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

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4.2nmol/L;化合物GYB-5对PI3Kα和HDAC1的IC50分别为1.3和4.8nmol/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.

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

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(PI3 Ks) 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 PI3 Kα(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 PI3 K and HDAC inhibitors.