設計與合成噴昔洛韋之環丙烷酸酯作為潛在前體化合物並評估其抗疱疹病毒活性

Abstract

中文摘要 本論文旨在設計合成一系列噴昔洛韋之環丙烷氨基酸酯作為潛在抗疱疹病毒試劑並評估其生物活性。 最近本德爾團隊發現環丙烷酸酯能夠有效提高化合物在酸鹸環境的穩定性，這對於核苷酸優化設計來說無疑是好消息。結合之前的前體藥物設計理念，一系列噴昔洛韋之環丙烷氨基酸酯 (26a, 26b, 26c) 被設計出來用來作為潛在的抗病毒試劑，但是很遺憾，在生物活性測試實驗中該系列化合物對於疱疹病毒基本沒有活性。在對該系列化合物水解穩定性研究後發現，由於其水解時間過長，半衰期最高可達96天，不能夠釋放出足夠的母體藥物來對抗病毒，導致其基本沒有活性。為了進一步驗證該設計，我們又合成了更昔洛韋之環丙烷酰胺化合物 36，同樣的，由於其水解時間過長，半衰期達279天，其生物活性更低。我們的研究進一步說明了前體藥物的活性取決於母體藥物，以及取決於母體藥物與載體藥物所形成的鍵對酵素水解或者化學水解的活性。 我們的實驗研究表明以噴昔洛韋和更昔洛韋為母體藥物并結合環丙烷酸作為前體藥物的設計雖然能夠使得化合物水溶解性得到提高但該系列化合物沒有表現出抗病毒的活性。

Abstract The aim of this dissertation is to design, synthesize and biologically evaluate penciclovir containing substituted cyclopropanecarboxylic acid esters as potential anti-HSV agents. Combining prodrug strategy and Bender’s research, cyclopropanecarboxylic acid ester prodrugs of penciclovir with enhanced hydrolytic stability was designed and expected to enhance permeation of penciclovir into the retinal and corneal tissues. But these compounds （26a, 26b, 26c） showed no activity against HSV-1 and HSV-2, a moderate activity against VZV. Even these compound possess a good water solubility, we found the half-life is too long, thus the parent drug penciclovir could not be released to inhibit the herpes. Furthermore, with an interest to modify the prodrug strategy, we turn to design the ganciclovir containing substituted cyclopropanecarboxylic amide 36. Even with a lot of efforts to synthesis this compound, it showed no activity against the herpes. And the analysis of the stability in phosphate buffer showed that it has a longer half-life of 279 days compared with penciclovir containing cyclopropanecarboxylic acid moiety probably because of the more stable feature of amide bond than the ester bond. These efforts and results suggest that the strategy of incorporating cyclopropanecarboxylic acid moiety to the penciclovir and ganciclovir were useful to improve the solubility but losing activity against herpes.