CN114230561A - 一种mdm2抑制剂类小分子化合物及用途 - Google Patents
一种mdm2抑制剂类小分子化合物及用途 Download PDFInfo
- Publication number
- CN114230561A CN114230561A CN202010939885.7A CN202010939885A CN114230561A CN 114230561 A CN114230561 A CN 114230561A CN 202010939885 A CN202010939885 A CN 202010939885A CN 114230561 A CN114230561 A CN 114230561A
- Authority
- CN
- China
- Prior art keywords
- small molecule
- derivatives
- mdm2 inhibitor
- mdm2
- inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 46
- 229940083338 MDM2 inhibitor Drugs 0.000 title claims abstract description 20
- 239000012819 MDM2-Inhibitor Substances 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 26
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 16
- 239000003112 inhibitor Substances 0.000 claims abstract description 11
- 150000003384 small molecules Chemical class 0.000 claims abstract description 8
- -1 small molecule compound Chemical class 0.000 claims description 24
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 claims description 19
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 claims description 19
- 229930012538 Paclitaxel Natural products 0.000 claims description 10
- 150000005624 indolones Chemical class 0.000 claims description 10
- 229960001592 paclitaxel Drugs 0.000 claims description 10
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 10
- QEEBRPGZBVVINN-UHFFFAOYSA-N Desacetyl-bufotalin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C1(O)CCC2C=1C=CC(=O)OC=1 QEEBRPGZBVVINN-UHFFFAOYSA-N 0.000 claims description 8
- 230000000259 anti-tumor effect Effects 0.000 claims description 8
- QEEBRPGZBVVINN-BMPKRDENSA-N bufalin Chemical compound C=1([C@H]2CC[C@]3(O)[C@H]4[C@@H]([C@]5(CC[C@H](O)C[C@H]5CC4)C)CC[C@@]32C)C=CC(=O)OC=1 QEEBRPGZBVVINN-BMPKRDENSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 6
- 229940127093 camptothecin Drugs 0.000 claims description 6
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 6
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 6
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical class C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 claims description 6
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 claims description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 4
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 4
- 229930192392 Mitomycin Natural products 0.000 claims description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 4
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 4
- 229960000975 daunorubicin Drugs 0.000 claims description 4
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 4
- 229930188854 dolastatin Natural products 0.000 claims description 4
- 229930013356 epothilone Natural products 0.000 claims description 4
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 claims description 4
- ANZJBCHSOXCCRQ-FKUXLPTCSA-N mertansine Chemical compound CO[C@@H]([C@@]1(O)C[C@H](OC(=O)N1)[C@@H](C)[C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(=O)CCS)CC(=O)N1C)\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 ANZJBCHSOXCCRQ-FKUXLPTCSA-N 0.000 claims description 4
- 229960003048 vinblastine Drugs 0.000 claims description 4
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 4
- 208000012902 Nervous system disease Diseases 0.000 claims description 3
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 claims description 3
- 229960004679 doxorubicin Drugs 0.000 claims description 3
- 229960000235 temsirolimus Drugs 0.000 claims description 3
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- MFRNYXJJRJQHNW-DEMKXPNLSA-N (2s)-2-[[(2r,3r)-3-methoxy-3-[(2s)-1-[(3r,4s,5s)-3-methoxy-5-methyl-4-[methyl-[(2s)-3-methyl-2-[[(2s)-3-methyl-2-(methylamino)butanoyl]amino]butanoyl]amino]heptanoyl]pyrrolidin-2-yl]-2-methylpropanoyl]amino]-3-phenylpropanoic acid Chemical class CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 MFRNYXJJRJQHNW-DEMKXPNLSA-N 0.000 claims description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 2
- 108010006654 Bleomycin Proteins 0.000 claims description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 2
- 229930186147 Cephalosporin Natural products 0.000 claims description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 2
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- 229930182555 Penicillin Natural products 0.000 claims description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 2
- 108010059993 Vancomycin Proteins 0.000 claims description 2
- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims description 2
- 229960004150 aciclovir Drugs 0.000 claims description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229960003805 amantadine Drugs 0.000 claims description 2
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 2
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 2
- 229940045985 antineoplastic platinum compound Drugs 0.000 claims description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 2
- 229960001561 bleomycin Drugs 0.000 claims description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 2
- 229960002092 busulfan Drugs 0.000 claims description 2
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical class C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 claims description 2
- 229960004562 carboplatin Drugs 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 230000003915 cell function Effects 0.000 claims description 2
- 229940124587 cephalosporin Drugs 0.000 claims description 2
- 150000001780 cephalosporins Chemical class 0.000 claims description 2
- 229960005091 chloramphenicol Drugs 0.000 claims description 2
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 claims description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 2
- 229960004316 cisplatin Drugs 0.000 claims description 2
- 229960002227 clindamycin Drugs 0.000 claims description 2
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 claims description 2
- 229960001338 colchicine Drugs 0.000 claims description 2
- 150000004814 combretastatins Chemical class 0.000 claims description 2
- 229960004397 cyclophosphamide Drugs 0.000 claims description 2
- 229960000684 cytarabine Drugs 0.000 claims description 2
- PPRGGNQLPSVURC-ZVTSDNJWSA-N deacetylvinblastine hydrazide Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)NN)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 PPRGGNQLPSVURC-ZVTSDNJWSA-N 0.000 claims description 2
- 229960001904 epirubicin Drugs 0.000 claims description 2
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 claims description 2
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 claims description 2
- 229960003276 erythromycin Drugs 0.000 claims description 2
- 229960002963 ganciclovir Drugs 0.000 claims description 2
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 claims description 2
- 229960005277 gemcitabine Drugs 0.000 claims description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 2
- 229960004768 irinotecan Drugs 0.000 claims description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 2
- 229960004961 mechlorethamine Drugs 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 231100000782 microtubule inhibitor Toxicity 0.000 claims description 2
- 229960004857 mitomycin Drugs 0.000 claims description 2
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 claims description 2
- 150000003058 platinum compounds Chemical class 0.000 claims description 2
- 150000003212 purines Chemical class 0.000 claims description 2
- 150000003230 pyrimidines Chemical class 0.000 claims description 2
- 229960000329 ribavirin Drugs 0.000 claims description 2
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 2
- 229960001225 rifampicin Drugs 0.000 claims description 2
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 2
- 229960003962 trifluridine Drugs 0.000 claims description 2
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 claims description 2
- 229960003165 vancomycin Drugs 0.000 claims description 2
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 2
- 229960004528 vincristine Drugs 0.000 claims description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 2
- 229960002555 zidovudine Drugs 0.000 claims description 2
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims description 2
- 208000025966 Neurological disease Diseases 0.000 claims 1
- 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 claims 1
- 229940045686 antimetabolites antineoplastic purine analogs Drugs 0.000 claims 1
- 229940045688 antineoplastic antimetabolites pyrimidine analogues Drugs 0.000 claims 1
- 229930195731 calicheamicin Natural products 0.000 claims 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims 1
- 229960001924 melphalan Drugs 0.000 claims 1
- 229940049954 penicillin Drugs 0.000 claims 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract description 10
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 6
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract description 3
- 206010028980 Neoplasm Diseases 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000002609 medium Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 206010009944 Colon cancer Diseases 0.000 description 5
- 239000006180 TBST buffer Substances 0.000 description 5
- 239000011543 agarose gel Substances 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 208000029742 colonic neoplasm Diseases 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000003384 imaging method Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 229910020257 Cl2F2 Inorganic materials 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108010087230 Sincalide Proteins 0.000 description 3
- 239000004599 antimicrobial Substances 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 229940044683 chemotherapy drug Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000000539 dimer Substances 0.000 description 3
- 238000001962 electrophoresis Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 201000008968 osteosarcoma Diseases 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DLKUYSQUHXBYPB-NSSHGSRYSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[3-methylbutanoyloxymethyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-(4-methylphenyl)pentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C DLKUYSQUHXBYPB-NSSHGSRYSA-N 0.000 description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 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
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 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
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 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
- 244000309466 calf Species 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 2
- 229960005542 ethidium bromide Drugs 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 230000005917 in vivo anti-tumor Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 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
- 239000002674 ointment Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 210000001541 thymus gland Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- HDTHCLKLBSPBIS-JBXNKDOXSA-N (2s)-2-[[8-[[(3s,5r,8r,9s,10s,13r,14s,16s,17r)-16-acetyloxy-14-hydroxy-10,13-dimethyl-17-(6-oxopyran-3-yl)-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl]oxy]-8-oxooctanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C=1([C@@H]2[C@@]3(C)CC[C@@H]4[C@@]5(C)CC[C@@H](C[C@H]5CC[C@H]4[C@@]3(O)C[C@@H]2OC(=O)C)OC(=O)CCCCCCC(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C=CC(=O)OC=1 HDTHCLKLBSPBIS-JBXNKDOXSA-N 0.000 description 1
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 description 1
- FRWNAQDBODEVAL-VMPITWQZSA-N (5e)-5-[(4-nitrophenyl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one Chemical compound C1=CC([N+](=O)[O-])=CC=C1\C=C\1C(=O)NC(=S)S/1 FRWNAQDBODEVAL-VMPITWQZSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- QNMKGMUGYVWVFQ-UHFFFAOYSA-N 2alpha-Hydroxyursolic acid Natural products CC12CC(O)C(O)C(C)(C)C1CCC1(C)C2CC=C2C3C(C)C(C)(C)CCC3(C(O)=O)CCC21C QNMKGMUGYVWVFQ-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 description 1
- NBGQZFQREPIKMG-UHFFFAOYSA-N 3beta-hydroxy-beta-boswellic acid Natural products C1CC(O)C(C)(C(O)=O)C2CCC3(C)C4(C)CCC5(C)CCC(C)C(C)C5C4=CCC3C21C NBGQZFQREPIKMG-UHFFFAOYSA-N 0.000 description 1
- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-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
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 1
- NBGQZFQREPIKMG-PONOSELZSA-N Boswellic acid Chemical compound C1C[C@@H](O)[C@](C)(C(O)=O)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C NBGQZFQREPIKMG-PONOSELZSA-N 0.000 description 1
- HDTHCLKLBSPBIS-UHFFFAOYSA-N Bufotoxin Natural products CC(=O)OC1CC2(O)C3CCC4CC(OC(=O)CCCCCCC(=O)NC(CCCN=C(N)N)C(O)=O)CCC4(C)C3CCC2(C)C1C=1C=CC(=O)OC=1 HDTHCLKLBSPBIS-UHFFFAOYSA-N 0.000 description 1
- BQENDLAVTKRQMS-SBBGFIFASA-L Carbenoxolone sodium Chemical compound [Na+].[Na+].C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C([O-])=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](OC(=O)CCC([O-])=O)C1(C)C BQENDLAVTKRQMS-SBBGFIFASA-L 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- JKLISIRFYWXLQG-UHFFFAOYSA-N Epioleonolsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4CCC3C21C JKLISIRFYWXLQG-UHFFFAOYSA-N 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 description 1
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 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 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229940121357 antivirals Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 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
- 108010044540 auristatin Proteins 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000530 carbenoxolone Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- MDZKJHQSJHYOHJ-UHFFFAOYSA-N crataegolic acid Natural products C1C(O)C(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MDZKJHQSJHYOHJ-UHFFFAOYSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960003720 enoxolone Drugs 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- ZVYVPGLRVWUPMP-FYSMJZIKSA-N exatecan Chemical compound C1C[C@H](N)C2=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC3=CC(F)=C(C)C1=C32 ZVYVPGLRVWUPMP-FYSMJZIKSA-N 0.000 description 1
- 229950009429 exatecan Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- MDZKJHQSJHYOHJ-LLICELPBSA-N maslinic acid Chemical compound C1[C@@H](O)[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MDZKJHQSJHYOHJ-LLICELPBSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000009125 negative feedback regulation Effects 0.000 description 1
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229940100243 oleanolic acid Drugs 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940055695 pancreatin 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
- 150000002960 penicillins Chemical class 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 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 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 238000010809 targeting technique Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000003781 tooth socket Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229930184737 tubulysin Natural products 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 description 1
- 229940096998 ursolic acid Drugs 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K47/545—Heterocyclic compounds
-
- 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
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- 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
- A61K47/55—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
-
- 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
- A61K47/554—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 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- 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
- C07B2200/07—Optical isomers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Genetics & Genomics (AREA)
- Botany (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
技术领域
本发明属于医药技术领域,具体涉及一种MDM2抑制剂类小分子化合物及用途。
背景技术
恶性肿瘤已成为严重危害人类健康的重大疾病之一,尽管对于恶性肿瘤的治疗已发展出如手术治疗、放疗、化疗、免疫疗法等多种治疗方法,在临床也取得不错的效果。但恶性肿瘤的死亡率仍居高不下,仅次于心脑血管疾病,仍需研发新型的治疗方法和药物。化疗药物在恶性肿瘤的治疗历史起到非常重要的作用,在很多国家,化疗药物仍然在临床肿瘤治疗药物中占有较高比例,但其存在了很多缺点如抑制肿瘤细胞生长的同时,也使得正常细胞的增殖收到影响,产生严重的副作用。因此,发展新的技术如靶向技术等降低传统化疗药物的毒副作用显得尤为重要。
MDM2蛋白在多种肿瘤高表达,与肿瘤的发生和发展息息相关。MDM2蛋白与抑癌基因p53蛋白形成负反馈调节,阻断p53-MDM2相互作用可以上调p53水平,导致肿瘤细胞凋亡,从而实现对肿瘤的靶向治疗。p53蛋白与MDM2蛋白相互作用是近年来研究较多的抗肿瘤靶标,针对该靶标研发多个小分子药物进入临床研究。然而由于p53-MDM2蛋白相互作用的特殊性,使得小分子抑制剂的开发具有较大的困难,目前仍未有该靶标的上市药物。
发明内容
本发明的第一目的是提供一种MDM2抑制剂类小分子化合物。
本发明的第二目的是提供一种所述MDM2抑制剂类小分子化合物在制备抗肿瘤药物、抗炎药物中的应用。
为了实现上述目的,本发明采用的技术方案如下:
本发明的第一方面,提供了一种MDM2抑制剂类小分子化合物或其药用盐,结构如通式I所示:
X-Y
I
X为p53-MDM2小分子抑制剂;
Y为药物;
所述p53-MDM2小分子抑制剂选自:
所述Y为能够调节或改变细胞功能的分子,包括药物活性化合物,这些药物可通过活性基团如羟基、氨基等与X的羧基基团连接。所述药物活性化合物可为本领域已知药物或其衍生形式,所述药物为细胞毒性、提高肿瘤通透性、抑制肿瘤细胞增殖、促进细胞凋亡、降低细胞中抗凋亡活性、增强细胞坏死的药物。适用本发明的药物包括但不限于激素、抗生素、抗微生物药、抗病毒药、抗癌药。所述细胞毒性的药物例如:环丙基苯并[e]吲哚酮类似物或其衍生物、开环-环丙基苯并[e]吲哚酮类似物、O-Ac-开环-环丙基苯并[e]吲哚酮类似物或其衍生物、Dolastatins类、Auristatin类、Tubulysin类、Combretastatin类、美登素类、DM1、埃博霉素类、紫杉醇及其衍生物、长春碱及其类似物、喜树碱及其类似物、秋水仙碱及其类似物、Daunorubicin类、Rhizomycin类、环磷酰胺、甲氨喋呤、博来霉素类、Temsirolimus类、丝裂霉素类、微管抑制剂、吡咯并苯二氮杂卓(pyrrolobenzodiazepines,PBD)二聚体类、环丙基苯并[e]吲哚酮类、Calicheamicin类、沙蟾毒精及其衍生物、蟾毒灵及其衍生物。其他可适用于本发明的药物包括大环内酯类抗肿瘤药物,化疗药如烷化剂氮芥、亚硝基脲、白消安、苯丙酸氮芥、卡铂、顺铂和其他铂类化合物,抗代谢药如阿糖胞苷、嘌呤类似物、嘧啶类似物及青霉素、头孢菌素、万古霉素、红霉素、克林霉素、利福平、氯霉素、氨基糖苷类抗生素和阿昔洛韦、三氟尿苷、更昔洛韦、齐多夫定、金刚烷胺、利巴韦林、吉西他滨和任何本领域认可的抗微生物化合物。
进一步的,本发明所述Y为Temsirolimus类、开环-环丙基苯并[e]吲哚酮类似物、吡咯并苯二氮杂卓(pyrrolobenzodiazepines,PBD)二聚体类、Calicheamicin类、喜树碱及其类似物、紫杉醇及其衍生物、长春碱及其类似物、Dolastatins类、Auristatin类、Tubulysin类、Combretastatin类、美登素类、DM1、埃博霉素类、丝裂霉素类、Daunorubicin类化合物、沙蟾毒精及其衍生物或蟾毒灵及其衍生物。
更进一步的,本发明所述Y为开环-环丙基苯并[e]吲哚酮类似物、吡咯并苯二氮杂卓(pyrrolobenzodiazepines,PBD)二聚体类、Calicheamicin类、喜树碱、7-乙基-10-羟基喜树碱(SN-38)、依喜替康(Exatecan)及其衍生物、7-环己基-21-氟喜树碱、DAVLBH、Tubulysin B、MMAE、MMAF、MMAF衍生物、DM1、紫杉醇及其衍生物、埃博霉素B、丝裂霉素C、沙蟾毒精及其衍生物、蟾毒灵及其衍生物、长春新碱、柔红霉素、多柔比星或表柔比星。优选的,本发明所述Y选自以下结构中的一种:
最优选的,所述MDM2抑制剂类小分子化合物的结构选自以下结构的一种:
本发明的MDM2抑制剂类小分子化合物可按照常规方法制备为药用盐的形式。
本发明所述MDM2抑制剂类小分子化合物的药用盐,由药学上可接受的无机酸和有机酸所形成的盐,其中较优的无机酸包括:盐酸、氢溴酸、磷酸、硝酸、硫酸;较优的有机酸包括:甲酸、乙酸、丙酸、丁二酸、萘二磺酸(1,5)、亚细亚酸、甘珀酸、甘草次酸、齐墩果酸、山楂酸、熊果酸、科罗索酸、白桦酸、乳香酸、草酸、酒石酸、乳酸、水杨酸、苯甲酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、乙磺酸、对甲苯磺酸、柠檬酸、氨基酸。
本发明的第二方面提供了一种所述MDM2抑制剂类小分子化合物或其药用盐在制备抗肿瘤药物、抗炎药物(Rialdi A,et al,Science,2016,352,6289;Pan P,J Med Chem,2018,61,8613.)中的应用。
本发明化合物的药理活性使其可以用于制备抗肿瘤、治疗心血管疾病、抗炎及抗神经系统疾病的药物(Rialdi A,et al,Science,2016,352,6289;Pan P,J Med Chem,2018,61,8613.)。
本发明的MDM2抑制剂类小分子化合物具有抗肿瘤活性,所述肿瘤包括食道、胃、肠、直肠、口腔、咽、喉、肺、结肠、乳腺、子宫、子宫内膜、卵巢、前列腺、睾丸、膀胱、肾、肝、胰腺、骨、结缔组织、皮肤、眼、脑和中枢神经系统等部位发生的癌症,以及甲状腺癌、白血病、霍金氏病、淋巴瘤和骨髓瘤等;尤其是结肠癌、肺癌、乳腺癌、骨肉瘤。
本发明的第三方面提供了一种药物组合物,包括所述MDM2抑制剂类小分子化合物或其药用盐,所述MDM2抑制剂类小分子化合物或其药用盐作为药物活性成分;或所述药物组合物还包括至少一种治疗剂,如化学治疗剂、免疫检查点抑制剂、炎症调节剂、抗高胆固醇血症剂、抗感染剂或放疗药物等(Fang D.,et al.J Immunother Cancer,2019,7,327;YiH.et al.J Exp Clin Cancer Res,2018,37,97)。
所述药物组合物可以是固体形式或是液体形式,还可用于制备下列药物:心脑血管疾病、炎症和神经系统疾病的治疗药物等(Rialdi A,et al,Science,2016,352,6289;Pan P,J Med Chem,2018,61,8613.)。
本发明的第四方面提供了一种药物制剂,包括所述MDM2抑制剂类小分子化合物或其药用盐。
本发明所述MDM2抑制剂类小分子化合物可以和药剂学上的常规药用辅料制成药物制剂。
所述药物制剂为:小容量注射剂、中容量注射剂、大容量注射剂、粉针注射剂、注射用乳剂、片剂、丸剂、胶囊剂、膏剂、霜剂、贴剂、搽剂、粉剂、喷雾剂、植入剂、滴剂、栓剂、软膏剂;各类纳米制剂;脂质体;相应的脂质体主要地制成以上所提及的注射剂。
本发明的第五方面提供了一种所述MDM2抑制剂类小分子化合物或其药用盐作为MDM2抑制剂或Topo I抑制剂的用途。
由于采用上述技术方案,本发明具有以下优点和有益效果:
本发明的化合物不仅具有抗肿瘤活性,而且可作为p53-MDM2小分子抑制剂,从而起到双重抗肿瘤作用。
附图说明
图1是实施例2制备的化合物I-2的Topo I抑制活性测试结果示意图(200μM)。
图2是实施例2制备的化合物I-2对MDM2蛋白调节的蛋白免疫印迹试验结果示意图。
具体实施方式
为了更清楚地说明本发明,下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解,下面所具体描述的内容是说明性的而非限制性的,不应以此限制本发明的保护范围。
实施例1
化合物I-1的制备
将RG7388(20mg,平湖正远公司)、EDCI(19mg)和DMAP(4mg)加入到5mL单口瓶中,然后加入3mL干燥的二氯甲烷搅拌15mins后成澄清溶液。加入紫杉醇(56mg)室温反应过夜。蒸去溶剂后柱色谱分离得21mg白色固体I-1(二氯甲烷:甲醇=100:2),收率为41.7%。1H NMR(300MHz,DMSO-d6)δ:10.54(s,1H),9.30(d,J=9.5Hz,1H),8.40(d,J=8.5Hz,1H),7.95(d,J=7.3Hz,2H),7.85(d,J=7.1Hz,2H),7.78–7.64(m,3H),7.63–7.43(m,10H),7.38(dd,J=12.4,9.0Hz,3H),7.25(t,J=7.1Hz,1H),6.31(s,1H),5.84(dd,J=18.1,9.2Hz,2H),5.46(dd,J=20.5,8.0Hz,2H),4.94(t,J=7.3Hz,2H),4.70(s,1H),4.61(d,J=7.7Hz,2H),4.41(s,1H),4.01(dd,J=33.3,23.6Hz,4H),3.78(s,3H),3.62(d,J=7.1Hz,1H),2.29(s,3H),2.10(s,3H),1.98(d,J=13.8Hz,1H),1.85(s,3H),1.73–1.58(m,3H),1.51(s,3H),1.37–1.24(m,6H),1.09–0.91(m,13H).ESI HRMS calcd C78H78Cl2F2N4O17[M+H]+m/z,1451.4707;found 1451.4780.
实施例2
化合物I-2的制备
参考实施例1的方法,以7-乙基-10-羟基喜树碱代替紫杉醇,得26mg白色固体I-2,收率为37.8%。1H NMR(600MHz,DMSO-d6)δ:10.61(s,1H),8.52(d,1H,J=8.4Hz),8.26(d,1H,J=9.0Hz),8.20(s,1H),7.89(d,1H,J=8.4Hz),7.82(m,2H),7.76(t,1H,J=14.4Hz),7.60(d,1H,J=12.6Hz),7.56(t,1H,J=15.0Hz),7.43(t,1H,J=16.8Hz),7.37(m,3H),6.55(s,1H),5.45(m,2H),5.34(s,2H),4.66(m,2H),4.44(t,1H,J=20.4Hz),4.02(d,4H,J=15.6Hz),3.21(m,2H),1.89(m,2H),1.68(m,1H),1.31(m,4H)0.91(t,3H,J=14.4Hz).13CNMR(150MHz,DMSO)δ172.87,171.90,164.65,160.81,159.14,157.24,156.85,155.21,152.43,150.44,149.81,148.15,147.02,146.31,145.86,135.20,132.48,131.74,131.38,130.48,129.00,127.55,126.20,125.73,124.11,119.92,119.48,117.92,115.99,111.93,97.10,72.80,65.69,65.06,63.68,56.49,50.58,49.97,44.33,30.74,30.52,29.93,22.67,14.29,8.17.HRMS(ESI,positive)m/z calcd for C53H47Cl2F2N5O8[M+H]+:990.2848;found 990.2841.
实施例3
化合物I-3的制备
参考实施例1的方法,以蟾毒灵代替紫杉醇,得10mg白色固体I-3,收率为30.8%。
1H NMR(300MHz,DMSO-d6)δ:10.51(s,1H),8.39(s,1H),7.94(s,1H),7.74(s,1H),7.69–7.50(m,4H),7.37(s,3H),7.19(s,1H),6.30(d,J=10.2Hz,1H),5.28(d,J=29.4Hz,2H),4.61(s,2H),4.42(s,1H),4.19(s,1H),3.94(s,4H),2.00(s,4H),1.70(d,J=43.0Hz,9H),1.32(d,J=12.5Hz,10H),0.98(s,9H),0.87(s,3H),0.61(s,3H).
实施例4
化合物I-4的制备
参考实施例1的方法,以多柔比星代替紫杉醇,得9mg橘红色固体I-4,收率为23.9%。
1H NMR(600MHz,DMSO-d6)δ:14.06(s,1H),13.29(s,1H),10.39(s,1H),8.28(d,J=8.5Hz,1H),7.93(d,J=12.0Hz,3H),7.72(t,J=7.0Hz,1H),7.65(d,J=9.6Hz,1H),7.60–7.50(m,3H),7.46(d,J=8.4Hz,1H),7.37(ddd,J=12.1,10.6,7.0Hz,4H),5.51(s,1H),5.29(s,1H),4.99(s,1H),4.87(t,J=6.3Hz,2H),4.58(dd,J=11.2,6.5Hz,4H),4.36(s,1H),4.24(d,J=6.8Hz,2H),4.02–3.87(m,7H),3.56(s,1H),3.00(q,J=17.9Hz,2H),2.25(d,J=12.2Hz,1H),2.19–2.05(m,2H),2.03–1.95(m,2H),1.34(d,J=9.1Hz,3H),0.96(s,9H).ESI HRMS calcd C58H56Cl2F2N4O14[M+H]+m/z,1141.3138;found 1141.3207.
实施例5
本发明化合物的体外抗肿瘤活性试验
对本发明实施例1~4制备的化合物进行了肿瘤细胞增殖抑制试验,试验方法采用CCK-8法。
细胞株HCT116(人结肠癌细胞)、A549(人肺癌细胞)、MCF-7(人乳腺癌细胞)、SW1990(人胰腺癌细胞)和SJSA-1(人骨肉瘤细胞)购自上海美轩科技有限公司(来自ATCC细胞库),由第二军医大学药物化学教研室冻存和传代。
用DMSO(Merck)溶解样品(实施例1~4制备的化合物),配制成10mM的浓度,最后用DMEM或McCoy's 5A 1640培养基三倍稀释成8个浓度梯度。
细胞培养符合测试要求时收集细胞培养液,取10μL于细胞计数板上涂布均匀,然后在显微镜下进行计数3次,取平均值计算出细胞密度;取96孔板(Corning,#3599),按6×103个/孔的细胞浓度,每孔各加200μL进行细胞接种,将接种后的96孔板置于37℃,含5%CO2的细胞培养箱中培养24h。
吸除旧培养基,每孔加入含起始浓度10μmol/L经3倍稀释的样品DMEM或McCoy's5A 1640培养基200μL,控制DMSO的含量为1%,置三个副孔,PBS作为空白对照,置上述培养箱中孵育72h。
将96孔板中的原有DMEM或McCoy's 5A 1640培养基以及最后一排的PBS缓冲液吸出,加入配制好的CCK-8溶液(90%的DMEM或McCoy's 5A 1640培养基+10%的CCK-8),置于孵育箱孵育,用Biotek酶标仪读取吸光度值。细胞生长抑制率IC%=(空白对照孔OD值-给药孔OD值)/空白对照孔OD值×100%。根据各个浓度的IC%值,用GraphPad软件进行线性回归,计算各化合物抑制细胞生长50%的药物浓度,即IC50。
试验结果见表1和表2,其中,样品是指相应实施例中制备的化合物。
表1化合物体外抗肿瘤活性
表2化合物I-2体外抗肿瘤活性
以上实验结果表明,本发明的化合物具有良好的抗肿瘤活性,并且对肺癌、乳腺癌、结肠癌、胰腺癌以及骨肉瘤等细胞株均显示出优秀的活性,因此本发明化合物及其盐类可以用于制备抗肿瘤药物。
实施例6
本发明化合物I-2的体内抗肿瘤活性试验
动物:BALB/C裸鼠(SPF级),雄性,18-20克。
取生长良好的人结肠癌细胞HCT116瘤块,无菌条件下切割成约3mm大小的均匀小块,用套管针每只小鼠右腋皮下接种一块。接种后第9天见瘤块体积平均约130mm3,根据肿瘤大小重新分组,淘汰肿瘤过大和过小的动物,每组肿瘤平均体积基本一致,开始按以下方案给药,给药体积为0.2mL/20g体重。自接种第9天起每周2次用数显电子卡尺测量肿瘤长径a(mm),及相垂直的肿瘤短径b(mm),肿瘤体积计算公式为:TV=ab2/2,相对肿瘤体积计算公式为:RTV=Vt/Vo,Vo为分笼时(即d1)测量所得肿瘤体积,Vt为每一次测量时的肿瘤体积。给药14天后处死动物,称体重,解剖取瘤块,称瘤重,结果判定根据以下公式:
肿瘤抑制率(%)=(对照组平均RTV-给药组平均RTV)/对照组平均RTV×100%
表3化合物I-2体内抗肿瘤活性
以上实验结果表明,本发明的化合物无论静脉还是口服给药均具有良好的体内抗肿瘤活性。因此本发明化合物及其盐类可以用于制备抗肿瘤药物。
实施例7
本发明实施例2制备的化合物I-2的Topo I抑制活性试验
小牛胸腺DNA Topo I、负超螺旋DNA质粒pBR322,均购自Takara。凝胶扫描定量采用Tanon 2500成像系统,HH-2恒温水浴锅。
将实施例2制备的化合物用DMSO(Merck)溶解,配成10mmol/L的样品备用,根据测试所需浓度再用双蒸水进行稀释。
实验操作:
第一步,称取1.5g琼脂糖用TEA配成1%的琼脂糖凝胶溶液置微波炉中,中火加热两次,每次15min。
第二步,依次向1.5ml EP管中加入10μL水,2μL 0.1%BSA,小牛胸腺DNA Topo I0.5U,0.5μL DNA,所有测试药物及对照药物0.02μL,定容到20μL。
第三步,将第一步配制的琼脂糖凝胶溶液趁热倒进电泳槽,同时,将齿梳插进琼脂糖凝胶溶液。将第二步的样品管置于37℃水浴中,加热30min。
第四步,将3.5μL loading buffer加入上述第三步加热后的样品管中,吸取样品加入对应的齿槽中。
第五步,110V电泳40-60min,用溴化乙锭(EtBr)染色30min,凝胶成像系统观察电泳结果。
实验结果如图1所示,图1是实施例2制备的化合物I-2的Topo I抑制活性测试结果示意图(200μM)。图中,Lane 1,supercoiled plasmid DNA;Lane 2,DNA+Topo I;其他泳道分别是DNA+Topo I+化合物。从图中可以看出,本发明的化合物具有良好的Topo I抑制活性,化合物I-2在200μM时对Topo I具有显著的抑制活性,因此本发明化合物及其盐类可以用于制备Topo I抑制剂类药物。
实施例8
本发明实施例2制备的化合物I-2对MDM2蛋白调节的蛋白免疫印迹试验
人结肠癌细胞(HCT116)培养,待细胞生长至70-80%时,加药处理。药物处理不同时间后,0.25%胰酶消化,离心收集细胞,胞浆蛋白核蛋白裂解液4℃裂解提取胞浆蛋白及核蛋白。采用12%SDS-PAGE凝胶电泳,将蛋白转移到固相支持膜上(PVDF膜),封闭液室温封闭1-2h,TBST洗膜5min,洗3次。采用TBST稀释抗体,4℃孵育过夜,TBST洗膜5min,洗3次。然后用TBST稀释HRP标记的二抗,室温孵育1h,TBST洗膜5min,洗3次。暗室内采用ECL显色,X光片曝光成像。以GAPDH为内参照,分析成像光片灰度值,并以control对照组为基准进行量化。
结果如图2所示,图2是化合物I-2对MDM2和p53蛋白的蛋白免疫印迹实验结果示意图。从图中可以看出,化合物能呈浓度梯度的上调p53蛋白,对MDM2蛋白也有一定的调节作用,表明化合物能抑制p53-MDM2蛋白相互作用,可作为p53-MDM2抑制剂。
以上所述仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭露如上,然而并非用以限定本发明,任何熟悉本专利的技术人员在不脱离本发明技术方案范围内,当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明方案的范围内。
Claims (10)
2.根据权利要求1所述的MDM2抑制剂类小分子化合物或其药用盐,其特征在于,所述药物为环丙基苯并[e]吲哚酮类似物或其衍生物、开环-环丙基苯并[e]吲哚酮类似物、O-Ac-开环-环丙基苯并[e]吲哚酮类似物或其衍生物、Dolastatins类、Auristatin类、Tubulysin类、Combretastatin类、美登素类、DM1、埃博霉素类、紫杉醇及其衍生物、长春碱及其类似物、喜树碱及其类似物、秋水仙碱及其类似物、Daunorubicin类、Rhizomycin类、环磷酰胺、甲氨喋呤、博来霉素类、Temsirolimus类、丝裂霉素类、微管抑制剂、吡咯并苯二氮杂卓二聚体类、环丙基苯并[e]吲哚酮类、Calicheamicin类、沙蟾毒精及其衍生物、蟾毒灵及其衍生物、烷化剂氮芥、亚硝基脲、白消安、苯丙酸氮芥、卡铂、顺铂和其他铂类化合物、阿糖胞苷、嘌呤类似物、嘧啶类似物及青霉素、头孢菌素、万古霉素、红霉素、克林霉素、利福平、氯霉素、氨基糖苷类抗生素、阿昔洛韦、三氟尿苷、更昔洛韦、齐多夫定、金刚烷胺、利巴韦林、吉西他滨。
3.根据权利要求2所述的MDM2抑制剂类小分子化合物或其药用盐,其特征在于,所述Y为Temsirolimus类、开环-环丙基苯并[e]吲哚酮类似物、吡咯并苯二氮杂卓二聚体类、Calicheamicin类、喜树碱及其类似物、紫杉醇及其衍生物、长春碱及其类似物、Dolastatins类、Auristatin类、Tubulysin类、Combretastatin类、美登素类、DM1、埃博霉素类、丝裂霉素类、Daunorubicin类、沙蟾毒精及其衍生物或蟾毒灵及其衍生物。
4.根据权利要求3所述的MDM2抑制剂类小分子化合物或其药用盐,其特征在于,所述Y为开环-环丙基苯并[e]吲哚酮类似物、吡咯并苯二氮杂卓二聚体类、Calicheamicin类、喜树碱、7-乙基-10-羟基喜树碱、依喜替康及其衍生物、7-环己基-21-氟喜树碱、DAVLBH、Tubulysin B、MMAE、MMAF、MMAF衍生物、DM1、紫杉醇及其衍生物、埃博霉素B、丝裂霉素C、沙蟾毒精及其衍生物、蟾毒灵及其衍生物、长春新碱、柔红霉素、多柔比星或表柔比星。
7.一种权利要求1至6任一项所述的MDM2抑制剂类小分子化合物或其药用盐在制备抗肿瘤药物、抗炎药物、治疗心血管疾病的药物、抗神经系统疾病的药物中的应用。
8.一种药物组合物,其特征在于,包括权利要求1至6任一项所述的MDM2抑制剂类小分子化合物或其药用盐,所述MDM2抑制剂类小分子化合物或其药用盐作为药物活性成分;或所述药物组合物还包括至少一种治疗剂。
9.一种药物制剂,其特征在于,包括权利要求1至6任一项所述的MDM2抑制剂类小分子化合物或其药用盐。
10.一种权利要求1至6任一项所述的MDM2抑制剂类小分子化合物或其药用盐作为MDM2抑制剂或Topo I抑制剂的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010939885.7A CN114230561B (zh) | 2020-09-09 | 2020-09-09 | 一种mdm2抑制剂类小分子化合物及用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010939885.7A CN114230561B (zh) | 2020-09-09 | 2020-09-09 | 一种mdm2抑制剂类小分子化合物及用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114230561A true CN114230561A (zh) | 2022-03-25 |
CN114230561B CN114230561B (zh) | 2024-03-19 |
Family
ID=80742556
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010939885.7A Active CN114230561B (zh) | 2020-09-09 | 2020-09-09 | 一种mdm2抑制剂类小分子化合物及用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114230561B (zh) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104271554A (zh) * | 2012-03-15 | 2015-01-07 | 霍夫曼-拉罗奇有限公司 | 取代的吡咯烷-2-甲酰胺 |
CN104529915A (zh) * | 2015-01-27 | 2015-04-22 | 山东大学 | 具有dna拓扑异构酶ii抑制活性的喹喔啉酮类似物及其制备方法和应用 |
-
2020
- 2020-09-09 CN CN202010939885.7A patent/CN114230561B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104271554A (zh) * | 2012-03-15 | 2015-01-07 | 霍夫曼-拉罗奇有限公司 | 取代的吡咯烷-2-甲酰胺 |
CN104529915A (zh) * | 2015-01-27 | 2015-04-22 | 山东大学 | 具有dna拓扑异构酶ii抑制活性的喹喔啉酮类似物及其制备方法和应用 |
Non-Patent Citations (2)
Title |
---|
BRIAN M. COCHRAN: ""Development of a Commercial Process To Prepare AMG 232 Using a Green Ozonolysis−Pinnick Tandem Transformation"", 《J. ORG. CHEM. 》, pages 4763 * |
MICKEL J. HANSEN: ""Photoactivation of MDM2 Inhibitors: Controlling Protein−Protein Interaction with Light"", 《 J. AM. CHEM. SOC.》, pages 13136 * |
Also Published As
Publication number | Publication date |
---|---|
CN114230561B (zh) | 2024-03-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Khaiwa et al. | Camptothecin's journey from discovery to WHO Essential Medicine: Fifty years of promise | |
US6380405B1 (en) | Taxane prodrugs | |
EP2341774B1 (en) | Treatment of neuroblastoma with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin | |
US8722698B2 (en) | Berbamine derivatives | |
EP2612857B1 (en) | Chemical synthesis and anti-tumor and anti-metastatic effects of dual functional conjugate | |
CN110143961B (zh) | 一种基于vhl配体诱导bet降解的吡咯并吡啶酮类双功能分子化合物 | |
CN110981870B (zh) | 基于pH和GSH双重响应的β-咔啉-环烯酮衍生物及其用途 | |
TW200412349A (en) | Eponemycin and epoxomicin analogs and uses thereof | |
RU2300535C2 (ru) | Полиморфная форма кристаллического гидрохлорида иринотекана, способ ее получения и фармацевтическая композиция на ее основе | |
JP2019509990A (ja) | チェックポイントキナーゼ1(chk1)阻害剤として有用な3,5−二置換ピラゾール、並びにその調製及び用途 | |
EP2836493B1 (en) | Functionalized thieno-indole derivatives for the treatment of cancer | |
WO2020177748A1 (zh) | 季铵化修饰紫杉烷衍生物、其药物组合物和用途 | |
WO2015096640A1 (zh) | 含噻唑基雷帕霉素类衍生物及其应用 | |
Yang et al. | Design, synthesis and antineoplastic activity of novel 20 (S)-acylthiourea derivatives of camptothecin | |
AU2019366819A1 (en) | Biomarkers of MetAP2 inhibitors and applications thereof | |
CN114230561B (zh) | 一种mdm2抑制剂类小分子化合物及用途 | |
CN109453183B (zh) | 香蜂草苷的肿瘤多药耐药逆转剂或抗肿瘤药物增敏剂及其应用 | |
JP2013538873A (ja) | 癌治療に有用な2つの化合物 | |
CN101941967B (zh) | 13a-(S)去氧娃儿藤宁的盐、其制法和药物组合物与用途 | |
US8637679B2 (en) | Process for the isolation of organic compounds useful for the treatment of cancer | |
CN113633780B (zh) | 一种小分子偶联物及其用途 | |
JP2014152171A (ja) | 新規生理活性組成物 | |
JP2018532780A (ja) | 二官能性プロドラッグ | |
CN111995629B (zh) | 大根香叶衍生物及其药物组合物和其在医药中的用途 | |
WO2022037704A1 (zh) | 一种水溶性抗肿瘤前药及其药物组合物和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |