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Eur J Med Chem. 2016 Nov 10;123:905-915. doi: 10.1016/j.ejmech.2016.08.008. Epub 2016 Aug 6.

Studies on the inhibition of sphingosine-1-phosphate lyase by stabilized reaction intermediates and stereodefined azido phosphates.

Author information

1
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.
2
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.
3
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.
4
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.

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.

KEYWORDS:

Enzyme inhibitor; Sphingolipids; Sphingosine lyase; Stereocontrolled; Synthesis

PMID:
27543882
DOI:
10.1016/j.ejmech.2016.08.008
[Indexed for MEDLINE]

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