Design, Synthesis, and Biological Evaluation of (E)-N-Aryl-2-arylethenesulfonamide Analogues as Potent and Orally Bioavailable Microtubule-Targeted Anticancer Agents

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• 作者：M. V. Ramana Reddy ; Muralidhar R. Mallireddigari ; Venkat R. Pallela ; Stephen C. Cosenza ; Vinay K. Billa ; Balaiah Akula ; D. R. C. Venkata Subbaiah ; E. Vijaya Bharathi ; Amol Padgaonkar ; Hua Lv ; James M. Gallo ; E. Premkumar Reddy
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 11, 2013
• 年：2013
• 卷：56
• 期：13
• 页码：5562-5586
• 全文大小：856K
• 年卷期：v.56,no.13(July 11, 2013)
• ISSN：1520-4804

文摘

A series of novel (E)-N-aryl-2-arylethenesulfonamides (6) were synthesized and evaluated for their anticancer activity. Some of the compounds in this series showed potent cytotoxicity against a wide spectrum of cancer cell-lines (IC₅₀ values ranging from 5 to 10 nM) including all drug resistant cell-lines. Nude mice xenograft assays with compound (E)-N-(3-amino-4-methoxyphenyl)-2-(2鈥?4鈥?6鈥?trimethoxyphenyl)ethenesulfonamide (6t) showed dramatic reduction in tumor size, indicating their in vivo potential as anticancer agents. A preliminary drug development study with compound 6t is predicted to have increased blood鈥揵rain barrier permeability relative to many clinically used antimitotic agents. Mechanistic studies indicate that 6t and some other analogues disrupted microtubule formation, formation of mitotic spindles, and arrest of cells in mitotic phase. Compound 6t inhibited purified tubulin polymerization in vitro and in vivo and circumvented drug resistance mediated by P-glycoprotein. Compound 6t specifically competed with colchicine binding to tubulin and with similar avidity as podophylltoxin, indicating its binding site on tubulin.