Buck Suzanne B, Huff Jacquelyn K, Himes Richard H, Georg Gunda I
Department of Medicinal Chemistry and Department of Molecular Biosciences, University of Kansas, 1251 Wescoe Drive, Lawrence, Kansas 66045-7582, USA.
J Med Chem. 2004 Jan 29;47(3):696-702. doi: 10.1021/jm030278c.
The unsubstituted, 3'-Cl, 4'-C1, and 3',4'-diCl C10 analogues of cryptophycin-24 were prepared via total synthesis and tested in vitro for cytotoxicity against MCF-7 and multi-drug-resistant MCF-7/ADR breast cancer cell lines and in a tubulin assembly assay. The ED(50) values ranged from 7.2 to 15.8 microM in the tubulin assay and from 0.05 to 3.4 nM in the cell assays. The presence of a 3'-C1 and/or 4'-C1 substituent on the C10 phenyl ring increased cytotoxicity in the MCF-7 cell line compared to the unsubstituted phenyl ring. The most potent compound in this series possessed a 3'-C1 substituent on the C10 phenyl ring. The 3'-C1 analogue had ED(50) values of 50 and 580 pM in the MCF-7 and MCF-7/ADR cell lines, respectively. Its activity was very similar to the parent compound cryptophycin-24. Substitution of the 4'-MeO group in cryptophycin-24 with a 4'-C1 moiety did not significantly affect cytotoxicity against MCF-7 and MCF-7/ADR cells compared to the parent compound. These results demonstrated that the 4'-MeO group in cryptophycin-24 is not essential and can be replaced with 3'-C1 or 4'-C1 substituents.
通过全合成制备了隐藻素 - 24的未取代、3'-氯、4'-氯和3',4'-二氯C10类似物，并在体外测试了它们对MCF - 7和多药耐药的MCF - 7/ADR乳腺癌细胞系的细胞毒性以及在微管蛋白组装试验中的活性。在微管蛋白试验中，ED(50)值范围为7.2至15.8 microM，在细胞试验中为0.05至3.4 nM。与未取代的苯环相比，C10苯环上存在3'-氯和/或4'-氯取代基会增加MCF - 7细胞系中的细胞毒性。该系列中最有效的化合物在C10苯环上具有3'-氯取代基。3'-氯类似物在MCF - 7和MCF - 7/ADR细胞系中的ED(50)值分别为50和580 pM。其活性与母体化合物隐藻素 - 24非常相似。与母体化合物相比，用4'-氯部分取代隐藻素 - 24中的4'-甲氧基基团对MCF - 7和MCF - 7/ADR细胞的细胞毒性没有显著影响。这些结果表明，隐藻素 - 24中的4'-甲氧基基团不是必需的，可以被3'-氯或4'-氯取代基取代。
