RESUMEN
It has been demonstrated that liver X receptors (LXR) play a significant role in cholesterol homeostasis. Agonists of LXR are expected to increase cellular cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of plant extracts using a LXR-SPA binding assay and bioassay-guided fractionation of a number of plant and marine gorgonian extracts led to the isolation of a number of active compounds. These included acanthoic acid (1) and alcohol (2), viperidone (3), polycarpol (4), rosacea acid (5), a cycloartane derivative (6), a new cycloartane analogue (7), betulinic acid (8), and gorgostane derivatives (9, 10, and 11). Of these compounds, 1, 4, and 11 exhibited potent binding affinity for alpha-receptor with IC(50) values of 0.25, 0.12, and 0.07 microM, respectively. Functionally they also showed strong coactivator association stimulation for LXRalpha receptor with EC50 values of 0.18, 0.03, and 0.05 microM, respectively. They also exhibited 15-, 8-, and 13-fold induction of the alpha-receptor in a transactivation assay in HEK-293 cells, respectively. In general these compounds were selective for the LXR alpha-receptor over the beta-receptor in all assays and were much better stimulators of the alpha-receptor than the endogenous steroid ligands.
Asunto(s)
Proteínas de Unión al ADN/agonistas , Diterpenos/aislamiento & purificación , Plantas Medicinales/química , Hidrocarburos Policíclicos Aromáticos/aislamiento & purificación , Receptores Citoplasmáticos y Nucleares/agonistas , Esteroides/aislamiento & purificación , Triterpenos/aislamiento & purificación , Animales , Annonaceae/química , Antozoos/química , Bahamas , Cactaceae/química , Campanulaceae/química , Células Cultivadas , Costa Rica , Diterpenos/química , Diterpenos/farmacología , Guyana , Humanos , Concentración 50 Inhibidora , Receptores X del Hígado , Estructura Molecular , Olacaceae/química , Receptores Nucleares Huérfanos , Triterpenos Pentacíclicos , Perú , Pinaceae/química , Hidrocarburos Policíclicos Aromáticos/química , Hidrocarburos Policíclicos Aromáticos/farmacología , Esteroides/química , Esteroides/farmacología , Triterpenos/química , Triterpenos/farmacología , Estados Unidos , Ácido BetulínicoRESUMEN
Parasite cGMP-dependent protein kinase (PKG) has been recently validated as a biochemical target for the treatment of coccidiosis. To discover new anticoccidial leads, we have screened our library of natural product extracts for inhibitors of parasite PKG. Bioassay-guided fractionation of the microbial extracts has led to the discovery of tenellones A (2) and B (3), two new highly substituted benzophenones. The isolation, structure, and activity of these compounds are described.
Asunto(s)
Benzofenonas/aislamiento & purificación , Inhibidores Enzimáticos/aislamiento & purificación , Hongos/química , Animales , Benzofenonas/química , Benzofenonas/farmacología , Proteínas Quinasas Dependientes de GMP Cíclico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Estructura Molecular , Plantas Medicinales/química , España , Toxoplasma/metabolismoRESUMEN
Liver X receptors (LXR) have been implicated in cholesterol homeostasis. Agonists of LXR are expected to increase cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of plant extracts using a LXR-SPA binding assay and bioassay-guided fractionation of the bark and stem extract of Garcinia humilis led to the discovery of a new polyisoprenylated benzophenone named guttiferone I (1). The IC(50) value for this compound in the LXRalpha-SPA binding assay was 3.4 muM. Details of the isolation, structure elucidation, and ligand binding activity of 1 are described.