Design, Synthesis, and Evaluation of Tricyclic, Conformationally Constrained Small-Molecule Mimetics of Second Mitochondria-Derived Activator of Caspases

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• 作者：Bin Zhang ; Zaneta Nikolovska-Coleska ; Yan Zhang ; Longchuan Bai ; Su Qiu ; Chao-Yie Yang ; Haiying Sun ; Shaomeng Wang ; Yikang Wu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：December 11, 2008
• 年：2008
• 卷：51
• 期：23
• 页码：7352-7355
• 全文大小：167K
• 年卷期：v.51,no.23(December 11, 2008)
• ISSN：1520-4804

文摘

A series of tricyclic, conformationally constrained Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 6 (WS-5) binds to XIAP, cIAP-1, and cIAP-2 with K_i of 18, 1.1, and 4.2 nM, respectively. Compound 6 antagonizes XIAP in a functional assay, induces cIAP-1 degradation, inhibits cell growth with an IC₅₀ of 68 nM in the MDA-MB-231 cancer cell line, and effectively induces cancer cells to undergo apoptosis.