Furanylazaindoles: Potent Anticancer Agents in Vitro and in Vivo

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• 作者：Hsueh-Yun Lee ; Shiow-Lin Pan ; Min-Chieh Su ; Yi-Min Liu ; Ching-Chuan Kuo ; Yi-Ting Chang ; Jian-Sung Wu ; Chih-Ying Nien ; Samir Mehndiratta ; Chi-Yen Chang ; Su-Ying Wu ; Mei-Jung Lai ; Jang-Yang Chang ; Jing-Ping Liou
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October 24, 2013
• 年：2013
• 卷：56
• 期：20
• 页码：8008-8018
• 全文大小：565K
• 年卷期：v.56,no.20(October 24, 2013)
• ISSN：1520-4804

文摘

Preliminary biological data on 7-anilino-6-azaindoles (8鈥?b>11) suggested that hydrophobic substituents at C7 contribute to enhancement of antiproliferative activity. A novel series of 7-aryl-6-azaindole-1-benzenesulfonamides (12鈥?b>22) were developed and showed improved cytotoxicity compared to ABT751 (5). The conversion of C7 phenyl rings into C7 heterocycles led to a remarkable improvement of antiproliferative activity. Among all the synthetic products, 7-(2-furanyl)-1-(4-methoxybenzenesulfonyl)-6-azaindole (21) exhibited the most potent anticancer activity against KB, HT29, MKN45, and H460 cancer cell lines with IC₅₀ values of 21.1, 32.0, 27.5, and 40.0 nM, respectively. Bioassays indicated that 21 not only inhibits tubulin polymerization by binding to tubulin at the colchicine binding site but also arrests the cell cycle at the G2/M phase with slight arrest at the sub-G1 phase. Compound 21 also functions as a vascular disrupting agent and dose-dependently inhibits tumor growth without significant change of body weight in an HT29 xenograft mouse model. Taken together, compound 21 has potential for further development as a novel class of anticancer agents.