Serge Labidalle

STRUCTURE-PROPERTY RELATIONSHIPS OF TRIMETAZIDINE DERIVATIVES AND MODEL COMPOUNDS AS POTENTIAL ANTIOXIDANTS

Twenty-five compounds (trimetazidine derivatives and other compounds, mostly having a free phenolic group) were examined for their radical scavenging and antioxidant properties. Their reaction with DPPH (2,2-diphenyl-1-picrylhydrazyl) as a measure of radical scavenging capacity was assessed by two parameters, namely EC50 (the concentration of antioxidant decreasing DPPH by 50%), and log Z, a kinetic parameter proposed here and derived from initial second-order rate constants and antioxidant/DPPH ratios. Antioxidant activities were determined by the inhibition of lipid peroxidation and albumin oxidation. The most active compounds were derivatives having a trolox or hydroquinone moiety. Physicochemical and structural properties were determined by molecular modeling as lipophilicity (virtual log P calculations) and H-Surf (solvent-accessible surface of hydroxyl hydrogen) and by quantum mechanical calculations (deltaH(ox) = oxidation enthalpy; deltaH(abs) = enthalpy of hydrogen abstraction). QSAR models were derived to identify molecular mechanisms responsible for the reactivity toward the DPPH radical and for the inhibition of lipid peroxidation. A useful prediction of antioxidant capacity could be achieved from calculated molecular properties and the kinetic parameter developed here.

Curcumin induces the mitochondrial permeability transition pore mediated by membrane protein thiol oxidation

Curcumin is a natural compound showing antiproliferative properties. Recent studies suggest that these properties might be due to its ability to induce apoptosis in tumor cells. As mitochondria play a pivotal role in the induction of the apoptotic process, we analyzed the effect of curcumin on mitochondrial function. Curcumin induced an increase in rat liver mitochondrial membrane permeability, resulting in swelling, loss of membrane potential and inhibition of ATP synthesis. These effects were mediated by the opening of the permeability transition pore. Curcumin pore induction involved the oxidation of membrane thiol functions and required the presence of low Ca2+ concentrations. These data suggest that mitochondria might be a target by which curcumin induces apoptosis of tumor cells.

Fluoride curcumin derivatives: new mitochondrial uncoupling agents

The mitochondrial effects of two fluoride curcumin derivatives were studied. They induced the collapse of mitochondrial membrane potential (Δψ), increased mitochondrial respiration, and decreased O2 − production and promoted Ca2+ release. These effects were reversed by the recoupling agent 6‐Ketocholestanol, but not by cyclosporin A, an inhibitor of the permeability transition pore (PTP), suggesting that these compounds act as uncoupling agents. This idea was reinforced by the analysis of the physico‐chemical properties of the compounds indicating, that they are mainly in the anionic form in the mitochondrial membrane. Moreover, they are able to induce PTP opening by promoting the oxidation of thiol groups and the release of cytochrome c, making these two molecules potential candidates for induction of apoptosis.

[3H]-Trimetazidine mitochondrial binding sites: regulation by cations, effect of trimetazidine derivatives and other agents and interaction with an endogenous substance

Trimetazidine, an antiischaemic drug, has been shown to restore impaired mitochondrial functions. Specific binding sites for [3H]‐trimetazidine have been previously detected in liver mitochondria. In the present study we confirm this observation and provide additional evidence for the involvement of these sites in the pharmacological effects of the drug. Inhibition experiments using a series of trimetazidine derivatives revealed the presence of three classes of binding sites. An N‐benzyl substituted analogue of trimetazidine exhibited a very high affinity (Ki=7 nM) for one of these classes of sites. Compounds from different pharmacological classes were evaluated for their ability to inhibit [3H]‐trimetazidine binding. Among the drugs tested pentazocine, ifenprodil, opipramol, perphenazine, haloperidol, and to a lower extent prenylamine, carbetapentane and dextromethorphan competed with high affinity, suggesting a similarity of high affinity [3H]‐trimetazidine sites with sigma receptors. [3H]‐Trimetazidine binding was modulated by pH. Neutral trimetazidine had about 10 fold higher affinity than protonated trimetazidine for its mitochondrial binding sites. Various cations also affected [3H]‐trimetazidine binding. Ca2+ was the most potent inhibitor and totally suppressed the binding of [3H]‐trimetazidine to the sites of medium affinity. An endogenous cytosolic ligand was able to displace [3H]‐trimetazidine from its binding sites. Its activity was not affected by boiling for 15 min, suggesting a non‐protein compound. These data suggest that mitochondrial [3H]‐trimetazidine binding sites could have a physiological relevance and be involved in the antiischaemic effects of the drug.

Dual effect of ebselen on mitochondrial permeability transition

This study reports an investigation on the effect of the seleno-organic compound ebselen on rat liver mitochondria. We show that low concentrations of ebselen induced an increase in rat liver mitochondrial membrane permeability, resulting in swelling and loss of membrane potential. These effects were mediated by the opening of the permeability transition pore. They required Ca(2+), were independent of pyridine nucleotide oxidation, and involved the oxidation of thiol groups. Ebselen pore induction is apparently promoted by the glutathione peroxidase mimicking activity of the drug. Opposite effects, that is, inhibition of both pore opening and thiol oxidation, were observed when concentrations higher than 20 micro M were used. These data demonstrate that ebselen is able to modulate the opening of the permeability transition pore and that it might be a critical event for both the proapoptotic and cytoprotective activities of the drug.

[3H]BHDP as a novel and selective ligand for σ1 receptors in liver mitochondria and brain synaptosomes of the rat

The binding profile of [3H]BHDP ([3H]N‐benzyl‐N′‐(2‐hydroxy‐3,4‐dimethoxybenzyl)‐piperazine) was evaluated. [3H]BHDP labelled a single class of binding sites with high affinity (K d=2–3 nM) in rat liver mitochondria and synaptic membranes. The pharmacological characterization of these sites using σ reference compounds revealed that these sites are σ receptors and, more particularly, σ1 receptors. Indeed, BHDP inhibited [3H]pentazocine binding, a marker for σ1 receptors, with high affinity in a competitive manner. BHDP is selective for σ1 receptors since it did not show any relevant affinity for most of the other receptors, ion channels or transporters tested. Moreover, in an in vitro model of cellular hypoxia, BHDP prevented the fall in adenosine triphosphate (ATP) levels caused by 24 h hypoxia in cultured astrocytes. Taken together, these results demonstrate that [3H]BHDP is a potent and selective ligand for σ1 receptors showing cytoprotective effects in astrocytes.

SYNTHESIS AND CHARACTERIZATION OF NEW AROMATIC THIONITRITES

Abstract Thionitrites (S-nitrosothiols) play an essential biological role as nitric oxide (NO.) carriers. Here, we present the synthesis. the characterization and the stability studies in solution of new aromatic thionitrites 1b-4b as potent nitric oxide donors. The four thionitrites were characterized by 1H NMR, UV-visible and IR spectroscopies. Their decomposition occurs within a few minutes in dichloromethane, and yields quantitatively the corresponding disulfide. NO. and the thiyl radicals coming from their decomposition were trapped by distinct spin traps to give characteristic EPR signals. 4b possesses the di-tert-butylphenol moiety responsible for the antioxidant properties of BHT and of the structurally-related drug probucol.

Synthesis and Extraction of Pentalongin, A Naphthoquinoid From Mitracarpus Scaber

Abstract This paper describes an efficient synthetic route to pentalongin (1H-naphtho[2,3-c]pyran-5,10-dione), a naphthoquinoid isolated from the aerial parts of Mitracarpus scaber, and to the structurally-related compound psychorubrin(3-hydroxy-1H-3, 4-dihydronaphtho[2,3-c]pyran-5,10-dione).

Phase-transfer-catalysed Preparation ofN-Alkylated Trihydroxamic Acids†

We describe a synthetic route involving phase transfer catalysis leading to a series of tripodal N-alkylated hydroxamic acids as models of desferrioxamine; iron(III) exchange reactions between their iron complexes and EDTA were investigated.