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Bioorg Med Chem. 2015 May 1;23(9):2004-9. doi: 10.1016/j.bmc.2015.03.019. Epub 2015 Mar 12.

The CERT antagonist HPA-12: first practical synthesis and individual binding evaluation of the four stereoisomers.

Author information

1
SPCMIB, UMR-CNRS 5068, Université Paul Sabatier-Toulouse III, 118, route de Narbonne, F-31062 Toulouse Cedex 9, France.
2
Unité de Service et de Recherche CNRS-Pierre Fabre n°3388 ETaC, CRDPF, 3 avenue H. Curien, 31035 Toulouse Cedex 01, France.
3
Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 81237 Bratislava, Slovakia.
4
Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 81237 Bratislava, Slovakia. Electronic address: dusan.berkes@stuba.sk.
5
URCOM, EA 3221, INC3M CNRS FR-3038, UFR Sciences & Techniques, University of Le Havre, 25, rue Philippe Lebon, B.P. 540, F-76058 Le Havre Cedex, France.
6
SPCMIB, UMR-CNRS 5068, Université Paul Sabatier-Toulouse III, 118, route de Narbonne, F-31062 Toulouse Cedex 9, France. Electronic address: ballereau@chimie.ups-tlse.fr.
7
SPCMIB, UMR-CNRS 5068, Université Paul Sabatier-Toulouse III, 118, route de Narbonne, F-31062 Toulouse Cedex 9, France. Electronic address: genisson@chimie.ups-tlse.fr.

Abstract

The first unified synthetic route to the four enantiopure HPA-12 stereoisomers in multi-gram scale is reported based on Crystallization-Induced Asymmetric Transformation (CIAT) technology. This preparative stereoselective synthesis allowed the unprecedented comparative evaluation of HPA-12 stereoisomers regarding their interaction with the CERT START domain. In vitro binding assay coupled to in silico docking approach indicate a possible interaction for the four derivatives. The first TR-FRET homogeneous-phase assay was developed to quantify their binding to the START domain, allowing complete determination of HPA-12 EC₅₀. Results indicate that not only the (1R,3S) lead to the strongest binding, but that both 1R and 3S stereocenters similarly contribute to extent of recognition This automated homogenous assay further opens up promising prospect for the identification of novel potential CERT antagonist by means of high throughput screening.

KEYWORDS:

CERT; CIAT; HPA-12; Sphingolipid; TR-FRET

PMID:
25818765
DOI:
10.1016/j.bmc.2015.03.019
[Indexed for MEDLINE]

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