Design, synthesis and antitumor evaluations of nucleoside base hydroxamic acid derivatives as DNMT and HDAC dual inhibitors

作     者：Qinsheng Sun Qiuzi Dai Cunlong Zhang Yan Chen Lei Zhao Zigao Yuan Yuyang Jiang Qinsheng Sun;Qiuzi Dai;Cunlong Zhang;Yan Chen;Lei Zhao;Zigao Yuan;Yuyang Jiang

作者机构：School of Life ScienceTsinghua UniversityBeijing 100084China National&Local United Engineering Lab for Personalized Anti-tumor DrugsThe State Key Laboratory of Chemical OncogenomicsKey Laboratory of Chemical BiologyTsinghua Shenzhen International Graduate SchoolTsinghua UniversityShenzhen 518055China Institute of Biomedical Health Technology and EngineeringShenzhen Bay LaboratoryShenzhen 518055China National&Local United Engineering Lab for Personalized Anti-tumor DrugsShenzhen Kivita Innovative Drug Discovery InstituteShenzhen 518110China School of Pharmaceutical SciencesTsinghua UniversityBeijing 100084China 

出 版 物：《Chinese Chemical Letters》 (中国化学快报（英文版）)

年 卷 期：2021年第32卷第8期

页      面：2479-2483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：financial supports from China Postdoctoral Science Foundation (No.2018M631825) Shenzhen Development and Reform Committee (No.2019156) Shenzhen Science,Technology and Innovation Commission (No.JCYJ20180306174248782) Department of Science and Technology of Guangdong Province (No.2017B030314083) Shenzhen Bay Laboratory Open Funding (No.SZBL2019062801009) 

主　　题：Epigenetic DNMT HDAC Multitarget Antitumor bioactivity 

摘      要：DNA methyl transferase(DNMT) and histone deacetylase(HDAC) are well recognized epigenetic targets for discovery of antitumor *** this study,we designed and synthesized a series of nucleoside base hydroxamic acid derivatives as DNMT and HDAC dual *** assays and enzymatic inhibitory activity tests indicated that compound 204 exhibited potent DNMT1 and HDAC1/6 inhibitory potency simultaneously in enzymatic levels and at cellular levels,inducing hypomethylation of p16 and hyperacetylation of histones H_(3) K9 and H4 ***,204 remarkably inhibited proliferation against cancer cells U937 by prompting G0/G1 cell cycle *** docking models explained the functional mechanism of 204 inhibiting DNMT1 and *** studies on metabolic profiles revealed that 204 showed desirable stability in liver *** study suggested that 204 inhibiting DNMT and HDAC concurrently can be a potential lead compound for epigenetic cancer therapy.