Antitumor Agents. 284. New Desmosdumotin B Analogues with Bicyclic B-Ring as Cytotoxic and Antitubulin Agents

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• 作者：Kyoko Nakagawa-Goto ; Pei-Chi Wu ; Chin-Yu Lai ; Ernest Hamel ; Hao Zhu ; Liying Zhang ; Takashi Kozaka ; Emika Ohkoshi ; Masuo Goto ; Kenneth F. Bastow ; Kuo-Hsiung Lee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 10, 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1244-1255
• 全文大小：1061K
• 年卷期：v.54,no.5(March 10, 2011)
• ISSN：1520-4804

文摘

We previously reported that the biological acti-vity of analogues of desmosdumotin B (1) was dramatically changed depending on the B-ring system. A naphthalene B-ring analogue 3 exerted potent in vitro activity against a diverse panel of human tumor cell lines with GI₅₀ values of 0.8鈭?.1 渭M. In contrast, 1 analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) overexpressing multidrug resistant cell line. We have now prepared and evaluated 1 analogues with bicyclic or tricyclic aromatic B-ring systems as in vitro inhibitors of human cancer cell line proliferation. Among all synthesized derivatives, 21 with a benzo[b]thiophenyl B-ring was highly active, with GI₅₀ values of 0.06鈭?.16 渭M, and this activity was not influenced by overexpression of P-gp. Furthermore, 21 inhibited tubulin assembly in vitro with an IC₅₀ value of 2.0 渭M and colchicine binding by 78% as well as cellular microtubule polymerization and spindle formation.