Synthèse biomimétique d'adduits catéchol-thioéthers dérivés de la méthylènedioxyméthamphétamine à partir d'orthoquinone électrogénérée (leur implication dans la neurotoxicité de l'ecstasy)

L injection ICV chez le rat de MDMA (ecstasy) ne reproduit pas les effets délétères observés à long terme après administration périphérique. Ainsi, des métabolites systémiques jouent un rôle clé dans le développement de la cytotoxicité. Chez l homme, le métabolite primaire est la 3,4-dihydroxyméthamphétamine (HHMA), oxydable en orthoquinone, qui réagit avec des thiols endogènes pour donner des adduits quinol-thioéthers. La première partie de la thèse traite de la synthèse one-pot d adduits racémiques quinol-thioéthers, en utilisant l oxydation électrochimique comme mime de l oxydation enzymatique. Dans la seconde partie, la synthèse du dérivé (R)-HHMA, précurseur des adduits énantiomériquement purs, a été réalisée à partir de la L-dopa (inducteur de chiralité). Dans la troisième partie, des essais in vitro montrent que certains adduits quinol-thioéthers induisent une cytotoxicité en générant des ROS, grâce à des processus redox cycliques engageant les espèces o-quinoniques.ICV injection of MDMA (ecstasy) in rats fails to reproduce long-term toxic effects observed after peripheral administration. Therefore, systemic metabolites play a key role in the development of cytotoxicity. In humans, the major metabolite is 3,4-dihydroxymethamphetamine (HHMA), easily oxidizable to the orthoquinone species. This can further react with endogenous thiol derivatives, yielding quinol-thioether conjugates. In the first part of the thesis, a one pot synthesis of racemic catechol-thioether metabolites has been developed, using anodic oxidation as a mimic of enzymatic oxidation. In the second part, the synthesis of (R)-HHMA, precursor of the enantiomerically pure quinol-thioether adducts, is described starting from L-dopa (inducer of chirality). The third part reports the results of in vitro assays which show that some catechol-thioether conjugates can induce toxic effects leading to the formation of ROS, through redox cycling processes involving o-quinonoid species.PARIS-BIUP (751062107) / SudocSudocFranceF

A convenient biomimetic synthesis of optically active putative neurotoxic metabolites of MDMA (“ecstasy”) from R-(−)- and S-(+)-N-methyl-α-methyldopamine precursors

International audienc

Bacterial Plate Assays and Electrochemical Methods: An Efficient Tandem for Evaluating the Ability of Catechol−Thioether Metabolites of MDMA (“Ecstasy”) to Induce Toxic Effects through Redox-Cycling

International audienc

Effects of lithium ion-pairing on the electrochemical oxidation of 4-hydroxycinnamate derivatives

International audienc

4-Hydroxycinnamic Ethyl Ester Derivatives and Related Dehydrodimers: Relationship between Oxidation Potential and Protective Effects against Oxidation of Low-Density Lipoproteins

International audienc

Polycyclic Polyprenylated Xanthones from Symphonia globulifera : Isolation and Biomimetic Electrosynthesis

International audienc

Protective Effects of 4-Hydroxycinnamic Ethyl Ester Derivatives and Related Dehydrodimers against Oxidation of LDL: Radical Scavengers or Metal Chelators?

International audienc

Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

The mechanism by which the recreational drug (±)-3,4-methylenedioxymethamphetamine (MDMA) destroys brain serotonin (5-HT) axon terminals is not understood. Recent studies have implicated MDMA metabolites, but their precise role remains unclear. To further evaluate the relative importance of metabolites versus the parent compound in neurotoxicity, we explored the relationship between pharmacokinetic parameters of MDMA, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) and indexes of serotonergic neurotoxicity in the same animals. We also further evaluated the neurotoxic potential of 5-(N-acetylcystein-S-yl)-HHMA (5-NAC-HHMA), an MDMA metabolite recently implicated in 5-HT neurotoxicity. Lasting serotonergic deficits correlated strongly with pharmacokinetic parameters of MDMA (Cmax and area under the concentration-time curve), more weakly with those of MDA, and not at all with those of HHMA or HMMA (total amounts of the free analytes obtained after conjugate cleavage). HHMA and HMMA could not be detected in the brains of animals with high brain MDMA concentrations and high plasma HHMA and HMMA concentrations, suggesting that HHMA and HMMA do not readily penetrate the blood-brain barrier (either in their free form or as sulfate or glucuronic conjugates) and that little or no MDMA is metabolized to HHMA or HMMA in the brain. Repeated intraparenchymal administration of 5-NAC-HHMA did not produce significant lasting serotonergic deficits in the rat brain. Taken together, these results indicate that MDMA and, possibly, MDA are more important determinants of brain 5-HT neurotoxicity in the rat than HHMA and HMMA and bring into question the role of metabolites (including 5-NAC-HHMA) in MDMA neurotoxicity