Synthesis and in Vitro Cytotoxicity Profile of the R-Enantiomer of 3,4-Dihydroxymethamphetamine (R-(−)-HHMA): Comparison with Related Catecholamines
| Autor: | Anne Felim, José-Enrique O'Connor, Martine Largeron, Manuel Blanco, Guadalupe Herrera, Anne Neudörffer |
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| Přispěvatelé: | CSIRO Energy Technology, Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5) |
| Rok vydání: | 2009 |
| Předmět: |
Stereochemistry
N-Methyl-3 4-methylenedioxyamphetamine [SDV]Life Sciences [q-bio] Metabolite Toxicology Levodopa 03 medical and health sciences chemistry.chemical_compound Catecholamines 0302 clinical medicine In vivo Cell Line Tumor Toxicity Tests medicine Humans [CHIM]Chemical Sciences Propidium iodide Enantiomeric excess ComputingMilieux_MISCELLANEOUS 030304 developmental biology 0303 health sciences [CHIM.ORGA]Chemical Sciences/Organic chemistry Total synthesis Stereoisomerism MDMA General Medicine Flow Cytometry 3. Good health Deoxyepinephrine chemistry [SDV.TOX]Life Sciences [q-bio]/Toxicology Enantiomer Chirality (chemistry) 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Chemical Research in Toxicology Chemical Research in Toxicology, American Chemical Society, 2010, 23 (1), pp.211-219. ⟨10.1021/tx9003374⟩ |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/tx9003374 |
| Popis: | (+/-)-3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a chiral drug that is essentially metabolized in humans through O-demethylenation into 3,4-dihydroxymethamphetamine (HHMA). There has recently been a resurgence of interest in the possibility that MDMA metabolites, especially 5-(N-acetylcystein-S-yl)-N-methyl-alpha-methyldopamine (designated as 5-NAC-HHMA), might play a role in MDMA neurotoxicity. However, the chirality of MDMA was not considered in previously reported in vivo studies because HHMA, the precursor of the 5-NAC-HHMA metabolite, was used as the racemate. Since the stereochemistry of this chiral drug needs to be considered, the first total synthesis of R-(-)-HHMA is reported. Using L-DOPA as the chiral source, the preparation of R-(-)-HHMA is achieved through seven steps, in 30% overall yield and 99.5% enantiomeric excess. The cytotoxicity of R-(-)-HHMA and related catecholamines has been further determined by flow cytometric analysis of propidium iodide uptake in human dopaminergic neuroblastoma SH-SY5Y cells and by an Escherichia coli plate assay, specific for the detection of oxidative toxicity. The good correlation between the toxicities observed in both systems suggests that SH-SY5Y cells are sensitive to oxidative toxicity and that cell death (necrosis) would be mediated by reactive oxygen species mainly generated from redox active quinonoid centers. In contrast, apoptosis was detected for 3,4-dimethoxymethamphetamine (MMMA), the synthetic precursor of HHMA possessing a protected catechol group. MMMA was not toxic in the bacterial assay, indicating that its toxicity is not related to increased oxidative stress. Finally, we can conclude that there is a need to distinguish the toxicity ascribed to MDMA itself, also bearing a protected catechol moiety, from that depending on MDMA biotransformation leading to catechol metabolites such as HHMA and the thioether conjugates. |
| Databáze: | OpenAIRE |
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