Design and synthesis of tri-substituted pyrimidine derivatives as bifunctional tumor immunotherapeutic agents targeting both A2A adenosine receptors and histone deacetylases  

作　　者：Ruiquan Liu Wenwen Duan Wenzhong Yan Jinfeng Zhang Jianjun Cheng 

机构地区：[1]iHuman Institute,ShanghaiTech University,Shanghai 201210,China [2]School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China

出　　处：《Chinese Chemical Letters》2024年第1期295-299,共5页中国化学快报（英文版）

基　　金：Lingang Laboratory(No.LG-QS-202205-03);ShanghaiTech University and the Shanghai Municipal Government.

摘　　要：The A_(2A)adenosine receptor(A_(2A)AR)has attracted attention as an emerging immunotherapeutic target with several antagonists being evaluated in clinical trials.However,A_(2A)AR antagonists show limited efficacy as monotherapies.Herein,we communicate our design and synthesis of a novel series of A_(2A)AR/histone deacetylase(HDAC)bifunctional inhibitors,based on the core structure of the A_(2A)AR antagonist The new compounds were designed using a pharmacophore-merging strategy and features a tri-substituted pyrimidine core.The binding affinity for A_(2A)AR and inhibitory activity against HDACs of all the new compounds were tested.A number of compounds exhibited nanomolar or subnanomolar activity against both targets and some showed equally potent antiproliferative activity against MC38,CT26 and HCT116 colon cancer lines compared to HDAC inhibitors SAHA and MGCD-0103 in vitro.The binding poses of compound 5a in both A_(2A)AR and HDAC1 were predicted by molecular docking studies.Collectively,these results suggest these tri-substituted pyrimidine derivatives are promising leads for developing A_(2A)AR/HDAC dual-acting compounds as novel antitumor agents.

关 键 词：BIFUNCTIONAL A_(2A)AR antagonism HDAC inhibition Cancer IMMUNOTHERAPY 

分 类 号：TQ463[化学工程—制药化工]