Cushman Mark, Yang Donglai, Gerhardt Stefan, Huber Robert, Fischer Markus, Kis Klaus, Bacher Adelbert
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
J Org Chem. 2002 Aug 9;67(16):5807-16. doi: 10.1021/jo0201631.
A series of 6-carboxyalkyl and 6-phosphonoxyalkyl derivatives of 7-oxo-8-D-ribityllumazine were synthesized as inhibitors of both Escherichia coli riboflavin synthase and Bacillus subtilis lumazine synthase. The compounds were designed to bind to both the ribitylpurine binding site and the phosphate binding site of lumazine synthase. In the carboxyalkyl series, maximum activity against both enzymes was observed with the 3'-carboxypropyl compound 22. Lengthening or shortening the chain linking the carboxyl group to the lumazine by one carbon resulted in decreased activity. In the phosphonoxyalkyl series, the 3'-phosphonoxypropyl compound 33 was more potent than the 4'-phosphonoxybutyl derivative 39 against lumazine synthase, but it was less potent against riboflavin synthase. Molecular modeling suggested that the terminal carboxyl group of 6-(3'-carboxypropyl)-7-oxo-8-D-ribityllumazine (22) may bind to the side chains of Arg127 and Lys135 of the enzyme. A hypothetical molecular model was also constructed for the binding of 6-(2'-carboxyethyl)-7-oxolumazine (15) in the active site of E. coli riboflavin synthase, which demonstrated that the active site could readily accommodate two molecules of the inhibitor.
合成了一系列7-氧代-8-D-核醇基蝶啶的6-羧烷基和6-膦酰氧基烷基衍生物，作为大肠杆菌核黄素合酶和枯草芽孢杆菌蝶啶合酶的抑制剂。设计这些化合物以结合蝶啶合酶的核醇基嘌呤结合位点和磷酸结合位点。在羧烷基系列中，3'-羧丙基化合物22对两种酶均表现出最大活性。将连接羧基与蝶啶的链延长或缩短一个碳原子会导致活性降低。在膦酰氧基烷基系列中，3'-膦酰氧基丙基化合物33对蝶啶合酶的活性比4'-膦酰氧基丁基衍生物39更强，但对核黄素合酶的活性较弱。分子模拟表明，6-(3'-羧丙基)-7-氧代-8-D-核醇基蝶啶(22)的末端羧基可能与该酶的Arg127和Lys135的侧链结合。还构建了大肠杆菌核黄素合酶活性位点中6-(2'-羧乙基)-7-氧代蝶啶(15)结合的假设分子模型，该模型表明活性位点可以轻松容纳两个抑制剂分子。
