title: Enantioselective inhibition of microbial lipolytic enzymes by nonracemic monocyclic enolphosphonate analogues of cyclophostin.
abstract: 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.
authors: CNRS, Aix-Marseille Université, Enzymologie Interfaciale et Physiologie de la Lipolyse, UMR 7282, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France.
authors: Vanessa
authors: V
authors: Point
authors: Raj K
authors: RK
authors: Malla
authors: Frederic
authors: F
authors: Carrière
authors: Stéphane
authors: S
authors: Canaan
authors: Christopher D
authors: CD
authors: Spilling
authors: Jean-François
authors: JF
authors: Cavalier
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D005656:Fungal Proteins / Q000037:antagonists & inhibitors*; D005670:Fusarium / Q000201:enzymology; D008049:Lipase / Q000037:antagonists & inhibitors; D008066:Lipolysis; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D001426:Bacterial Proteins; D005656:Fungal Proteins; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C083659:cyclophostin; D002265:Carboxylic Ester Hydrolases; C019952:cutinase; D008994:Monoacylglycerol Lipases; D008049:Lipase