Design, synthesis and biological evaluation of water-soluble phenytoin prodrugs considering the substrate recognition ability of human carboxylesterase 1
Design, synthesis and biological evaluation of water-soluble phenytoin prodrugs considering the substrate recognition ability of human carboxylesterase 1
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DOI：
10.1016/j.ejps.2020.105455
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发表时间：
2020-09-01
影响因子：
4.6
通讯作者：
Hosokawa, Masakiyo
中科院分区：
文献类型：
--
作者：
Takahashi, Masato;Lee, Yeon Joo;Hosokawa, Masakiyo
人羧酸酯酶1（hCES 1）是一种水解酶，主要在肝和肺中表达，在酯型前药的代谢活化中起着最重要的作用。本研究利用hCES 1的底物识别能力，设计、合成并评价了水溶性苯妥英前药。苯妥英前体药物的合成在两个步骤中没有柱层析。已证实，所有前药在人肝微粒体（HLM）溶液中均有效转化为苯妥英（高达54.6 nmol/mg蛋白质/min）。虽然一些前药在强碱性溶液中降解，但所有前药在pH 7.4和8.3的缓冲溶液中的溶解度均大于苯妥英。在合成的苯妥英前药中，3，3-二甲基戊二酸酯前药在溶解度和稳定性方面是上级的，其显示出10 mg/mL或更高的溶解度（苯妥英：
Human carboxylesterase 1 (hCES1) is a hydrolase that is mainly expressed in the liver and lung and plays the most important role in the metabolic activation of ester-type prodrugs. In this study, design, synthesis and evaluation of water-soluble phenytoin prodrugs were performed with consideration of the substrate recognition ability of hCES1. The phenytoin prodrugs were synthesized in two steps without column chromatography. It was confirmed that all prodrugs are efficiently converted to phenytoin in a human liver microsome (HLM) solution (up to 54.6 nmol/mg protein/min). Although some of the prodrugs were degraded in strongly basic solution, the solubility of all prodrugs was greater than that of phenytoin in buffer solutions at pH 7.4 and 8.3. Among the synthesized phenytoin prodrugs, the 3,3-dimethylglutarate prodrug was superior in terms of solubility and stability, and it showed solubility of 10 mg/mL or more (phenytoin: