Arylthioindole Inhibitors of Tubulin Polymerization. 3. Biological Evaluation, Structure-Activity Relationships and Molecular Modeling Studies

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• 作者：Giuseppe La Regina ; Michael C. Edler ; Andrea Brancale ; Sahar Kandil ; Antonio Coluccia ; Francesco Piscitelli ; Ernest Hamel ; Gabriella De Martino ; Ruth Matesanz ; José ; Fernando D&iacute ; az ; Anna I
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：June 14, 2007
• 年：2007
• 卷：50
• 期：12
• 页码：2865 - 2874
• 全文大小：266K
• 年卷期：v.50,no.12(June 14, 2007)
• ISSN：1520-4804

文摘

The new arylthioindole (ATI) derivatives 10, 14-18, and 21-24, which bear a halogen atom or a smallsize ether group at position 5 of the indole moiety, were compared with the reference compounds colchicineand combretastatin A-4 for biological activity. Derivatives 10, 11, 16, and 21-24 inhibited MCF-7 cellgrowth with IC₅₀ values <50 nM. A halogen atom (14-17) at position 5 caused a significant reduction inthe free energy of binding of compound to tubulin, with a concomitant reduction in cytotoxicity. In contrast,methyl (21) and methoxy (22) substituents at position 5 caused an increase in cytotoxicity. Compound 16,the most potent antitubulin agent, led to a large increase (56%) in HeLa cells in the G₂/M phase at 24 h, andat 48 h, 26% of the cells were hyperploid. Molecular modeling studies showed that, despite the absence ofthe ester moiety present in the previously examined analogues, most of the compounds bind in the colchicinesite in the same orientation as the previously studied ATIs. Binding to images/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-tubulin involved formation of ahydrogen bond between the indole and Thr179 and positioning of the trimethoxy phenyl group in ahydrophobic pocket near Cys241.