Design,synthesis and biological evaluation of novel phthalazinone acridine derivatives as dual PARP and Topo inhibitors for potential anticancer agents  

作　　者：Qiuzi Dai Jiwei Chen Chunmei Gao Qinsheng Sun Zigao Yuan Yuyang Jiang 

机构地区：[1]Department of Chemistry,Tsinghua University,Beijing 100084,China [2]The State Key Laboratory of Chemical Oncogenomics,Key Laboratory of Chemical Biology,The Graduate School at Shenzhen,Tsinghua University,Shenzhen 518055,China [3]College of Chemistry and Chemical Engineering,Shenzhen University,Shenzhen 518060,China [4]Department of Pharmacology and Pharmaceutical Sciences,School of Medicine,Tsinghua University,Beijing 100084,China

出　　处：《Chinese Chemical Letters》2020年第2期404-408,共5页中国化学快报（英文版）

基　　金：financial supports from the Shenzhen Development and Reform Committee(Nos.20151961 and 2019156);Department of Science and Technology of Guangdong Province(No.2017B030314083)。

摘　　要：In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors.MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation.In addition,all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L,and also possessed good PARP-1 inhibitory activities.Subsequent mechanistic studies showed that compound 9 a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells.Our study suggested that 9 a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors.MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation.In addition,all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L,and also possessed good PARP-1 inhibitory activities.Subsequent mechanistic studies showed that compound 9 a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells.Our study suggested that 9 a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.

关 键 词：TOPO PARP Multitarget ACRIDINES ANTITUMOR bioactivity 

分 类 号：TQ460.1[化学工程—制药化工]