Structure鈥揂ctivity Relationships of Carboline and Carbazole Derivatives as a Novel Class of ATP-Competitive Kinesin Spindle Protein Inhibitors

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• 作者：Tomoki Takeuchi ; Shinya Oishi ; Toshiaki Watanabe ; Hiroaki Ohno ; Jun-ichi Sawada ; Kenji Matsuno ; Akira Asai ; Naoya Asada ; Kazuo Kitaura ; Nobutaka Fujii
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 14, 2011
• 年：2011
• 卷：54
• 期：13
• 页码：4839-4846
• 全文大小：1004K
• 年卷期：v.54,no.13(July 14, 2011)
• ISSN：1520-4804

文摘

The kinesin spindle protein (KSP) is a mitotic kinesin involved in the establishment of a functional bipolar mitotic spindle during cell division. It is considered to be an attractive target for cancer chemotherapy with reduced side effects. Based on natural product scaffold-derived fused indole-based inhibitors and known biphenyl-type KSP inhibitors, various carboline and carbazole derivatives were synthesized and biologically evaluated. 尾-Carboline and lactam-fused carbazole derivatives exhibited remarkably potent KSP inhibitory activity and mitotic arrest in prometaphase with formation of an irregular monopolar spindle. The planar tri- and tetracyclic analogs inhibited KSP ATPase in an ATP-competitive manner just like biphenyl-type inhibitors.