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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2012 Oct 26

PMID 23095026

Citations 12

Authors

Vanessa Point

Raj K Malla

Sadia Diomande

Benjamin P Martin

Vincent Delorme

Frederic Carriere

Stephane Canaan

Nigam P Rath

Christopher D Spilling

Jean-Francois Cavalier

Affiliations

Soon will be listed here.

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.

Citing Articles

Cyclophostin and Cyclipostins analogues counteract macrolide-induced resistance mediated by erm(41) in Mycobacterium abscessus.

Sarrazin M, Poncin I, Fourquet P, Audebert S, Camoin L, Denis Y J Biomed Sci. 2024; 31(1):103.

PMID: 39623375 PMC: 11613490. DOI: 10.1186/s12929-024-01091-w.

Efficient Synthesis of Novel Phostone and Phostam Derivatives Regioselective Intramolecular Heck Cyclizations of (2-Iodobenzyl)buta-1,3-dienylphosphonates, (2-Iodophenyl)buta-1,3-dienylphosphonates, and....

Sanaa H, Touil S, Durandetti M, Samarat A ACS Omega. 2024; 9(44):44542-44548.

PMID: 39524664 PMC: 11541441. DOI: 10.1021/acsomega.4c06616.

Identification of cell wall synthesis inhibitors active against Mycobacterium tuberculosis by competitive activity-based protein profiling.

Li M, Patel H, Cognetta 3rd A, Smith 2nd T, Mallick I, Cavalier J Cell Chem Biol. 2021; 29(5):883-896.e5.

PMID: 34599873 PMC: 8964833. DOI: 10.1016/j.chembiol.2021.09.002.

Anti-tubercular derivatives of rhein require activation by the monoglyceride lipase Rv0183.

Abrahams K, Hu W, Li G, Lu Y, Richardson E, Loman N Cell Surf. 2020; 6:100040.

PMID: 32743152 PMC: 7389528. DOI: 10.1016/j.tcsw.2020.100040.

The Chemistry and Biology of Cyclophostin, the Cyclipostins and Related Compounds.

Spilling C Molecules. 2019; 24(14).

PMID: 31315184 PMC: 6681047. DOI: 10.3390/molecules24142579.

References

Belle V, Fournel A, Woudstra M, Ranaldi S, Prieri F, Thome V . Probing the opening of the pancreatic lipase lid using site-directed spin labeling and EPR spectroscopy. Biochemistry. 2007; 46(8):2205-14. DOI: 10.1021/bi0616089. View

Carriere F, Renou C, Ransac S, Lopez V, De Caro J, Ferrato F . Inhibition of gastrointestinal lipolysis by Orlistat during digestion of test meals in healthy volunteers. Am J Physiol Gastrointest Liver Physiol. 2001; 281(1):G16-28. DOI: 10.1152/ajpgi.2001.281.1.G16. View

Mishra K, de Chastellier C, Narayana Y, Bifani P, Brown A, Besra G . Functional role of the PE domain and immunogenicity of the Mycobacterium tuberculosis triacylglycerol hydrolase LipY. Infect Immun. 2007; 76(1):127-40. PMC: 2223678. DOI: 10.1128/IAI.00410-07. View

De Caro J, Sias B, Grandval P, Ferrato F, Halimi H, Carriere F . Characterization of pancreatic lipase-related protein 2 isolated from human pancreatic juice. Biochim Biophys Acta. 2004; 1701(1-2):89-99. DOI: 10.1016/j.bbapap.2004.06.005. View

Hadvary P, Sidler W, Meister W, Vetter W, WOLFER H . The lipase inhibitor tetrahydrolipstatin binds covalently to the putative active site serine of pancreatic lipase. J Biol Chem. 1991; 266(4):2021-7. View

Cavalier J, Ransac S, Verger R, Buono G . Inhibition of human gastric and pancreatic lipases by chiral alkylphosphonates. A kinetic study with 1,2-didecanoyl-sn-glycerol monolayer. Chem Phys Lipids. 2000; 100(1-2):3-31. DOI: 10.1016/s0009-3084(99)00028-6. View

Nelson R, Miles J . The use of orlistat in the treatment of obesity, dyslipidaemia and Type 2 diabetes. Expert Opin Pharmacother. 2005; 6(14):2483-91. DOI: 10.1517/14656566.6.14.2483. View

Cavalier J, Buono G, Verger R . Covalent inhibition of digestive lipases by chiral phosphonates. Acc Chem Res. 2000; 33(9):579-89. DOI: 10.1021/ar990150i. View

Sheldrick G . A short history of SHELX. Acta Crystallogr A. 2007; 64(Pt 1):112-22. DOI: 10.1107/S0108767307043930. View

10.

Du J, Wang Z . Therapeutic potential of lipase inhibitor orlistat in Alzheimer's disease. Med Hypotheses. 2009; 73(5):662-3. DOI: 10.1016/j.mehy.2009.04.046. View

11.

Verger R . Interfacial enzyme kinetics of lipolysis. Annu Rev Biophys Bioeng. 1976; 5:77-117. DOI: 10.1146/annurev.bb.05.060176.000453. View

12.

Egmond M, de Vlieg J . Fusarium solani pisi cutinase. Biochimie. 2000; 82(11):1015-21. DOI: 10.1016/s0300-9084(00)01183-4. View

13.

Ransac S, Gargouri Y, Marguet F, Buono G, Beglinger C, Hildebrand P . Covalent inactivation of lipases. Methods Enzymol. 1997; 286:190-231. DOI: 10.1016/s0076-6879(97)86012-0. View

14.

Roussel A, Miled N, Berti-Dupuis L, Riviere M, Spinelli S, Berna P . Crystal structure of the open form of dog gastric lipase in complex with a phosphonate inhibitor. J Biol Chem. 2001; 277(3):2266-74. DOI: 10.1074/jbc.M109484200. View

15.

Seeliger D, de Groot B . Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J Comput Aided Mol Des. 2010; 24(5):417-22. PMC: 2881210. DOI: 10.1007/s10822-010-9352-6. View

16.

Laine C, Mornet E, Lemiegre L, Montier T, Cammas-Marion S, Neveu C . Folate-equipped pegylated archaeal lipid derivatives: synthesis and transfection properties. Chemistry. 2008; 14(27):8330-40. DOI: 10.1002/chem.200800950. View

17.

Dhouib R, Ducret A, Hubert P, Carriere F, Dukan S, Canaan S . Watching intracellular lipolysis in mycobacteria using time lapse fluorescence microscopy. Biochim Biophys Acta. 2011; 1811(4):234-41. DOI: 10.1016/j.bbalip.2011.01.001. View

18.

Egloff M, Marguet F, Buono G, Verger R, Cambillau C, van Tilbeurgh H . The 2.46 A resolution structure of the pancreatic lipase-colipase complex inhibited by a C11 alkyl phosphonate. Biochemistry. 1995; 34(9):2751-62. DOI: 10.1021/bi00009a003. View

19.

Fernandez S, Jannin V, Rodier J, Ritter N, Mahler B, Carriere F . Comparative study on digestive lipase activities on the self emulsifying excipient Labrasol, medium chain glycerides and PEG esters. Biochim Biophys Acta. 2007; 1771(5):633-40. DOI: 10.1016/j.bbalip.2007.02.009. View

20.

Schmid R, Verger R . Lipases: Interfacial Enzymes with Attractive Applications. Angew Chem Int Ed Engl. 2018; 37(12):1608-1633. DOI: 10.1002/(SICI)1521-3773(19980703)37:12<1608::AID-ANIE1608>3.0.CO;2-V. View