title: Studies on the inhibition of sphingosine-1-phosphate lyase by stabilized reaction intermediates and stereodefined azido phosphates.
abstract: Two kinds of inhibitors of the PLP-dependent enzyme sphingosine-1-phosphate lyase have been designed and tested on the bacterial (StS1PL) and the human (hS1PL) enzymes. Amino phosphates 1, 12, and 32, mimicking the intermediate aldimines of the catalytic process, were weak inhibitors on both enzyme sources. On the other hand, a series of stereodefined azido phosphates, resulting from the replacement of the amino group of the natural substrates with an azido group, afforded competitive inhibitors in the low micromolar range on both enzyme sources. This similar behavior represents an experimental evidence of the reported structural similarities for both enzymes at their active site level. Interestingly, the anti-isomers of the non-natural enantiomeric series where the most potent inhibitors on hS1PL.
authors.affiliation: Spanish National Research Council (CSIC), Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Research Unit on Bioactive Molecules (RUBAM), Department of Biomedicinal Chemistry, Jordi Girona 18-26, 08034, Barcelona, Spain; University of Barcelona (UB), Faculty of Pharmacy, Department of Pharmacology, Toxicology and Medicinal Chemistry, Unit of Pharmaceutical Chemistry (Associated Unit to CSIC), Avda. Joan XXIII s/n, 08028, Barcelona, Spain.
authors.forename: Pol
authors.initials: P
authors.lastname: Sanllehí
authors.affiliation: Spanish National Research Council (CSIC), Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Research Unit on Bioactive Molecules (RUBAM), Department of Biomedicinal Chemistry, Jordi Girona 18-26, 08034, Barcelona, Spain.
authors.forename: José-Luís
authors.initials: JL
authors.lastname: Abad
authors.affiliation: Spanish National Research Council (CSIC), Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Department of Biological Chemistry and Molecular Modelling, Jordi Girona 18-26, 08034, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Bujons
authors.affiliation: Spanish National Research Council (CSIC), Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Research Unit on Bioactive Molecules (RUBAM), Department of Biomedicinal Chemistry, Jordi Girona 18-26, 08034, Barcelona, Spain.
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.affiliation: Spanish National Research Council (CSIC), Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Research Unit on Bioactive Molecules (RUBAM), Department of Biomedicinal Chemistry, Jordi Girona 18-26, 08034, Barcelona, Spain; University of Barcelona (UB), Faculty of Pharmacy, Department of Pharmacology, Toxicology and Medicinal Chemistry, Unit of Pharmaceutical Chemistry (Associated Unit to CSIC), Avda. Joan XXIII s/n, 08028, Barcelona, Spain. Electronic address: delgado@rubam.net.
authors.forename: Antonio
authors.initials: A
authors.lastname: Delgado
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001386:Azides / Q000737:chemistry*; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D010710:Phosphates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011487:Protein Conformation; D013237:Stereoisomerism
chemical_list: D001386:Azides; D004791:Enzyme Inhibitors; D010710:Phosphates; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase)
keywords: Enzyme inhibitor; Sphingolipids; Sphingosine lyase; Stereocontrolled; Synthesis