Jean Maignan

Identification of synthetic retinoids with selectivity for human nuclear retinoic acid receptor γ

The action of retinoids on gene regulation is mediated by three distinct nuclear retinoic acid receptor (RAR) subtypes called RAR alpha, beta and gamma. Since RAR gamma is predominantly expressed in adult skin, specific ligands for this subtype could (i) represent valuable tools to evaluate the biological role of RAR gamma in skin and (ii) provide therapeutic entities with a higher therapeutic index at lower teratogenic risk. Using in vitro binding studies and a functional transactivation assay, we have identified three compounds with high RAR gamma selectivity.

A re-investigation of resveratrol synthesis by Perkins reaction. Application to the synthesis of aryl cinnamic acids

A re-investigation of resveratrol synthesis by Perkins reaction allowed to improve this method and to determine the configuration of the intermediates. The results were applied to the synthesis of several aryl cinnamic acids for biological evaluation.

Synthesis of (+)-(R)-5-hydroxy-6-hydroxymethyl-7-methoxy-8-methylflavanone

Abstract The synthesis of (+)-( R )-5-hydroxy-6-hydroxymethyl-7-methoxy-8-methylflavanone is described. A new chromylation method of β-ketosulfoxide 9 leading to the Michael acceptor 12 has been developed. Dilithium tetrachlorocuprate was shown to be a very efficient catalyst for the conjugate addition reaction of phenyl magnesium bromide to the α,β-unsaturated sulfoxide 12 . The instability of the obtained adducts 10 represents a limitation in terms of yield. It was confirmed that the natural flavanone leridol does not possess the structure of title compound 1 .

BIOMIMETIC SYNTHESIS OF THE FLAVANONE LERIDOL, REVISION OF THE STRUCTURE OF THE NATURAL PRODUCT

Two independent syntheses of 5-hydroxy-6-hydroxymethyl-7-methoxy-8-methylflavanone (1), which was supposed to be natural leridol, demonstrated that this structure assignment was wrong and that the natural flavanone leridol was indeed 5-hydroxy-8-hydroxymethyl-7-methoxy-6-methylflavanone (2).

Direct observation of the reaction of the quinone-methide from 5,6-dihydroxyindole with the nucleophilic azide ion

Investigation of the oxidation of melanagenic intermediates and, in particular, the ultimate oxidative polymerisation of 5,6-dihydroxyindole (1) is important for a comprehensive understanding of the biosynthesis of melanin. Oxidation of 1 leads to the formation of its corresponding quinone methide, a reactive intermediate. We report a novel approach using a fast reaction technique to produce the quinone methide of 1in situ and study its chemistry. In aqueous solution at pH 9, the quinone methide has a lifetime of < 0.1 s due to interaction with the solvent. As an example of the chemistry of the quinone methide of 1, it was demonstrated that it interacts with the nucleophilic azide ion. From comparison with the corresponding reactions of the quinone-methide from 5-methoxy-6-hydroxyindole (2), it is inferred that the indoloquinone of 1 is involved in the pathways to melanin formation. The importance of the involvement of the quinone methide of 1 in the pathway to melanin formation is in contrast to the pathway involving dimer products arising from 1.

Aromatic ring synthesis by 1,3-michael-claisen annulation: Application to a trolox analogue and to precocene II

Abstract A Trolox analogue, 3,4-dihydro-2-ethoxycarbonyl-6-methoxy-7-hydroxy- benzopyran and Precocene II, were prepared from substituted α-methylene-δ- valerolactone and 1,1-bis-(methylthio)-2-propanone or butanone, via a 1,3-Michael- Claisen annulation.

Aromatic ring synthesis by 1,3-Michael-Claisen annulation: Formation of dihydrobenzofurans and tetrahydrochromans from α-methylene γ-butyrolactone and δ-valerolactone

Abstract Substituted dihydrobenzofurans and tetrahydrochromans have been prepared from respectively α-methylene-γ-butyrolactone and δ-valerolactone via a 1,3-Michael-Claisen reaction from two 3-carbon units, 1,1-bis-(methylthio)-2-propanone or butanone, and an α-methylene lactone.

Preparation and complexation ability of zwitterionic derivatives of cyclodextrins

Abstract Zwitterionic derivatives of β-cyclodextrin were obtained by acylation of 6 1 -amino-6 1 -deoxycyclomaltoheptaose with commercially available partially protected derivatives of aspartic and glutamic acids followed by removal of the protective groups. These products exhibited high solubility in water and were used to form soluble inclusion complexes of 5-fluorouracil.

Synthesis of 1,2:5,6-di-O-isopropylidene-D-glucofuranos-3-yl and 1,2:3,4-di-O-isopropylidene-D-galactopyranos-6-yl-(N-diphenylmethylene) glycinates

Abstract 1,2:3,4-di-O-isopropylidene-D-galactopyranos-6-yl-(N-diphenylmethylene)-glycinate 3 , was prepared via a trans-esterification process from ethyl (N-diphenylmethylene)-glycinate and 1,2:5,6-di-O-isopropylidene-D-glucofuranos-3-yl-(N-diphenylmethylene) glycinate 9 , via a trans-imination reaction from 1,2:5,6-di-O-isopropylidene-D-glucofuranos-3-yl glycinate 6 and diphenyl-ketiminium chloride.

Characterisation of the intermediates produced upon one-electron oxidation of 4-, 5-, 6- and 7-hydroxyindoles by the azide radical

One-electron oxidation of a series of monohydroxylated indoles (HI) by the azide radical in the pH range 5–9 has been studied using the technique of pulse radiolysis with spectrophotometric detection. One-electron oxidation of 4-, 5-, 6- and 7-hydroxyindoles results in the formation of the corresponding indoloxyl radicals, the optical absorption spectra of which are independent of pH (5–9). It is confirmed, using the N(1)-methyl substituted analogue of 6-HI, that deprotonation of the resulting radical cation of the hydroxyindoles occurs preferentially from the hydroxy group to yield the corresponding indoloxyl radical. Such deprotonation would be consistent with the resulting indoloxyl radical having a low pKa.With the exception of 4-HI, the indoloxyl radicals decay bimolecularly in the dose/pulse range of 1–30 Gy to yield semi-permenent products (2k= 2–4 × 109 dm3 mol–1 s–1). With 4-HI, the decay of the indoloxyl radical changes from second-order to first-order kinetics on lowering the dose/pulse. At 1 Gy/pulse, the first-order kinetics are dependent upon the concentration of 4-HI. The second-order rate constant for reaction of the indoloxyl radical with 4-HI was determined to be 4.8 × 107 dm3 mol–1 s–1. The decay of these semi-permanent products from the indoloxyl radicals is first order and depends upon the concentration of azide. The second-order rate constants determined for this reaction depend markedly on the hydroxyindole used (k= 159–821 dm3 mol–1 s–1). The semi-permanent product arising from the bimolecular decay of the indoloxyl radicals is discussed in terms of the formation of reactive quinone-methides and/or -imines.