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（英文）

发布时间：2022-07-12 15:44

　　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. 

【文章页数】：59 页

【文章目录】：
1 Introduction
2 Results and discussion
    2.1 Chemistry
    2.2 Biological activity
    2.3 Binding mode of GYB-5
    2.4 Structure-activity relationships
3 Conclusions
4 Experimental
    4.1 Chemistry
        4.1.1 Instruments and reagents
        4.1.2 Synthesis of 5-bromo-2-methoxy-3-nitropyridine(1)
        4.1.3 Synthesis of 5-bromo-2-methoxypyridin-3-amine(2)
        4.1.4 Synthesis of N-(5-bromo-2-methoxypyridin-3-yl)-2,4-difluoroben-zenesulfonamide(3)
        4.1.5 2,4-Difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide(4)
        4.1.6 General procedure for the preparation of 5a～5e
        4.1.7 General procedure for the preparation of 5f～5j
        4.1.8 General procedure for the preparation of 6a～6j
        4.1.9 General procedure for the preparation of GYA1-5(7a～7e)and GYB1～GYB5(7f～7g)
    4.2 In vitro kinase inhibition assay
    4.3 In vitro HDAC inhibition fluorescence assay
    4.4 In vitro antiproliferation assay
    4.5 Docking
辅助材料(Supporting Information)
    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
        Biological assay
        Copies of 1H and 13C NMR spectra
        HRMS chromatograms
        Reference



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