两种10-羟基喜树碱碳酸酯的合成及其抗结肠癌活性研究
Synthesis and anti-colon cancer activity of 10-hydroxycamptothecin carbonates
王维 1陈家美 2贺欢欢 1刘静 1杨俊 2梁光平2
作者信息
- 1. 遵义医科大学附属医院临床医学公共实验中心,贵州遵义 563000
- 2. 遵义医药高等专科学校药学系,贵州 遵义 563006
- 折叠
摘要
目的 寻找高效低毒的10-羟基喜树碱新型衍生物.方法 以4-氨基丁醇为起始原料,羟基端通过酯化反应与N-苄氧羰基甘氨酰-L-脯氨酸保护,N端进一步与对硝基苯基氯甲酸酯反应后,再分别与10-羟基喜树碱、7-乙基-10-羟基喜树碱反应得到两种碳酸酯类衍生物,其结构经HR-MS、1H-NMR、13C-NMR表征确认.以伊立替康为阳性对照,采用CCK8法测试它们对人结肠癌细胞(HCT-116、Caco2)、人结肠癌耐药细胞(HCT-15/Taxol、HCT-8/V、HCT-116/5-FU)、人正常结肠上皮细胞(NCM-460)的抑制活性.HPLC初步分析衍生物在不同pH下的稳定性.结果 两种碳酸酯类衍生物对五种结肠癌细胞具有显著的抑制作用,且来源于7-乙基-10-羟基喜树碱的衍生物对HCT-15/Taxol、HCT-8/V、HCT-116/5-FU等结肠癌耐药细胞的抑制活性优于非耐药结肠癌细胞 HCT-116、Caco2,IC50分别为 2.56、2.70、1.42 μmol·L-1.其对 HCT-8/V、HCT-116/5-FU的选择指数(SI)也优于阳性对照伊立替康.在pH 1.0下,该衍生物3 h内可稳定在70％左右,4h后急剧下降到10％以下;在pH 7.4下,12h内可稳定在80％～90％.结论 来源于7-乙基-10-羟基喜树碱的碳酸酯衍生物可作为抗结肠癌药物做进一步研究.
Abstract
Objective To find novel 10-hydroxycamptothecin derivatives with high efficiency and low toxicity.Methods The 4-aminobutanol was used as the starting material,the hydroxyl group was protected by Z-Gly-Pro-OH through esterification reaction,and the N-terminal was further reacted with p-nitrophenylchloroformate,and then reacted with 10-hydroxycamptothecin or 7-ethyl-10-hydroxycamptothecin to obtain two carbonic acid derivatives,whose structures were confirmed by HR-MS,1H-NMR and 13C-NMR.CCK8 assay was used to test the inhibition of irinotecan on human colon cancer cells(HCT-116 and Caco2),human colon cancer drug resistant cells(HCT-15/Taxol,HCT-8/V,and HCT-116/5-FU)and human normal colon epithelial cells(NCM-460)with irinotecan as positive control.The stability at different pH values was analyzed by HPLC.Results Both carbonic acid derivatives had significant inhibition on 5 colon cancer cells.The derivative derived from 7-ethyl-10-hydroxycamptothecin showed better inhibition on HCT-15/Taxol,HCT-8/V and HCT-116/5-FU cells(with IC50 values being 2.56,2.70 and 1.42 μmol·L-1,respectively)than that on HCT-116 and Caco2 cells.The selection index of HCT-8/V and HCT-116/5-FU was better than that of irinotecan.At pH 1.0,the original drug stabilized at about 70％for 3 h,and then drop sharply to less than 10％after 4 h.At pH 7.4,the original drug stabilized at about 80％～90％within 12 h.Conclusion Carbonic acid derivatives from 7-ethyl-10-hydroxycamptothecin can be further studied as anti-colon cancer drugs.
关键词
10-羟基喜树碱/衍生物/结肠癌Key words
10-hydroxycamptothecin/derivative/colon cancer引用本文复制引用
出版年
2024
NETL
NSTL
万方数据