Synthesis and Kinetic Evaluation of Cyclophostin and Cyclipostins Phosphonate Analogs As Selective and Potent Inhibitors of Microbial Lipases

Vanessa Point (1) , Raj Malla , Sadia Diomande , Benjamin Martin , Vincent Delorme , Frederic Carriere , Stephane Canaan (1) , Nigam Rath , Christopher Spilling , Jean-François Cavalier (1)

1 LISM - Laboratoire d'ingénierie des systèmes macromoléculaires

A new series of customizable diastereomeric cisand 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.

Mots clés: cyclic phosphonates; microbial lipase; selective inhibition

Domaines: Chimie organique; Biochimie [q-bio.BM]

Vanessa Point, Raj Malla, Sadia Diomande, Benjamin Martin, Vincent Delorme, et al.. Synthesis and Kinetic Evaluation of Cyclophostin and Cyclipostins Phosphonate Analogs As Selective and Potent Inhibitors of Microbial Lipases. Journal of Medicinal Chemistry, 2012, 55 (22), pp.10204-10219. ⟨10.1021/jm301216x⟩. ⟨hal-03798450⟩