阿昔洛韦棕榈酰酯的高效合成、结构表征及其体外抗乙肝病毒的作用  

High yield synthesis,structure confirm of acyclovir palmitate and its role in inhibiting hepatitics B in vitro

作　　者：蔡钦生[1] 冯美卿[1] 黄海[1] 周珮[1] 

机构地区：[1]复旦大学药学院生物合成教研室,上海200032

出　　处：《复旦学报（医学版）》2007年第4期486-490,共5页Fudan University Journal of Medical Sciences

基　　金：上海市科委重点项目(024319204)

摘　　要：目的提高阿昔洛韦抗乙肝能力,合成其前体药物阿昔洛韦棕榈酰酯并制成脂质体。方法利用阿昔洛韦和棕榈酰氯在60℃吡啶中合成阿昔洛韦的前体药物阿昔洛韦棕榈酰酯,然后应用脱氧胆酸钠法将其制备成脂质体,并通过HepG22.2.15细胞进行体外抗乙肝病毒作用研究。结果合成反应的收率为68%,合成化合物通过紫外光谱、质谱、红外光谱、1H NMR谱、13C NMR谱、重水交换NMR谱、1H-1HCOSY谱、1H-1HTOCSY谱、BB-DEPT谱、HSQC谱及HMBC谱进行了结构验证,证明为阿昔洛韦棕榈酰酯。脱氧胆酸钠法制备的阿昔洛韦棕榈酰酯脂质体平均粒径为61nm,粒径分布在20~100nm之间。脂质体中的阿昔洛韦棕榈酰酯在浓度为0.044μmol/mL、0.088μmol/mL、0.222μmol/mL时,对HBsAg和HBeAg的抑制率分别达到20.3%、52.6%、68.4%和29.3%、42.4%、53.5%。结论阿昔洛韦和棕榈酰氯在无水吡啶中经60℃24h高效合成了阿昔洛韦棕榈酰酯;脱氧胆酸钠法可将其制备成平均粒径为61nm脂质体;脂质体中阿昔洛韦棕榈酰酯的体外抗乙肝病毒作用明显优于其母药阿昔洛韦。Purpose To improve the antiHBV activity of acyclovir,its prodrug,acyclovir palmitate, was synthesized. Liposomes of acyclovir palmitate was prepared. Methods Based on acyclovir and palmitoyl chloride,prodrug acyclovir palmitate was synthesized at 60℃ for 24 h in pyridine. Furtherly liposomes of acyclovir palmitate was prepared by sodium deoxycholate dialysis. Its ability to inhibit hepatitis B virus HBsAg and HBeAg secretion was studied by a HBV-transfectted cell line （HepG2 2.2.15 cells）. Results With a yield of 68% acyclovir palmitate was synthesized and its structure was confirmed by Uv-Vis, IR,MS,^1 H NMR,^13C NMR,D2O exchange NMR,BB-DEPT,^1 H -^1 H COSY, ^ H- ^1 HTOCSY,HSQC and HMBC. Liposomes of acyclovir palmitate 61 nm, 20-100 nm. The test reveal that the acyclovir palmitate concentration of liposomes that inhibited HBsAg secreteion by 20.3%, 52.6% ,68.4%and HBeAg secretion by 29.3% ,42.4% ,and 53.5% at 0. 044 μmol/mL,0. 088 μmol/ mL,and 0. 222 μmol/mL respectively.. Conclusions Acyclovir palmitate was synthesized at 60℃ for 24 h in pyridine with a high yield. Liposomes of acyclovir palmitate with 61 nm mean size was prepared by sodium deoxycholate dialysis and its ability to inhibit hepatitis B virus HBsAg and HBeAg secretion better than the parent drug.

关 键 词：阿昔洛韦 阿昔洛韦棕榈酰酯 脂质体 抗乙肝病毒 前体药物 

分 类 号：R914.5[医药卫生—药物化学]