左氧氟沙星与噻二唑类组蛋白去乙酰化酶抑制剂缀合物的合成和抗肿瘤活性

发布时间：2018-03-13 17:34

本文选题：喹诺酮类药物　切入点：组蛋白去乙酰化酶抑制剂　出处：《药学学报》2017年04期 　论文类型：期刊论文

【摘要】：以喹诺酮类药物左氧氟沙星为原料,对其进行结构改造,在左氧氟沙星C-3位羧基上引入噻二唑类组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitor,HDACi)单元,合成了18个新化合物,其结构均经过~1H NMR、~13C NMR和HR-MS进行确证。采用了组蛋白去乙酰化酶(HDACs)试剂盒和CCK8试剂盒测试了目标缀合物的HDACs抑制活性和体外抗肿瘤活性。初步的生物活性测试结果表明,所合成的左氧氟沙星-HDACi缀合物均展现出了较强的HDACs抑制活性,其中肟酸类缀合物对HDACs的抑制活性强于羧酸类和苯甲酰胺类缀合物,尤其是缀合物5d对HDAC1(IC_(50)=0.031±0.011μmol·L~(-1))和HDAC6(IC_(50)=0.019±0.006μmol·L~(-1))的抑制活性最强,强于阳性药物伏立诺他(SAHA);通过分子对接研究发现,缀合物5d除了肟酸基团与HDACs活性口袋底部的氨基酸残基和锌离子相互作用外,其噻二唑基团在HDAC6中还能与氨基酸残基F679形成氢键;在体外抗肿瘤活性中,这些缀合物对SW620、MGC-803、PC-3、NCIH460、MCF-7和Hep G2 6种肿瘤细胞均有较强的抑制作用,其中缀合物5d对肿瘤细胞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))抑制活性是阳性药物SAHA的3.1倍以上。此外,缀合物对正常的胃黏膜上皮细胞GES~(-1)基本没有毒性,而SAHA却表现出了一定的毒性。
[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 卤0.011 渭 mol 路L ~ (-1) and HDAC6(IC_(50)=0.019 卤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 卤0.011 渭 mol 路L ~ (-1) and HDAC6(IC_(50)=0.019 卤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 卤0. 05 渭 mol 路L ~ (-1) MGC-803(IC_(50)=0.7 卤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 卤0. 26 渭 mol 路L ~ (-1)) has no toxicity to normal gastric mucosal epithelial cells.
【作者单位】：长江职业学院;
【基金】：湖北技能型人才培养研究中心项目(2016JA005)
【分类号】：R914.5;R96

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