title: Asymmetric Synthesis and Binding Study of New Long-Chain HPA-12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT.
abstract: A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA-12 with long aliphatic chains were prepared as their (1R,3S)-syn and (1R,3R)-anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization-induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA-12 analogues in concise 4- to 6-step reaction sequences. Ten compounds were evaluated regarding their ability to bind to the CERT START domain by using the recently developed time-resolved FRET-based homogeneous (HTR-FRET) binding assay. The introduction of a lipophilic appendage on the phenyl moiety led to an overall 10- to 1000-fold enhancement of the protein binding, with the highest effect being observed for a n-hexyl residue in the meta position. The importance of the phenyl ring for the activity was indicated by the reduced potency of the 3-deoxyphytoceramide aliphatic analogues. The 1,3-syn stereoisomers were systematically more potent than their 1,3-anti analogues. In silico studies were used to rationalized these trends, leading to a model of protein recognition coherent with the stronger binding of (1R,3S)-syn HPAs.
authors.affiliation: Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 81237, Bratislava, Slovak Republic), Fax.
authors.forename: Andrej
authors.initials: A
authors.lastname: Ďuriš
authors.affiliation: Normandie Univ, UNIHAVRE, CNRS, URCOM, 76600, Le Havre (France), CNRS INC3M, FR 3038, EA 3221, UFR des Sciences et Techniques, 25 rue Philippe Lebon, B.P. 1123, 76063, Le Havre Cedex, France), Fax. adam.daich@univ-lehavre.fr.
authors.forename: Adam
authors.initials: A
authors.lastname: Daïch
authors.affiliation: SPCMIB, UMR5068, CNRS-Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse, 31062, France), Fax.
authors.forename: Cécile
authors.initials: C
authors.lastname: Santos
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n° 3388 ETaC, CRDPF, 3 avenue H. Curien, 31035, Toulouse cedex 01, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Fleury
authors.affiliation: Unité de Service et de Recherche CNRS-Pierre Fabre n° 3388 ETaC, CRDPF, 3 avenue H. Curien, 31035, Toulouse cedex 01, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Ausseil
authors.affiliation: SPCMIB, UMR5068, CNRS-Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse, 31062, France), Fax.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rodriguez
authors.affiliation: SPCMIB, UMR5068, CNRS-Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse, 31062, France), Fax.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Ballereau
authors.affiliation: SPCMIB, UMR5068, CNRS-Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse, 31062, France), Fax. genisson@chimie.ups-tlse.fr.
authors.forename: Yves
authors.initials: Y
authors.lastname: Génisson
authors.affiliation: Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 81237, Bratislava, Slovak Republic), Fax. dusan.berkes@stuba.sk.
authors.forename: Dušan
authors.initials: D
authors.lastname: Berkeš
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000378:metabolism; D001692:Biological Transport; D002518:Ceramides / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry*
chemical_list: C000611369:3-deoxyphytoceramide; D000577:Amides; D002518:Ceramides; D008024:Ligands; C441643:N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide; D013876:Thiophenes; D017346:Protein Serine-Threonine Kinases
keywords: acylation; antitumor agents; enantioselectivity; sphingolipids; synthetic methods