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。 The quinolone levofloxacin was structurally modified to introduce a novel thiadiazole histone deacetylase inhibitor (HDACi) unit on the carboxyl group of C-3 of levofloxacin, and 18 new compounds were synthesized Their structures were confirmed by ~ 1H NMR, ~ 13C NMR and HR-MS. The HDACs inhibitory activity and in vitro anti-tumor activity of the target conjugates were tested using the histone deacetylases (HDACs) kit and the CCK8 kit. The preliminary bioassay results showed that all the levofloxacin-HDACi conjugates exhibited strong inhibitory activity against HDACs, and the inhibitory activity of hydroxamic acid conjugates on HDACs was stronger than that of carboxylic acids and benzamides The effect of conjugates, especially conjugate 5d, on HDAC1 (IC 50 = 0.031 ± 0.011 μmol·L -1) and HDAC 6 (IC 50 = 0.019 ± 0.006 μmol·L -1) (SAHA). The results of molecular docking showed that the conjugate 5d, except for the interaction of the hydroxamic acid group with the amino acid residues at the bottom of HDACs active pocket and Zn 2+, The thiadiazole group can also form a hydrogen bond with the amino acid residue F679 in HDAC6. In vitro antitumor activity, these conjugates have high affinity for SW620, MGC-803, PC-3, NCIH460, MCF-7 and Hep G2 6 (IC 50 = 0.7 ± 0.05 μmol·L -1) and NCIH 460 (IC 50 = 2.3 ± 10 5) 0.421μmol·L -1), MCF-7 (IC 50 = 1.6 ± 0.56μmol·L -1) and Hep G2 (IC 50 = 3.9 ± 0.26μmol·L -1) 1)) inhibitory activity is 3.1 times higher than the positive drug SAHA. In addition, the conjugate had almost no toxicity to normal gastric epithelial cells GES ~ (-1), while SAHA showed some toxicity.