TW202317521A - 化合物 - Google Patents
化合物 Download PDFInfo
- Publication number
- TW202317521A TW202317521A TW111122847A TW111122847A TW202317521A TW 202317521 A TW202317521 A TW 202317521A TW 111122847 A TW111122847 A TW 111122847A TW 111122847 A TW111122847 A TW 111122847A TW 202317521 A TW202317521 A TW 202317521A
- Authority
- TW
- Taiwan
- Prior art keywords
- amino
- methyl
- bis
- chloroethyl
- benzimidazol
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 291
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 52
- 239000003814 drug Substances 0.000 claims abstract description 42
- 238000011282 treatment Methods 0.000 claims abstract description 26
- 206010035226 Plasma cell myeloma Diseases 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
- 206010025323 Lymphomas Diseases 0.000 claims abstract description 23
- 208000034578 Multiple myelomas Diseases 0.000 claims abstract description 23
- 208000032839 leukemia Diseases 0.000 claims abstract description 12
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 10
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 10
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 10
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 10
- 201000005202 lung cancer Diseases 0.000 claims abstract description 10
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 10
- 201000008968 osteosarcoma Diseases 0.000 claims abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 331
- 125000000217 alkyl group Chemical group 0.000 claims description 150
- -1 Substituted Chemical class 0.000 claims description 138
- 239000000203 mixture Substances 0.000 claims description 111
- 229910052736 halogen Inorganic materials 0.000 claims description 95
- 150000002367 halogens Chemical class 0.000 claims description 94
- HHEQAKRJDZSCPG-KRWDZBQOSA-N N[C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C1=CC=CC=C1)C(O)=O Chemical compound N[C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C1=CC=CC=C1)C(O)=O HHEQAKRJDZSCPG-KRWDZBQOSA-N 0.000 claims description 71
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 70
- FFMCIRXOBIKKJX-ZCYQVOJMSA-N CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C1=CC=CC=C1)N)=O)=O Chemical class CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C1=CC=CC=C1)N)=O)=O FFMCIRXOBIKKJX-ZCYQVOJMSA-N 0.000 claims description 56
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 56
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 55
- 150000003839 salts Chemical class 0.000 claims description 55
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 50
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 43
- 229910052757 nitrogen Inorganic materials 0.000 claims description 37
- 201000011510 cancer Diseases 0.000 claims description 34
- 229940125904 compound 1 Drugs 0.000 claims description 28
- 150000001408 amides Chemical class 0.000 claims description 26
- 150000002148 esters Chemical class 0.000 claims description 25
- 229910052801 chlorine Inorganic materials 0.000 claims description 24
- 229910052731 fluorine Inorganic materials 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 20
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims description 18
- 229940079593 drug Drugs 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 229940124597 therapeutic agent Drugs 0.000 claims description 15
- 125000004434 sulfur atom Chemical group 0.000 claims description 13
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- SUZKWFGTZDTIDY-WMZOPIPTSA-N CC(C)C[C@@H](C(O)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CC(C)C[C@@H](C(O)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O SUZKWFGTZDTIDY-WMZOPIPTSA-N 0.000 claims description 11
- 239000003112 inhibitor Substances 0.000 claims description 11
- 239000012453 solvate Substances 0.000 claims description 11
- 229940125810 compound 20 Drugs 0.000 claims description 10
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims description 10
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 10
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 9
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 9
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 8
- 102000003964 Histone deacetylase Human genes 0.000 claims description 8
- 108090000353 Histone deacetylase Proteins 0.000 claims description 8
- 229940079156 Proteasome inhibitor Drugs 0.000 claims description 8
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 8
- 229940127573 compound 38 Drugs 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 8
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 8
- 239000003207 proteasome inhibitor Substances 0.000 claims description 8
- TXFLGZOGNOOEFZ-UHFFFAOYSA-N bis(2-chloroethyl)amine Chemical compound ClCCNCCCl TXFLGZOGNOOEFZ-UHFFFAOYSA-N 0.000 claims description 7
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims description 6
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 claims description 6
- BZICDSFLCBLKSZ-HKUYNNGSSA-N CCOC([C@H](CC(C)C)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O BZICDSFLCBLKSZ-HKUYNNGSSA-N 0.000 claims description 6
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940125844 compound 46 Drugs 0.000 claims description 6
- 229940127271 compound 49 Drugs 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 5
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 claims description 5
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 5
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 claims description 5
- JJJPSDKCHKVYLH-QUCCMNQESA-N CCOC([C@H](CC(C)C)NC([C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O JJJPSDKCHKVYLH-QUCCMNQESA-N 0.000 claims description 5
- 229940126657 Compound 17 Drugs 0.000 claims description 5
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 5
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 229940125773 compound 10 Drugs 0.000 claims description 5
- 229940126086 compound 21 Drugs 0.000 claims description 5
- 229940125877 compound 31 Drugs 0.000 claims description 5
- 229940126540 compound 41 Drugs 0.000 claims description 5
- 229940125898 compound 5 Drugs 0.000 claims description 5
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 5
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 claims description 4
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 4
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 claims description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 4
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 4
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 4
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 claims description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 4
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 claims description 4
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 4
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 claims description 4
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 claims description 4
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 4
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 4
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 4
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 claims description 4
- JNIDAWDUBHQHEC-HKUYNNGSSA-N CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC2=CC(N(CCCl)CCCl)=CN=C2N1C)N)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC2=CC(N(CCCl)CCCl)=CN=C2N1C)N)=O)=O JNIDAWDUBHQHEC-HKUYNNGSSA-N 0.000 claims description 4
- 229940126639 Compound 33 Drugs 0.000 claims description 4
- 229940127007 Compound 39 Drugs 0.000 claims description 4
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 claims description 4
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 4
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 claims description 4
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 claims description 4
- 238000011467 adoptive cell therapy Methods 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims description 4
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229940125797 compound 12 Drugs 0.000 claims description 4
- 229940126543 compound 14 Drugs 0.000 claims description 4
- 229940125758 compound 15 Drugs 0.000 claims description 4
- 229940126142 compound 16 Drugs 0.000 claims description 4
- 229940126208 compound 22 Drugs 0.000 claims description 4
- 229940125833 compound 23 Drugs 0.000 claims description 4
- 229940125961 compound 24 Drugs 0.000 claims description 4
- 229940125846 compound 25 Drugs 0.000 claims description 4
- 229940125851 compound 27 Drugs 0.000 claims description 4
- 229940127204 compound 29 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 229940125878 compound 36 Drugs 0.000 claims description 4
- 229940125807 compound 37 Drugs 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000003949 imides Chemical class 0.000 claims description 4
- 230000002519 immonomodulatory effect Effects 0.000 claims description 4
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 claims description 4
- 230000025308 nuclear transport Effects 0.000 claims description 4
- 150000003431 steroids Chemical class 0.000 claims description 4
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 claims description 3
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- RSEIQUQDQWTKAX-HKUYNNGSSA-N CC(C)C[C@@H](C(NC)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CC(C)C[C@@H](C(NC)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O RSEIQUQDQWTKAX-HKUYNNGSSA-N 0.000 claims description 3
- VTCCCLHIVZLAKQ-ICSRJNTNSA-N CC(C)C[C@@H](C(OC(C)C)=O)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CC(C)C[C@@H](C(OC(C)C)=O)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O VTCCCLHIVZLAKQ-ICSRJNTNSA-N 0.000 claims description 3
- DAEMXBCFRPKUNT-HKUYNNGSSA-N CC(C)C[C@@H](C(OC)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CC(C)C[C@@H](C(OC)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O DAEMXBCFRPKUNT-HKUYNNGSSA-N 0.000 claims description 3
- CIYDPSMBVOIFAH-KXBFYZLASA-N CC(C)[C@@H](C(O)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CC(C)[C@@H](C(O)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O CIYDPSMBVOIFAH-KXBFYZLASA-N 0.000 claims description 3
- JJJPSDKCHKVYLH-UYAOXDASSA-N CCOC([C@@H](CC(C)C)NC([C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O Chemical compound CCOC([C@@H](CC(C)C)NC([C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O JJJPSDKCHKVYLH-UYAOXDASSA-N 0.000 claims description 3
- JJJPSDKCHKVYLH-AZUAARDMSA-N CCOC([C@@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O Chemical compound CCOC([C@@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O JJJPSDKCHKVYLH-AZUAARDMSA-N 0.000 claims description 3
- YEOGEAXIFNRLIB-JXFKEZNVSA-N CCOC([C@H](C(C)C)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O Chemical compound CCOC([C@H](C(C)C)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O YEOGEAXIFNRLIB-JXFKEZNVSA-N 0.000 claims description 3
- XARWTYOSJMPPKJ-SFTDATJTSA-N CCOC([C@H](CC(C)C)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(C)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(C)=O)=O)=O XARWTYOSJMPPKJ-SFTDATJTSA-N 0.000 claims description 3
- UXUZWFDLHDVJFM-FPOVZHCZSA-N CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC)=O)=O UXUZWFDLHDVJFM-FPOVZHCZSA-N 0.000 claims description 3
- 239000012625 DNA intercalator Substances 0.000 claims description 3
- 230000002424 anti-apoptotic effect Effects 0.000 claims description 3
- 229940125936 compound 42 Drugs 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- SIXPYQRGUMWUKC-RDJZCZTQSA-N CC(C)C[C@@H](C(O)=O)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CC(C)C[C@@H](C(O)=O)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O SIXPYQRGUMWUKC-RDJZCZTQSA-N 0.000 claims description 2
- RRYSHNSZPMVVNF-GMAHTHKFSA-N CC(C)C[C@@H](C(O)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C1=CC=CC=C1)N)=O Chemical compound CC(C)C[C@@H](C(O)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C1=CC=CC=C1)N)=O RRYSHNSZPMVVNF-GMAHTHKFSA-N 0.000 claims description 2
- PZCVEMLDNJZESR-KAOUJKNGSA-N CC(C)C[C@@H](C(OC(C)COC)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CC(C)C[C@@H](C(OC(C)COC)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O PZCVEMLDNJZESR-KAOUJKNGSA-N 0.000 claims description 2
- OREHADRGDQWJBH-WMZOPIPTSA-N CC(C)C[C@@H](C(OC)=O)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CC(C)C[C@@H](C(OC)=O)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O OREHADRGDQWJBH-WMZOPIPTSA-N 0.000 claims description 2
- ZYCXSOYRDCIPBZ-GMAHTHKFSA-N CC(C)C[C@@H](C(OCCCN(C)C)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CC(C)C[C@@H](C(OCCCN(C)C)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O ZYCXSOYRDCIPBZ-GMAHTHKFSA-N 0.000 claims description 2
- OCHSEGSCUMISBV-GMAHTHKFSA-N CC(C)C[C@@H](C(OCCOC(C)C)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CC(C)C[C@@H](C(OCCOC(C)C)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O OCHSEGSCUMISBV-GMAHTHKFSA-N 0.000 claims description 2
- JWYBORSRQBZFCJ-FPOVZHCZSA-N CN1C(C=CC(N(CCCl)CCCl)=C2)=C2N=C1CC[C@@H](C(N[C@@H](CC(C=C1)=CC=C1F)C(O)=O)=O)N Chemical compound CN1C(C=CC(N(CCCl)CCCl)=C2)=C2N=C1CC[C@@H](C(N[C@@H](CC(C=C1)=CC=C1F)C(O)=O)=O)N JWYBORSRQBZFCJ-FPOVZHCZSA-N 0.000 claims description 2
- VKJXWUJEFIQCNF-LBPRGKRZSA-N CN1C(C=CC(N(CCCl)CCCl)=C2)=C2N=C1CC[C@@H](C(O)=O)N Chemical compound CN1C(C=CC(N(CCCl)CCCl)=C2)=C2N=C1CC[C@@H](C(O)=O)N VKJXWUJEFIQCNF-LBPRGKRZSA-N 0.000 claims description 2
- DVRXEVBZHWAIRZ-NSHDSACASA-N CN1C(C=CC(N(CCCl)CCCl)=C2)=C2N=C1C[C@@H](C(O)=O)N Chemical compound CN1C(C=CC(N(CCCl)CCCl)=C2)=C2N=C1C[C@@H](C(O)=O)N DVRXEVBZHWAIRZ-NSHDSACASA-N 0.000 claims description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims 1
- 229940088872 Apoptosis inhibitor Drugs 0.000 claims 1
- KBTMEGPTOYZGTL-HVCNVCAESA-N CCOC([C@H](CC(C)C)NC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O)=O KBTMEGPTOYZGTL-HVCNVCAESA-N 0.000 claims 1
- 230000006909 anti-apoptosis Effects 0.000 claims 1
- 239000000158 apoptosis inhibitor Substances 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 231100000433 cytotoxic Toxicity 0.000 abstract description 8
- 230000001472 cytotoxic effect Effects 0.000 abstract description 8
- 108091005804 Peptidases Proteins 0.000 abstract description 5
- 102000035195 Peptidases Human genes 0.000 abstract description 5
- 235000019833 protease Nutrition 0.000 abstract description 3
- 238000011321 prophylaxis Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 173
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 107
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 96
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 91
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 89
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 88
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 87
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
- 239000012043 crude product Substances 0.000 description 80
- 239000007787 solid Substances 0.000 description 73
- 238000006243 chemical reaction Methods 0.000 description 71
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 64
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 64
- 210000004027 cell Anatomy 0.000 description 56
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 54
- 239000002904 solvent Substances 0.000 description 53
- 238000005481 NMR spectroscopy Methods 0.000 description 49
- 235000019439 ethyl acetate Nutrition 0.000 description 49
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 47
- 150000001335 aliphatic alkanes Chemical group 0.000 description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 239000000543 intermediate Substances 0.000 description 39
- 239000002585 base Substances 0.000 description 38
- 238000000746 purification Methods 0.000 description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 125000006630 butoxycarbonylamino group Chemical group 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- 238000004237 preparative chromatography Methods 0.000 description 33
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 31
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 239000002207 metabolite Substances 0.000 description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 26
- 239000003921 oil Substances 0.000 description 25
- 239000012071 phase Substances 0.000 description 25
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 23
- 239000000460 chlorine Substances 0.000 description 23
- 239000000463 material Substances 0.000 description 22
- 230000002829 reductive effect Effects 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 230000002378 acidificating effect Effects 0.000 description 21
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 21
- 229960002707 bendamustine Drugs 0.000 description 21
- 239000012267 brine Substances 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 20
- 125000002947 alkylene group Chemical group 0.000 description 20
- 238000012360 testing method Methods 0.000 description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
- 239000002253 acid Substances 0.000 description 17
- 229960001924 melphalan Drugs 0.000 description 17
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 238000002953 preparative HPLC Methods 0.000 description 15
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 description 14
- 239000000872 buffer Substances 0.000 description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000007821 HATU Substances 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 239000008346 aqueous phase Substances 0.000 description 13
- 231100000135 cytotoxicity Toxicity 0.000 description 13
- 230000003013 cytotoxicity Effects 0.000 description 13
- 229910052805 deuterium Inorganic materials 0.000 description 12
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- 238000000338 in vitro Methods 0.000 description 11
- 239000000377 silicon dioxide Substances 0.000 description 11
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000010926 purge Methods 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 108020004414 DNA Proteins 0.000 description 9
- 231100000277 DNA damage Toxicity 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 235000015165 citric acid Nutrition 0.000 description 9
- 239000006260 foam Substances 0.000 description 9
- 230000003834 intracellular effect Effects 0.000 description 9
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000005778 DNA damage Effects 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 235000011167 hydrochloric acid Nutrition 0.000 description 8
- 238000003328 mesylation reaction Methods 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- 108020005196 Mitochondrial DNA Proteins 0.000 description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 7
- 239000013058 crude material Substances 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 230000002489 hematologic effect Effects 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- 239000003039 volatile agent Substances 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Substances CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 5
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 5
- 241000287828 Gallus gallus Species 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 201000005787 hematologic cancer Diseases 0.000 description 5
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 210000001161 mammalian embryo Anatomy 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 5
- 235000019260 propionic acid Nutrition 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 102100022749 Aminopeptidase N Human genes 0.000 description 4
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 4
- CKNHCNGYAOMSMX-GMAHTHKFSA-N CC(C)C[C@@H](C(O)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N(C)C(OC(C)(C)C)=O)=O Chemical compound CC(C)C[C@@H](C(O)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N(C)C(OC(C)(C)C)=O)=O CKNHCNGYAOMSMX-GMAHTHKFSA-N 0.000 description 4
- LWTNHOVUUWFYOG-UWJYYQICSA-N CCOC([C@H](C(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O Chemical compound CCOC([C@H](C(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O LWTNHOVUUWFYOG-UWJYYQICSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- QZFWNEASXBNLCD-UHFFFAOYSA-N [chloro(dimethylamino)methylidene]-dimethylazanium Chemical compound CN(C)C(Cl)=[N+](C)C QZFWNEASXBNLCD-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000002152 alkylating effect Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 229960002092 busulfan Drugs 0.000 description 4
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 4
- SKKTUOZKZKCGTB-UHFFFAOYSA-N butyl carbamate Chemical group CCCCOC(N)=O SKKTUOZKZKCGTB-UHFFFAOYSA-N 0.000 description 4
- 229960004630 chlorambucil Drugs 0.000 description 4
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 4
- 210000002950 fibroblast Anatomy 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 230000000717 retained effect Effects 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
- 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 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- LDLCZOVUSADOIV-LNLMKGTHSA-N 2-bromo-1,1,2,2-tetradeuterioethanol Chemical compound [2H]C([2H])(O)C([2H])([2H])Br LDLCZOVUSADOIV-LNLMKGTHSA-N 0.000 description 3
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 description 3
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- FNEFCDVSKNSNBT-LBPRGKRZSA-N CC(C)(C)OC(N[C@@H](CCC1=NC(C=C(C=C2)N)=C2N1C)C(OC)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCC1=NC(C=C(C=C2)N)=C2N1C)C(OC)=O)=O FNEFCDVSKNSNBT-LBPRGKRZSA-N 0.000 description 3
- XUQSEKSVUDFZOS-JTQLQIEISA-N CC(C)(C)OC(N[C@@H](CCC1=NC2=CC([N+]([O-])=O)=CN=C2N1C)C(O)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCC1=NC2=CC([N+]([O-])=O)=CN=C2N1C)C(O)=O)=O XUQSEKSVUDFZOS-JTQLQIEISA-N 0.000 description 3
- TXRFTHNEDCZLHZ-FPOVZHCZSA-N CC(C)C[C@@H](C(O)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(OC(C)(C)C)=O)=O Chemical compound CC(C)C[C@@H](C(O)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(OC(C)(C)C)=O)=O TXRFTHNEDCZLHZ-FPOVZHCZSA-N 0.000 description 3
- JJJPSDKCHKVYLH-ICSRJNTNSA-N CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O JJJPSDKCHKVYLH-ICSRJNTNSA-N 0.000 description 3
- LVCFSSZJEIXMBI-XCZPVHLTSA-N CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C1=CC=CC=C1)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C1=CC=CC=C1)NC(OC(C)(C)C)=O)=O)=O LVCFSSZJEIXMBI-XCZPVHLTSA-N 0.000 description 3
- FFFUXKXHJYMYCH-UNMCSNQZSA-N CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC2=CC(N(CCCl)CCCl)=CN=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC2=CC(N(CCCl)CCCl)=CN=C2N1C)NC(OC(C)(C)C)=O)=O)=O FFFUXKXHJYMYCH-UNMCSNQZSA-N 0.000 description 3
- QGIRDXJTSNTVKI-GMAHTHKFSA-N CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O Chemical class CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O QGIRDXJTSNTVKI-GMAHTHKFSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 101100278318 Dictyostelium discoideum dohh-2 gene Proteins 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 208000017604 Hodgkin disease Diseases 0.000 description 3
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 3
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 3
- 102000018251 Hypoxanthine Phosphoribosyltransferase Human genes 0.000 description 3
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 description 3
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 description 3
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 3
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 3
- 108091093105 Nuclear DNA Proteins 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- CXGXDTSWFKGIHD-CLCIBRLLSA-N [(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] (2S,4aS,6aR,6aS,6bR,8aR,10S,12aS,14bR)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-3,4,5,6,6a,7,8,8a,10,11,12,14b-dodecahydro-1H-picene-2-carboxylate Chemical compound CC1(C)[C@@H](O)CC[C@@]2(C)[C@H]1CC[C@]1(C)[C@@H]2C(=O)C=C2[C@@H]3C[C@](C)(CC[C@]3(C)CC[C@@]12C)C(=O)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O CXGXDTSWFKGIHD-CLCIBRLLSA-N 0.000 description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- AJNWGKMIJZNIBI-UHFFFAOYSA-N butanoic acid;dihydrochloride Chemical compound Cl.Cl.CCCC(O)=O AJNWGKMIJZNIBI-UHFFFAOYSA-N 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000002659 cell therapy Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000002784 cytotoxicity assay Methods 0.000 description 3
- 231100000263 cytotoxicity test Toxicity 0.000 description 3
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 3
- LCFXLZAXGXOXAP-QPJJXVBHSA-N ethyl (2e)-2-cyano-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(=N\O)\C#N LCFXLZAXGXOXAP-QPJJXVBHSA-N 0.000 description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 238000013467 fragmentation Methods 0.000 description 3
- 238000006062 fragmentation reaction Methods 0.000 description 3
- 238000007429 general method Methods 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000000155 isotopic effect Effects 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- 229960005181 morphine Drugs 0.000 description 3
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000001294 propane Substances 0.000 description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- ARXJGSRGQADJSQ-UHFFFAOYSA-N 1-methoxypropan-2-ol Chemical compound COCC(C)O ARXJGSRGQADJSQ-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 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 2
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 2
- RAUWPNXIALNKQM-UHFFFAOYSA-N 4-nitro-1,2-phenylenediamine Chemical compound NC1=CC=C([N+]([O-])=O)C=C1N RAUWPNXIALNKQM-UHFFFAOYSA-N 0.000 description 2
- PQMGRVXQAFKVMO-UHFFFAOYSA-N 4-nitro-1-n-phenylbenzene-1,2-diamine Chemical compound NC1=CC([N+]([O-])=O)=CC=C1NC1=CC=CC=C1 PQMGRVXQAFKVMO-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- TZTLRBBGAXOBGZ-KRWDZBQOSA-N CC(C)(C)OC(N[C@@H](CCC(NC1=CC([N+]([O-])=O)=CN=C1NC)=O)C(OCC1=CC=CC=C1)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCC(NC1=CC([N+]([O-])=O)=CN=C1NC)=O)C(OCC1=CC=CC=C1)=O)=O TZTLRBBGAXOBGZ-KRWDZBQOSA-N 0.000 description 2
- BGHWJPYTAMSOQL-CYBMUJFWSA-N CC(C)(C)OC(N[C@H](CCC(NC(C=C(C=C1)[N+]([O-])=O)=C1NC)=O)C(OC)=O)=O Chemical compound CC(C)(C)OC(N[C@H](CCC(NC(C=C(C=C1)[N+]([O-])=O)=C1NC)=O)C(OC)=O)=O BGHWJPYTAMSOQL-CYBMUJFWSA-N 0.000 description 2
- IHHZMXMLHIGWGV-LLVKDONJSA-N CC(C)(C)OC(N[C@H](CCC1=NC(C=C(C=C2)N)=C2N1C)C(O)=O)=O Chemical compound CC(C)(C)OC(N[C@H](CCC1=NC(C=C(C=C2)N)=C2N1C)C(O)=O)=O IHHZMXMLHIGWGV-LLVKDONJSA-N 0.000 description 2
- GHANLFULNUTPDR-LLVKDONJSA-N CC(C)(C)OC(N[C@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)C(O)=O)=O Chemical compound CC(C)(C)OC(N[C@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)C(O)=O)=O GHANLFULNUTPDR-LLVKDONJSA-N 0.000 description 2
- WXSKDVXOGZYRKQ-HKUYNNGSSA-N CC(C)C[C@@H](C(O)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC)=O Chemical compound CC(C)C[C@@H](C(O)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC)=O WXSKDVXOGZYRKQ-HKUYNNGSSA-N 0.000 description 2
- ASCDRQUDNVECBP-JKSUJKDBSA-N CC(C)C[C@H](C(O)=O)NC([C@H](CC(C=C1)=CC=C1F)NC(OC(C)(C)C)=O)=O Chemical compound CC(C)C[C@H](C(O)=O)NC([C@H](CC(C=C1)=CC=C1F)NC(OC(C)(C)C)=O)=O ASCDRQUDNVECBP-JKSUJKDBSA-N 0.000 description 2
- QOPLUTOSYJZVMP-GGAORHGYSA-N CCOC([C@H](CC(C)C)NC([C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(OC(C)(C)C)=O)=O)=O QOPLUTOSYJZVMP-GGAORHGYSA-N 0.000 description 2
- BQTAHTIHCHNYHX-WMZOPIPTSA-N CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC2=CC([N+]([O-])=O)=CN=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC2=CC([N+]([O-])=O)=CN=C2N1C)NC(OC(C)(C)C)=O)=O)=O BQTAHTIHCHNYHX-WMZOPIPTSA-N 0.000 description 2
- RTCWAFKIMOITNX-UNMCSNQZSA-N CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O Chemical compound CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O)=O RTCWAFKIMOITNX-UNMCSNQZSA-N 0.000 description 2
- LWTSQEPMCSLDIZ-ZDUSSCGKSA-N CCOC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CCOC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O LWTSQEPMCSLDIZ-ZDUSSCGKSA-N 0.000 description 2
- NTWZZGGFHSHSCQ-AWEZNQCLSA-N CCOC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CCOC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O NTWZZGGFHSHSCQ-AWEZNQCLSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 108010019670 Chimeric Antigen Receptors Proteins 0.000 description 2
- ROHFNLRQFUQHCH-RXMQYKEDSA-N D-leucine Chemical compound CC(C)C[C@@H](N)C(O)=O ROHFNLRQFUQHCH-RXMQYKEDSA-N 0.000 description 2
- 229930182819 D-leucine Natural products 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- 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 2
- 108090000371 Esterases Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 102000004157 Hydrolases Human genes 0.000 description 2
- 108090000604 Hydrolases Proteins 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- 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 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 239000012979 RPMI medium Substances 0.000 description 2
- MMEXLQDBXCXJEL-UHFFFAOYSA-N S=S=S.[Na+] Chemical compound S=S=S.[Na+] MMEXLQDBXCXJEL-UHFFFAOYSA-N 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 206010042971 T-cell lymphoma Diseases 0.000 description 2
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 2
- UYJXRRSPUVSSMN-UHFFFAOYSA-P ammonium sulfide Chemical compound [NH4+].[NH4+].[S-2] UYJXRRSPUVSSMN-UHFFFAOYSA-P 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 210000000601 blood cell Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 2
- 229960001076 chlorpromazine Drugs 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- QIGLJVBIRIXQRN-ZETCQYMHSA-N ethyl (2s)-2-amino-4-methylpentanoate Chemical compound CCOC(=O)[C@@H](N)CC(C)C QIGLJVBIRIXQRN-ZETCQYMHSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- FGKJLKRYENPLQH-UHFFFAOYSA-N isocaproic acid Chemical compound CC(C)CCC(O)=O FGKJLKRYENPLQH-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- WIAVVDGWLCNNGT-UHFFFAOYSA-M lithium;butanoate Chemical compound [Li+].CCCC([O-])=O WIAVVDGWLCNNGT-UHFFFAOYSA-M 0.000 description 2
- 238000007477 logistic regression Methods 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 229940099690 malic acid Drugs 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000002503 metabolic effect Effects 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
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 201000005962 mycosis fungoides Diseases 0.000 description 2
- 201000000050 myeloid neoplasm Diseases 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- YWRUAYGJVVNKFK-UHFFFAOYSA-N n-methyl-3,5-dinitropyridin-2-amine Chemical compound CNC1=NC=C([N+]([O-])=O)C=C1[N+]([O-])=O YWRUAYGJVVNKFK-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000011593 sulfur Chemical group 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 210000003171 tumor-infiltrating lymphocyte Anatomy 0.000 description 2
- AQTUACKQXJNHFQ-ZCFIWIBFSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanedioic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)CCC(O)=O AQTUACKQXJNHFQ-ZCFIWIBFSA-N 0.000 description 1
- RCXSXRAUMLKRRL-NSHDSACASA-N (2s)-3-(4-fluorophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(F)C=C1 RCXSXRAUMLKRRL-NSHDSACASA-N 0.000 description 1
- CVZUKWBYQQYBTF-ZDUSSCGKSA-N (4s)-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxo-5-phenylmethoxypentanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CCC(O)=O)C(=O)OCC1=CC=CC=C1 CVZUKWBYQQYBTF-ZDUSSCGKSA-N 0.000 description 1
- ZAYAFKXUQMTLPL-ZETCQYMHSA-N (4s)-5-methoxy-4-[(2-methylpropan-2-yl)oxycarbonylamino]-5-oxopentanoic acid Chemical compound OC(=O)CC[C@@H](C(=O)OC)NC(=O)OC(C)(C)C ZAYAFKXUQMTLPL-ZETCQYMHSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- RHTVQEPJVKUMPI-UHFFFAOYSA-N 2,4-dinitro-n-phenylaniline Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC=C1NC1=CC=CC=C1 RHTVQEPJVKUMPI-UHFFFAOYSA-N 0.000 description 1
- ZOAMZFNAPHWBEN-UHFFFAOYSA-N 2-$l^{1}-oxidanylpropane Chemical compound CC(C)[O] ZOAMZFNAPHWBEN-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- ZSDQQJHSRVEGTJ-UHFFFAOYSA-N 2-(6-amino-1h-indol-3-yl)acetonitrile Chemical compound NC1=CC=C2C(CC#N)=CNC2=C1 ZSDQQJHSRVEGTJ-UHFFFAOYSA-N 0.000 description 1
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- QLHVJBXAQWPEDI-UHFFFAOYSA-N 2-chloro-3,5-dinitropyridine Chemical compound [O-][N+](=O)C1=CN=C(Cl)C([N+]([O-])=O)=C1 QLHVJBXAQWPEDI-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- SKMJUJOLGJLTOJ-UHFFFAOYSA-N 2-n-methyl-5-nitropyridine-2,3-diamine Chemical compound CNC1=NC=C([N+]([O-])=O)C=C1N SKMJUJOLGJLTOJ-UHFFFAOYSA-N 0.000 description 1
- HCGFUIQPSOCUHI-UHFFFAOYSA-N 2-propan-2-yloxyethanol Chemical compound CC(C)OCCO HCGFUIQPSOCUHI-UHFFFAOYSA-N 0.000 description 1
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- GREMYELDEKAPAQ-UHFFFAOYSA-N 3,3-dibutylheptan-1-amine Chemical group C(CCC)C(CCN)(CCCC)CCCC GREMYELDEKAPAQ-UHFFFAOYSA-N 0.000 description 1
- CZZPSVORNFBYEX-UHFFFAOYSA-N 3,3-diethylpentan-1-amine Chemical group CCC(CC)(CC)CCN CZZPSVORNFBYEX-UHFFFAOYSA-N 0.000 description 1
- VMZXTHCNVOQXRZ-UHFFFAOYSA-N 3,4-dioxohexanedioic acid Chemical compound OC(=O)CC(=O)C(=O)CC(O)=O VMZXTHCNVOQXRZ-UHFFFAOYSA-N 0.000 description 1
- PYSGFFTXMUWEOT-UHFFFAOYSA-N 3-(dimethylamino)propan-1-ol Chemical compound CN(C)CCCO PYSGFFTXMUWEOT-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- WVKOPZMDOFGFAK-UHFFFAOYSA-N 4-hydroperoxycyclophosphamide Chemical compound OOC1=NP(O)(N(CCCl)CCCl)OCC1 WVKOPZMDOFGFAK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000002008 AIDS-Related Lymphoma Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 125000006847 BOC protecting group Chemical group 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- BGHWJPYTAMSOQL-ZDUSSCGKSA-N CC(C)(C)OC(N[C@@H](CCC(NC(C=C(C=C1)[N+]([O-])=O)=C1NC)=O)C(OC)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCC(NC(C=C(C=C1)[N+]([O-])=O)=C1NC)=O)C(OC)=O)=O BGHWJPYTAMSOQL-ZDUSSCGKSA-N 0.000 description 1
- JHGCOSWZHDEGQP-SFHVURJKSA-N CC(C)(C)OC(N[C@@H](CCC(NC(C=C(C=C1)[N+]([O-])=O)=C1NC1=CC=CC=C1)=O)C(OC)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCC(NC(C=C(C=C1)[N+]([O-])=O)=C1NC1=CC=CC=C1)=O)C(OC)=O)=O JHGCOSWZHDEGQP-SFHVURJKSA-N 0.000 description 1
- QGTPZZQOQLASTF-DEOSSOPVSA-N CC(C)(C)OC(N[C@@H](CCC(NC(C=C(C=C1)[N+]([O-])=O)=C1NC1=CC=CC=C1)=O)C(OCC1=CC=CC=C1)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCC(NC(C=C(C=C1)[N+]([O-])=O)=C1NC1=CC=CC=C1)=O)C(OCC1=CC=CC=C1)=O)=O QGTPZZQOQLASTF-DEOSSOPVSA-N 0.000 description 1
- FKTZMZCGDOOCNL-HNNXBMFYSA-N CC(C)(C)OC(N[C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)C(O)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)C(O)=O)=O FKTZMZCGDOOCNL-HNNXBMFYSA-N 0.000 description 1
- IOVSFEGYKWDDJM-NRFANRHFSA-N CC(C)(C)OC(N[C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C1=CC=CC=C1)C(OC)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C1=CC=CC=C1)C(OC)=O)=O IOVSFEGYKWDDJM-NRFANRHFSA-N 0.000 description 1
- GHANLFULNUTPDR-NSHDSACASA-N CC(C)(C)OC(N[C@@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)C(O)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)C(O)=O)=O GHANLFULNUTPDR-NSHDSACASA-N 0.000 description 1
- IDUXWJZOVPJZEC-KRWDZBQOSA-N CC(C)(C)OC(N[C@@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C1=CC=CC=C1)C(OC)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C1=CC=CC=C1)C(OC)=O)=O IDUXWJZOVPJZEC-KRWDZBQOSA-N 0.000 description 1
- FKTZMZCGDOOCNL-OAHLLOKOSA-N CC(C)(C)OC(N[C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)C(O)=O)=O Chemical compound CC(C)(C)OC(N[C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)C(O)=O)=O FKTZMZCGDOOCNL-OAHLLOKOSA-N 0.000 description 1
- WYMNSBNTKVYDJG-ICSRJNTNSA-N CC(C)C[C@@H](C(N(C)C)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O Chemical compound CC(C)C[C@@H](C(N(C)C)=O)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)N)=O WYMNSBNTKVYDJG-ICSRJNTNSA-N 0.000 description 1
- YAKQWETVFNQNPY-IRXDYDNUSA-N CC(C)C[C@@H](C(N[C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)C(O)=O)=O)N Chemical compound CC(C)C[C@@H](C(N[C@@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)C(O)=O)=O)N YAKQWETVFNQNPY-IRXDYDNUSA-N 0.000 description 1
- OJVWNOUTBWUTLL-PKOBYXMFSA-N CCOC([C@@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N)=C2N1C)NC(OC(C)(C)C)=O)=O)=O OJVWNOUTBWUTLL-PKOBYXMFSA-N 0.000 description 1
- GCXJUUGIUMSWCB-PKOBYXMFSA-N CCOC([C@@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O GCXJUUGIUMSWCB-PKOBYXMFSA-N 0.000 description 1
- DLTRWGPRAAFVRU-LPHOPBHVSA-N CCOC([C@H](C(C)C)NC([C@H](CC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](C(C)C)NC([C@H](CC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O DLTRWGPRAAFVRU-LPHOPBHVSA-N 0.000 description 1
- RJFDJTDNFBGAKN-JXFKEZNVSA-N CCOC([C@H](C(C)C)NC([C@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](C(C)C)NC([C@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O RJFDJTDNFBGAKN-JXFKEZNVSA-N 0.000 description 1
- FKKCAYUWBWVILD-VXKWHMMOSA-N CCOC([C@H](CC(C)C)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(OC(C)(C)C)=O)=O)=O FKKCAYUWBWVILD-VXKWHMMOSA-N 0.000 description 1
- KIVILAXMPLIXMX-ROUUACIJSA-N CCOC([C@H](CC(C)C)NC([C@H](CC1=NC(C=C(C=C2)N)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CC1=NC(C=C(C=C2)N)=C2N1C)NC(OC(C)(C)C)=O)=O)=O KIVILAXMPLIXMX-ROUUACIJSA-N 0.000 description 1
- LFQVLDKDVGWTPX-ROUUACIJSA-N CCOC([C@H](CC(C)C)NC([C@H](CC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O LFQVLDKDVGWTPX-ROUUACIJSA-N 0.000 description 1
- QOPLUTOSYJZVMP-GMAHTHKFSA-N CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(OC(C)(C)C)=O)=O)=O QOPLUTOSYJZVMP-GMAHTHKFSA-N 0.000 description 1
- GDFJYONWNPYDNB-UPVQGACJSA-N CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N)=C2N1C1=CC=CC=C1)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)N)=C2N1C1=CC=CC=C1)NC(OC(C)(C)C)=O)=O)=O GDFJYONWNPYDNB-UPVQGACJSA-N 0.000 description 1
- GCXJUUGIUMSWCB-HKUYNNGSSA-N CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O GCXJUUGIUMSWCB-HKUYNNGSSA-N 0.000 description 1
- VJOODFZYPZPBPQ-WMZOPIPTSA-N CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC2=CC(N)=CN=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C)C)NC([C@H](CCC1=NC2=CC(N)=CN=C2N1C)NC(OC(C)(C)C)=O)=O)=O VJOODFZYPZPBPQ-WMZOPIPTSA-N 0.000 description 1
- NKCJRBZEHYZFKG-ZEQRLZLVSA-N CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(C)=O)=O)=O Chemical compound CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(C)=O)=O)=O NKCJRBZEHYZFKG-ZEQRLZLVSA-N 0.000 description 1
- ZEQXRWXVULADHM-SFTDATJTSA-N CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O ZEQXRWXVULADHM-SFTDATJTSA-N 0.000 description 1
- NHUJFWHWHNFCOY-ZCYQVOJMSA-N CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(C)=O)=O)=O Chemical compound CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(C)=O)=O)=O NHUJFWHWHNFCOY-ZCYQVOJMSA-N 0.000 description 1
- ZPHDYWVINMHKPO-AHWVRZQESA-N CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC(OC(C)(C)C)=O)=O)=O ZPHDYWVINMHKPO-AHWVRZQESA-N 0.000 description 1
- TUDFYOOSPUPDLK-UNMCSNQZSA-N CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O Chemical compound CCOC([C@H](CC(C=C1)=CC=C1F)NC([C@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O)=O TUDFYOOSPUPDLK-UNMCSNQZSA-N 0.000 description 1
- YWUCOHVXLMHKOP-UNMCSNQZSA-N CCOC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC([C@H](CC(C=C1)=CC=C1F)N)=O)=O Chemical compound CCOC([C@H](CC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC([C@H](CC(C=C1)=CC=C1F)N)=O)=O YWUCOHVXLMHKOP-UNMCSNQZSA-N 0.000 description 1
- XVTCCGQJLOJCIO-IBGZPJMESA-N CCOC([C@H](CC1=NC(C=C(C=C2)N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=C2N1C)NC(OC(C)(C)C)=O)=O Chemical compound CCOC([C@H](CC1=NC(C=C(C=C2)N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=C2N1C)NC(OC(C)(C)C)=O)=O XVTCCGQJLOJCIO-IBGZPJMESA-N 0.000 description 1
- RQKLWBRFBSLHJM-VIFPVBQESA-N CCOC([C@H](CC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)N)=O Chemical compound CCOC([C@H](CC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)N)=O RQKLWBRFBSLHJM-VIFPVBQESA-N 0.000 description 1
- KVOHYIHAMBXPDP-ZDUSSCGKSA-N CCOC([C@H](CC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O Chemical compound CCOC([C@H](CC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C)NC(OC(C)(C)C)=O)=O KVOHYIHAMBXPDP-ZDUSSCGKSA-N 0.000 description 1
- PXXQOWKPNKESEX-VXKWHMMOSA-N CCOC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC([C@H](CC(C=C1)=CC=C1F)N)=O)=O Chemical compound CCOC([C@H](CCC1=NC(C=C(C=C2)N(CCCl)CCCl)=C2N1C)NC([C@H](CC(C=C1)=CC=C1F)N)=O)=O PXXQOWKPNKESEX-VXKWHMMOSA-N 0.000 description 1
- 108010049990 CD13 Antigens Proteins 0.000 description 1
- SVFHSKUDYTUIKP-MRVPVSSYSA-N CN1C(C=CC([N+]([O-])=O)=C2)=C2N=C1CC[C@H](C(O)=O)N Chemical compound CN1C(C=CC([N+]([O-])=O)=C2)=C2N=C1CC[C@H](C(O)=O)N SVFHSKUDYTUIKP-MRVPVSSYSA-N 0.000 description 1
- JYKLDYXWRXXVSY-AWEZNQCLSA-N COC([C@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C1=CC=CC=C1)N)=O Chemical compound COC([C@H](CCC1=NC(C=C(C=C2)[N+]([O-])=O)=C2N1C1=CC=CC=C1)N)=O JYKLDYXWRXXVSY-AWEZNQCLSA-N 0.000 description 1
- 239000012275 CTLA-4 inhibitor Substances 0.000 description 1
- 229940045513 CTLA4 antagonist Drugs 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- MPONAPFARZGDTH-UHFFFAOYSA-N Cl.OS(O)=O Chemical compound Cl.OS(O)=O MPONAPFARZGDTH-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-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
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- VYZAHLCBVHPDDF-UHFFFAOYSA-N Dinitrochlorobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 VYZAHLCBVHPDDF-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 101000757160 Homo sapiens Aminopeptidase N Proteins 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 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
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 229910013596 LiOH—H2O Inorganic materials 0.000 description 1
- 206010025312 Lymphoma AIDS related Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
- MDXGYYOJGPFFJL-QMMMGPOBSA-N N(alpha)-t-butoxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OC(C)(C)C MDXGYYOJGPFFJL-QMMMGPOBSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000012269 PD-1/PD-L1 inhibitor Substances 0.000 description 1
- VONGZNXBKCOUHB-UHFFFAOYSA-N Phenylmethyl butanoate Chemical group CCCC(=O)OCC1=CC=CC=C1 VONGZNXBKCOUHB-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010036711 Primary mediastinal large B-cell lymphomas Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 208000009359 Sezary Syndrome Diseases 0.000 description 1
- 208000021388 Sezary disease Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors 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
- 238000012288 TUNEL assay Methods 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical class O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- NOUDPBCEONUCOV-FJXQXJEOSA-N [(2s)-1-ethoxy-4-methyl-1-oxopentan-2-yl]azanium;chloride Chemical compound Cl.CCOC(=O)[C@@H](N)CC(C)C NOUDPBCEONUCOV-FJXQXJEOSA-N 0.000 description 1
- VKJXWUJEFIQCNF-UGTAFXKHSA-N [2H]C([2H])(C([2H])([2H])Cl)N(C([2H])([2H])C([2H])([2H])Cl)C(C=C1)=CC2=C1N(C)C(CC[C@@H](C(O)=O)N)=N2 Chemical compound [2H]C([2H])(C([2H])([2H])Cl)N(C([2H])([2H])C([2H])([2H])Cl)C(C=C1)=CC2=C1N(C)C(CC[C@@H](C(O)=O)N)=N2 VKJXWUJEFIQCNF-UGTAFXKHSA-N 0.000 description 1
- VIIMMOROKRYFHF-ZFDGGRCRSA-N [2H]C([2H])(C([2H])([2H])OS(C)(=O)=O)N(C([2H])([2H])C([2H])([2H])OS(C)(=O)=O)C(C=C1)=CC2=C1N(C)C(CC[C@@H](C(OC)=O)NC(OC(C)(C)C)=O)=N2 Chemical compound [2H]C([2H])(C([2H])([2H])OS(C)(=O)=O)N(C([2H])([2H])C([2H])([2H])OS(C)(=O)=O)C(C=C1)=CC2=C1N(C)C(CC[C@@H](C(OC)=O)NC(OC(C)(C)C)=O)=N2 VIIMMOROKRYFHF-ZFDGGRCRSA-N 0.000 description 1
- BLQCQNFLEGAHPA-RRKCRQDMSA-N [[(2r,3s,5r)-5-(5-bromo-2,4-dioxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O1[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C(Br)=C1 BLQCQNFLEGAHPA-RRKCRQDMSA-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
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000014619 adult acute lymphoblastic leukemia Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000011543 agarose gel Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 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
- 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 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 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 description 1
- 239000011449 brick Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 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 description 1
- 229960002438 carfilzomib Drugs 0.000 description 1
- 108010021331 carfilzomib Proteins 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 208000018805 childhood acute lymphoblastic leukemia Diseases 0.000 description 1
- 201000011633 childhood acute lymphocytic leukemia Diseases 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 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 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- PQZTVWVYCLIIJY-UHFFFAOYSA-N diethyl(propyl)amine Chemical group CCCN(CC)CC PQZTVWVYCLIIJY-UHFFFAOYSA-N 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 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
- 238000006073 displacement reaction Methods 0.000 description 1
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 230000001909 effect on DNA Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- NOUDPBCEONUCOV-OGFXRTJISA-N ethyl (2r)-2-amino-4-methylpentanoate;hydrochloride Chemical compound Cl.CCOC(=O)[C@H](N)CC(C)C NOUDPBCEONUCOV-OGFXRTJISA-N 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000004175 fluorobenzyl group Chemical group 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 239000000138 intercalating agent Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- MXAYKZJJDUDWDS-LBPRGKRZSA-N ixazomib Chemical compound CC(C)C[C@@H](B(O)O)NC(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl MXAYKZJJDUDWDS-LBPRGKRZSA-N 0.000 description 1
- 229960003648 ixazomib Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- AXMOZGKEVIBBCF-UHFFFAOYSA-M lithium;propanoate Chemical compound [Li+].CCC([O-])=O AXMOZGKEVIBBCF-UHFFFAOYSA-M 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000031852 maintenance of location in cell Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229950002736 marizomib Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical group ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- QVDXUKJJGUSGLS-ZCFIWIBFSA-N methyl (2r)-2-amino-4-methylpentanoate Chemical compound COC(=O)[C@H](N)CC(C)C QVDXUKJJGUSGLS-ZCFIWIBFSA-N 0.000 description 1
- RFNZPQBRSIZDHQ-UHFFFAOYSA-N methyl 2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound COC(=O)C(CC)NC(=O)OC(C)(C)C RFNZPQBRSIZDHQ-UHFFFAOYSA-N 0.000 description 1
- QVDXUKJJGUSGLS-LURJTMIESA-N methyl L-leucinate Chemical compound COC(=O)[C@@H](N)CC(C)C QVDXUKJJGUSGLS-LURJTMIESA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- DLMICMXXVVMDNV-UHFFFAOYSA-N n,n-di(propan-2-yl)propan-1-amine Chemical group CCCN(C(C)C)C(C)C DLMICMXXVVMDNV-UHFFFAOYSA-N 0.000 description 1
- ZUHZZVMEUAUWHY-UHFFFAOYSA-N n,n-dimethylpropan-1-amine Chemical group CCCN(C)C ZUHZZVMEUAUWHY-UHFFFAOYSA-N 0.000 description 1
- XCVNDBIXFPGMIW-UHFFFAOYSA-N n-ethylpropan-1-amine Chemical compound CCCNCC XCVNDBIXFPGMIW-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- HNBDRPTVWVGKBR-UHFFFAOYSA-N n-pentanoic acid methyl ester Natural products CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 1
- CWYZDPHNAGSFQB-UHFFFAOYSA-N n-propylbutan-1-amine Chemical group CCCCNCCC CWYZDPHNAGSFQB-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- LBZIZUJIQNHKKB-UHFFFAOYSA-N oxadiazole;1,3-thiazole Chemical compound C1=CON=N1.C1=CSC=N1 LBZIZUJIQNHKKB-UHFFFAOYSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical class C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 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 description 1
- 229960005184 panobinostat Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229940121653 pd-1/pd-l1 inhibitor Drugs 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
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 108010086662 phytohemagglutinin-M Proteins 0.000 description 1
- 208000031223 plasma cell leukemia Diseases 0.000 description 1
- 208000010626 plasma cell neoplasm Diseases 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229960000688 pomalidomide Drugs 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
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000001556 precipitation Methods 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
- 230000035935 pregnancy Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004889 salicylic acid 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
- 238000005070 sampling Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 229950010613 selinexor Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 1
- 229960001183 venetoclax Drugs 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 239000006226 wash reagent Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- 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
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/008—Peptides; Proteins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06043—Leu-amino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06052—Val-amino acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB2108818.2A GB202108818D0 (en) | 2021-06-18 | 2021-06-18 | Compounds |
| GB2108818.2 | 2021-06-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW202317521A true TW202317521A (zh) | 2023-05-01 |
Family
ID=77050583
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW111122847A TW202317521A (zh) | 2021-06-18 | 2022-06-20 | 化合物 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US20240316059A1 (https=) |
| EP (1) | EP4355370A1 (https=) |
| JP (1) | JP2024523411A (https=) |
| KR (1) | KR20240047965A (https=) |
| CN (1) | CN117794580A (https=) |
| AR (1) | AR126191A1 (https=) |
| AU (1) | AU2022294069A1 (https=) |
| BR (1) | BR112023026452A2 (https=) |
| CA (1) | CA3221513A1 (https=) |
| GB (1) | GB202108818D0 (https=) |
| IL (1) | IL309360A (https=) |
| MX (1) | MX2023015149A (https=) |
| TW (1) | TW202317521A (https=) |
| WO (1) | WO2022263679A1 (https=) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB202218493D0 (en) | 2022-12-08 | 2023-01-25 | Oncopeptides Ab | Novel therapeutic combinations |
| WO2024121349A1 (en) | 2022-12-08 | 2024-06-13 | Oncopeptides Ab | Therapeutic treatment for haematological cancer based on the level of t-cell function |
| GB202219097D0 (en) | 2022-12-16 | 2023-02-01 | Oncopeptides Ab | Pharmaceutical preparations |
| WO2026057823A1 (en) | 2024-09-13 | 2026-03-19 | Oncopeptides Ab | Bis-chloroethylamino derivatives for treating leukemia |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1374907A3 (en) * | 2002-06-24 | 2004-01-07 | Ghanem Elias c/o Institut Jules Bordet Ghanem | Drug transport and delivery system |
-
2021
- 2021-06-18 GB GBGB2108818.2A patent/GB202108818D0/en not_active Ceased
-
2022
- 2022-06-20 EP EP22735845.4A patent/EP4355370A1/en active Pending
- 2022-06-20 US US18/570,814 patent/US20240316059A1/en active Pending
- 2022-06-20 CA CA3221513A patent/CA3221513A1/en active Pending
- 2022-06-20 AU AU2022294069A patent/AU2022294069A1/en active Pending
- 2022-06-20 CN CN202280055577.5A patent/CN117794580A/zh active Pending
- 2022-06-20 MX MX2023015149A patent/MX2023015149A/es unknown
- 2022-06-20 KR KR1020247001733A patent/KR20240047965A/ko active Pending
- 2022-06-20 IL IL309360A patent/IL309360A/en unknown
- 2022-06-20 JP JP2023577977A patent/JP2024523411A/ja active Pending
- 2022-06-20 TW TW111122847A patent/TW202317521A/zh unknown
- 2022-06-20 WO PCT/EP2022/066756 patent/WO2022263679A1/en not_active Ceased
- 2022-06-20 BR BR112023026452A patent/BR112023026452A2/pt unknown
- 2022-06-21 AR ARP220101620A patent/AR126191A1/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB202108818D0 (en) | 2021-08-04 |
| AR126191A1 (es) | 2023-09-27 |
| JP2024523411A (ja) | 2024-06-28 |
| IL309360A (en) | 2024-02-01 |
| MX2023015149A (es) | 2024-04-01 |
| BR112023026452A2 (pt) | 2024-03-05 |
| CN117794580A (zh) | 2024-03-29 |
| US20240316059A1 (en) | 2024-09-26 |
| WO2022263679A1 (en) | 2022-12-22 |
| AU2022294069A1 (en) | 2024-01-25 |
| CA3221513A1 (en) | 2022-12-22 |
| KR20240047965A (ko) | 2024-04-12 |
| EP4355370A1 (en) | 2024-04-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11667673B2 (en) | Therapeutically active compounds and their methods of use | |
| JP6228130B2 (ja) | 治療活性化合物およびそれらの使用方法 | |
| TW202317521A (zh) | 化合物 | |
| US20190023737A1 (en) | Therapeutically active compounds and their methods of use | |
| EA050420B1 (ru) | Конъюгаты пептидов с лекарственными средствами | |
| HK1198439B (en) | Lactam derivates useful as inhibitors of mutant idh1 |