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 

机构地区：[1]School of Life Science,Tsinghua University,Beijing 100084,China [2]National&Local United Engineering Lab for Personalized Anti-tumor Drugs,The State Key Laboratory of Chemical Oncogenomics,Key Laboratory of Chemical Biology,Tsinghua Shenzhen International Graduate School,Tsinghua University,Shenzhen 518055,China [3]Institute of Biomedical Health Technology and Engineering,Shenzhen Bay Laboratory,Shenzhen 518055,China [4]National&Local United Engineering Lab for Personalized Anti-tumor Drugs,Shenzhen Kivita Innovative Drug Discovery Institute,Shenzhen 518110,China [5]School of Pharmaceutical Sciences,Tsinghua University,Beijing 100084,China

出　　处：《Chinese Chemical Letters》2021年第8期2479-2483,共5页中国化学快报（英文版）

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)。

摘　　要：DNA methyl transferase(DNMT) and histone deacetylase(HDAC) are well recognized epigenetic targets for discovery of antitumor agents.In this study,we designed and synthesized a series of nucleoside base hydroxamic acid derivatives as DNMT and HDAC dual inhibitors.MTT 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 K8.Besides,204 remarkably inhibited proliferation against cancer cells U937 by prompting G0/G1 cell cycle arrest.Molecular docking models explained the functional mechanism of 204 inhibiting DNMT1 and HDAC.Preliminary studies on metabolic profiles revealed that 204 showed desirable stability in liver microsomes.Our study suggested that 204 inhibiting DNMT and HDAC concurrently can be a potential lead compound for epigenetic cancer therapy.

关 键 词：EPIGENETIC DNMT HDAC Multitarget Antitumor bioactivity 

分 类 号：TQ460.1[化学工程—制药化工]