UMR 8638 CNRS, Universite Paris Descartes, Synthese et Structure de Molecules d'Interet Pharmacologique, Faculte des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75270 Paris cedex 06, France.
Chem Res Toxicol. 2010 Jan;23(1):211-9. doi: 10.1021/tx9003374.
(+/-)-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.
（+/-）-3,4-亚甲二氧基甲基苯丙胺（MDMA，也称为“摇头丸”）是一种手性药物，在人体内主要通过 O-去甲基化代谢为 3,4-二羟甲基苯丙胺（HHMA）。最近，人们重新关注 MDMA 代谢物，特别是 5-(N-乙酰半胱氨酸-S-基）-N-甲基-α-甲基多巴胺（指定为 5-NAC-HHMA），可能在 MDMA 神经毒性中发挥作用的可能性。然而，在以前报道的体内研究中没有考虑 MDMA 的手性，因为 HHMA 是 5-NAC-HHMA 代谢物的前体，被用作外消旋体。由于需要考虑这种手性药物的立体化学，因此首次报道了 R-(-)-HHMA 的全合成。使用 L-DOPA 作为手性源，通过七步反应，以 30%的总收率和 99.5%的对映体过量制备 R-(-)-HHMA。通过碘化丙啶摄取的流式细胞术分析和大肠杆菌平板测定，进一步确定了 R-(-)-HHMA 和相关儿茶酚胺的细胞毒性，大肠杆菌平板测定特异性检测氧化毒性。在两种系统中观察到的毒性之间的良好相关性表明，SH-SY5Y 细胞对氧化毒性敏感，细胞死亡（坏死）将主要由来自氧化还原活性醌式中心的活性氧介导。相比之下，检测到 3,4-二甲氧基甲基苯丙胺（MMMA）的凋亡，HHMA 的合成前体具有保护的儿茶酚基团。MMMA 在细菌测定中没有毒性，表明其毒性与增加的氧化应激无关。最后，我们可以得出结论，需要区分归因于 MDMA 本身的毒性，MDMA 本身也带有保护的儿茶酚部分，以及取决于导致 HHMA 和硫醚缀合物等儿茶酚代谢物的 MDMA 生物转化的毒性。
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