环丙沙星与组蛋白去乙酰化酶抑制剂缀合物的合成及抗肿瘤活性  

Synthesis and anti-tumor activity of ciprofloxacin-histone deacetylase inhibitor conjugates

作　　者：裴婷[1] 刘芳[2] 邓艾平[1] 

机构地区：[1]武汉市中心医院药学部,湖北武汉430014 [2]中南民族大学药学院,湖北武汉430071

出　　处：《药学学报》2016年第12期1871-1880,共10页Acta Pharmaceutica Sinica

摘　　要：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。Eighteen novel ciprofloxacin-histone deacetylase inhibitor（HDACi） conjugates were designed and synthesized from suberic acid and ciprofloxacin via esterification and amidation reaction. All conjugates were confirmed by the application of 1H NMR and HR-MS spectra, their activities against HDACs were evaluated by HDACs assay kit and the anti-tumor activities were evaluated in five cancer cells with CCK-8 assay. The preliminary biological results showed that these conjugates displayed potent activity against HDACs and significant anti-proliferative effect on the cancer cells. Some conjugates exhibited activities better than that of the parent compound ciprofloxacin and drug SAHA. Specifically, compound 12 b exhibited the most potent anti-HDAC1（IC50 = 0.041 ± 0.005 μmol·L^-1） and HDAC6（IC50 = 0.039 ± 0.006 μmol·L^-1） activities, and also showed the greatest potency against NCI-H460（IC50 = 0.7 ± 0.04 μmol·L^-1） and A549（IC50 = 0.9 ± 0.12 μmol·L^-1）. These results suggest that the histone deacetylase inhibitors have significant anti-tumor activities, which can enhance the anti-tumor activity of quinolones.

关 键 词：环丙沙星-组蛋白去乙酰化酶抑制剂缀合物 组蛋白去乙酰化酶抑制剂 合成 抗肿瘤活性 

分 类 号：R916[医药卫生—药学]