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

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journal contribution
posted on 10.03.2011, 00:00 by 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
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 0.8−2.1 μM. 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 0.06−0.16 μM, 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 μM and colchicine binding by 78% as well as cellular microtubule polymerization and spindle formation.