多靶點藥物已成為一種有廣闊前景的藥物,特別是對抗腫瘤藥物的研發(fā).基于候選藥物GSK2126458和上市藥物Vorinostat的結構特點,設計并合成了一系列新型的磷脂酰肌醇3-激酶（PI3Ks）和組蛋白脫乙酰酶（HDACs）雙重抑制劑.生物活性研究發(fā)現(xiàn),化合物GYB-4對PI3Kα和HDAC1的IC50分別為1.0和4.2nmol/L;化合物GYB-5對PI3Kα和HDAC1的IC50分別為1.3和4.8nmol/L.對所有化合物在HCT116,PC3和A2780細胞株上進行了增殖抑制活性研究,相關的構效關系研究將為PI3K和HDAC雙靶點抑制劑的進一步優(yōu)化提供思路. 

【文章頁數(shù)】：59 頁

【文章目錄】：
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
輔助材料(Supporting Information)
    新型吡啶苯磺酰胺聯(lián)喹啉基異羥肟酸類PI3K/HDAC雙靶點抑制劑的設計、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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