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个人信息Personal Information
教授
硕士生导师
性别：男
毕业院校：大连理工大学
学位：硕士
所在单位：化工学院
学科：有机化学. 应用化学
电子邮箱：chenhb@dlut.edu.cn
Fragment-based design, synthesis, and biological evaluation of N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide derivatives as novel Mcl-1 inhibitors
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论文类型：期刊论文
发表时间：2013-02-01
发表刊物：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
收录刊物：SCIE、PubMed、Scopus
卷号：60
页面范围：410-420
ISSN号：0223-5234
关键字：Fragment-based; Apoptosis; Mcl-1; LE; FQ
摘要：We have previously reported a nanomolar inhibitor of antiapoptotic Mcl-1 protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1). S1 plays its function by binding to the BH3 groove of Mcl-1. Basing on this spacial structural characteristic, we developed a novel class of Mcl-1 inhibitor using fragment-based drug discovery approach. By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment. In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments. A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds Mcl-1 with an IC50 value of 54 nM was obtained. Compound 12c demonstrated a better aqueous solubility than S1. (C) 2012 Elsevier Masson SAS. All rights reserved.