Asymmetric Synthesis and Binding Study of New Long-Chain HPA-12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT.
Identifieur interne : 000083 ( Main/Exploration ); précédent : 000082; suivant : 000084Asymmetric Synthesis and Binding Study of New Long-Chain HPA-12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT.
Auteurs : Andrej Uriš ; Adam Daïch [France] ; Cécile Santos ; Laurence Fleury [France] ; Frédéric Ausseil [France] ; Frédéric Rodriguez ; Stéphanie Ballereau ; Yves Génisson [France] ; Dušan Berkeš [Slovaquie]Source :
- Chemistry (Weinheim an der Bergstrasse, Germany) [ 1521-3765 ] ; 2016.
English descriptors
- KwdEn :
- Amides (chemistry), Amides (metabolism), Biological Transport, Ceramides (chemistry), Ceramides (metabolism), Ligands, Models, Molecular, Protein Binding, Protein-Serine-Threonine Kinases (antagonists & inhibitors), Protein-Serine-Threonine Kinases (chemistry), Protein-Serine-Threonine Kinases (metabolism), Stereoisomerism, Structure-Activity Relationship, Thiophenes (chemistry).
- MESH :
- chemical , antagonists & inhibitors : Protein-Serine-Threonine Kinases.
- chemical , chemistry : Amides, Ceramides, Protein-Serine-Threonine Kinases, Thiophenes.
- chemical , metabolism : Amides, Ceramides, Protein-Serine-Threonine Kinases.
- Biological Transport, Ligands, Models, Molecular, Protein Binding, Stereoisomerism, Structure-Activity Relationship.
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.
DOI: 10.1002/chem.201505121
PubMed: 27031925
Affiliations:
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Curien, 31035, Toulouse cedex 01, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Unité de Service et de Recherche CNRS-Pierre Fabre n° 3388 ETaC, CRDPF, 3 avenue H. Curien, 31035, Toulouse cedex 01</wicri:regionArea><placeName><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Midi-Pyrénées</region><settlement type="city">Toulouse</settlement></placeName></affiliation></author><author><name sortKey="Ausseil, Frederic" sort="Ausseil, Frederic" uniqKey="Ausseil F" first="Frédéric" last="Ausseil">Frédéric Ausseil</name><affiliation wicri:level="3"><nlm:affiliation>Unité de Service et de Recherche CNRS-Pierre Fabre n° 3388 ETaC, CRDPF, 3 avenue H. Curien, 31035, Toulouse cedex 01, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Unité de Service et de Recherche CNRS-Pierre Fabre n° 3388 ETaC, CRDPF, 3 avenue H. Curien, 31035, Toulouse cedex 01</wicri:regionArea><placeName><region type="region" nuts="2">Occitanie (région administrative)</region><region type="old region" nuts="2">Midi-Pyrénées</region><settlement type="city">Toulouse</settlement></placeName></affiliation></author><author><name sortKey="Rodriguez, Frederic" sort="Rodriguez, Frederic" uniqKey="Rodriguez F" first="Frédéric" last="Rodriguez">Frédéric Rodriguez</name><affiliation><nlm:affiliation>SPCMIB, UMR5068, CNRS-Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse, 31062, France), Fax.</nlm:affiliation><wicri:noCountry code="subField">Fax</wicri:noCountry></affiliation></author><author><name sortKey="Ballereau, Stephanie" sort="Ballereau, Stephanie" uniqKey="Ballereau S" first="Stéphanie" last="Ballereau">Stéphanie Ballereau</name><affiliation><nlm:affiliation>SPCMIB, UMR5068, CNRS-Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse, 31062, France), Fax.</nlm:affiliation><wicri:noCountry code="subField">Fax</wicri:noCountry></affiliation></author><author><name sortKey="Genisson, Yves" sort="Genisson, Yves" uniqKey="Genisson Y" first="Yves" last="Génisson">Yves Génisson</name><affiliation wicri:level="1"><nlm:affiliation>SPCMIB, UMR5068, CNRS-Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse, 31062, France), Fax. genisson@chimie.ups-tlse.fr.</nlm:affiliation><country wicri:rule="url">France</country></affiliation></author><author><name sortKey="Berkes, Dusan" sort="Berkes, Dusan" uniqKey="Berkes D" first="Dušan" last="Berkeš">Dušan Berkeš</name><affiliation wicri:level="1"><nlm:affiliation>Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 81237, Bratislava, Slovak Republic), Fax. dusan.berkes@stuba.sk.</nlm:affiliation><country wicri:rule="url">Slovaquie</country></affiliation></author></analytic><series><title level="j">Chemistry (Weinheim an der Bergstrasse, Germany)</title><idno type="eISSN">1521-3765</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amides (chemistry)</term><term>Amides (metabolism)</term><term>Biological Transport</term><term>Ceramides (chemistry)</term><term>Ceramides (metabolism)</term><term>Ligands</term><term>Models, Molecular</term><term>Protein Binding</term><term>Protein-Serine-Threonine Kinases (antagonists & inhibitors)</term><term>Protein-Serine-Threonine Kinases (chemistry)</term><term>Protein-Serine-Threonine Kinases (metabolism)</term><term>Stereoisomerism</term><term>Structure-Activity Relationship</term><term>Thiophenes (chemistry)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Protein-Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Amides</term><term>Ceramides</term><term>Protein-Serine-Threonine Kinases</term><term>Thiophenes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Amides</term><term>Ceramides</term><term>Protein-Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Biological Transport</term><term>Ligands</term><term>Models, Molecular</term><term>Protein Binding</term><term>Stereoisomerism</term><term>Structure-Activity Relationship</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>France</li><li>Slovaquie</li></country><region><li>Midi-Pyrénées</li><li>Occitanie (région administrative)</li></region><settlement><li>Toulouse</li></settlement></list><tree><noCountry><name sortKey=" Uris, Andrej" sort=" Uris, Andrej" uniqKey=" Uris A" first="Andrej" last=" Uriš">Andrej Uriš</name><name sortKey="Ballereau, Stephanie" sort="Ballereau, Stephanie" uniqKey="Ballereau S" first="Stéphanie" last="Ballereau">Stéphanie Ballereau</name><name sortKey="Rodriguez, Frederic" sort="Rodriguez, Frederic" uniqKey="Rodriguez F" first="Frédéric" last="Rodriguez">Frédéric Rodriguez</name><name sortKey="Santos, Cecile" sort="Santos, Cecile" uniqKey="Santos C" first="Cécile" last="Santos">Cécile Santos</name></noCountry><country name="France"><noRegion><name sortKey="Daich, Adam" sort="Daich, Adam" uniqKey="Daich A" first="Adam" last="Daïch">Adam Daïch</name></noRegion><name sortKey="Ausseil, Frederic" sort="Ausseil, Frederic" uniqKey="Ausseil F" first="Frédéric" last="Ausseil">Frédéric Ausseil</name><name sortKey="Fleury, Laurence" sort="Fleury, Laurence" uniqKey="Fleury L" first="Laurence" last="Fleury">Laurence Fleury</name><name sortKey="Genisson, Yves" sort="Genisson, Yves" uniqKey="Genisson Y" first="Yves" last="Génisson">Yves Génisson</name></country><country name="Slovaquie"><noRegion><name sortKey="Berkes, Dusan" sort="Berkes, Dusan" uniqKey="Berkes D" first="Dušan" last="Berkeš">Dušan Berkeš</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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