Synthesis of reversible PAD4 inhibitors via copper-catalyzed C-H arylation of benzimidazole

作     者：Zhengwei Guo Lai Shi Bo Wang Gang He Yanming Wang Gong Chen 

作者机构：State Key Laboratory and Institute of Elemento-Organic ChemistryCollege of ChemistryNankai University School of Life SciencesHenan University Department of Biochemistry and Molecular BiologyThe Pennsylvania State University 

出 版 物：《Science China Chemistry》 (中国科学（化学英文版）)

年 卷 期：2019年第62卷第5期

页      面：592-596页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(21502098,21672105,21725204,91753124) Natural Science Foundation of Tianjin(17JCYBJC19700,18JCZDJC32800) Qingdao National Laboratory for Marine Science and Technology the State Key Laboratory of Elemento-Organic Chemistry at Nankai University 

主　　题：C–H arylation benzimidazoles PAD4 inhibitor copper catalysis 

摘      要：PAD4 is a promising epigenetic drug target for various cancers and immune diseases. In this work, we applied a Cu-catalyzed C–H arylation reaction of N-heteroarene to the synthesis of complex non-covalent PAD4 inhibitors bearing a bi-heteroaryl pharmacophore. This strategy allowed us to access various analogs of C_2-aryl substituted benzimidazoles from a common benzimidazole core and easily accessible aryl iodides. Preliminary SAR studies revealed the indole motif of GSK-484 is critical to its activity. Replacing the N-cyclopropylmethyl group to N-benzyl group on the indole ring of GSK-484 resulted in more than5-fold increase in cell killing efficacy against 4T1 cell line.