UMYMFOR   05516
UNIDAD DE MICROANALISIS Y METODOS FISICOS EN QUIMICA ORGANICA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Synthesis and Liver X Receptor activity of cholestenoic acid analogues
Autor/es:
GRINMAN, DIEGO; SAMAJA, GISELA; DANSEY, MARIA V.; ALVAREZ, LAUTARO D.; DEL FUEYO, M. CELESTE; VELEIRO, ADRIANA S.; PECCI, ADALI; BURTON, GERARDO
Lugar:
Moscú
Reunión:
Simposio; 5th International Symposium on Advances in Synthetic and Medicinal Chemistry; 2013
Institución organizadora:
European Federation for Medicinal Chemistry
Resumen:
In the nematode Caenorhabditis elegans, the nuclear receptor DAF-12 has been shown to be one of the key components that modulate life span in response to environmental cues.[1] Using sequence similarity searches, LXR was identified as one of the human NHRs, the protein sequence of which is most similar to ceDAF-12.[2] Once activated, LXR induces the expression of genes involved in cholesterol metabolism and modulates immune and inflammatory responses in macrophages. Considering that alterations in lipid metabolism and development of a chronic inflammatory state are associated to cardiovascular diseases (e.g.atherosclerosis), LXR has been proposed as a candidate to affect human life span.[2] Dafachronic acids (DAs) are the natural ligands of DAF-12, 1 being one of the most active and abundant in the nematode.[3] Interestingly, the closely related cholestenoic acids 2, bind both to DAF-12 and LXR receptors.[4] The configuration at C-25 of DAs is an important determinant on the activity of the ligand-receptor complex, 25S-DAs being more active than the 25R diastereomers.[3] Recently, we showed that removal of the C-25 methyl would not impede the strong interaction of the carboxylate with the ceDAF-12 receptor.[5] Accordingly, we found that compound 3 induces DAF-12 response in HEK-293T cells co-transfected with the pGAL4-DAF-12 expression vector and the GAL4-LUC reporter gene.[6] Based on the homology between the LXR and DAF-12 receptors, we report the synthesis and the in vitro biological activity of 4 and 5, 27-nor-analogues of the cholestenoic acids 2. Compound 4 showed positive synergistic effects at low concentrations ([10-7M] to [10-6M]) and an antagonistic activity at 10-5M, when coincubated with the LXR agonist GW3965 [10-6M] in HEK-293T cells, co-transfected with pLXRâ and pLRE-LUC reporter gene. Neither 4 nor 5 showed agonist activity per se at 10-5M. Moreover, compound 4 also inhibited GW3965 mediated expression induction of endogenous Fatty Acid Synthase gene