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生命过程小分子调节剂的研究:Design, Synthesis, and Evaluation of Tricyclic, Conformationally Constrained ...

  • 关键字: Design, Synthesis, and Evaluation of Tricyclic 发布者:Bin Zhang, Shaomeng Wang* and Yikang Wu* 发布时间:2009-03-03 08:03:45 点击数: 3953次

J. Med. Chem., 2008, 51, 7352–7355.
Design, Synthesis, and Evaluation of Tricyclic, Conformationally Constrained Small-Molecule Mimetics of Second Mitochondria-Derived Activator of Caspases
Bin Zhang, Zaneta Nikolovska-Coleska, Yan Zhang, Longchuan Bai, Su Qiu, Chao-Yie Yang, Haiying Sun, Shaomeng Wang* and Yikang Wu*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China, and Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, U. S. A.
 
Abstract. 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 Ki 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.