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以辛二酸、环丙沙星为原料,通过酯化或酰胺化反应在环丙沙星C-3位羧基上引入组蛋白去乙酰化酶抑制剂(HDACi)单元,合成了18个未见文献报道的新化合物,其结构经核磁共振氢谱和高分辨质谱确证。采用组蛋白去乙酰化酶(HDAC)和CCK-8试剂盒测试了目标化合物对HDAC的抑制活性和抗肿瘤细胞增殖活性。初步的生物活性结果表明,这些目标缀合物均展现出了较强的HDACs抑制活性及体外抗肿瘤活性,部分化合物对HDACs的抑制活性和抗肿瘤活性与先导化合物环丙沙星和阳性药物SAHA(vorinostat,伏立诺他)相比均有提高。尤其是化合物12b不仅对HDAC1(IC50=0.041±0.005μmol·L~(-1))和HDAC6(IC50=0.039±0.006μmol·L~(-1))展现出了最强的抑制活性,同时对肿瘤细胞NCI-H460(IC50=0.7±0.04μmol·L~(-1))和A549(IC50=0.9±0.12μmol·L~(-1))也有最强的抑制活性。结果表明,组蛋白去乙酰化酶抑制剂(HDACi)是一类重要的抗肿瘤靶点药物,能够提高喹诺酮类药物的抗肿瘤活性。
Using suberic acid and ciprofloxacin as raw materials, Histone deacetylase inhibitor (HDACi) units were introduced into the carboxyl group of C-3 of ciprofloxacin by esterification or amidation reaction. Eighteen unselected The new compounds reported in the literature, the structure confirmed by 1H nuclear magnetic resonance and high resolution mass spectrometry. The target compounds were tested for HDAC inhibitory activity and anti-tumor cell proliferative activity using histone deacetylase (HDAC) and CCK-8 kits. Preliminary biological activity results showed that these target conjugates showed strong HDACs inhibitory activity and in vitro anti-tumor activity, some of the compound HDACs inhibitory activity and anti-tumor activity with the lead compound ciprofloxacin and the positive drug SAHA (vorinostat, vorinostat) compared to improve. In particular, compound 12b not only showed the strongest inhibitory activity against HDAC1 (IC50 = 0.041 ± 0.005μmol·L -1) and HDAC6 (IC50 = 0.039 ± 0.006μmol·L -1) The tumor cells NCI-H460 (IC50 = 0.7 ± 0.04μmol·L -1) and A549 (IC50 = 0.9 ± 0.12μmol·L -1) also had the strongest inhibitory activity. The results showed that histone deacetylase inhibitor (HDACi) is a kind of important anti-tumor target drugs, which can improve the anti-tumor activity of quinolones.