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

作者：Nakagawa Goto Kyoko^*; Wu Pei Chi; Lai Chin Yu; Hamel Ernest; Zhu Hao; Zhang Liying; Kozaka Takashi; Ohkoshi Emika; Goto Masuo; Bastow Kenneth F; Lee Kuo Hsiung

来源：Journal of Medicinal Chemistry, 2011, 54(5): 1244-1255.

DOI：10.1021/jm1011947

We previously reported that the biological activity 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 GI(50) values of 0.8-2.1 mu M. In contrast, 1 analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) over-expressing 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 GI(50) values of 0.06-0.16 mu M, and this activity was not influenced by overexpression of P-gp. Furthermore, 21 inhibited tubulin assembly in vitro with an IC(50) value of 2.0 mu M and colchicine binding by 7896 as well as cellular microtubule polymerization and spindle formation.

• 出版日期2011-3-10
• 单位中国医科大学