An electrochemical access to 2-amino-2,3-dihydro-1,4-benzodioxanes derived from hydroxytyrosol.

The anodic oxidation of a natural antioxidative catechol, hydroxytyrosol, was developed in an acetonitrile/dimethylsulfoxide (or acetonitrile/water) solvent mixture to produce in a stable way the resulting non-activated -quinone and generate structural analogues. 2-Amino-2,3-dihydro-1,4-benzodioxane derivatives were obtained as two regioisomers in good to high overall yields (65-90%) and 1 : 3 ratios, through an inverse electron demand Diels-Alder (IEDDA) reaction between the electrogenerated -quinone and tertiary enamines. The insertion of an electron withdrawing (or electron donating) group on the catechol modified their relative proportions, so that the reaction became regiospecific.

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

(±)-3,4-Methylenedioxymethamphetamine (MDMA, also known as "ecstasy") is a psychoactive drug with selective neurotoxic potential toward brain serotonin (5-HT) neurons. One hypothesis holds that MDMA neurotoxicity may at least partially be a consequence of its metabolism. In most species (including primates), O-demethylenated MDMA metabolites such as N-methyl-α-methyldopamine (HHMA) have been postulated to serve as precursors for toxic thioether conjugates.

Synthesis and neurotoxicity profile of 2,4,5-trihydroxymethamphetamine and its 6-(N-acetylcystein-S-yl) conjugate.

The purpose of the present study was to determine if trihydroxymethamphetamine (THMA), a metabolite of methylenedioxymethamphetamine (MDMA, "ecstasy"), or its thioether conjugate, 6-(N-acetylcystein-S-yl)-2,4,5-trihydroxymethamphetamine (6-NAC-THMA), play a role in the lasting effects of MDMA on brain serotonin (5-HT) neurons. To this end, novel high-yield syntheses of THMA and 6-NAC-THMA were developed. Lasting effects of both compounds on brain serotonin (5-HT) neuronal markers were then examined.

Synthesis and in vitro cytotoxicity profile of the R-enantiomer of 3,4-dihydroxymethamphetamine (R-(-)-HHMA): comparison with related catecholamines.

(+/-)-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.

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.

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.

Several catechol-thioether metabolites of MDMA (ecstasy), three monoadducts, 5-(glutathion-S-yl)-N-methyl-alpha-methyldopamine (1), 5-(N-acetylcystein-S-yl)-N-methyl-alpha-methyldopamine (2), and 5-(cystein-S-yl)-N-methyl-alpha-methyldopamine (3), and two bi-adducts, 2,5-bis(glutathion-S-yl)-N-methyl-alpha-methyldopamine (4) and 2,5-bis(N-acetylcystein-S-yl)-N-methyl-alpha-methyldopamine (5), have been synthesized through an environmentally friendly one-pot electrochemical procedure. Their cytotoxicity profiles were further characterized using simple Escherichia coli plate assays and compared with those of N-methyl-alpha-methyldopamine (HHMA), dopamine (DA), and its corresponding catechol-thioether conjugates (monoadducts 6-8 and bi-adducts 9 and 10). Toxicity mediated by reactive oxygen species (ROS-TOX) was detected in the OxyR- assay, using cells sensitive to oxidative stress due to a deficiency in the OxyR protein.

Protective effects of 4-hydroxycinnamic ethyl ester derivatives and related dehydrodimers against oxidation of LDL: radical scavengers or metal chelators?

4-Hydroxycinnamate derivatives are known to be potent protectors against oxidation of low-density lipoproteins (LDL), via a combination of free radical scavenging and transition metal chelation. Through a series of 4-hydroxycinnamic ethyl ester derivatives and related 8-8 dehydrodimers, we have tried to bring out the structural requirements for radical scavenging and cupric ion chelation. We found that the monomeric compounds, except for highly lipophilic tert-butyl derivative 3, exhibited rather low radical scavenging properties.

4-hydroxycinnamic ethyl ester derivatives and related dehydrodimers: Relationship between oxidation potential and protective effects against oxidation of low-density lipoproteins.

The electrochemical oxidation potential of a series of monomeric and dimeric 4-hydroxycinnamic ethyl ester derivatives has been compared with their antioxidant activity toward copper-catalyzed human low-density lipoproteins (LDL) oxidation. Within the series of monomeric hydroxycinnamate derivatives, both oxidation potential and IC50 values decreased in the following order: sinapate > ferulate > p-coumarate. Among the 4-hydroxycinnamate dehydrodimer derivatives, noncyclized 8-8 diphenol dehydrodimers followed the same aforementioned sequence order and were found to be better antioxidants than their monomer counterparts.