摘要
作为I亚族组蛋白去乙酰化酶(histone deacetylase,HDAC)成员,HDAC8是重要的抗肿瘤靶点。本研究基于课题组前期构建的HDAC8药效团模型,以喹啉作为母核,设计并合成了13个目标化合物,其中SDFZ-E2和SDFZ-E3具有较好的HDAC8抑制活性和亚型选择性;在细胞实验中,SDFZ-E2和SDFZ-E3表现出优于HDAC8选择性抑制剂PCI-34051的抗肿瘤细胞增殖活性;还通过分子对接和分子动力学模拟研究了SDFZ-E2与HDAC8的结合模式。该项工作是以喹啉为母核发展HDAC8选择性抑制剂的一次探索,相关活性化合物可以作为先导化合物进行进一步的结构改造。
As a member of class I histone deacetylase(HDACs),HDAC8 is an important anticancer drug target.Based on our previously developed pharmacophore model for the HDAC8 inhibitor,we designed and synthesized 13 quinoline acid derivatives as new HDAC8 inhibitors.Among them,the compound SDFZ-E2 and SDFZ-E3 exhibited good HDAC8 inhibitory activities and isoform selectivity.In cell experiments,the target compounds SDFZ-E2 and SDFZ-E3 showed better antiproliferation activities than the known HDAC8 selective inhibitor PCI-34051.In addition,the proposed binding mode of SDFZ-E2 was investigated using molecular docking and molecular dynamics simulation.This work is a new attempt to develop HDAC8 selective inhibitor using quinoline as the scaffold,and the active compounds could serve as lead compounds for further structural optimization.
作者
周易
邵文晴
杨新颖
侯旭奔
方浩
ZHOU Yi;SHAO Wen-qing;YANG Xin-ying;HOU Xu-ben;FANG Hao(Department of Pharmacy,Shandong Provincial Hospital Affiliated to Shandong First Medical University,Ji'nan 250021,China;Key Laboratory of Chemical Biology(Ministry of Education),School of Pharmaceutical Science,Cheeloo College of Medicine,Shandong University,Ji'nan 250012,China)
出处
《药学学报》
CAS
CSCD
北大核心
2024年第4期979-986,共8页
Acta Pharmaceutica Sinica
基金
国家自然科学基金资助项目(8187428882204198).
关键词
喹啉衍生物
组蛋白去乙酰化酶8抑制剂
抗肿瘤活性
药效团
quinoline derivative
histone deacetylase 8 inhibitor
anti-tumor activity
pharmacophore model
