Total synthesis and antitubulin activity of C10 analogues of cryptophycin-24

被引:12
作者
Buck, SB
Huff, JK
Himes, RH
Georg, GI
机构
[1] Univ Kansas, Dept Med Chem, Lawrence, KS 66045 USA
[2] Univ Kansas, Dept Mol Biosci, Lawrence, KS 66045 USA
关键词
D O I
10.1021/jm030278c
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The unsubstituted, 3'-C1, 4'-C1, and 3',4'-diC1 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 ED50 values ranged from 7.2 to 15.8 muM 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 X-Cl substituent on the C10 phenyl ring. The X-Cl analogue had ED50 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 X-Cl or 4'-C1 substituents.
引用
收藏
页码:696 / 702
页数:7
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