吡硫醇丙酯前体药物的合成及其降解动力学

Synthesis of pyritinol tetrapropionate ester prodrug and its degradation kinetics

目的：合成吡硫醇前体药物,并研究其在不同pH缓冲溶液中及血浆中的水解动力学。方法：以吡硫醇和丙酸酐为原料,经过简单的酯化反应合成吡硫醇丙酯,利用RP-HPLC法测定前体药物的油水分配系数、溶解度、在不同pH值缓冲溶液中及血浆中的降解动力学。结果：经UV,IR,MS和NMR确证目标化合物的结构。前体药物的水解曲线呈V-型分布,pH值在5-6最稳定,血浆中前药可迅速转化成吡硫醇。结论：吡硫醇丙酯是具有良好前景的前体药物。

Objective：To synthesize pyritinol tetrapropionate ester prodrug, determine its aqueous stability at various pH values and bioreversion kinetics in rat plasma. Methods：Pyritinol tetrapropionate ester prodrug was synthesized by esterification reaction using pyritinol and propionic anhydride as the starting materials. Prodrug hydrolysis was studied in aqueous buffer solutions with pH 2 - 10 as well as 80% rat plasma solution by the reversed-phase high performance liquid chromatography （RP-HPLC） method, meanwhile the solubility and the partition coefficient of the prodrug were investigated. Results： The structure of systhesized prodrug was confirmed by IR, UV, MS and ^1H-NMR spectroscopy and it＇s purity was deteced by RP-HPLC. The prodrug exhibited a typical V-shape of a carboxylic ester with maximum stability at slight acidic pH 5.0 - 6.0. It could be hydrolyzed fastly by enzymes in 80% rat plasma. Conclusion： Pyritinol tetrapropionate ester prodrug is a promising prodrug.