿瘤生长31天。5mg/kg剂量的偶联物232,308和327不能完全根除肿瘤。抑制肿瘤生长数据如下:
偶联物 | 肿瘤生长延迟期 |
T-DM1 | 31days |
308 | 39days |
327 | 46days |
232 | 52days |
476 | 65days |
483 | 66days |
339 | 66days |
500 | 67days |
Claims (7)
2.偶联物,其具有式F2-1,F2-2,F2-3,F2-4,F2-5,F2-6,F2-7,F2-8,F2-9,F2-10,F2-11,F2-12,F2-13,F2-14,F2-15,F2-16,F2-17,F2-18,F2-19,F2-20,F2-21,F2-22,F2-23,F2-24,F2-25,F2-26,F2-27,F2-28,F2-29,F2-30,F2-31,F2-32,F2-33,F2-34,F2-35,F2-36,F2-37,F2-38,F2-39,F2-40,F2-41,F2-42,F2-43,167,173,220,232,234,235,238,239,261,268,273,281,289,293,296,307,308,313,318,326,327,339,344,345,354,355,360,361,371,377,379,381,391,393,395,404,411,418,420,428,430,432,434,439,443,452,458,463,467,470,473,476,478,481,483,494,496,498,500,506和508的结构:
其中mAb是抗体或抗体片段。
4.一种药物组合物,其包含治疗有效量的权利要求2的偶联物或药学上可接受的盐,以及载体或赋形剂或其组合,其特征在于可用于治疗或预防癌症,或自身免疫疾病或传染病。
5.一种药物组合产品,其包含权利要求2的偶联物以及其他药物,所述其他药物选自化学治疗剂,免疫治疗剂,自身免疫病症剂,抗感染剂或其他偶联物。
6.权利要求2的偶联物,其用于和放射疗法一起组合使用。
7.根据权利要求5所述的药物组合产品,其特征在于所述的其他药物选自以下药物中的一种或几种:Abatacept,醋酸阿比特龙,对乙酰氨基酚/氢可酮,阿杜单抗,阿达木单抗,ADXS31-142,ADXS-HER2,阿法替尼二马来酸盐,alemtuzumab,阿维A酸,曲妥珠单抗emtansine,苯丙胺混合盐,阿那曲唑,阿立哌唑,阿扎那韦,Atezolizumab,阿托伐他汀,阿昔替尼,Avelumab,belinostat,贝伐单抗,Cabazitaxel,Cabozantinib,贝沙罗汀,blinatumomab,Bortezomib,波舒替尼,brentuximab vedotin,布地奈德,布地奈德/福莫特罗,丁丙诺啡,卡培他滨,carfilzomib,塞来昔布,赛替尼,西妥昔单抗,Ciclosporin,Cinacalcet,crizotinib,Cosentyx,CTL019,达比加群,达拉菲尼,Daratum umab,Darbepoetin alfa,Darunavir,甲磺酸伊马替尼,达沙替尼,denileukin diftitox,Denosumab,Depakote,右兰索拉唑,右旋哌甲酯,地塞米松,Dinutuximab,多西环素,度洛西汀,Duvelisib,elotuzumab,Emtricitabine/Ril-pivirine/Tenofovir disoproxil富马酸盐,Emtricitbine/替诺福韦/依法韦仑,依诺肝素,Enzalutamide,依泊汀α,厄洛替尼,埃索美拉唑,艾司佐匹克隆,依那西普,依维莫司,依泽替米贝,依泽替米贝/辛伐他汀,非诺贝特,非格司亭,芬戈莫德,丙酸氟替卡松,氟替卡松/沙美特罗,氟维司群,gazy va,吉非替尼,格拉替雷,醋酸戈舍瑞林,伊替替尼,伊马替尼,伊布替莫单抗tiuxeta n,ibrutinib,idelalisib,英夫利西单抗,伊尼帕利布,门冬胰岛素,地特胰岛素,甘精胰岛素,胰岛素赖脯胰岛素,干扰素β1a,干扰素β1b,拉帕替尼,伊匹单抗,异丙托溴铵/沙丁胺醇,Ixazomi,Kanuma,醋酸兰瑞肽,来那度胺,甲磺酸仑尼替尼,来曲唑,左旋甲状腺素,利多卡因,利奈唑胺,利拉鲁肽,Lisdexamfetamine,LN-144,MEDI4736,美金刚,哌醋甲酯,美托洛尔,Mekinist,莫达非尼,莫米松,Nilotinib,niraparib,Nivolumab,奥法木单抗,obinutuzumab,奥拉帕尼,奥美沙坦,奥美沙坦/氢氯噻嗪,奥马珠单抗,奥米加-3脂肪酸乙酯,奥司他韦,羟考酮,palbociclib,帕利珠单抗,帕尼单抗,panobinostat,帕唑帕尼,派姆单抗,培美曲塞,帕妥珠单抗,肺炎球菌偶合疫苗,pomalidomide,普瑞巴林,ProscaVax,普萘洛尔,奎硫平,雷贝拉唑,镭223氯化物,雷洛昔芬,拉替拉韦,雷莫芦单抗,Ranibizumab,瑞格菲尼,利妥昔单抗,利伐沙班,罗米地辛,罗苏伐他汀,鲁索替尼磷酸盐,沙丁胺醇,司维拉姆,西地那非,siltux imab,西他列汀,西他列汀/二甲双胍,索利那新,索拉尼单抗,索拉非尼,舒尼替尼,他达拉非,他莫昔芬,Tafinlar,Telaprevir,temsirolimus,替诺福韦/恩曲他滨,睾酮凝胶,沙利度胺,噻托溴铵,托瑞米芬,trametinib,曲妥珠单抗,维甲酸,优特克单抗,缬沙坦,veliparib,凡德他尼,威罗菲尼,伏立诺他,ziv-阿柏西普,Zostavax及其药学上可接受的盐,或其组合。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310180812.8A CN116143678A (zh) | 2016-11-14 | 2016-11-14 | 偶联连接体,含有此连接体的细胞结合分子-药物偶联物及其制备和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/CN2016/105799 WO2018086139A1 (en) | 2016-11-14 | 2016-11-14 | Conjugation linkers, cell binding molecule-drug conjugates containing the likers, methods of making and uses such conjugates with the linkers |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310180812.8A Division CN116143678A (zh) | 2016-11-14 | 2016-11-14 | 偶联连接体,含有此连接体的细胞结合分子-药物偶联物及其制备和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110099682A CN110099682A (zh) | 2019-08-06 |
CN110099682B true CN110099682B (zh) | 2023-03-31 |
Family
ID=62109093
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680090956.2A Active CN110099682B (zh) | 2016-11-14 | 2016-11-14 | 偶联连接体,含有此连接体的细胞结合分子-药物偶联物及其制备和应用 |
CN202310180812.8A Pending CN116143678A (zh) | 2016-11-14 | 2016-11-14 | 偶联连接体,含有此连接体的细胞结合分子-药物偶联物及其制备和应用 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310180812.8A Pending CN116143678A (zh) | 2016-11-14 | 2016-11-14 | 偶联连接体,含有此连接体的细胞结合分子-药物偶联物及其制备和应用 |
Country Status (11)
Country | Link |
---|---|
US (6) | US20210308277A1 (zh) |
EP (2) | EP3888691A1 (zh) |
JP (2) | JP7138350B2 (zh) |
KR (7) | KR20220150408A (zh) |
CN (2) | CN110099682B (zh) |
AU (3) | AU2016429272A1 (zh) |
CA (1) | CA3042442C (zh) |
MX (1) | MX2019005583A (zh) |
NZ (1) | NZ752394A (zh) |
PH (1) | PH12019501056A1 (zh) |
WO (1) | WO2018086139A1 (zh) |
Families Citing this family (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUE048574T2 (hu) | 2012-07-12 | 2020-08-28 | Hangzhou Dac Biotech Co Ltd | Sejthez kötõdõ molekulák citotoxikus szerekkel képzett konjugátumai |
US11873281B2 (en) | 2012-07-12 | 2024-01-16 | Hangzhou Dac Biotech Co., Ltd. | Conjugates of cell binding molecules with cytotoxic agents |
US10292961B2 (en) | 2015-07-15 | 2019-05-21 | Hangzhou Dac Biotech Co., Ltd. | Disulfur bridge linkers for conjugation of a cell-binding molecule |
KR20230149857A (ko) | 2016-07-07 | 2023-10-27 | 더 보드 어브 트러스티스 어브 더 리랜드 스탠포드 주니어 유니버시티 | 항체-애쥬번트 접합체 |
KR20240023684A (ko) | 2016-09-13 | 2024-02-22 | 알레간 인코포레이티드 | 안정화된 비단백질 클로스트리듐 독소 조성물 |
WO2018134254A1 (en) | 2017-01-17 | 2018-07-26 | Heparegenix Gmbh | Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death |
US10093731B2 (en) | 2017-02-24 | 2018-10-09 | Kindred Biosciences, Inc. | Anti-IL31 antibodies for veterinary use |
JP6802384B2 (ja) * | 2017-08-18 | 2020-12-16 | アサヒビール株式会社 | 非甘味性飲料 |
CA3095071A1 (en) * | 2017-08-18 | 2019-02-21 | Sichuan Baili Pharm Co. Ltd | Non-natural amatoxin-type antibody conjugate |
CA3085634C (en) | 2017-12-31 | 2023-11-14 | Hangzhou Dac Biotech Co., Ltd | A conjugate of a tubulysin analog with branched linkers |
WO2020142474A1 (en) | 2018-12-31 | 2020-07-09 | Dow Silicones Corporation | Acrylate-functional branched organosilicon compound, method of preparing same, and copolymer formed therewith |
US20220119597A1 (en) | 2018-12-31 | 2022-04-21 | Dow Silicones Corporation | Branched organosilicon compound, method of preparing same, and copolymer formed therewith |
KR20210110641A (ko) | 2018-12-31 | 2021-09-08 | 다우 도레이 캄파니 리미티드 | 조성물, 공중합체의 제조 방법, 및 이의 방법 및 최종 용도 |
KR20210114430A (ko) | 2018-12-31 | 2021-09-23 | 다우 실리콘즈 코포레이션 | 분지형 유기규소 화합물, 그의 제조 방법, 및 그로 형성된 공중합체 |
EA202192137A1 (ru) * | 2019-01-31 | 2021-10-25 | Ханчжоу Дэк Биотек Ко., Лтд | Конъюгат аматоксинового аналога с разветвленными линкерами |
EP3937984A1 (en) | 2019-03-15 | 2022-01-19 | Bolt Biotherapeutics, Inc. | Immunoconjugates targeting her2 |
AU2019452577B2 (en) * | 2019-06-29 | 2023-08-24 | Hangzhou Dac Biotech Co., Ltd. | Cell-binding molecule-Tubulysin derivative conjugate and preparation method therefor |
CN112341521B (zh) * | 2019-08-09 | 2024-06-25 | 上海翰森生物医药科技有限公司 | 一种小分子活性化合物及其抗体偶联物、其制备方法和医药用途 |
KR102365464B1 (ko) * | 2019-12-24 | 2022-02-22 | 강원대학교산학협력단 | 지카바이러스 재조합 서브유닛 백신의 개발 및 이의 제조방법 |
CN115003308A (zh) * | 2020-01-07 | 2022-09-02 | 普渡研究基金会 | 靶向类固醇化合物 |
CN111297876B (zh) * | 2020-01-16 | 2021-04-27 | 武汉理工大学 | 一种塞来昔布胶束和和厚朴酚胶束药物联用控释系统及其制备方法 |
EP3862023A1 (en) * | 2020-02-05 | 2021-08-11 | Hangzhou DAC Biotech Co, Ltd | Conjugates of cell-binding molecules with cytotoxic agents |
US11045546B1 (en) | 2020-03-30 | 2021-06-29 | Cytodyn Inc. | Methods of treating coronavirus infection |
CA3174407A1 (en) * | 2020-04-15 | 2021-10-21 | Dechun Wu | Antibody-drug conjugate |
CN111393346B (zh) * | 2020-06-02 | 2020-08-25 | 凯莱英生命科学技术(天津)有限公司 | N-Boc-Dolaproine及Boc-Dap DCHA的合成方法 |
CN114401749B (zh) * | 2020-06-29 | 2024-04-16 | 北京拓界生物医药科技有限公司 | 一种放射性核素标记物及其应用 |
CN114605367B (zh) * | 2020-12-03 | 2023-06-27 | 中国人民解放军军事科学院军事医学研究院 | 含香豆素的连接子及含该连接子的抗体偶联药物 |
KR20220100546A (ko) * | 2021-01-08 | 2022-07-15 | 가톨릭대학교 산학협력단 | 암세포의 항암 면역치료를 위한 항체-폴리에틸렌글리콜-광감각제 접합체 |
CN113214403B (zh) * | 2021-04-25 | 2023-06-09 | 重庆威斯腾前沿生物研究院有限责任公司 | 一种链霉亲和素磁珠及其制备方法 |
KR20220158181A (ko) * | 2021-05-21 | 2022-11-30 | 주식회사 레고켐 바이오사이언스 | Ror1 및 b7-h3에 결합하는 항체-약물 접합체 및 그 용도 |
WO2022253051A1 (zh) * | 2021-06-01 | 2022-12-08 | 南京明德新药研发有限公司 | 多肽偶联药物及其应用 |
KR20240095442A (ko) * | 2021-11-03 | 2024-06-25 | 항저우 디에이씨 바이오테크 씨오, 엘티디 | 항체의 특이적 접합 |
CN114377715B (zh) * | 2022-01-12 | 2024-04-16 | 山西大学 | 一种钴掺杂碳点纳米酶及其制备方法和应用 |
WO2023244517A1 (en) * | 2022-06-16 | 2023-12-21 | Merck Sharp & Dohme Llc | Interleukin-2 prodrugs |
WO2024026099A1 (en) * | 2022-07-29 | 2024-02-01 | The Trustees Of The University Of Pennsylvania | Lymphatic targeted anti-coagulant for the prevention of lymphatic thrombosis |
CN115353599B (zh) * | 2022-08-29 | 2023-10-03 | 嘉兴学院 | 一种离子液体/离子型共价有机框架复合材料的制备方法及应用 |
US20240117424A1 (en) * | 2022-09-16 | 2024-04-11 | Illumina, Inc. | Reusable Flow Cells Having Signal Intensity Retention, Methods of Retaining Signal Intensity in Reusable Flow Cells and Reagents and Kits Therefor |
WO2024113195A1 (en) | 2022-11-30 | 2024-06-06 | Dow Toray Co., Ltd. | A solid particle of organosilicon-functional co-polymer, manufacturing processthereof, and cosmetics comprising said solid particle |
CN116813710B (zh) * | 2023-07-05 | 2024-07-12 | 重庆药友制药有限责任公司 | 一种卡非佐米的制备方法 |
CN118126057B (zh) * | 2024-05-06 | 2024-07-19 | 四川大学华西第二医院 | 一种化合物RCPH及其合成方法、作为比率型pH探针的应用和产品 |
Family Cites Families (354)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2292506A (en) | 1940-03-29 | 1942-08-11 | Gen Chemical Corp | Manufacture of titanium salt solutions |
US4000304A (en) | 1974-05-06 | 1976-12-28 | Mead Johnson & Company | Diuretic antiturombogenic and antiarrhythmic processes using N-substituted indole dimers and pyrrolobenzodia-zepine rearrangement products thereof |
US4169888A (en) | 1977-10-17 | 1979-10-02 | The Upjohn Company | Composition of matter and process |
US4307016A (en) | 1978-03-24 | 1981-12-22 | Takeda Chemical Industries, Ltd. | Demethyl maytansinoids |
US4256746A (en) | 1978-11-14 | 1981-03-17 | Takeda Chemical Industries | Dechloromaytansinoids, their pharmaceutical compositions and method of use |
JPS55102583A (en) | 1979-01-31 | 1980-08-05 | Takeda Chem Ind Ltd | 20-acyloxy-20-demethylmaytansinoid compound |
JPS55162791A (en) | 1979-06-05 | 1980-12-18 | Takeda Chem Ind Ltd | Antibiotic c-15003pnd and its preparation |
JPS5645483A (en) | 1979-09-19 | 1981-04-25 | Takeda Chem Ind Ltd | C-15003phm and its preparation |
EP0028683A1 (en) | 1979-09-21 | 1981-05-20 | Takeda Chemical Industries, Ltd. | Antibiotic C-15003 PHO and production thereof |
JPS5645485A (en) | 1979-09-21 | 1981-04-25 | Takeda Chem Ind Ltd | Production of c-15003pnd |
US4491632A (en) | 1979-10-22 | 1985-01-01 | The Massachusetts General Hospital | Process for producing antibodies to hepatitis virus and cell lines therefor |
US4444887A (en) | 1979-12-10 | 1984-04-24 | Sloan-Kettering Institute | Process for making human antibody producing B-lymphocytes |
US4391904A (en) | 1979-12-26 | 1983-07-05 | Syva Company | Test strip kits in immunoassays and compositions therein |
EP0043718B1 (en) | 1980-07-07 | 1984-11-28 | National Research Development Corporation | Improvements in or relating to cell lines |
US4341761A (en) | 1980-07-25 | 1982-07-27 | E. I. Du Pont De Nemours And Company | Antibodies to immunogenic peptides and their use to purify human fibroblast interferon |
WO1982001188A1 (en) | 1980-10-08 | 1982-04-15 | Takeda Chemical Industries Ltd | 4,5-deoxymaytansinoide compounds and process for preparing same |
US4450254A (en) | 1980-11-03 | 1984-05-22 | Standard Oil Company | Impact improvement of high nitrile resins |
US4315929A (en) | 1981-01-27 | 1982-02-16 | The United States Of America As Represented By The Secretary Of Agriculture | Method of controlling the European corn borer with trewiasine |
US4313946A (en) | 1981-01-27 | 1982-02-02 | The United States Of America As Represented By The Secretary Of Agriculture | Chemotherapeutically active maytansinoids from Trewia nudiflora |
US4466917A (en) | 1981-02-12 | 1984-08-21 | New York University | Malaria vaccine |
US4493890A (en) | 1981-03-23 | 1985-01-15 | Miles Laboratories, Inc. | Activated apoglucose oxidase and its use in specific binding assays |
US4451570A (en) | 1981-03-26 | 1984-05-29 | The Regents Of The University Of California | Immunoglobulin-secreting human hybridomas from a cultured human lymphoblastoid cell line |
JPS57192389A (en) | 1981-05-20 | 1982-11-26 | Takeda Chem Ind Ltd | Novel maytansinoid |
US4414205A (en) | 1981-08-28 | 1983-11-08 | University Patents, Inc. | Cell growth inhibitory substances |
US4399121A (en) | 1981-11-04 | 1983-08-16 | Miles Laboratories, Inc. | Iodothyronine immunogens and antibodies |
US4427783A (en) | 1981-12-14 | 1984-01-24 | Hoffmann-La Roche Inc. | Immunoassay of thymosin α1 |
US4671958A (en) | 1982-03-09 | 1987-06-09 | Cytogen Corporation | Antibody conjugates for the delivery of compounds to target sites |
US4464467A (en) | 1982-07-26 | 1984-08-07 | Bristol-Myers Company | Antitumor antibiotics produced by new streptomyces |
US4508647A (en) | 1982-07-26 | 1985-04-02 | Bristol-Myers Company | Antitumor antibiotics BBM-2040A and BBM-2040B |
US4427587A (en) | 1982-11-10 | 1984-01-24 | Bristol-Myers Company | Total synthesis of antitumor antibiotics BBM-2040A and BBM-2040B |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US4663453A (en) | 1983-05-18 | 1987-05-05 | Hoechst-Roussel Pharmaceuticals Inc. | Benzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepines having dopamine receptor activity |
US4761412A (en) | 1983-05-18 | 1988-08-02 | Hoechst-Roussel Pharmaceuticals Inc. | Benzopyrrolobenzodiazepines and quinobenzodiazepines useful for the treatment of psychoses |
US4764616A (en) | 1983-05-18 | 1988-08-16 | Hoechst-Roussel Pharmaceuticals Inc. | Benzopyrrolobenzodiazepines and quinobenzodiazepines |
US4723003A (en) | 1983-05-18 | 1988-02-02 | Hoechst-Roussel Pharmaceuticals Inc. | Benzopyrrolobenzodiazepines and quinobenzodiazepines |
US4723007A (en) | 1983-05-18 | 1988-02-02 | Hoechst-Roussel Pharmaceuticals Inc. | Benzopyrrolobenzodiazepines and quinobenzodiazepines |
US4493795A (en) | 1983-10-17 | 1985-01-15 | Syntex (U.S.A.) Inc. | Synthetic peptide sequences useful in biological and pharmaceutical applications and methods of manufacture |
US5169774A (en) | 1984-02-08 | 1992-12-08 | Cetus Oncology Corporation | Monoclonal anti-human breast cancer antibodies |
US6054561A (en) | 1984-02-08 | 2000-04-25 | Chiron Corporation | Antigen-binding sites of antibody molecules specific for cancer antigens |
US4753894A (en) | 1984-02-08 | 1988-06-28 | Cetus Corporation | Monoclonal anti-human breast cancer antibodies |
US4912227A (en) | 1984-02-21 | 1990-03-27 | The Upjohn Company | 1,2,8,8A-tetrahydrocyclopropa(c)pyrrolo(3,2-e)-indol-4-(5H)-ones and related compounds |
US4978757A (en) | 1984-02-21 | 1990-12-18 | The Upjohn Company | 1,2,8,8a-tetrahydrocyclopropa (C) pyrrolo [3,2-e)]-indol-4(5H)-ones and related compounds |
US4764368A (en) | 1984-08-29 | 1988-08-16 | Dana-Farber Cancer Institute, Inc. | Acid-cleavable compound |
US4970198A (en) | 1985-10-17 | 1990-11-13 | American Cyanamid Company | Antitumor antibiotics (LL-E33288 complex) |
US4683230A (en) | 1985-02-25 | 1987-07-28 | Bristol-Myers Company | BMY-28121, a new antitumor antibiotic |
US4935362A (en) | 1985-02-25 | 1990-06-19 | Bristol-Myers Company | BMY-28121, a new antitumor antibiotic |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
JPH0684377B1 (zh) | 1986-04-17 | 1994-10-26 | Kyowa Hakko Kogyo Kk | |
EP0247730A3 (en) | 1986-04-28 | 1989-04-12 | Antibody Technology Limited | Antibodies, their preparation and use and products containing them |
US5332837A (en) | 1986-12-19 | 1994-07-26 | The Upjohn Company | CC-1065 analogs |
US5108912A (en) | 1987-01-30 | 1992-04-28 | American Cyanamid Company | Antitumor antibiotics (LL-E33288 complex) |
US4816444A (en) | 1987-07-10 | 1989-03-28 | Arizona Board Of Regents, Arizona State University | Cell growth inhibitory substance |
US4975278A (en) | 1988-02-26 | 1990-12-04 | Bristol-Myers Company | Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells |
US5773435A (en) | 1987-08-04 | 1998-06-30 | Bristol-Myers Squibb Company | Prodrugs for β-lactamase and uses thereof |
US5053394A (en) | 1988-09-21 | 1991-10-01 | American Cyanamid Company | Targeted forms of methyltrithio antitumor agents |
US5606040A (en) | 1987-10-30 | 1997-02-25 | American Cyanamid Company | Antitumor and antibacterial substituted disulfide derivatives prepared from compounds possessing a methyl-trithio group |
US5770701A (en) | 1987-10-30 | 1998-06-23 | American Cyanamid Company | Process for preparing targeted forms of methyltrithio antitumor agents |
US4952394A (en) | 1987-11-23 | 1990-08-28 | Bristol-Myers Company | Drug-monoclonal antibody conjugates |
US4994578A (en) | 1987-11-27 | 1991-02-19 | Meiji Seika Kaisha, Ltd. | Certain anti-tumor duocarmycin antibiotics from streptomyces |
IL106992A (en) | 1988-02-11 | 1994-06-24 | Bristol Myers Squibb Co | Noble hydrazonic history of anthracycline and methods for their preparation |
EP0329184A3 (en) | 1988-02-19 | 1990-05-23 | Neorx Corporation | Antimers and antimeric conjugation |
US5147786A (en) | 1988-04-22 | 1992-09-15 | Monsanto Company | Immunoassay for the detection of α-haloacetamides |
US4943628A (en) | 1988-06-13 | 1990-07-24 | Ortho Pharmaceutical Corporation | HIV peptide-inducted T cell stimulation |
JP2642165B2 (ja) | 1988-07-22 | 1997-08-20 | 協和醗酵工業株式会社 | 新規dc−89化合物およびその製造法 |
US5084468A (en) | 1988-08-11 | 1992-01-28 | Kyowa Hakko Kogyo Co., Ltd. | Dc-88a derivatives |
US5223409A (en) | 1988-09-02 | 1993-06-29 | Protein Engineering Corp. | Directed evolution of novel binding proteins |
JP2598116B2 (ja) | 1988-12-28 | 1997-04-09 | 協和醗酵工業株式会社 | 新規物質dc113 |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US4978744A (en) | 1989-01-27 | 1990-12-18 | Arizona Board Of Regents | Synthesis of dolastatin 10 |
WO1990009799A1 (en) | 1989-02-23 | 1990-09-07 | Colorado State University Research Foundation | GnRH ANALOGS FOR DESTROYING GONADOTROPHS |
US4879278A (en) | 1989-05-16 | 1989-11-07 | Arizona Board Of Regents | Isolation and structural elucidation of the cytostatic linear depsipeptide dolastatin 15 |
US5187186A (en) | 1989-07-03 | 1993-02-16 | Kyowa Hakko Kogyo Co., Ltd. | Pyrroloindole derivatives |
JP2510335B2 (ja) | 1989-07-03 | 1996-06-26 | 協和醗酵工業株式会社 | Dc―88a誘導体 |
US5286637A (en) | 1989-08-07 | 1994-02-15 | Debiopharm, S.A. | Biologically active drug polymer derivatives and method for preparing same |
US5208323A (en) | 1989-08-10 | 1993-05-04 | Universite Laval | Coupling of an anti-tumor to an antibody using glutaraldehyde preactivated anti-tumor agent |
US5495009A (en) | 1989-10-24 | 1996-02-27 | Gilead Sciences, Inc. | Oligonucleotide analogs containing thioformacetal linkages |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5334528A (en) | 1989-10-30 | 1994-08-02 | The Regents Of The University Of California | Monoclonal antibodies to cyclodiene insecticides and method for detecting the same |
US5165923A (en) | 1989-11-20 | 1992-11-24 | Imperial Cancer Research Technology | Methods and compositions for the treatment of hodgkin's disease |
US5859205A (en) | 1989-12-21 | 1999-01-12 | Celltech Limited | Humanised antibodies |
FR2656555B1 (fr) | 1989-12-29 | 1994-10-28 | Serimer | Systeme mecanique de guidage automatique d'une ou plusieurs torches d'une unite de soudage a l'arc. |
EP0463151B1 (en) | 1990-01-12 | 1996-06-12 | Cell Genesys, Inc. | Generation of xenogeneic antibodies |
US6673986B1 (en) | 1990-01-12 | 2004-01-06 | Abgenix, Inc. | Generation of xenogeneic antibodies |
US6150584A (en) | 1990-01-12 | 2000-11-21 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
US6075181A (en) | 1990-01-12 | 2000-06-13 | Abgenix, Inc. | Human antibodies derived from immunized xenomice |
IT1238675B (it) | 1990-01-26 | 1993-09-01 | Ist Naz Stud Cura Dei Tumori | Anticorpo monoclonale in grado di riconoscere uno specifico epitopo di glicosidi antraciclinici e ibridoma secernente tale anticorpo |
CA2078118C (en) | 1990-04-25 | 1999-11-16 | Paul A. Aristoff | Cc-1065 analogs |
US5427908A (en) | 1990-05-01 | 1995-06-27 | Affymax Technologies N.V. | Recombinant library screening methods |
WO1991017158A1 (en) | 1990-05-07 | 1991-11-14 | Scripps Clinic And Research Foundation | Intermediates in the formation of the calicheamicin and esperamicin oligosaccharides |
US5767236A (en) | 1990-05-09 | 1998-06-16 | Biomeasure, Inc. | Linear therapeutic peptides |
US5137877B1 (en) | 1990-05-14 | 1996-01-30 | Bristol Myers Squibb Co | Bifunctional linking compounds conjugates and methods for their production |
US6172197B1 (en) | 1991-07-10 | 2001-01-09 | Medical Research Council | Methods for producing members of specific binding pairs |
GB9015198D0 (en) | 1990-07-10 | 1990-08-29 | Brien Caroline J O | Binding substance |
DE69121334T2 (de) | 1990-07-26 | 1997-03-20 | Kyowa Hakko Kogyo Kk | DC-89-Derivate als Antitumor-Wirkstoffe |
GB9017024D0 (en) | 1990-08-03 | 1990-09-19 | Erba Carlo Spa | New linker for bioactive agents |
US5625126A (en) | 1990-08-29 | 1997-04-29 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5814318A (en) | 1990-08-29 | 1998-09-29 | Genpharm International Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5770429A (en) | 1990-08-29 | 1998-06-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5633425A (en) | 1990-08-29 | 1997-05-27 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US5661016A (en) | 1990-08-29 | 1997-08-26 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
DE69127627T2 (de) | 1990-08-29 | 1998-02-19 | Genpharm Int | Produktion und Nützung nicht-menschliche transgentiere zur Produktion heterologe Antikörper |
US5789650A (en) | 1990-08-29 | 1998-08-04 | Genpharm International, Inc. | Transgenic non-human animals for producing heterologous antibodies |
US5545806A (en) | 1990-08-29 | 1996-08-13 | Genpharm International, Inc. | Ransgenic non-human animals for producing heterologous antibodies |
US5877397A (en) | 1990-08-29 | 1999-03-02 | Genpharm International Inc. | Transgenic non-human animals capable of producing heterologous antibodies of various isotypes |
US5874299A (en) | 1990-08-29 | 1999-02-23 | Genpharm International, Inc. | Transgenic non-human animals capable of producing heterologous antibodies |
US6797492B2 (en) | 1991-05-17 | 2004-09-28 | Merck & Co., Inc. | Method for reducing the immunogenicity of antibody variable domains |
WO1994004679A1 (en) | 1991-06-14 | 1994-03-03 | Genentech, Inc. | Method for making humanized antibodies |
DK0590058T3 (da) | 1991-06-14 | 2004-03-29 | Genentech Inc | Humaniseret heregulin-antistof |
US5264586A (en) | 1991-07-17 | 1993-11-23 | The Scripps Research Institute | Analogs of calicheamicin gamma1I, method of making and using the same |
SG87056A1 (en) | 1991-08-09 | 2002-03-19 | Teikoku Hormone Mfg Co Ltd | Novel tetrapeptide derivative |
ATE463573T1 (de) | 1991-12-02 | 2010-04-15 | Medimmune Ltd | Herstellung von autoantikörpern auf phagenoberflächen ausgehend von antikörpersegmentbibliotheken |
US5622929A (en) | 1992-01-23 | 1997-04-22 | Bristol-Myers Squibb Company | Thioether conjugates |
CA2076465C (en) | 1992-03-25 | 2002-11-26 | Ravi V. J. Chari | Cell binding agent conjugates of analogues and derivatives of cc-1065 |
GB9314960D0 (en) | 1992-07-23 | 1993-09-01 | Zeneca Ltd | Chemical compounds |
JP3514490B2 (ja) | 1992-08-21 | 2004-03-31 | 杏林製薬株式会社 | トリフルオロメチルピロロインドールカルボン酸エステル誘導体及びその製造方法 |
US5288514A (en) | 1992-09-14 | 1994-02-22 | The Regents Of The University Of California | Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support |
US6015562A (en) | 1992-09-22 | 2000-01-18 | American Cyanamid Company | Targeted forms of methyltrithio antitumor agents |
US5324483B1 (en) | 1992-10-08 | 1996-09-24 | Warner Lambert Co | Apparatus for multiple simultaneous synthesis |
DE4236237A1 (de) | 1992-10-27 | 1994-04-28 | Behringwerke Ag | Prodrugs, ihre Herstellung und Verwendung als Arzneimittel |
US5635483A (en) | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
US6034065A (en) | 1992-12-03 | 2000-03-07 | Arizona Board Of Regents | Elucidation and synthesis of antineoplastic tetrapeptide phenethylamides of dolastatin 10 |
US6569834B1 (en) | 1992-12-03 | 2003-05-27 | George R. Pettit | Elucidation and synthesis of antineoplastic tetrapeptide w-aminoalkyl-amides |
US5410024A (en) | 1993-01-21 | 1995-04-25 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide amides |
US5780588A (en) | 1993-01-26 | 1998-07-14 | Arizona Board Of Regents | Elucidation and synthesis of selected pentapeptides |
US5436149A (en) | 1993-02-19 | 1995-07-25 | Barnes; Wayne M. | Thermostable DNA polymerase with enhanced thermostability and enhanced length and efficiency of primer extension |
US5475011A (en) | 1993-03-26 | 1995-12-12 | The Research Foundation Of State University Of New York | Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment |
DE4314091A1 (de) | 1993-04-29 | 1994-11-03 | Boehringer Mannheim Gmbh | Immunologisches Nachweisverfahren für Triazine |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
EP0699051A4 (en) | 1993-05-20 | 1998-11-25 | Univ California | MACROMOLECULAR CONTRAST AGENT FOR MAGNETIC RESONANCE IMAGING |
US5621039A (en) | 1993-06-08 | 1997-04-15 | Hallahan; Terrence W. | Factor IX- polymeric conjugates |
AU7113594A (en) | 1993-06-21 | 1995-01-17 | Enzon, Inc. | Site specific synthesis of conjugated peptides |
AU689131B2 (en) | 1993-10-01 | 1998-03-26 | Teikoku Hormone Mfg. Co., Ltd. | Novel peptide derivative |
GB9320575D0 (en) | 1993-10-06 | 1993-11-24 | Amp Gmbh | Coaxial connector having improved locking mechanism |
US5880131A (en) | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5824701A (en) | 1993-10-20 | 1998-10-20 | Enzon, Inc. | Taxane-based prodrugs |
CA2174350A1 (en) | 1993-10-20 | 1995-04-27 | Richard B. Greenwald | 2'- and/or 7- substituted taxoids |
US5840900A (en) | 1993-10-20 | 1998-11-24 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5965566A (en) | 1993-10-20 | 1999-10-12 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US5919455A (en) | 1993-10-27 | 1999-07-06 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
US5643575A (en) | 1993-10-27 | 1997-07-01 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
US5922545A (en) | 1993-10-29 | 1999-07-13 | Affymax Technologies N.V. | In vitro peptide and antibody display libraries |
US5951974A (en) | 1993-11-10 | 1999-09-14 | Enzon, Inc. | Interferon polymer conjugates |
US5786377A (en) | 1993-11-19 | 1998-07-28 | Universidad De Santiago De Compostela | Pyrrolo 3,2-E!indol derivatives, process for the preparation thereof and applications |
PT705833E (pt) | 1994-04-22 | 2004-11-30 | Kyowa Hakko Kogyo Kk | Derivado de dc-89 |
JPH07309761A (ja) | 1994-05-20 | 1995-11-28 | Kyowa Hakko Kogyo Co Ltd | デュオカルマイシン誘導体の安定化法 |
US5773001A (en) | 1994-06-03 | 1998-06-30 | American Cyanamid Company | Conjugates of methyltrithio antitumor agents and intermediates for their synthesis |
US5730990A (en) | 1994-06-24 | 1998-03-24 | Enzon, Inc. | Non-antigenic amine derived polymers and polymer conjugates |
US5521284A (en) | 1994-08-01 | 1996-05-28 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide amides and esters |
US5530097A (en) | 1994-08-01 | 1996-06-25 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory peptide amides |
AU694546C (en) | 1994-08-19 | 2001-09-06 | La Region Wallonne | Compounds, pharmaceutical composition and diagnostic device comprising same and their use |
US5554725A (en) | 1994-09-14 | 1996-09-10 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Synthesis of dolastatin 15 |
US6111166A (en) | 1994-09-19 | 2000-08-29 | Medarex, Incorporated | Transgenic mice expressing human Fcα and β receptors |
US5738846A (en) | 1994-11-10 | 1998-04-14 | Enzon, Inc. | Interferon polymer conjugates and process for preparing the same |
US5599902A (en) | 1994-11-10 | 1997-02-04 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Cancer inhibitory peptides |
KR100395083B1 (ko) | 1994-11-29 | 2004-02-05 | 자이단호오징 사가미 츄오 카가쿠겡큐쇼 | 아크릴아미드유도체및그제조방법 |
US5663149A (en) | 1994-12-13 | 1997-09-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide heterocyclic and halophenyl amides |
ES2141467T5 (es) | 1995-01-18 | 2006-07-16 | Roche Diagnostics Gmbh | Anticuerpos anti-cd30 que evitan la escision proteolitica y liberacion del antigeno cd30 fijado a la membrana. |
DK0831100T3 (da) | 1995-04-21 | 2001-01-02 | Teikoku Hormone Mfg Co Ltd | Nye peptidderivater |
ATE381948T1 (de) | 1995-05-10 | 2008-01-15 | Kyowa Hakko Kogyo Kk | Cytotoxinkonjugate umfassend dipeptide |
US5686237A (en) | 1995-06-05 | 1997-11-11 | Al-Bayati; Mohammed A. S. | Use of biomarkers in saliva to evaluate the toxicity of agents and the function of tissues in both biomedical and environmental applications |
US5714586A (en) | 1995-06-07 | 1998-02-03 | American Cyanamid Company | Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates |
US5712374A (en) | 1995-06-07 | 1998-01-27 | American Cyanamid Company | Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates |
GB9517001D0 (en) | 1995-08-18 | 1995-10-18 | Denny William | Enediyne compounds |
SE9503380D0 (sv) | 1995-09-29 | 1995-09-29 | Pharmacia Ab | Protein derivatives |
CA2233936A1 (en) | 1995-10-03 | 1997-04-10 | The Scripps Research Institute | Cbi analogs of cc-1065 and the duocarmycins |
EP0774464B1 (en) | 1995-10-17 | 2004-07-28 | Combichem, Inc. | A template for solution phase synthesis of combinatorial libraries |
WO1997023243A1 (en) | 1995-12-22 | 1997-07-03 | Bristol-Myers Squibb Company | Branched hydrazone linkers |
FR2742751B1 (fr) | 1995-12-22 | 1998-01-30 | Rhone Poulenc Rorer Sa | Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent |
US6143901A (en) | 1996-07-31 | 2000-11-07 | Genesoft, Inc. | Complex formation between dsDNA and pyrrole imidazole polyamides |
WO1997032850A1 (en) | 1996-03-08 | 1997-09-12 | The Scripps Research Institute | Mcbi analogs of cc-1065 and the duocarmycins |
NZ332960A (en) | 1996-05-31 | 2000-05-26 | Scripps Research Inst | tetrahydro-cyclopropan[c]benz[e]-indol-4-one and tetrahydro-cyclopropan[c]benzo[e]-indole derivatives and medicaments |
US5728560A (en) | 1996-06-14 | 1998-03-17 | Enzon, Inc. | Method of treating CD4+ T cell lymphopenia in immuno-compromised patients |
US5741892A (en) | 1996-07-30 | 1998-04-21 | Basf Aktiengesellschaft | Pentapeptides as antitumor agents |
US6130237A (en) | 1996-09-12 | 2000-10-10 | Cancer Research Campaign Technology Limited | Condensed N-aclyindoles as antitumor agents |
JPH1087666A (ja) | 1996-09-18 | 1998-04-07 | Kyorin Pharmaceut Co Ltd | デュオカルマイシンsa及びその誘導体の製造中間体と製造方法 |
DE19638870B4 (de) | 1996-09-23 | 2009-05-14 | Helmholtz-Zentrum für Infektionsforschung GmbH | Tubulysine, Verfahren zu ihrer Gewinnung und sie enthaltende Mittel |
US5916771A (en) | 1996-10-11 | 1999-06-29 | Abgenix, Inc. | Production of a multimeric protein by cell fusion method |
US5880122A (en) | 1996-11-01 | 1999-03-09 | American Home Products Corporation | 3-Carboxamide derivatives of 5H-pyrrolo 2,1-c! 1,4!-benzodiazepines |
US6759509B1 (en) | 1996-11-05 | 2004-07-06 | Bristol-Myers Squibb Company | Branched peptide linkers |
US5811452A (en) | 1997-01-08 | 1998-09-22 | The Research Foundation Of State University Of New York | Taxoid reversal agents for drug-resistance in cancer chemotherapy and pharmaceutical compositions thereof |
US5804183A (en) | 1997-01-31 | 1998-09-08 | Enzon, Inc. | Arginine deminase derived from mycoplasma arthritidis and polymer conjugates containing the same |
JP2002513402A (ja) | 1997-02-25 | 2002-05-08 | アリゾナ ボード オブ リーゼンツ | 細胞増殖抑制性の鎖状および環状デプシペプチドであるドラスタチン16、ドラスタチン17およびドラスタチン18の単離と構造決定 |
US5965537A (en) | 1997-03-10 | 1999-10-12 | Basf Aktiengesellschaft | Dolastatin 15 derivatives with carbonyl and heterocyclic functionalities at the C-terminus |
US6306393B1 (en) | 1997-03-24 | 2001-10-23 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
CA2285259A1 (en) | 1997-03-28 | 1998-10-08 | The Scripps Research Institute | Sandramycin analogs |
ES2230687T3 (es) * | 1997-04-24 | 2005-05-01 | Henry M. Jackson Foundation For The Advancement Of Military Medicine | Copulacion de proteinas nomodificadas con polisacaridos derivados de haloacilo o de dihaloacilo para la preparacion de vacunas que incluyen proteinas-polisacaridos. |
WO1998050432A1 (en) | 1997-05-07 | 1998-11-12 | Bristol-Myers Squibb Company | Recombinant antibody-enzyme fusion proteins |
DE69825048D1 (de) | 1997-05-22 | 2004-08-19 | Scripps Research Inst | Analoga von duocarmycin and cc-1065 |
US5900402A (en) | 1997-05-29 | 1999-05-04 | Enzon, Inc. | Method of reducing side effects associated with administration of oxygen-carrying proteins |
US6143721A (en) | 1997-07-18 | 2000-11-07 | Basf Aktiengesellschaft | Dolastatin 15 derivatives |
US6011042A (en) | 1997-10-10 | 2000-01-04 | Enzon, Inc. | Acyl polymeric derivatives of aromatic hydroxyl-containing compounds |
US6262271B1 (en) | 1997-10-14 | 2001-07-17 | The Scripps Research Institute | ISO-CBI and ISO-CI analogs of CC-1065 and the duocarmycins |
JPH11137291A (ja) | 1997-11-12 | 1999-05-25 | Mori Sangyo Kk | アマニチン類の製造法 |
NZ504884A (en) | 1997-12-08 | 2002-10-25 | Scripps Research Inst | Synthesis of the dihydroindole C-ring of CC-1065/duocarmycin analogs and certain intermediates |
US6180095B1 (en) | 1997-12-17 | 2001-01-30 | Enzon, Inc. | Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents |
US5981709A (en) | 1997-12-19 | 1999-11-09 | Enzon, Inc. | α-interferon-polymer-conjugates having enhanced biological activity and methods of preparing the same |
US5965119A (en) | 1997-12-30 | 1999-10-12 | Enzon, Inc. | Trialkyl-lock-facilitated polymeric prodrugs of amino-containing bioactive agents |
EP1045858B1 (en) | 1998-01-09 | 2004-12-08 | ARIZONA BOARD OF REGENTS, A BODY CORPORATE OF THE STATE OF ARIZONA acting for and on behalf of ARIZONA STATE UNIVERSITY | Anti-cryptococcal peptides |
US6162930A (en) | 1998-03-06 | 2000-12-19 | Baylor University | Anti-mitotic agents which inhibit tubulin polymerization |
US5981564A (en) | 1998-07-01 | 1999-11-09 | Universite Laval | Water-soluble derivatives of paclitaxel, method for producing same and uses thereof |
ATE294803T1 (de) | 1998-08-27 | 2005-05-15 | Spirogen Ltd | Pyrrolobenzodiazepine |
GB9818731D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Compounds |
GB9818730D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collections of compounds |
GB9818732D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collection of compounds |
JP3045706B1 (ja) | 1998-09-14 | 2000-05-29 | 科学技術振興事業団 | Dnaの特定塩基配列をアルキル化する化合物及びその合成法 |
US6344451B1 (en) | 1999-02-04 | 2002-02-05 | American Home Products | Pyrrolobenzodiazepine carboxyamide vasopressin agonists |
JP4926320B2 (ja) | 1999-04-28 | 2012-05-09 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | Vegfの選択的阻害による癌処置のための組成物および方法 |
US6909006B1 (en) | 1999-08-27 | 2005-06-21 | Spirogen Limited | Cyclopropylindole derivatives |
US6323315B1 (en) | 1999-09-10 | 2001-11-27 | Basf Aktiengesellschaft | Dolastatin peptides |
US7303749B1 (en) | 1999-10-01 | 2007-12-04 | Immunogen Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
JP2003514903A (ja) | 1999-11-24 | 2003-04-22 | イムノージェン インコーポレーテッド | タキサンを含有する細胞傷害薬とその治療への利用 |
DE60031793T2 (de) | 1999-12-29 | 2007-08-23 | Immunogen Inc., Cambridge | Doxorubicin- und daunorubicin-enthaltende, zytotoxische mittel und deren therapeutische anwendung |
IT1317731B1 (it) | 2000-01-18 | 2003-07-15 | Indena Spa | Tassani semisintetici con attivita' antitumorale ed antiangiogenetica. |
DE10008089A1 (de) | 2000-02-22 | 2001-10-31 | Biotechnolog Forschung Gmbh | Syntheseverfahren zur Herstellung von Tubulysinen |
US6555693B2 (en) | 2000-03-16 | 2003-04-29 | Genesoft, Inc. | Charged compounds comprising a nucleic acid binding moiety and uses therefor |
US7097840B2 (en) | 2000-03-16 | 2006-08-29 | Genentech, Inc. | Methods of treatment using anti-ErbB antibody-maytansinoid conjugates |
JP4061819B2 (ja) | 2000-05-12 | 2008-03-19 | 独立行政法人科学技術振興機構 | インターストランドクロスリンク剤の合成方法 |
JP2004510702A (ja) | 2000-06-14 | 2004-04-08 | メダレックス,インコーポレイティド | イソロイシンを有するプロドラッグ化合物 |
WO2002000263A2 (en) | 2000-06-14 | 2002-01-03 | Medarex, Inc. | Tripeptide prodrug compounds |
US6333410B1 (en) | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
US6596541B2 (en) | 2000-10-31 | 2003-07-22 | Regeneron Pharmaceuticals, Inc. | Methods of modifying eukaryotic cells |
US7090843B1 (en) | 2000-11-28 | 2006-08-15 | Seattle Genetics, Inc. | Recombinant anti-CD30 antibodies and uses thereof |
US20020169125A1 (en) | 2001-03-21 | 2002-11-14 | Cell Therapeutics, Inc. | Recombinant production of polyanionic polymers and uses thereof |
EP1243276A1 (en) | 2001-03-23 | 2002-09-25 | Franciscus Marinus Hendrikus De Groot | Elongated and multiple spacers containing activatible prodrugs |
US7064120B2 (en) | 2001-04-12 | 2006-06-20 | Wyeth | Tricyclic pyridyl carboxamides and derivatives thereof tocolytic oxytocin receptor antagonists |
US7326700B2 (en) | 2001-04-12 | 2008-02-05 | Wyeth | Cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists |
US7202239B2 (en) | 2001-04-12 | 2007-04-10 | Wyeth | Cyclohexylphenyl carboxamides tocolytic oxytocin receptor antagonists |
US7109193B2 (en) | 2001-04-12 | 2006-09-19 | Wyeth | Tricyclic diazepines tocolytic oxytocin receptor antagonists |
US7022699B2 (en) | 2001-04-12 | 2006-04-04 | Wyeth | Cyclohexenyl phenyl diazepines vasopressin and oxytocin receptor modulators |
US6977254B2 (en) | 2001-04-12 | 2005-12-20 | Wyeth | Hydroxy cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists |
US6884869B2 (en) | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
US7087600B2 (en) | 2001-05-31 | 2006-08-08 | Medarex, Inc. | Peptidyl prodrugs and linkers and stabilizers useful therefor |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
MXPA03010961A (es) | 2001-05-31 | 2004-02-27 | Vertex Pharma | Compuestos de tiazol utiles como inhibidores de proteinas cinasas. |
US6897034B2 (en) | 2001-06-11 | 2005-05-24 | Medarex, Inc. | CD10-activated prodrug compounds |
US7098305B2 (en) | 2001-09-06 | 2006-08-29 | Ardana Bioscience Limited | Sustained release of microcrystalline peptide suspensions |
US7091186B2 (en) | 2001-09-24 | 2006-08-15 | Seattle Genetics, Inc. | p-Amidobenzylethers in drug delivery agents |
US6716821B2 (en) | 2001-12-21 | 2004-04-06 | Immunogen Inc. | Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same |
US6660856B2 (en) | 2002-03-08 | 2003-12-09 | Kaohsiung Medical University | Synthesis of pyrrolo[2,1-c][1,4]benzodiazepine analogues |
US6534660B1 (en) | 2002-04-05 | 2003-03-18 | Immunogen, Inc. | CC-1065 analog synthesis |
US6756397B2 (en) | 2002-04-05 | 2004-06-29 | Immunogen, Inc. | Prodrugs of CC-1065 analogs |
DK1507556T3 (en) | 2002-05-02 | 2016-09-12 | Wyeth Holdings Llc | Calicheamicin derivative-carrier conjugates |
US6596757B1 (en) | 2002-05-14 | 2003-07-22 | Immunogen Inc. | Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use |
US7767803B2 (en) | 2002-06-18 | 2010-08-03 | Archemix Corp. | Stabilized aptamers to PSMA and their use as prostate cancer therapeutics |
US20040249130A1 (en) | 2002-06-18 | 2004-12-09 | Martin Stanton | Aptamer-toxin molecules and methods for using same |
EP1523493B1 (de) | 2002-07-09 | 2013-09-04 | Dömling, Alexander | Neue tubulysinanaloga |
US7776814B2 (en) | 2002-07-09 | 2010-08-17 | R&D-Biopharmaceuticals Gmbh | Tubulysin conjugates |
DE10230872A1 (de) | 2002-07-09 | 2004-01-22 | Morphochem AG Aktiengesellschaft für kombinatorische Chemie | Verfahren zur Herstellung von substituierten Thiazol-2-ylmethylestern |
DK1545613T3 (da) | 2002-07-31 | 2011-11-14 | Seattle Genetics Inc | Auristatinkonjugater og deres anvendelse til behandling af cancer, en autoimmun sygdom eller en infektiøs sygdom |
AU2003259163B2 (en) | 2002-08-16 | 2008-07-03 | Immunogen, Inc. | Cross-linkers with high reactivity and solubility and their use in the preparation of conjugates for targeted delivery of small molecule drugs |
DE10241152A1 (de) | 2002-09-05 | 2004-03-18 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Tubulysin-Biosynthese-Gene |
GB0226593D0 (en) | 2002-11-14 | 2002-12-24 | Consultants Ltd | Compounds |
DE10254439A1 (de) | 2002-11-21 | 2004-06-03 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Tubulysine, Herstellungsverfahren und Tubulysin-Mittel |
US20040102719A1 (en) * | 2002-11-22 | 2004-05-27 | Velocimed, L.L.C. | Guide wire control catheters for crossing occlusions and related methods of use |
ES2347959T3 (es) | 2003-02-20 | 2010-11-26 | Seattle Genetics, Inc. | Conjugados de anticuerpos anti-cd70-farmaco y su uso para el tratamiento del cancer. |
DE10310082A1 (de) | 2003-03-07 | 2004-09-16 | Ktb Tumorforschungsgesellschaft Mbh | Protein-bindende Doxorubicin-Peptid-Derivate |
US6800622B1 (en) | 2003-03-25 | 2004-10-05 | Council Of Scientific And Industrial Research | Pyrene-linked pyrrolo[2,1-c][1,4]benzodiazepine hybrids useful as anti-cancer agents |
US7015215B2 (en) | 2003-03-31 | 2006-03-21 | Council Of Scientific And Industrial Research | Pyrrolo[2,1-c][1,4] benzodiazepines compounds and process thereof |
US6884799B2 (en) | 2003-03-31 | 2005-04-26 | Council Of Scientific And Industrial Research | Non-cross-linking pyrrolo[2,1-c][1,4]benzodiazepines and process thereof |
US8088387B2 (en) | 2003-10-10 | 2012-01-03 | Immunogen Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
US7276497B2 (en) | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
US7902338B2 (en) | 2003-07-31 | 2011-03-08 | Immunomedics, Inc. | Anti-CD19 antibodies |
EP1648512A4 (en) | 2003-07-31 | 2009-01-21 | Immunomedics Inc | ANTI-CD19 ANTIBODIES |
GB0321295D0 (en) | 2003-09-11 | 2003-10-15 | Spirogen Ltd | Synthesis of protected pyrrolobenzodiazepines |
EP1675857B1 (en) | 2003-10-22 | 2011-07-13 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto |
KR101520209B1 (ko) | 2003-11-06 | 2015-05-13 | 시애틀 지네틱스, 인크. | 리간드에 접합될 수 있는 모노메틸발린 화합물 |
CA2758460C (en) | 2003-12-16 | 2014-09-23 | Nektar Therapeutics | Methods of preparing monodisperse oligo (ethylene glycol) reagent compositions |
EP1718667B1 (en) | 2004-02-23 | 2013-01-09 | Genentech, Inc. | Heterocyclic self-immolative linkers and conjugates |
GB0404577D0 (en) | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
DK2270010T3 (da) | 2004-03-01 | 2012-05-14 | Spirogen Ltd | 11-hydroxy-5h-pyrrolo[2,1-c][1,4]benzodiazepin-5-on-derivater som vigtige mellemprodukter i fremstillingen af c2-substituerede pyrrolobenzodiazepiner |
AU2005218642B2 (en) | 2004-03-02 | 2011-04-28 | Seagen Inc. | Partially loaded antibodies and methods of their conjugation |
EP1723152B1 (en) | 2004-03-09 | 2015-02-11 | Spirogen Sàrl | Pyrrolobenzodiazepines |
US7056913B2 (en) | 2004-03-30 | 2006-06-06 | Council Of Scientific And Industrial Research | C8—linked pyrrolo[2,1-c][1,4]benzodiazepine-acridone/acridine hybrids |
US6951853B1 (en) | 2004-03-30 | 2005-10-04 | Council Of Scientific And Industrial Research | Process for preparing pyrrolo[2, 1-c] [1,4] benzodiazepine hybrids |
US7189710B2 (en) | 2004-03-30 | 2007-03-13 | Council Of Scientific And Industrial Research | C2-fluoro pyrrolo [2,1−c][1,4]benzodiazepine dimers |
FR2869231B1 (fr) | 2004-04-27 | 2008-03-14 | Sod Conseils Rech Applic | Composition therapeutique contenant au moins un derive de la pyrrolobenzodiazepine et la fludarabine |
AU2005245396A1 (en) | 2004-05-14 | 2005-12-01 | Immunogen, Inc. | A facile method for synthesizing baccatin III compounds |
DE102004030227A1 (de) | 2004-06-23 | 2006-01-26 | Dömling, Alexander, Dr. | Wirkstoffe mit antiangiogenetischen Eigenschaften |
US6979684B1 (en) | 2004-06-30 | 2005-12-27 | Council Of Scientific And Industrial Research | Pyrrolo[2,1-c][1,4]benzodiazepine-napthalimide conjugates linked through piperazine moiety and process for preparation thereof |
KR20070039593A (ko) | 2004-07-21 | 2007-04-12 | 암브룩스, 인코포레이티드 | 비천연적으로 코딩된 아미노산을 이용한 생합성 폴리펩티드 |
WO2006033913A2 (en) | 2004-09-16 | 2006-03-30 | Synta Pharmaceuticals Corp. | Bis (thio-hydrazide amides) for treament of hyperplasia |
ES2579805T3 (es) | 2004-09-23 | 2016-08-16 | Genentech, Inc. | Anticuerpos y conjugados modificados por ingeniería genética con cisteína |
EP1814988A2 (en) | 2004-11-26 | 2007-08-08 | Pieris AG | Compound with affinity for the cytotoxic t lymphocyte-associated antigen (ctla-4) |
EP1661584A1 (en) | 2004-11-26 | 2006-05-31 | Heinz Dr. Faulstich | Use of conjugates of amatoxins and phallotoxins with macromolecules for cancer and inflammation therapy |
EP1669358A1 (en) | 2004-12-07 | 2006-06-14 | Aventis Pharma S.A. | Cytotoxic agents comprising new taxanes |
EP1688415A1 (en) | 2004-12-07 | 2006-08-09 | Aventis Pharma S.A. | Cytotoxic agents comprising new C-2 modified taxanes |
CA2927595C (en) | 2004-12-22 | 2023-01-31 | Ambrx, Inc. | Compositions containing, methods involving, and uses of non-natural amino acids and polypeptides |
US7173026B2 (en) | 2004-12-27 | 2007-02-06 | Council Of Scientific And Industrial Research | Pyrrolo [2,1-c][1,4]benzodiazepine-anthraquinone conjugates useful as antitumour agents |
JP2008526864A (ja) * | 2005-01-06 | 2008-07-24 | ネオス テクノロジーズ インコーポレイテッド | 糖断片を用いる糖結合 |
US7301019B2 (en) | 2005-01-21 | 2007-11-27 | Immunogen, Inc. | Method for the preparation of maytansinoid esters |
US7691848B2 (en) | 2005-03-02 | 2010-04-06 | Wyeth | Pyrrolobenzodiazepine arylcarboxamides and derivatives thereof as follicle-stimulating hormone receptor antagonists |
WO2006096754A2 (en) | 2005-03-07 | 2006-09-14 | Archemix Corp. | Stabilized aptamers to psma and their use as prostate cancer therapeutics |
WO2006104970A1 (en) | 2005-03-30 | 2006-10-05 | Saladax Biomedical Inc. | Doxorubicin immunoassay |
PL1879901T3 (pl) | 2005-04-21 | 2010-06-30 | Medimmune Ltd | Pirolobenzodiazepiny |
US7678787B2 (en) | 2005-06-09 | 2010-03-16 | Wyeth | Pyrrolobenzodiazepine pyridine carboxamides and derivatives as follicle-stimulating hormone receptor antagonists |
DK1945647T3 (da) | 2005-11-08 | 2012-05-07 | Immunogen Inc | Fremgangsmåder til fremstilling af maytansinol |
DE112005003752T5 (de) | 2005-11-10 | 2008-11-13 | Council Of Scientific & Industrial Research | Neues Pyrrolo[2,1-c][1,4]benzodiapezinhybrid und ein Verfahren zu dessen Herstellung |
AU2006315347A1 (en) | 2005-11-16 | 2007-05-24 | Ambrx, Inc. | Methods and compositions comprising non-natural amino acids |
SI1813614T1 (sl) | 2006-01-25 | 2012-01-31 | Sanofi 174 | Citotoksična sredstva, ki obsegajo nove tomajmicinske derivate |
EP1832577A1 (en) | 2006-03-07 | 2007-09-12 | Sanofi-Aventis | Improved prodrugs of CC-1065 analogs |
CA2650035C (en) * | 2006-04-27 | 2015-02-03 | Intezyne Technologies, Inc. | Poly (ethylene glycol) containing chemically disparate endgroups |
US20080096819A1 (en) | 2006-05-02 | 2008-04-24 | Allozyne, Inc. | Amino acid substituted molecules |
EP2395099A3 (en) | 2006-05-02 | 2012-05-16 | Allozyne, Inc. | Amino acid substituted molecules |
ITMI20061624A1 (it) | 2006-08-11 | 2008-02-12 | Bioker Srl | Mono-coniugati sito-specifici di g-csf |
WO2008020456A2 (en) | 2006-08-14 | 2008-02-21 | Council Of Scientific & Industrial Research | Pyrrolo[2,1-c][1,4]benzodiazepine hybrids and a process for the preparation thereof |
WO2008020455A2 (en) | 2006-08-14 | 2008-02-21 | Council Of Scientific & Industrial Research | Pyrrolo[2,1-c][1,4]benzodiazepine hybrids and a process for the preparation thereof |
US7985783B2 (en) | 2006-09-21 | 2011-07-26 | The Regents Of The University Of California | Aldehyde tags, uses thereof in site-specific protein modification |
TW201509433A (zh) | 2006-12-13 | 2015-03-16 | Cerulean Pharma Inc | 用於醫物傳遞之以環糊精為基之聚合物 |
EP1955712A1 (en) * | 2007-02-09 | 2008-08-13 | Scil proteins GmbH | Multimeric conjugate |
EP2489372A3 (en) | 2007-03-14 | 2013-01-02 | Endocyte, Inc. | Binding ligand linked drug delivery conjugates of tubulysins |
WO2008125116A2 (en) | 2007-03-31 | 2008-10-23 | Aarhus Universitet | Upar inhibition |
WO2008122039A2 (en) | 2007-04-02 | 2008-10-09 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Selenocysteine mediated hybrid antibody molecules |
CA2683568A1 (en) | 2007-05-08 | 2008-11-20 | Genentech, Inc. | Cysteine engineered anti-muc16 antibodies and antibody drug conjugates |
CA2723671C (en) | 2007-05-10 | 2018-06-19 | R & D Biopharmaceuticals Gmbh | Tubulysine derivatives |
CA2690943A1 (en) | 2007-06-25 | 2008-12-31 | Endocyte, Inc. | Conjugates containing hydrophilic spacer linkers |
PL2019104T3 (pl) | 2007-07-19 | 2014-03-31 | Sanofi Sa | Środki cytotoksyczne obejmujące nowe pochodne tomaymycyny i ich zastosowanie terapeutyczne |
WO2009134279A1 (en) | 2007-07-20 | 2009-11-05 | The Regents Of The University Of California | Tubulysin d analogues |
US20110263650A1 (en) | 2007-07-20 | 2011-10-27 | Helmholtz-Zentrum Für Infektions-Forschung Gmbh | Tubulysin D Analogues |
JP2010536790A (ja) | 2007-08-17 | 2010-12-02 | パーデュー・リサーチ・ファウンデーション | Psma結合性リガンド−リンカー結合体及び使用方法 |
JP2011500835A (ja) | 2007-10-25 | 2011-01-06 | エンドサイト,インコーポレイテッド | チューブリシン類および調製プロセス |
US9212208B2 (en) | 2008-01-30 | 2015-12-15 | Pieris Ag | Muteins with tear lipocalin having affinity to human c-Met receptor tyrosine kinase and methods for obtaining the same |
EP2265613B1 (en) | 2008-03-05 | 2013-07-24 | Council Of Scientific & Industrial Research | Quinazoline linked pyrrolo[2,1-c][1, 4]benzodiazepine hybrids as potential anticancer agents and process for the preparation thereof |
EP2349274A4 (en) | 2008-09-17 | 2014-12-17 | Endocyte Inc | CONJUGATES OF ANTIFOLATES BINDING THE FOLATE RECEPTOR |
EP2174947A1 (en) | 2008-09-25 | 2010-04-14 | Universität des Saarlandes | Bioactive pre-tubulysins and use thereof |
US8791245B2 (en) * | 2008-10-03 | 2014-07-29 | Glycan Bioscience LLC | Anionic conjugates of glycosylated bacterial metabolite |
EP2376647B1 (en) | 2009-01-12 | 2014-03-05 | Sutro Biopharma, Inc. | Mono charging system for selectively introducing non-native amino acids into proteins using an in vitro protein synthesis system |
CN105175434A (zh) | 2009-02-05 | 2015-12-23 | 伊缪诺金公司 | 新型苯并二氮杂*衍生物 |
WO2010096394A2 (en) | 2009-02-17 | 2010-08-26 | Redwood Biosciences, Inc. | Aldehyde-tagged protein-based drug carriers and methods of use |
IT1394860B1 (it) | 2009-07-22 | 2012-07-20 | Kemotech S R L | Composti farmaceutici |
US8394922B2 (en) | 2009-08-03 | 2013-03-12 | Medarex, Inc. | Antiproliferative compounds, conjugates thereof, methods therefor, and uses thereof |
JP5532333B2 (ja) | 2010-10-21 | 2014-06-25 | 株式会社パトライト | 壁に取り付け可能な機器 |
JP5936702B2 (ja) | 2011-11-11 | 2016-06-22 | ライナット ニューロサイエンス コーポレイション | Trop−2に対して特異的な抗体およびこれらの使用 |
US9717803B2 (en) | 2011-12-23 | 2017-08-01 | Innate Pharma | Enzymatic conjugation of polypeptides |
AU2013270686B2 (en) * | 2012-06-07 | 2016-11-10 | Ambrx, Inc. | Prostate-specific membrane antigen antibody drug conjugates |
GB201210770D0 (en) | 2012-06-18 | 2012-08-01 | Polytherics Ltd | Novel conjugation reagents |
HUE048574T2 (hu) | 2012-07-12 | 2020-08-28 | Hangzhou Dac Biotech Co Ltd | Sejthez kötõdõ molekulák citotoxikus szerekkel képzett konjugátumai |
WO2014043403A1 (en) | 2012-09-12 | 2014-03-20 | Agensys, Inc. | Amatoxin derivatives and cell-permeable conjugates thereof as inhibitors of rna polymerase |
WO2014059028A1 (en) * | 2012-10-09 | 2014-04-17 | Igenica, Inc. | Anti-c16orf54 antibodies and methods of use thereof |
NO2789793T3 (zh) | 2012-10-24 | 2018-01-27 | ||
US9310374B2 (en) | 2012-11-16 | 2016-04-12 | Redwood Bioscience, Inc. | Hydrazinyl-indole compounds and methods for producing a conjugate |
US10131682B2 (en) * | 2012-11-24 | 2018-11-20 | Hangzhou Dac Biotech Co., Ltd. | Hydrophilic linkers and their uses for conjugation of drugs to a cell binding molecules |
US9695189B2 (en) * | 2013-03-01 | 2017-07-04 | Mark Quang Nguyen | Chemical crosslinkers and compositions thereof |
RU2708314C2 (ru) | 2013-03-11 | 2019-12-05 | Джензим Корпорейшн | Гипергликозилированные связывающие полипептиды |
US11229711B2 (en) * | 2013-06-06 | 2022-01-25 | Magenta Therapeutics, Inc. | Linkers for antibody-drug conjugates and related compounds, compositions, and methods of use |
WO2016057936A1 (en) * | 2014-10-09 | 2016-04-14 | The Regents Of The University Of Colorado, A Body Corporate | Linkers for protein interaction profiling and methods of making and using the same |
WO2016059628A1 (en) | 2014-10-12 | 2016-04-21 | Korol Oleg | System and method for determining watering needs for field or landscape irrigation |
CN105641707B (zh) * | 2014-11-11 | 2020-11-24 | 杭州多禧生物科技有限公司 | 细胞毒素分子同细胞结合受体分子的共轭体 |
US9856285B2 (en) * | 2015-03-17 | 2018-01-02 | Kaohsiung Medical University | Reagents for universal site-specific labeling and modifications of nucleic acids |
JP6700321B2 (ja) | 2015-07-04 | 2020-05-27 | ハンジョウ ディーエーシー バイオテック シーオー.,エルティディ.Hangzhou Dac Biotech Co.,Ltd. | 細胞結合分子の特異的共役体 |
CA2991973C (en) * | 2015-07-12 | 2021-12-07 | Suzhou M-Conj Biotech Co., Ltd. | Bridge linkers for conjugation of a cell-binding molecule |
US10292961B2 (en) * | 2015-07-15 | 2019-05-21 | Hangzhou Dac Biotech Co., Ltd. | Disulfur bridge linkers for conjugation of a cell-binding molecule |
CN115300640A (zh) * | 2015-08-10 | 2022-11-08 | 杭州多禧生物科技有限公司 | 新型连接体及其用于药物和生物分子的特异性偶联 |
CA3209672A1 (en) * | 2016-02-04 | 2016-04-21 | Hangzhou Dac Biotech Co., Ltd. | Specific conjugation linkers, specific immunoconjugates thereof, methods of making and uses such conjugates thereof |
EP3445401A4 (en) * | 2016-04-20 | 2019-11-20 | Hangzhou DAC Biotech Co, Ltd | DERIVATIVES OF AMANITA TOXINES AND THEIR CONJUGATION TO A CELL BINDING MOLECULE |
-
2016
- 2016-11-14 KR KR1020227036868A patent/KR20220150408A/ko not_active Application Discontinuation
- 2016-11-14 NZ NZ752394A patent/NZ752394A/en unknown
- 2016-11-14 CN CN201680090956.2A patent/CN110099682B/zh active Active
- 2016-11-14 KR KR1020227036869A patent/KR20220147719A/ko not_active Application Discontinuation
- 2016-11-14 EP EP21171676.6A patent/EP3888691A1/en active Pending
- 2016-11-14 KR KR1020217032860A patent/KR102459469B1/ko active Application Filing
- 2016-11-14 KR KR1020217032859A patent/KR102459468B1/ko active IP Right Grant
- 2016-11-14 AU AU2016429272A patent/AU2016429272A1/en not_active Abandoned
- 2016-11-14 EP EP16921340.2A patent/EP3538080A4/en active Pending
- 2016-11-14 KR KR1020197017166A patent/KR102345175B1/ko active IP Right Grant
- 2016-11-14 JP JP2019524954A patent/JP7138350B2/ja active Active
- 2016-11-14 MX MX2019005583A patent/MX2019005583A/es unknown
- 2016-11-14 WO PCT/CN2016/105799 patent/WO2018086139A1/en active Application Filing
- 2016-11-14 KR KR1020227036871A patent/KR20220147721A/ko not_active Application Discontinuation
- 2016-11-14 CN CN202310180812.8A patent/CN116143678A/zh active Pending
- 2016-11-14 KR KR1020227036870A patent/KR20220147720A/ko not_active Application Discontinuation
- 2016-11-14 US US16/348,749 patent/US20210308277A1/en active Pending
- 2016-11-14 CA CA3042442A patent/CA3042442C/en active Active
-
2019
- 2019-05-14 PH PH12019501056A patent/PH12019501056A1/en unknown
-
2021
- 2021-01-29 AU AU2021200562A patent/AU2021200562B2/en active Active
-
2022
- 2022-06-08 US US17/835,081 patent/US20220313836A1/en active Pending
- 2022-06-08 US US17/835,311 patent/US20220313837A1/en active Pending
- 2022-06-08 US US17/835,419 patent/US20230071112A1/en active Pending
- 2022-06-08 US US17/835,395 patent/US20220313838A1/en active Pending
- 2022-06-08 US US17/835,041 patent/US20220323602A1/en active Pending
- 2022-08-30 JP JP2022136679A patent/JP2022188016A/ja active Pending
-
2023
- 2023-05-18 AU AU2023203116A patent/AU2023203116A1/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110099682B (zh) | 偶联连接体,含有此连接体的细胞结合分子-药物偶联物及其制备和应用 | |
US20210052747A1 (en) | Specific conjugation linkers, specific immunoconjugates thereof, methods of making and uses such conjugates thereof | |
CN108289964B (zh) | 新型连接体及其用于药物和生物分子的特异性偶联 | |
KR102655301B1 (ko) | 비스-링키지를 사용한 세포독성 약물의 접합 | |
KR20240095442A (ko) | 항체의 특이적 접합 | |
JP2024023191A (ja) | 架橋ピロロベンゾジアゼピン二量体(pbd)誘導体及びその共役体 | |
KR20230034957A (ko) | 캄프토테신 유사체를 갖는 세포-결합 분자의 접합체 | |
KR20230075530A (ko) | 분지형 링커를 갖는 튜불리신 유사체의 접합체 | |
CN113350518A (zh) | 与细胞结合分子的共轭偶联的桥连接体 | |
CN113698335A (zh) | 细胞结合分子的特异性偶联 | |
CN113423430A (zh) | 含支链连接子的鹅膏毒素偶联物 | |
CN114040781A (zh) | Tubulysin衍生物与细胞结合分子偶联物的制剂配方 | |
JP2023159139A (ja) | 新規な連結体及び生体分子と薬物との特異的共役におけるその使用 | |
EA044827B1 (ru) | Конъюгирование цитотоксических лекарственных средств посредством бис-связывания | |
NZ744940B2 (en) | Conjugation linkers, antibody-drug conjugates thereof, and methods of synthesis and use of such conjugates |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20191024 Address after: 310018 12 from the science and Technology Park 260, No. 6 Avenue, Hangzhou economic and Technological Development Zone, Hangzhou, Zhejiang. Applicant after: HANGZHOU DAC BIOTECH Co.,Ltd. Address before: 310018 12 from the science and Technology Park 260, No. 6 Avenue, Hangzhou economic and Technological Development Zone, Hangzhou, Zhejiang. Applicant before: HANGZHOU DAC BIOTECH Co.,Ltd. Applicant before: SUZHOU M-CONJ BIOTECH Co.,Ltd. |
|
TA01 | Transfer of patent application right | ||
GR01 | Patent grant | ||
GR01 | Patent grant |