Enantioselective Inhibition of Microbial Lipolytic Enzymes by Nonracemic Monocyclic Enolphosphonate Analogues of Cyclophostin

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• 作者：Vanessa Point ; Raj K. Malla ; Frederic Carri猫re ; St茅phane Canaan ; Christopher D. Spilling ; Jean-Fran莽ois Cavalier
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4393-4401
• 全文大小：463K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

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 (S_p) configuration using (S_c) inhibitors, whereas no obvious stereopreference at phosphorus was observed with (R_c) compounds. Conversely, Rv0183 exhibited strong enantioselective discrimination for (S_p) configuration regardless of the chirality at the asymmetric carbon atom. Lastly, LipY discriminated only the unusual diastereoisomeric configuration (R_c, R_p) 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.