Lumazine合酶的核糖基氨基嘧啶底物和核黄素合酶产物的<i>S-</i>核苷类似物的合成及酶抑制活性,The Journal of Organic Chemistry

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Lumazine合酶的核糖基氨基嘧啶底物和核黄素合酶产物的S-核苷类似物的合成及酶抑制活性
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2007-08-16 00:00:00 , DOI: 10.1021/jo0709495
Arindam Talukdar ₁ , Boris Illarionov ₁ , Adelbert Bacher ₁ , Markus Fischer ₁ , Mark Cushman ₁

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Lumazine合酶和核黄素合酶催化核黄素生物合成中的最后两个步骤。为了获得这两种酶的结构和机理探针，以及作为抗生素具有潜在价值的抑制剂，设计了玉米嗪合成酶催化反应的嘧啶底物的硫类似物和核黄素合成酶催化反应的产物。轻松合成S-核苷5-氨基-6-（d-核糖硫基）嘧啶-2,4（1 H，3 H）-二酮盐酸盐（15）及其硝基前体5-nitro-6-（d-核糖硫基））嘧啶-2,4（1 H，3 H）-二酮（14）进行了说明。对这些化合物针对从多种微生物获得的lumazine合酶和核黄素合酶进行了测试。发现化合物14和15是核黄素合酶和鲁嗪合酶的抑制剂。化合物14是枯草芽孢杆菌lumazine合酶（K _i 26μM ），粟酒裂殖酵母lumazine合酶（K _i 2.0μM ），结核分枝杆菌lumazine合酶（K _i 11μM ），大肠杆菌核黄素合成酶（K _i 2.7μM ）的抑制剂，和结核分枝杆菌核黄素合酶（K _i 0.56μM ），而化合物15是枯草芽孢杆菌lumazine合酶（K _i 2.6μM ），S。pombe lumazine合酶（K _i 0.16μM ），结核分枝杆菌lumazine合酶（K _i 31μM），大肠杆菌核黄素合酶（K _i 47μM）和结核分枝杆菌核黄素合酶（K _i 2.5μM）。

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Synthesis and Enzyme Inhibitory Activity of the S-Nucleoside Analogue of the Ribitylaminopyrimidine Substrate of Lumazine Synthase and Product of Riboflavin Synthase

Lumazine synthase and riboflavin synthase catalyze the last two steps in the biosynthesis of riboflavin. To obtain structural and mechanistic probes of these two enzymes, as well as inhibitors of potential value as antibiotics, a sulfur analogue of the pyrimidine substrate of the lumazine synthase-catalyzed reaction and product of the riboflavin synthase-catalyzed reaction was designed. Facile syntheses of the S-nucleoside 5-amino-6-(d-ribitylthio)pyrimidine-2,4(1H,3H)-dione hydrochloride (15) and its nitro precursor 5-nitro-6-(d-ribitylthio)pyrimidine-2,4(1H,3H)-dione (14) are described. These compounds were tested against lumazine synthase and riboflavin synthase obtained from a variety of microorganisms. Compounds 14 and 15 were found to be inhibitors of both riboflavin synthase and lumazine synthase. Compound 14 is an inhibitor of Bacillus subtilis lumazine synthase (K_i 26 μM), Schizosaccharomyces pombe lumazine synthase (K_i 2.0 μM), Mycobacterium tuberculosis lumazine synthase (K_i 11 μM), Escherichia coli riboflavin synthase (K_i 2.7 μM), and Mycobacterium tuberculosis riboflavin synthase (K_i 0.56 μM), while compound 15 is an inhibitor of B. subtilis lumazine synthase (K_i 2.6 μM), S. pombe lumazine synthase (K_i 0.16 μM), M. tuberculosis lumazine synthase (K_i 31 μM), E. coli riboflavin synthase (K_i 47 μM), and M. tuberculosis riboflavin synthase (K_i 2.5 μM).

更新日期：2007-08-16

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