文献类型：期刊文献

中文题名：二氢乳清酸脱氢酶抑制剂前药的合成和稳定性及活性评价

英文题名：Synthesis,stability and activity of the prodrugs of dihydroorotate dehydrogenase inhibitors

作者：单继伟[1];齐甜甜[1];李洪林[1];朱丽丽[1];赵振江[1]

机构：[1]华东理工大学药学院,上海市新药设计重点实验室,上海200237

年份：2018

卷号：53

期号：3

起止页码：410

中文期刊名：药学学报

外文期刊名：Acta Pharmaceutica Sinica

收录：CSTPCD;;Scopus;北大核心:【北大核心2017】；CSCD:【CSCD2017_2018】；PubMed;

基金：国家自然科学基金资助项目(21372078)

语种：中文

中文关键词：二氢乳清酸脱氢酶抑制剂;前药设计;药物稳定性;活性评价

外文关键词：dihydroorotate dehydrogenase inhibitor;prodrug design;drug stability;inhibitory activityevaluation

摘要：本文以课题组前期发现的高活性DHODH抑制剂A为基础,依据前药合成策略,对其羧基进行酯化修饰得到12个前药分子,旨在优化化合物A的稳定性。分子水平抑制活性显示12个前药分子中只有A1~A5有微弱活性,与其作用机制和前药设计相符;随后评价了A1~A12在有机溶剂甲醇和pH为2.0、9.0的缓冲液中的稳定性,结果显示A12在甲醇中能较好的抑制先导分子内成环,A1~A8在酸性条件下易于水解,A9~A12在碱性条件易于水解;最后评价了A1~A12的细胞增殖抑制活性,其中A12表现出很好活性,其IC_(50)值为0.63μmol·L^(-1),与布奎那相当。这些结果为开展进一步体内活性研究奠定了基础。
This study was conducted to improve structural instability of a highly active DHODH inhibitor Afound in our group.Twelve prodrugs were synthesized by modifying the carboxyl group.The enzyme activity test of 12 prodrugs A1-A12 demonstrated that A1-A5 displayed weak inhibitory activity,and A6-A12 displayed no activity,which met the action mechanism of designed prodrug.The structural stability of A1-A12 in methanol and pH 2.0,9.0 buffers were tested,and the results showed that A12 could avoid intramolecular ring-formation in CH_(3)OH,A1-A8 were easily hydrolyzed under acidic conditions,and A9-A12 were inclined to hydrolyze under alkaline conditions.The cell proliferation inhibitory activity of 12 prodrugs were evaluated,in which compound A12 displayed excellent activity(IC_(50)=0.63μmol·L^(-1))similar to brequinar.These results laid a good foundation for conducting further vivo studies.