本文選題：喹諾酮類藥物　切入點：組蛋白去乙�；敢种苿�　出處：《藥學(xué)學(xué)報》2017年04期 　論文類型：期刊論文

【摘要】：以喹諾酮類藥物左氧氟沙星為原料,對其進行結(jié)構(gòu)改造,在左氧氟沙星C-3位羧基上引入噻二唑類組蛋白去乙�；敢种苿�(histone deacetylase inhibitor,HDACi)單元,合成了18個新化合物,其結(jié)構(gòu)均經(jīng)過~1H NMR、~13C NMR和HR-MS進行確證。采用了組蛋白去乙�；�(HDACs)試劑盒和CCK8試劑盒測試了目標綴合物的HDACs抑制活性和體外抗腫瘤活性。初步的生物活性測試結(jié)果表明,所合成的左氧氟沙星-HDACi綴合物均展現(xiàn)出了較強的HDACs抑制活性,其中肟酸類綴合物對HDACs的抑制活性強于羧酸類和苯甲酰胺類綴合物,尤其是綴合物5d對HDAC1(IC_(50)=0.031±0.011μmol·L~(-1))和HDAC6(IC_(50)=0.019±0.006μmol·L~(-1))的抑制活性最強,強于陽性藥物伏立諾他(SAHA);通過分子對接研究發(fā)現(xiàn),綴合物5d除了肟酸基團與HDACs活性口袋底部的氨基酸殘基和鋅離子相互作用外,其噻二唑基團在HDAC6中還能與氨基酸殘基F679形成氫鍵;在體外抗腫瘤活性中,這些綴合物對SW620、MGC-803、PC-3、NCIH460、MCF-7和Hep G2 6種腫瘤細胞均有較強的抑制作用,其中綴合物5d對腫瘤細胞MGC-803(IC_(50)=0.7±0.05μmol·L~(-1))、NCIH460(IC_(50)=2.3±0.421μmol·L~(-1))、MCF-7(IC_(50)=1.6±0.56μmol·L~(-1))和Hep G2(IC_(50)=3.9±0.26μmol·L~(-1))抑制活性是陽性藥物SAHA的3.1倍以上。此外,綴合物對正常的胃黏膜上皮細胞GES~(-1)基本沒有毒性,而SAHA卻表現(xiàn)出了一定的毒性。
[Abstract]:Using levofloxacin, a quinolone drug, as raw material, 18 new compounds were synthesized from levofloxacin by introducing histone deacetylase inhibitor HDACiCiunit on the C-3 carboxyl group of levofloxacin. Their structures were confirmed by 1H NMRA 13C NMR and HR-MS. The HDACs inhibitory activity of the target conjugate and the antitumor activity in vitro were tested by histone deacetylase (histone deacetylase) kit and CCK8 kit. The synthesized levofloxacin -HDACi conjugates showed strong HDACs inhibitory activity. The inhibitory activity of oximic acid conjugates on HDACs was stronger than that on carboxylic acids and benzoyl amines, especially on HDAC1(IC_(50)=0.031 鹵0.011 渭 mol 路L ~ (-1) and HDAC6(IC_(50)=0.019 鹵0.006 渭 mol 路L ~ (-1) 路L ~ (-1) conjugate for 5 days, and the inhibitory activity of oximic acid conjugates on HDACs was the highest, especially on HDAC1(IC_(50)=0.031 鹵0.011 渭 mol 路L ~ (-1) and HDAC6(IC_(50)=0.019 鹵0.006 渭 mol 路L ~ (-1) 路L ~ (-1). It was found by molecular docking that the conjugate could interact with amino acid residues and zinc ions in the bottom of HDACs active pocket except oximate group in 5 days. The thiadiazole group can also form a hydrogen bond with amino acid residues F679 in HDAC6, and these conjugates have strong inhibitory effects on SW620 MGC-803, PC-3, NCIH460MF-7 and Hep G2 tumor cells in vitro. The inhibitory activity of the conjugate on MGC-803(IC_(50)=0.7 鹵0. 05 渭 mol 路L ~ (-1) MGC-803(IC_(50)=0.7 鹵0. 05 渭 mol 路L ~ (-1) is more than 3.1 times of that of the positive drug SAHA. In addition, the conjugate has little toxicity to normal gastric mucosal epithelial cells, but SAHA has no toxicity to normal gastric mucosal epithelial cells (GESS-1), and Hep G2IC50 (3. 9 鹵0. 26 渭 mol 路L ~ (-1)) has no toxicity to normal gastric mucosal epithelial cells.
【作者單位】： 長江職業(yè)學(xué)院;
【基金】：湖北技能型人才培養(yǎng)研究中心項目(2016JA005)
【分類號】：R914.5;R96

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