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首页> 外文期刊>Chemistry: A European journal >Reversible and efficient inhibition of UDP-galactopyranose mutase by electrophilic, constrained and unsaturated UDP-galactitol analogues
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Reversible and efficient inhibition of UDP-galactopyranose mutase by electrophilic, constrained and unsaturated UDP-galactitol analogues

机译：亲电的，受约束的和不饱和的UDP-半乳糖醇类似物可逆和有效地抑制UDP-吡喃半乳糖突变酶

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摘要

A series of UDP-galactitols were designed as analogues of high-energy intermediates of the UDP-galactopyranose mutase (UGM) catalyzed furanose/pyranose interconversion, an essential step of Mycobacterium tuberculosis cell wall biosynthesis. The final compounds structurally share the UDP and the galactitol substructures that were connected by four distinct electrophilic connections (epoxide, lactone and Michael acceptors). All molecules were synthesized from a common perbenzylated acyclic galactose precursor that was derivatized by alkenylation, alkynylation and cyclopropanation. The inhibition study against UGM could clearly show that slight changes in the relative orientation of the UDP and the galactitol moieties resulted in dramatic variations of binding properties. Compared to known inhibitors, the epoxide derivative displayed a very tight, reversible, inhibition profile. Moreover, a time-dependent inactivation study showed that none of these electrophilic structures could react with UGM, or its FAD cofactor, the catalytic nucleophile of this still intriguing reaction. Shedding inhibitors: UDP-Galactopyranose mutase (UGM) is a validated target for treating tuberculosis. Its mechanism involves formation of a key covalent FAD-substrate intermediate, 1. A series of electrophilic UDP-galactitols were synthesized and assayed as inhibitors or inactivators of UGM. Strong inhibitions were observed, especially with epoxide 2. Interestingly, none of the molecules displayed an irreversible inhibition mode.
机译：设计了一系列UDP半乳糖醇作为UDP半乳糖吡喃糖糖突变酶（UGM）催化的呋喃糖/吡喃糖相互转化的高能中间体的类似物，这是结核分枝杆菌细胞壁生物合成的重要步骤。最终化合物在结构上共享UDP和半乳糖醇亚结构，它们通过四个不同的亲电子连接（环氧化物，内酯和迈克尔受体）相连。所有分子均由常见的过苄基无环半乳糖前体合成，该前体通过烯基化，炔基化和环丙烷化作用衍生化。对UGM的抑制作用研究可以清楚地表明，UDP和半乳糖醇部分的相对方向发生细微变化会导致结合特性发生巨大变化。与已知的抑制剂相比，环氧衍生物显示出非常紧密的，可逆的抑制曲线。此外，一项随时间变化的灭活研究表明，这些亲电子结构均无法与UGM或其FAD辅因子（仍是这种引人入胜的反应的催化亲核试剂）反应。脱落抑制剂：UDP-半乳糖苷酶（UGM）是治疗结核病的有效靶标。其机制涉及关键的共价FAD底物中间体1的形成。合成了一系列亲电UDP-半乳糖醇，并将其检测为UGM的抑制剂或灭活剂。观察到强烈的抑制作用，尤其是对环氧化物2而言。有趣的是，没有一个分子显示出不可逆的抑制模式。

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