有机化学 ›› 2020, Vol. 40 ›› Issue (1): 95-107.DOI: 10.6023/cjoc201908021 上一篇    下一篇

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a, 吕晓庆b, 马晓东c, 张浩健a, 嵇媛媛a, 丁婉婧a, 沈立a   

  1. 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 出版日期:2020-01-25 发布日期:2019-09-18
  • 通讯作者: 沈立 E-mail:shenli@zju.edu.cn
  • 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.

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

Gu Yiyua, Lü Xiaoqingb, Ma Xiaodongc, Zhang Haojiana, Ji Yuanyuana, Ding Wanjinga, Shen Lia   

  1. 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:2019-08-13 Revised:2019-09-05 Online:2020-01-25 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).

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

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