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Jacques Lebreton

Publications and source records attributed to Jacques Lebreton.

12 recordsLinked to original sources
PubMed2006

Flexible synthesis and biological evaluation of novel 5-deoxyadenophorine analogues.

Adenophorine and its 5-deoxy analogue have been identified as natural iminosugars with efficient glycosidase inhibitory effects. The syntheses and biological evaluation of two new series of 5-deoxyadenophorine analogues in their racemic form are reported. The compounds 12e and 13d bearing a C11 and C7 alkyl chain, respectively, were found to be potent inhibitors of the beta-glucosidase from almond with Ki near to 60 microM. The compounds 13a,d which possess a 3,4-cis stereochemistry were efficient on glucosidases but also on the beta-galactosidase, what was not observed with the 3,4-trans series 12.

Alkylation↗
PubMed2005

Nicotine demethylation in Nicotiana cell suspension cultures: N'-formylnornicotine is not involved.

Nicotine or nornicotine enriched with stable isotopes in either the N'-methyl group or the pyrrolidine-N were fed to Nicotiana plumbaginifolia suspension cell cultures that do not form endogenous nicotine. The metabolism of these compounds was investigated by analysing the incorporation of isotope into other alkaloids using gas chromatography-mass spectroscopy (GC-MS). Nicotine metabolism primarily resulted in the accumulation of nornicotine, the N'-demethylation product. In addition, six minor metabolites appeared during the course of nicotine metabolism, four of which were identified as cotinine, myosmine, N'-formylnornicotine and N'-carboethoxynornicotine. While cotinine was formed from [(13)C,(2)H(3)-methyl]nicotine without dilution of label, N'-formylnornicotine was labelled at only about 6% of the level of nicotine and N'-carboethoxynornicotine was unlabelled. Feeding with [1'-(15)N]nornicotine resulted in incorporation without dilution of label into both N'-formylnornicotine and N'-carboethoxynornicotine. This pattern strongly indicates that, while nornicotine and cotinine are derived directly from nicotine, N'-formylnornicotine and N'-carboethoxynornicotine are metabolites of nornicotine. Thus, it is directly demonstrated that N'-formylnornicotine is not an intermediate in nicotine demethylation.

Alkaloids↗
PubMed2005

Determination of the natural abundance delta15N of nicotine and related alkaloids by gas chromatography/isotope ratio mass spectrometry.

A method is described by which the natural abundance delta15N values of nicotine, analogues, and metabolites can be determined. The alkaloids are extracted from their biological matrix by solid-phase extraction and analysis is conducted using isotope ratio mass spectrometry interfaced to gas chromatography. Repeatability and precision are sufficient to allow differences in the delta15N values of less than 1.0 per thousand to be satisfactorily measured, with a standard deviation routinely less than 0.5 per thousand. The methodology has been tested by determining the changes in the delta15N values of nicotine, N-methyl-2-phenylpyrrolidine and their respective demethylation products, nornicotine and 2-phenylpyrrolidine, during biotransformation by cell suspension cultures of Nicotiana species. Sufficient precision and reproducibility were obtained to allow the kinetic isotope effects associated with the demethylation reaction to be calculated.

Alkaloids↗
PubMed2005

Stereoselectivity of the demethylation of nicotine piperidine homologues by Nicotiana plumbaginifolia cell suspension cultures.

The metabolism of (R,S)-N-methylanabasine and (R,S)-N-methylanatabine has been studied in a cell suspension culture of Nicotiana plumbaginifolia. Both substrates are effectively demethylated, anabasine or anatabine, respectively, accumulating in the medium. Similarly, there is strong stereoselectivity for the (R)-isomers of both substrates. The kinetics of metabolism of (R,S)-N-methylanabasine differ significantly from those of nicotine in that no further degradation of the initial demethylation product occurs. (R,S)-N-Methylanatabine, however, shows kinetics closer to those of nicotine, with loss of alkaloid from the system. Further more, (R,S)-N-methylanabasine does not diminish (S)-nicotine demethylation, indicating a lack of competition. However, the metabolism of (S)-nicotine is affected by the presence of (R,S)-N-methylanabasine. Hence, the demethylation of the piperidine homologues of nicotine is seen to be similar but not identical to that of the pyridine analogues. The implications of these different metabolic profiles in relation to the demethylation activity are discussed.

Alkaloids↗
PubMed2004

A possible improvement for structure-based drug design illustrated by the discovery of a Tat HIV-1 inhibitor.

The HIV-1 Tat protein is a promising target for AIDS therapy, due to its extra-cellular roles against the immune system. From the 2D-NMR structure of Tat, we have designed molecules, called TDS, able to bind to Tat and inhibit HIV-1 replication in vitro. This new family of antivirals is composed of a triphenylene aromatic ring substituted with at least one carbon chain bearing a succinimide group. These ligands are prepared from triphenylene or 2,6,10-trimethylphenylene in 3-6 steps depending on the target molecule.

Anti-HIV Agents↗
PubMed2004

First total synthesis of 1-O-beta-D-glucopyranosyl-5-deoxyadenophorine and its aglycon congener: determination of the absolute configuration.

The first total synthesis of the potent glycosidase inhibitors 1-O-beta-D-glucopyranosyl-5-deoxyadenophorine and its aglycon congener is described in respectively 13 steps (9% overall yield) and 9 steps (29% overall yield) from (R)-Garner aldehyde. The synthesis takes advantage of several key reactions including a diastereoselective allylation of a chiral imine, a stereoselective epoxidation, and a glycoside coupling. In addition this study established unambiguously the absolute configuration of the natural products.

Carbohydrate Conformation↗
PubMed2003

The nicotinic pharmacophore: thermodynamics of the hydrogen-bonding complexation of nicotine, nornicotine, and models.

The thermodynamics of the hydrogen-bonding complexation of the acetylcholine agonists nicotine and nornicotine and of model pyridines, pyrrolidines, and N-methylpyrrolidines has been measured in CCl(4) by FTIR spectrometry toward a reference hydrogen-bond donor, 4-fluorophenol. Various methods are devised for measuring separately the hydrogen-bond acceptor strength of each nitrogen of nicotine and nornicotine: variation of the stoichiometry of complexation; correlations with electrostatic potentials on nitrogens and with substituent constants in the series of 3-substituted pyridines, 2-substituted pyrrolidines, and 2-substituted N-methylpyrrolidines; and linear free energy relationships between 4-fluorophenol and hydrogen fluoride hydrogen-bonded complexes. It is consistently found that nicotine and nornicotine have two active hydrogen-bond acceptor sites, the pyridine and pyrrolidine nitrogens, and that ca. 90% (for nicotine) and 80% (for nornicotine) of the 1:1 hydrogen-bonded complexes are formed to the pyridine nitrogen, although the pyrrolidine nitrogen is the first protonation site of nicotine and nornicotine in water. The low hydrogen-bond basicity of the pyrrolidine nitrogen in nicotine is mainly explained by the inductive electron-withdrawing and steric effects of the 2-(3-pyridyl) substituent. The partition of the Gibbs energy of the isomerism of complexation (AH...Nsp(2) <==> AH...Nsp(3)) into enthalpic and entropic contributions shows that the selectivity in favor of the pyridine nitrogen is driven by entropy. It is important to recognize the bifunctionality of nicotine in hydrogen bonding for understanding its lipophilicity and molecular recognition in non protonic media. When monoprotonated on their sp(3) nitrogen, nicotine and nornicotine keep, through their sp(2) nitrogen, a significant hydrogen-bond basicity which is greater than that of the ester group of acetylcholine.

Hydrogen Bonding↗
PubMed2002

A highly stereoselective asymmetric synthesis of (--)-lobeline and (--)-sedamine.

A highly stereoselective asymmetric synthesis of (--)-sedamine and (--)-lobeline is described from benzaldehyde in 16 and 17 steps with an overall yield of 20% and 14%, respectively. The key intermediate syn-3,4-epoxyalcohol was prepared in a highly diastereomeric fashion (>99% ee, dr) and served as a common intermediate for both alkaloids.

Alkaloids↗
PubMed2002

Site of protonation of nicotine and nornicotine in the gas phase: pyridine or pyrrolidine nitrogen?

The gas-phase basicities (GBs) of nornicotine, nicotine, and model pyrrolidines have been measured by FT-ICR. These experimental GBs are compared with those calculated (for the two sites of protonation in the case of nicotine and nornicotine) at the B3LYP/6-311+G(3df,2p)//B3LYP/6-31G(d,p) level, or those estimated from substituent effects on the GBs of 2-substituted pyrrolidines, 2-substituted N-methylpyrrolidines, and 3-substituted pyridines. It is found that, in contrast to the Nsp(3) protonation in water, in the gas phase nornicotine is protonated on the pyridine nitrogen, because the effects of an intramolecular CH.Nsp(3) hydrogen bond and of the polarizability of the 3-(pyrrolidin-2-yl) substituent add up on the Nsp(2) basicity, while the polarizability effect of the 2-(3-pyridyl) substituent on the Nsp(3) basicity is canceled by its field/inductive electron-withdrawing effect. The same structural effects operate on the Nsp(3) and Nsp(2) basicities of nicotine, but here, the polarizability effect of the methyl group puts the pyrrolidine nitrogen basicity very close to that of pyridine. Consequently, protonated nicotine is a mixture of the Nsp(3) and Nsp(2) protonated forms.

Binding Sites↗
PubMed2002

Evidence for the involvement of tetrahydrofolate in the demethylation of nicotine by Nicotiana plumbaginifolia cell-suspension cultures.

The conversion of nicotine to nornicotine by Nicotiana plumbaginifolia Viv. cells was investigated by analysing the redistribution of label during feeding experiments with (R,S)-[2H- methyl]nicotine, (R,S)-[13C- methyl]nicotine and (R,S)-[14C- methyl]nicotine, and the results show that the N-methyl group of nicotine can be recycled into primary metabolism. Nuclear magnetic resonance (NMR) analysis of ethanolic extracts of cells grown in the presence of (R,S)-[13C- methyl]nicotine, using 1H-13C correlation spectroscopy (HMQC, HMBC), revealed the presence of [3-13C]serine and [13C- methyl]methionine. Label was also identified in a cysteinyl derivative and in several methoxylated compounds, but no evidence was obtained with either NMR or ion-trap mass spectrometry for the presence of any intermediate between nicotine and nornicotine. However, experiments with (R,S)-[14C- methyl]nicotine indicated that 70-75% of the metabolised label was released as carbon dioxide. These results are consistent with a pathway in which the oxidative hydrolysis of the nicotine methyl produces an unstable intermediate, N'-hydroxymethylnornicotine, that breaks down spontaneously to nornicotine and formaldehyde, with the formaldehyde being metabolised either directly to formate and carbon dioxide, or through the tetrahydrofolate-mediated pathways of one-carbon metabolism. However since the key intermediate, N-hydroxymethylnornicotine, could not be detected, the possibility of a direct methyl group transfer to tetrahydrofolate cannot be excluded.

Carbon Radioisotopes↗
PubMedDate not supplied

Copper complex-assisted DNA hybridization.

2,2'-Bipyridine (bpy) or 1,10-phenanthroline (phen) metal-binding domains were covalently attached to oligonucleotides, and the influence of metal ions on the hybridization of the conjugates was investigated. Metal-binding domains were attached to oligonucleotides at 3'- and 5'-terminal positions, thus placing them in juxtaposed positions after hybridization to a common target strand. While the ligands alone had a positive effect (increased Tm) on hybrid stability, the duplex was further stabilized by the addition of copper(I) and/or copper(II) through the formation of a metal complex in which the two short sequences are linked through {Cu(bpy)2}, {Cu(phen)}, or {Cu(bpy)(phen)} domains. The increase in Tm, due to formation of the {Cu(bpy)2}, {Cu(phen)2}, {Cu(bpy)(phen)} motifs is reversed upon addition of EDTA, consistent with the stripping of copper from the ligands. The effect of metal complex formation on the duplex strength was shown to be highest if the two metal-coordinating ligand strands are placed as close to each other as possible.

Copper↗