Liguzinediol芳酸单酯前药的合成、理化性质及血浆酶解评价  

Synthesis,physicochemical properties and bioconversion of the mono substituted benzoate prodrugs of liguzinediol

作　　者：张静[1] 李伟[1] 文红梅[1] 王天麟[1] 朱浩浩[1] 程冬[1] 杨坤玓 陈昱清 

机构地区：[1]南京中医药大学药学院,南京210023

出　　处：《中国新药杂志》2015年第3期325-330,共6页Chinese Journal of New Drugs

基　　金：国家自然科学基金(81072542);高等学校博士学科点专项科研基金(20123237110010);江苏省自然科学基金(BK2011077;BK20131262);江苏高校优势学科建设工程资助项目

摘　　要：目的:设计合成系列liguzinediol的芳酸单酯前药,通过理化性质和人体血浆酶解特性研究,筛选出适合liguzinediol口服给药的候选前药。方法:以吡啶催化的酰氯与醇的酯合成法及DMAP催化的酸与醇的DCC缩合法,共合成6个liguzinediol的芳酸单酯类前药,用红外、质谱、核磁共振氢谱和碳谱进行结构确认。采用高效液相色谱法测定化合物的容量因子、溶解度、p H 7.4的化学稳定性以及体外80%人血浆中酯酶水解的释放特性。结果:liguzinediol的糠酸单酯、3-氯苯甲酸单酯与苯甲酸单酯血浆酶解速率过快;4-二甲氨基苯甲酸单酯化学稳定性较差;4-甲氧基苯甲酸单酯化学稳定性高,酶解释放速率适中。结论:liguzinediol的4-甲氧基苯甲酸单酯化学稳定性较高,体外80%人血浆酶解liguzinediol释放速率合适,可以作为liguzinediol口服给药形式的候选药物前体。Objective： To prepare six mono substituted benzoate prodrugs of liguzinediol, and investigate their physicochemical properties and bioconversion in human plasma in order to obtain a promising prodrug of ligu- zinediol suitable to be administrated orally. Methods： Liguzinediol was coupled with acyl chloride by the catalytic action of pyridine as conventional procedures, or treated with corresponding benzoic acid via the DMAP-catalyzed DCC method to give six mono substituted benzoate prodrugs of liguzinediol. All the prodrugs were characterized by IR, MS, 1H-NMR and 13C-NMR. Their solubility, lipophilicity, chemical stability at pH 7.4, and metabolic sta- bility by esterase in 80% human plasma were determined by HPLC. Results： Benzoate, 3-chlorobenzoate and furo- ic acid ester released liguzinediol too fast to be a controlled prodrug, and 4-dimethylaminobenzoate was chemically unstable. Of six ester prodrugs, 4-methoxybenzoate not only released liguzinediol slowly but also showed highly chemical stability. Conclusion： The 4-methoxybenzoate may be a promising prodrug to be dosed orally with the ad- vantages of highly chemical stability and controlled releasing behavior.

关 键 词：LIGUZINEDIOL 前药 化学稳定性 血浆酶解 4-甲氧基苯甲酸单酯 

分 类 号：R914.5[医药卫生—药物化学]