Chinese Journal of Organic Chemistry ›› 2020, Vol. 40 ›› Issue (1): 95-107.DOI: 10.6023/cjoc201908021 Previous Articles     Next Articles

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).

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