Enantioselective inhibition of microbial lipolytic enzymes by nonracemic monocyclic enolphosphonate analogues of cyclophostin.
Enantioselective inhibition of microbial lipolytic enzymes by nonracemic monocyclic enolphosphonate analogues of cyclophostin.
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DOI：
10.1021/jm4000787
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发表时间：
2013-05
影响因子：
7.3
通讯作者：
V. Point;R. Malla;F. Carrière;S. Canaan;C. Spilling;J. Cavalier
中科院分区：
文献类型：
--
作者：
V. Point;R. Malla;F. Carrière;S. Canaan;C. Spilling;J. Cavalier
通过不对称合成得到了4个非外消旋的环磷素烯醇膦酸酯类似物，并明确地归属了它们在磷和C-5碳手性中心的绝对构型。通过测试这四种立体异构体对三种微生物脂肪酶的脂解活性的抑制作用来研究手性的影响：茄病镰刀菌角质酶，Rv 0183和结核分枝杆菌的LipY。角质酶是高度非对映选择性的（Sp）配置使用（Sc）抑制剂，而没有明显的立体参照在磷观察（Rc）化合物。相反，Rv 0183表现出很强的对映选择性歧视（Sp）构型的不对称碳原子的手性。最后，LipY仅区分导致最有效抑制剂的不寻常的非对映异构体构型（Rc，Rp）。这一工作为理解非外消旋烯醇式膦酸酯的立体选择性与其抑菌活性之间的关系提供了基本前提，也为设计和合成高度特异性的对映体选择性抗菌剂开辟了新的前景。
Four nonracemic enolphosphonate analogues of Cyclophostin were obtained by asymmetric synthesis, and their absolute configurations at both phosphorus and C-5 carbon chiral centers were unambiguously assigned. The influence of chirality was studied by testing the inhibitory effects of these four stereoisomers toward the lipolytic activity of three microbial lipases: Fusarium solani cutinase, Rv0183, and LipY from Mycobacterium tuberculosis . Cutinase was highly diastereoselective for the (Sp) configuration using (Sc) inhibitors, whereas no obvious stereopreference at phosphorus was observed with (Rc) compounds. Conversely, Rv0183 exhibited strong enantioselective discrimination for (Sp) configuration regardless of the chirality at the asymmetric carbon atom. Lastly, LipY discriminated only the unusual diastereoisomeric configuration (Rc, Rp) leading to the most potent inhibitor. This work, which provides a fundamental premise for the understanding of the stereoselective relationships between nonracemic enolphosphonates and their inhibitory activity, also opens new prospects on the design and synthesis of highly specific enantioselective antimicrobial agents.