基于京尼平结构的衍生物设计与合成及其对HepG2细胞毒性的研究  

Design,Synthesis and Toxicity on HepG2 Cells of Derivatives Based on the Structure of Genipin

作　　者：孙丽[1] 苗健 王丽丽[1] 张帆 董振科 SUN Li;MIAO Jian;WANG Lili;ZHANG Fan;DONG Zhenke(Hefei Stomatological Hospital/Hefei Stomatological Clinical College,Anhui Medical University,Hefei Anhui 230000,China;Beijing Mundipharma Pharmaceutical Co.Ltd,Hefei Anhui 230001,China)

机构地区：[1]合肥市口腔医院/安徽医科大学合肥口腔临床学院,安徽合肥230000 [2]萌蒂(中国)制药有限公司,安徽合肥230001

出　　处：《中医药导报》2024年第4期71-74,共4页Guiding Journal of Traditional Chinese Medicine and Pharmacy

摘　　要：目的:设计并合成一系列基于京尼平结构的环烯醚萜类衍生物,并探讨其对HepG2细胞的毒性作用,为寻找具有肝保护作用的药物提供一定的理论指导。方法:以京尼平为起始物,以三氟化硼乙醚为催化剂,在低温无水无氧体系下与低碳醇(甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇)进行S_(N)1取代反应,获得的产物经^(1)H-NMR进行结构表征;采用CCK-8法评价化合物对HepG2细胞的细胞毒性,并以谷胱甘肽为阳性对照,以IC_(50)值表示其毒性强弱。结果:设计并合成了6个京尼平衍生物,分别是1-O-甲基京尼平、1-O-乙基京尼平、1-O-正丙基京尼平、1-O-异丙基京尼平、1-O-正丁基京尼平、1-O-叔丁基京尼平,经^(1)H-NMR表征其结构正确。细胞实验显示,谷胱甘肽的IC_(50)值>1 000μmol/L,京尼平的IC_(50)值为(558.70±22.81)μmol/L,1-O-正丙基京尼平、1-O-正丁基京尼平的IC_(50)值分别为(537.40±188.10)μmol/L、(586.10±42.41)μmol/L,细胞毒性均低于谷胱甘肽,但与京尼平相近;1-O-异丙基京尼平的IC_(50)值为(628.30±38.72)μmol/L,低于谷胱甘肽,但高于京尼平;1-O-甲基京尼平、1-O-乙基京尼平、1-O-叔丁基京尼平的IC_(50)值分别为(324.30±55.67)μmol/L、(111.95±18.06)μmol/L、(91.10±15.20)μmol/L,均低于谷胱甘肽和京尼平。结论:合成了6个京尼平衍生物,获得了一条简单的、可控的京尼平衍生物的合成方法;其中京尼平衍生物1-O-正丙基京尼平、1-O-异丙基京尼平、1-O-正丁基京尼平对HepG2细胞毒性较小。Objective:To design and synthesize a series of iridoid derivatives based on the structure of genipin,and to investigate their toxic effects on HepG2 cells,in order to provide theoretical guidance for the search of hepatoprotective drugs.Methods:The S_(N)1 substitution reaction was performed with low carbon alcohols(methanol,ethanol,n-propanol,isopropanol,n-butanol,t-butanol)in low temperature anhydrous and anaerobic system using genipin as starting material and boron trifluoride ether as catalyst.The structure of the products were characterized by^(1)H-NMR.The cytotoxicity of the compounds to HepG2 cells were evaluated by CCK-8 method.Glutathione was used as a positive control and IC_(50) was used to indicate its toxicity.Results:Six genipin derivatives were designed and synthesized,which were 1-0-methyl genipin,1-0-ethyl genipin,1-O-n-propyl genipin,1-0-isopropyl genipin,1-0-n-butyl genipin,1-0-t-butyl genipin.Their structures were correctly characterized by ^(1)H-NMR.The IC_(50) of glutathione was greater than 1000μmol/L,the IC_(50) of genipin was(558.70±22.81)μmol/L,and the IC_(50) of 1-0-n-propyl genipin and 1-0-n-butyl genipin were(537.40±188.10)μmol/L and(586.10±42.41)μmol/L,respectively.The cytotoxicity was lower than that of glutathione,but similar to that of genipin.The IC_(50) value of 1-0-isopropyl genipin was(628.30±38.72)μmol/L,which was lower than that of glutathione and higher than that of genipin.The IC_(50) values of 1-O-methyl genipin,10-ethyl genipin and 1-0-t-butanol genipin were as follows:(324.30±55.67)μmol/L,(111.95±18.06)μmol/L,(91.10±15.20)μumol/L,which were lower than glutathione and genipin.Conclusion:Six genipin derivatives were synthesized.A simple and controllable method for the synthesis of genipin derivatives was obtained.Among them,genipin derivatives 1-0-n-propyl genipin,1-0-isopropyl genipin and 1-0-n-butyl genipin were less toxic to HepG2 cells.

关 键 词：京尼平 京尼平衍生物 HEPG2细胞 肝细胞毒性 肝保护作用 

分 类 号：R284.3[医药卫生—中药学]