Asymmetric Synthesis and Binding Study of New Long-Chain HPA-12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT

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 re...

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Bibliographic Details
Published in:Chemistry : a European journal 2016-05, Vol.22 (19), p.6676-6686
Main Authors: Ďuriš, Andrej, Daïch, Adam, Santos, Cécile, Fleury, Laurence, Ausseil, Frédéric, Rodriguez, Frédéric, Ballereau, Stéphanie, Génisson, Yves, Berkeš, Dušan
Format: Article
Language:English
Subjects:
Acids
acylation
Aliphatic compounds
Alkanes
Amides - chemistry
Amides - metabolism
antitumor agents
Assaying
Asymmetric synthesis
Asymmetry
Binding
Biological Transport
Ceramide
Ceramides - chemistry
Ceramides - metabolism
Chains
Chemical Sciences
Chemistry
Coherence
Coupling
Crystallization
Enantiomers
enantioselectivity
Fluorescence resonance energy transfer
Fretting
Hydrodesulfurization
Intermediates
Ligands
Lipophilic
Models, Molecular
Phenyls
Protein Binding
Protein folding
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - chemistry
Protein-Serine-Threonine Kinases - metabolism
Proteins
Recognition
Reduction
Sequences
sphingolipids
Stereoisomerism
Stereoisomers
Structure-Activity Relationship
synthetic methods
Thiophenes - chemistry
Transformations
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Summary: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. Analogues of the Cer transfer protein (CERT) antagonist HPA‐12 were prepared as their (1R,3S)‐syn and (1R,3R)‐anti stereoisomers from pivotal enantiopure oxoamino acids in 4–6 steps. The sequence relied on a practical crystallization‐induced asymmetric transformation (CIAT) process followed by Sonogashira coupling and triple bond reduction in tandem or not and hydrodesulfurization of the thiophene ring into corresponding alkane moieties (see scheme).
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201505121