摘要/Abstract

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


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