Bruno Charpentier

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.

Selective Synthetic Ligands for Human Nuclear Retinoic Acid Receptors

From a series of naphthalene and benzoic acid derivatives we have identified synthetic retinoic acid analogues exhibiting high selectivity for the nuclear retinoic acid receptors RAR alpha (Am 580), RAR beta (CD 2019) and RAR gamma (CD 437) as well as ligands sharing high affinities for all RAR subtypes (CD 367). The compounds were evaluated in two complementary screening systems: (1) binding to nuclear proteins extracted from COS-7 cells after transfection with the appropriate expression vectors, and (2) induction of plasminogen activator in the embryonic mouse teratocarcinoma cell line F9. All compounds behaved as retinoic acid agonists in the F9 test.

NEW SYNTHETIC RETINOIDS OBTAINED BY PALLADIUM-CATALYZED TANDEM CYCLISATION-HYDRIDE CAPTURE PROCESS

Abstract A new series of conformationally restricted retinoids (3-aryl-3-methyl-2,3-dihydro-benzofurans) have been prepared through a palladium-catalyzed tandem cyclisation-hydride capture. The use of enantiopure BINAP-Pd catalyst allowed asymmetric synthesis of bioactive molecules.

Differentiation of F9 Embryonal Carcinoma Cells by Synthetic Retinoids: Amplitude of Plasminogen Activator Production Does Not Depend on Retinoid Potency or Affinity for F9 Nuclear Retinoic Acid Receptors

Retinoic acid and analogues (retinoids) are able to induce the differentiation of F9 murine embryonal carcinoma stem cells into endoderm-like cells. The secretion of plasminogen activator (PA) which accompanies this differentiation is a good index of the biological response of F9 cells to retinoids. We have previously reported that the potency of a series of natural and synthetic retinoids, evaluated by the concentration which provokes half-maximal induction of PA, correlates well with the affinity of these compounds for the endogenous F9 nuclear retinoic acid receptors, but not for the cytosolic retinoic acid binding protein, CRABP. In this paper we show that various retinoids differ, not only in terms of potency, i.e. the dilution at which they are active, but also in terms of the amount of PA that they induce. This parameter, called amplitude, is used to quantify the extent of PA induction by a given retinoid relative to retinoic acid. The amplitude parameters of synthetic retinoids are found to vary over a wide range and are independent of both potency and binding affinity for F9 retinoic acid receptors. It is proposed that the amplitude of the biological response to a given retinoid is the resultant of three factors: (i) the total or partial agonist character of the retinoid; (ii) the binding spectrum of the retinoid for the various types of retinoic acid receptors; (iii) the chemical and metabolic stability of the retinoid in the test system.

Synthesis and biological activities of new heterocyclic aromatic retinoids

Abstract A series of 3-aryl-2H-1-benzopyrancarboxylic acid derivatives was synthesized and evaluated as Retinoic Acid Receptor (RAR) agonists. By modifications of the 3-aryl group, we have obtained new retinoids exhibiting potent cellular differentiating activities and high affinities for RARs. Moreover, hydrogenation of the 2H-1-benzopyran ring led to the 3-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-naphthalen-2-yl)-3,4-dihydro-2H-1-benzopyran-7-yl carboxylic acid, characterized by a RARs binding profile.

Chemoenzymatic synthesis of enantiomers of a new retinoid to investigate the role of chirality in the biological response

Abstract We have prepared both enantiomers of a new retinoid ( IIa and IIb ) partly by using lipase resolution of 1-acetoxy-1-(5, 6, 7, 8 - tetrahydro - 5, 5, 8, 8-tetramethyl-2-naphthyl) ethane. Absolute configuration of resulting secondary carbinols ( 4a and 4b ) was assigned using lanthanide induced shifts NMR experiments on MTPA esters of 4a and 4b . Only the enantiomer (R-(−)- IIa ) is active on the differentiation of F9 embryonal teratocarcinoma cells (F9 cells).