UMYMFOR   05516
UNIDAD DE MICROANALISIS Y METODOS FISICOS EN QUIMICA ORGANICA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Synthesis, molecular modelling and Liver X Receptor activity of cholestenoic acid analogues
Autor/es:
ALVAREZ, LAUTARO D.; DANSEY, MARÍA V.; GRINMAN, DIEGO; SAMAJA, GISELA; DEL FUEYO, M. CELESTE; NAVALESI, DANIELA; PECCI, ADALÍ; VELEIRO, ADRIANA S.; BURTON, GERARDO
Lugar:
Londres
Reunión:
Simposio; 15th Tetrahedron Symposium; 2014
Institución organizadora:
Elsevier Science
Resumen:
LXR receptors are involved in many physiological functions such as cholesterol metabolism, excretion and detoxification of bile acids and lipids, and metastasis in mouse models of breast cancer.1-3 LXRs have been proposed as key factors affecting human life span, thus the development of novel LXR ligands that possess tissue-specific agonist/antagonist properties provides a promising avenue for drug discovery. Oxidized cholesterol metabolites (oxysterols, e.g. 1) are endogenous LXR ligands, 25R-cholestenoic acid (2) is also a potent LXR activator. Here we report the synthesis, the in vitro activity and molecular modelling of two cholestenoic acid analogues (3 and 4) with a simplified side chain. Compounds 3 and 4 were prepared from hyodesoxycholic acid (5) by conversion to cholenaldehyde 6 followed by a 2-carbon homologation (7). The key step for this transformation was a Wittig reaction with in situ generation of the stabilized ylide. Both compounds showed antagonistic activity when co-incubated with the LXR agonist GW3965 in HEK-293T cells. Moreover, these compounds also inhibited GW3965 mediated expression induction of several genes involved in lipogenesis and cholesterol efflux (e.g. Fatty Acid Synthase gene). Finally, in order to investigate the molecular basis of the antagonistic action of compound 3, molecular dynamics (MD) simulations were carried out starting from the crystal structure of LXRb bound to compound 1. By comparison of the dynamic behaviour between the LXRb/compound 1 complex (agonist system) and the LXRb/compound 3 complex (antagonist system), we found that the presence of the carboxylic group on the steroid side chain, altered the interaction between His435 (Helix 11) and Trp457 (Helix 12), an interaction considered essential to maintain the agonist receptor conformation. The MD results suggest that the antagonism of compound 3 may originate, in principle, in the destabilization produced by this ligand in the AF-2 domain of the receptor, a region involved in coactivator recruitment