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2020 , Vol. 40 >Issue 1: 95 - 107

DOI: https://doi.org/10.6023/cjoc201908021

研究论文

新型吡啶苯磺酰胺联喹啉基异羟肟酸类PI3K/HDAC双靶点抑制剂的设计、合成和生物活性研究

  • 顾依钰 ,
  • 吕晓庆 ,
  • 马晓东 ,
  • 张浩健 ,
  • 嵇媛媛 ,
  • 丁婉婧 ,
  • 沈立
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  • a 浙江大学海洋学院 浙江舟山 316021;
    b 嘉兴学院医学院 浙江嘉兴 314001;
    c 安徽中医药大学药学院 合肥 230012

收稿日期: 2019-08-13

  修回日期: 2019-09-05

  网络出版日期: 2019-09-18

基金资助

国家自然科学基金青年基金（No.81402845）和舟山市科技计划（No.2018C81035）资助项目.

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Design, Synthesis and Biological Evaluation of Novel (Quinolinyl-3-pyridinyl)benzenesulfonamide-Based Hydroxamic Acids as PI3K and HDAC Dual Targeting Inhibitors

  • Gu Yiyu ,
  • Lü Xiaoqing ,
  • Ma Xiaodong ,
  • Zhang Haojian ,
  • Ji Yuanyuan ,
  • Ding Wanjing ,
  • Shen Li
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  • a Ocean College, Zhejiang University, Zhoushan, Zhejiang 316021;
    b College of Medicine, Jiaxing University, Jiaxing, Zhejiang 314001;
    c School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012

Received date: 2019-08-13

  Revised date: 2019-09-05

  Online published: 2019-09-18

Supported by

Project supported by the National Natural Science Foundation for Young Scientists of China (No. 81402845) and the Foundation for the Science and Technology Project of Zhoushan City (No. 2018C81035).

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摘要

多靶点药物已成为一种有广阔前景的药物，特别是对抗肿瘤药物的研发.基于候选药物GSK2126458和上市药物Vorinostat的结构特点，设计并合成了一系列新型的磷脂酰肌醇3-激酶（PI3Ks）和组蛋白脱乙酰酶（HDACs）双重抑制剂.生物活性研究发现，化合物GYB-4对PI3Kα和HDAC1的IC50分别为1.0和4.2 nmol/L；化合物GYB-5对PI3Kα和HDAC1的IC50分别为1.3和4.8 nmol/L.对所有化合物在HCT116，PC3和A2780细胞株上进行了增殖抑制活性研究，相关的构效关系研究将为PI3K和HDAC双靶点抑制剂的进一步优化提供思路.

关键词： 磷脂酰肌醇3-激酶; 组蛋白去乙酰化酶; 双靶点抑制剂; 生物活性

本文引用格式

顾依钰 , 吕晓庆 , 马晓东 , 张浩健 , 嵇媛媛 , 丁婉婧 , 沈立 . 新型吡啶苯磺酰胺联喹啉基异羟肟酸类PI3K/HDAC双靶点抑制剂的设计、合成和生物活性研究[J]. 有机化学, 2020 , 40(1) : 95 -107 . DOI: 10.6023/cjoc201908021

Abstract

Polypharmacology has emerged as a promising approach to drug discovery, especially antitumor drug. This study reports the design, synthesis, and biological evaluation of novel phosphatidylinositol 3-kinases (PI3Ks) and histone deacetylases (HDACs) dual inhibitors on the basis of GSK2126458 under clinical evaluation and vorinostat approved. Among these hybrid molecules, GYB-4 and GYB-5 possessed potent inhibition against both PI3Kα (1.0 and 1.3 nmol/L, respectively) and HDAC1 (4.2 and 4.8 nmol/L, respectively). Antiproliferative assays with HCT116, PC3 and A2780 cell lines subsequently were performed. The structure-activity relationship study will guide to optimization of dual PI3K and HDAC inhibitors.

Key words： phosphatidylinositol 3-kinases (PI3K); histone deacetylases (HDAC); dual targeting inhibitor; bioactivity

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