9-Benzylidene-naphtho[2,3-b]thiophen-4-ones as Novel Antimicrotubule Agents-Synthesis, Antiproliferative Activity, and Inhibition of Tubulin Polymerization

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• 作者：Anne Zuse ; Peter Schmidt ; Silke Baasner ; Konrad J. Bö ; hm ; Klaus Mü ; ller ; Matthias Gerlach ; Eckhard G. Gü ; nther ; Eberhard Unger ; Helge Prinz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：December 28, 2006
• 年：2006
• 卷：49
• 期：26
• 页码：7816 - 7825
• 全文大小：200K
• 年卷期：v.49,no.26(December 28, 2006)
• ISSN：1520-4804

文摘

A novel series of 9-benzylidene-naphtho[2,3-b]thiophen-4-ones and structurally related compounds weresynthesized and evaluated for their ability to inhibit tubulin polymerization. The 4-hydroxy-3,5-dimethoxy-benzylidene analogue 15d was identified as a potent cytotoxic agent in an assay based on K562 leukemiacells. Antiproliferative activity of 15d and the 2,4-dimethoxy-3-hydroxy-benzylidene analogue 15e wasadditionally evaluated against a panel of 12 tumor cell lines, including multidrug resistant phenotypes. Allresistant cell lines were sensitive to these compounds. Concentration-dependent flow cytometric studiesshowed that K562 cells as well as KB/HeLa cells treated by 15d were arrested in the G2/M phases of thecell cycle. Moreover, four compounds strongly inhibited tubulin polymerization with activities higher orcomparable to those of the reference compounds. In competition experiments, the most active compoundsstrongly displaced radiolabeled colchicine from its binding site in the tubulin, showing IC₅₀ values virtually3- to 4-fold lower than that of colchicine.