摘要
目的设计、合成左氧氟沙星与川芎嗪缀合物并研究其抑制微管蛋白聚合作用和抗肿瘤活性。方法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位羧基上引入川芎嗪单元,并采用微管蛋白聚合试剂盒和MTT法测试所合成目标缀合物对微管蛋白聚合的抑制活性和体外抗A549、HepG2、MCF-7、MDA-MB-231、PC-3这5种肿瘤细胞的活性。结果合成了3个新化合物(4,8,9),其结构均经过1H NMR和HR-MS进行确证。初步的生物活性结果测试表明,所合成的左氧氟沙星-川芎嗪缀合物对微管蛋白聚合的抑制作用与阳性药物秋水仙碱相当,并对A549、HepG2、MCF-7、MDA-MB-231、PC-3这5种肿瘤细胞均有较强的抑制活性,特别是缀合物9[IC50=(0.3±0.2)μmol/L]对MCF-7展现出了最强的抑制活性,分别是先导化合物左氧氟沙星[IC50=(61.5±5.8)μmol/L]和川芎嗪[IC50=(14.7±1.6)μmol/L]的205和49倍;同时,这些左氧氟沙星-川芎嗪缀合物对正常乳腺上皮细胞MCF-10A均没有毒性。结论川芎嗪是一个抗肿瘤药效团,能够增强喹诺酮类药物的抗肿瘤活性。
Objective To synthesize levofloxacin-ligustrazine conjugates and investigate their inhibition of tubulin polymerization and anti-tumor activities in vitro.Methods A series of levofloxacin-ligustrazine conjugates were designed and synthesized by introduction of ligustrazine unit at C-3 position of levofloxacin.Conjugates inhibition of tubulin polymerization was evaluated by tubulin polymerization assay kit,and their anti-tumor activities in vitro were evaluated in A549,HepG2,MCF-7,MDA-MB-231 and PC-3 cells by MTT assays.Results Three novel levofloxacin-ligustrazine conjugates（4,8,9）were synthesized,whose structures were characterized by 1 H NMR and HR-MS.The results indicated that three conjugates showed potent inhibitory effects on tubulin polymerization,which were even equipotent to reference drug CA-4.Conjugates 4,8,9 also displayed potent inhibitory effect on the proliferation of five cancer cells,which were more effective than lead compound levofloxacin.Specifically,nine[IC50=（0.3±0.2）μmol/L]stood out among three conjugates and showed the most significant cytotoxic activity against MCF-7,which was 205-and 49-fold more potent than levofloxacin[IC50=（61.5±5.8）μmol/L]and ligustrazine[IC50=（14.7±1.6）μmol/L],respectively.Moreover,three conjugates were not toxic to normal MCF-10 Acells.Conclusion The ligustrazine moiety is a pharmacophore,and can enhance the anti-tumor activities of quinolones.
作者
卢颖洁
岳方
Lu Yingjie;Yue Fang(Department of Clinical Laboratory,Wuhan No.1 Hospital,Wuhan 430022,China;Department of Cell Biology,College of Life Sciences;Department of Chemistry,College of Chemistry and Molecular Sciences,Wuhan University,Wuhan 430072,China)
出处
《华中科技大学学报（医学版）》
CAS
CSCD
北大核心
2018年第4期410-416,共7页
Acta Medicinae Universitatis Scientiae et Technologiae Huazhong
关键词
左氧氟沙星
川芎嗪
缀合物
抗肿瘤活性
levofloxacin
ligustrazine
conjugates
antiproliferative activity
