title: Synthesis and kinetic evaluation of cyclophostin and cyclipostins phosphonate analogs as selective and potent inhibitors of microbial lipases.
abstract: A new series of customizable diastereomeric cis- and trans-monocyclic enol-phosphonate analogs to Cyclophostin and Cyclipostins were synthesized. Their potencies and mechanisms of inhibition toward six representative lipolytic enzymes belonging to distinct lipase families were examined. With mammalian gastric and pancreatic lipases no inhibition occurred with any of the compounds tested. Conversely, Fusarium solani Cutinase and lipases from Mycobacterium tuberculosis (Rv0183 and LipY) were all fully inactivated. The best inhibitors displayed a cis conformation (H and OMe) and exhibited higher inhibitory activities than the lipase inhibitor Orlistat toward the same enzymes. Our results have revealed that chemical group at the γ-carbon of the phosphonate ring strongly impacts the inhibitory efficiency, leading to a significant improvement in selectivity toward a target lipase over another. The powerful and selective inhibition of microbial (fungal and mycobacterial) lipases suggests that these seven-membered monocyclic enol-phosphonates should provide useful leads for the development of novel and highly selective antimicrobial agents.
authors.affiliation: CNRS - Aix-Marseille Université , Enzymologie Interfaciale et Physiologie de la Lipolyse, UMR 7282, 31 chemin Joseph Aiguier, 13402 Marseille cedex 20, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Point
authors.forename: Raj K
authors.initials: RK
authors.lastname: Malla
authors.forename: Sadia
authors.initials: S
authors.lastname: Diomande
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Martin
authors.forename: Vincent
authors.initials: V
authors.lastname: Delorme
authors.forename: Frederic
authors.initials: F
authors.lastname: Carriere
authors.forename: Stephane
authors.initials: S
authors.lastname: Canaan
authors.forename: Nigam P
authors.initials: NP
authors.lastname: Rath
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Spilling
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Cavalier
mesh_terms: D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005670:Fusarium / Q000201:enzymology; D007700:Kinetics; D008049:Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D063065:Organophosphonates / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D002265:Carboxylic Ester Hydrolases; D004791:Enzyme Inhibitors; D008049:Lipase; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C560841:cyclipostin P; C083659:cyclophostin; C019952:cutinase; C518354:PNLIP protein, human; C485982:LIPF protein, human