Synthesis of new chimical inducers of Parkinson's disease : structure/activity relationship study
Identifieur interne : 000054 ( Hal/Checkpoint ); précédent : 000053; suivant : 000055Synthesis of new chimical inducers of Parkinson's disease : structure/activity relationship study
Auteurs : Narimane Zeghbib [France]Source :
Descripteurs français
English descriptors
Abstract
A N-aryl pyridinium derivative (PF) has shown promising results as a chemical inducer of Parkinson's disease (PD). Its in vitro and in vivo administration has induced the appearance of characteristical cellular markers of PD but following a much slower kinetics than currently available PD inducers. These preliminary studies have suggested the existence of a link between the N-aryl pyridinium moiety and the ability of the molecule bearing it to chemically induce PD. These results have therefore led to the preparation of structurally related compounds, able to mimic more closely the biochemical mechanisms involved in the onset of PD.Using the same starting material - an aniline derivative - two synthetic pathways have been followed and have led to diversely functionalized N-aryl pyridiniums. The first pathway, based on the Zincke reaction, afforded compounds without hydroxyl group on the pyridinium ring. The second pathway, including a key step of anodic activation and inspired the preparation of PF, led to 3-hydroxy-N-aryl pyridiniums. For both synthetic routes, the nature of the starting material has implied the modification of previously protocols described to gain access to the targeted molecules. The toxicological evaluation of these N-aryl pyridiniums gave rise to a structure / activity relationship study. The results of this study have led to the identification of structural elements allowing both the inhibition of complex I of the mitochondrial respiratory chain and the induction of in vitro neurotoxicity. It was also possible to identify for the first time, a parameter for the modulation of dopaminergic cell penetration and hence the activity of these chemical inducers of PD
Url:
Links toward previous steps (curation, corpus...)
Links to Exploration step
Hal:tel-01459525Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Synthesis of new chimical inducers of Parkinson's disease : structure/activity relationship study</title><title xml:lang="fr">Synthèse de nouveaux inducteurs chimiques de la maladie de Parkinson : étude relation structure/activité</title><author><name sortKey="Zeghbib, Narimane" sort="Zeghbib, Narimane" uniqKey="Zeghbib N" first="Narimane" last="Zeghbib">Narimane Zeghbib</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-24508" status="VALID"> <orgName>Institut de Chimie et des Matériaux Paris-Est</orgName> <orgName type="acronym">ICMPE</orgName> <desc> <address> <addrLine>2 à 8 rue Henri Dunant 94320 THIAIS</addrLine> <country key="FR"></country> </address> </desc> <listRelation> <relation active="#struct-420786" type="direct"></relation> <relation name="UMR7182" active="#struct-441569" type="direct"></relation> </listRelation><tutelles><tutelle active="#struct-420786" type="direct"><org type="institution" xml:id="struct-420786" status="VALID"> <orgName>Université Paris-Est Créteil Val-de-Marne - Paris 12</orgName> <orgName type="acronym">UPEC UP12</orgName> <desc> <address> <addrLine>61 avenue du Général de Gaulle - 94010 Créteil cedex</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.u-pec.fr/</ref> </desc></org></tutelle><tutelle name="UMR7182" active="#struct-441569" type="direct"><org type="institution" xml:id="struct-441569" status="VALID"> <idno type="IdRef">02636817X</idno> <idno type="ISNI">0000000122597504</idno> <orgName>Centre National de la Recherche Scientifique</orgName> <orgName type="acronym">CNRS</orgName> <date type="start">1939-10-19</date> <desc> <address> <country key="FR"></country> </address> <ref type="url">http://www.cnrs.fr/</ref> </desc></org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">HAL</idno><idno type="RBID">Hal:tel-01459525</idno><idno type="halId">tel-01459525</idno><idno type="halUri">https://tel.archives-ouvertes.fr/tel-01459525</idno><idno type="url">https://tel.archives-ouvertes.fr/tel-01459525</idno><date when="2016-04-14">2016-04-14</date><idno type="wicri:Area/Hal/Corpus">000A78</idno><idno type="wicri:Area/Hal/Curation">000A78</idno><idno type="wicri:Area/Hal/Checkpoint">000054</idno><idno type="wicri:explorRef" wicri:stream="Hal" wicri:step="Checkpoint">000054</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Synthesis of new chimical inducers of Parkinson's disease : structure/activity relationship study</title><title xml:lang="fr">Synthèse de nouveaux inducteurs chimiques de la maladie de Parkinson : étude relation structure/activité</title><author><name sortKey="Zeghbib, Narimane" sort="Zeghbib, Narimane" uniqKey="Zeghbib N" first="Narimane" last="Zeghbib">Narimane Zeghbib</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-24508" status="VALID"> <orgName>Institut de Chimie et des Matériaux Paris-Est</orgName> <orgName type="acronym">ICMPE</orgName> <desc> <address> <addrLine>2 à 8 rue Henri Dunant 94320 THIAIS</addrLine> <country key="FR"></country> </address> </desc> <listRelation> <relation active="#struct-420786" type="direct"></relation> <relation name="UMR7182" active="#struct-441569" type="direct"></relation> </listRelation><tutelles><tutelle active="#struct-420786" type="direct"><org type="institution" xml:id="struct-420786" status="VALID"> <orgName>Université Paris-Est Créteil Val-de-Marne - Paris 12</orgName> <orgName type="acronym">UPEC UP12</orgName> <desc> <address> <addrLine>61 avenue du Général de Gaulle - 94010 Créteil cedex</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.u-pec.fr/</ref> </desc></org></tutelle><tutelle name="UMR7182" active="#struct-441569" type="direct"><org type="institution" xml:id="struct-441569" status="VALID"> <idno type="IdRef">02636817X</idno> <idno type="ISNI">0000000122597504</idno> <orgName>Centre National de la Recherche Scientifique</orgName> <orgName type="acronym">CNRS</orgName> <date type="start">1939-10-19</date> <desc> <address> <country key="FR"></country> </address> <ref type="url">http://www.cnrs.fr/</ref> </desc></org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author></analytic></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="mix" xml:lang="en"><term>Chimical inducers</term><term>N-Aryle pyridinium</term><term>Parkinson's disease</term><term>Structure/activity relationship</term></keywords><keywords scheme="mix" xml:lang="fr"><term>Inducteurs chimiques</term><term>Maladie de Parkinson</term><term>N-Aryle pyridiniums</term><term>Relation structure/activité</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">A N-aryl pyridinium derivative (PF) has shown promising results as a chemical inducer of Parkinson's disease (PD). Its in vitro and in vivo administration has induced the appearance of characteristical cellular markers of PD but following a much slower kinetics than currently available PD inducers. These preliminary studies have suggested the existence of a link between the N-aryl pyridinium moiety and the ability of the molecule bearing it to chemically induce PD. These results have therefore led to the preparation of structurally related compounds, able to mimic more closely the biochemical mechanisms involved in the onset of PD.Using the same starting material - an aniline derivative - two synthetic pathways have been followed and have led to diversely functionalized N-aryl pyridiniums. The first pathway, based on the Zincke reaction, afforded compounds without hydroxyl group on the pyridinium ring. The second pathway, including a key step of anodic activation and inspired the preparation of PF, led to 3-hydroxy-N-aryl pyridiniums. For both synthetic routes, the nature of the starting material has implied the modification of previously protocols described to gain access to the targeted molecules. The toxicological evaluation of these N-aryl pyridiniums gave rise to a structure / activity relationship study. The results of this study have led to the identification of structural elements allowing both the inhibition of complex I of the mitochondrial respiratory chain and the induction of in vitro neurotoxicity. It was also possible to identify for the first time, a parameter for the modulation of dopaminergic cell penetration and hence the activity of these chemical inducers of PD</div></front></TEI><hal api="V3"> <titleStmt> <title xml:lang="en">Synthesis of new chimical inducers of Parkinson's disease : structure/activity relationship study</title> <title xml:lang="fr">Synthèse de nouveaux inducteurs chimiques de la maladie de Parkinson : étude relation structure/activité</title> <author role="aut"> <persName> <forename type="first">Narimane</forename> <surname>Zeghbib</surname> </persName> <idno type="halauthorid">1481254</idno> <idno type="IdRef">http://www.idref.fr/198065760</idno> <affiliation ref="#struct-24508"></affiliation> </author> <editor role="depositor"> <persName> <forename>ABES</forename> <surname>STAR</surname> </persName> <email type="md5">f5aa7f563b02bb6adbba7496989af39a</email> <email type="domain">abes.fr</email> </editor> </titleStmt> <editionStmt> <edition n="v1" type="current"> <date type="whenSubmitted">2017-02-07 12:44:14</date> <date type="whenModified">2017-02-11 01:06:08</date> <date type="whenReleased">2017-02-10 15:43:31</date> <date type="whenProduced">2016-04-14</date> <date type="whenEndEmbargoed">2017-02-07</date> <ref type="file" target="https://tel.archives-ouvertes.fr/tel-01459525/document"> <date notBefore="2017-02-07"></date> </ref> <ref type="file" subtype="author" n="1" target="https://tel.archives-ouvertes.fr/tel-01459525/file/TH2016PESC1168.pdf"> <date notBefore="2017-02-07"></date> </ref> </edition> <respStmt> <resp>contributor</resp> <name key="131274"> <persName> <forename>ABES</forename> <surname>STAR</surname> </persName> <email type="md5">f5aa7f563b02bb6adbba7496989af39a</email> <email type="domain">abes.fr</email> </name> </respStmt> </editionStmt> <publicationStmt> <distributor>CCSD</distributor> <idno type="halId">tel-01459525</idno> <idno type="halUri">https://tel.archives-ouvertes.fr/tel-01459525</idno> <idno type="halBibtex">zeghbib:tel-01459525</idno> <idno type="halRefHtml">Chimie thérapeutique. Université Paris-Est, 2016. Français. <NNT : 2016PESC1168></idno> <idno type="halRef">Chimie thérapeutique. Université Paris-Est, 2016. Français. <NNT : 2016PESC1168></idno> </publicationStmt> <seriesStmt> <idno type="stamp" n="STAR">STAR - Dépôt national des thèses électroniques</idno> <idno type="stamp" n="CNRS">CNRS - Centre national de la recherche scientifique</idno> <idno type="stamp" n="UPEC-UPEM">UPEC-UPEM</idno> <idno type="stamp" n="INC-CNRS">Institut de Chimie du CNRS</idno> </seriesStmt> <notesStmt></notesStmt> <sourceDesc> <biblStruct> <analytic> <title xml:lang="en">Synthesis of new chimical inducers of Parkinson's disease : structure/activity relationship study</title> <title xml:lang="fr">Synthèse de nouveaux inducteurs chimiques de la maladie de Parkinson : étude relation structure/activité</title> <author role="aut"> <persName> <forename type="first">Narimane</forename> <surname>Zeghbib</surname> </persName> <idno type="halauthorid">1481254</idno> <idno type="IdRef">http://www.idref.fr/198065760</idno> <affiliation ref="#struct-24508"></affiliation> </author> </analytic> <monogr> <idno type="nnt">2016PESC1168</idno> <imprint> <date type="dateDefended">2016-04-14</date> </imprint> <authority type="institution">Université Paris-Est</authority> <authority type="school">Sciences, Ingénierie et Environnement (Champs-sur-Marne, Seine-et-Marne ; 2015-....)</authority> <authority type="supervisor">Thierry Martens</authority> <authority type="jury">Jean-Pierre Hurvois [Président]</authority> <authority type="jury">Samir Messaoudi [Rapporteur]</authority> <authority type="jury">Emmanuel Brouillet</authority> <authority type="jury">Michäel Rivard</authority> <authority type="jury">Christophe Morin</authority> </monogr> </biblStruct> </sourceDesc> <profileDesc> <langUsage> <language ident="fr">French</language> </langUsage> <textClass> <keywords scheme="author"> <term xml:lang="en">Parkinson's disease</term> <term xml:lang="en">Chimical inducers</term> <term xml:lang="en">N-Aryle pyridinium</term> <term xml:lang="en">Structure/activity relationship</term> <term xml:lang="fr">N-Aryle pyridiniums</term> <term xml:lang="fr">Relation structure/activité</term> <term xml:lang="fr">Maladie de Parkinson</term> <term xml:lang="fr">Inducteurs chimiques</term> </keywords> <classCode scheme="halDomain" n="chim.ther">Chemical Sciences/Medicinal Chemistry</classCode> <classCode scheme="halDomain" n="sdv.neu.nb">Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology</classCode> <classCode scheme="halTypology" n="THESE">Theses</classCode> </textClass> <abstract xml:lang="en">A N-aryl pyridinium derivative (PF) has shown promising results as a chemical inducer of Parkinson's disease (PD). Its in vitro and in vivo administration has induced the appearance of characteristical cellular markers of PD but following a much slower kinetics than currently available PD inducers. These preliminary studies have suggested the existence of a link between the N-aryl pyridinium moiety and the ability of the molecule bearing it to chemically induce PD. These results have therefore led to the preparation of structurally related compounds, able to mimic more closely the biochemical mechanisms involved in the onset of PD.Using the same starting material - an aniline derivative - two synthetic pathways have been followed and have led to diversely functionalized N-aryl pyridiniums. The first pathway, based on the Zincke reaction, afforded compounds without hydroxyl group on the pyridinium ring. The second pathway, including a key step of anodic activation and inspired the preparation of PF, led to 3-hydroxy-N-aryl pyridiniums. For both synthetic routes, the nature of the starting material has implied the modification of previously protocols described to gain access to the targeted molecules. The toxicological evaluation of these N-aryl pyridiniums gave rise to a structure / activity relationship study. The results of this study have led to the identification of structural elements allowing both the inhibition of complex I of the mitochondrial respiratory chain and the induction of in vitro neurotoxicity. It was also possible to identify for the first time, a parameter for the modulation of dopaminergic cell penetration and hence the activity of these chemical inducers of PD</abstract> <abstract xml:lang="fr">Un composé de type N-aryle pyridinium (PF) a montré un réel potentiel en tant qu’inducteur chimique de la maladie de Parkinson (MP). Son administration in vitro et in vivo a permis d’induire l’apparition des marqueurs cellulaires caractéristiques de la MP mais suivant une cinétique d’action beaucoup plus lente que les inducteurs parkinsoniens actuellement disponibles. Ces travaux préliminaires ont suggéré l’existence d’un lien entre le motif N-aryle pyridinium et la capacité pour la molécule qui le porte à induire chimiquement la MP. Ces résultats ont dès lors laissé envisager la préparation de composés structurellement inspirés, capables de mimer plus fidèlement les mécanismes biochimiques impliqués lors de l’apparition de la MP. Partant du même composé de départ – un dérivé de l’aniline – deux voies de synthèse ont été suivies et ont permis d’aboutir à des N-aryle pyridiniums diversement fonctionnalisés. La première voie d’accès, exploitant la réaction de Zincke, a permis d’aboutir à des composés ne portant pas de groupement hydroxyle sur le noyau pyridinium. La deuxième voie d’accès, comprenant une étape-clé d’activation anodique et inspirée de la préparation du PF, a permis d’aboutir à des N-aryle pyridiniums 3-hydroxylés. Pour ces deux voies de synthèse, la nature du composé de départ a contraint à la modification des protocoles opératoires décrits dans la littérature afin de pouvoir accéder aux molécules ciblées. L’évaluation toxicologique de ces N-aryle pyridiniums a donné lieu à une étude de relation structure/activité. Les résultats de cette étude ont permis d’identifier les éléments structuraux permettant à la fois l’inhibition du complexe I de la chaine respiratoire mitochondriale et l’induction d’une neurotoxicité in vitro. Il a également été possible d’identifier, pour la première fois, un paramètre permettant la modulation de la pénétration cellulaire dopaminergique et par suite, de l’activité de ces inducteurs chimiques de la MP</abstract> </profileDesc> </hal></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/ParkinsonFranceV1/Data/Hal/Checkpoint
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000054 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Hal/Checkpoint/biblio.hfd -nk 000054 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= ParkinsonFranceV1
|flux= Hal
|étape= Checkpoint
|type= RBID
|clé= Hal:tel-01459525
|texte= Synthesis of new chimical inducers of Parkinson's disease : structure/activity relationship study
}}
| This area was generated with Dilib version V0.6.29. |  |