RESUMO
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.
Assuntos
Proteínas de Ligação a DNA/agonistas , Diterpenos/isolamento & purificação , Plantas Medicinais/química , Hidrocarbonetos Policíclicos Aromáticos/isolamento & purificação , Receptores Citoplasmáticos e Nucleares/agonistas , Esteroides/isolamento & purificação , Triterpenos/isolamento & purificação , Animais , Annonaceae/química , Antozoários/química , Bahamas , Cactaceae/química , Campanulaceae/química , Células Cultivadas , Costa Rica , Diterpenos/química , Diterpenos/farmacologia , Guiana , Humanos , Concentração Inibidora 50 , Receptores X do Fígado , Estrutura Molecular , Olacaceae/química , Receptores Nucleares Órfãos , Triterpenos Pentacíclicos , Peru , Pinaceae/química , Hidrocarbonetos Policíclicos Aromáticos/química , Hidrocarbonetos Policíclicos Aromáticos/farmacologia , Esteroides/química , Esteroides/farmacologia , Triterpenos/química , Triterpenos/farmacologia , Estados Unidos , Ácido BetulínicoRESUMO
Human CCR5 is a G-coupled receptor that binds to the envelope protein gp120 and CD4 and mediates the HIV-1 viral entry into the cells. The blockade of this binding by a small molecule receptor antagonist could lead to a new mode of action agent for HIV-1 and AIDS. Screening of natural product extracts led to the identification of anibamine (1), a novel pyridine quaternary alkaloid as a TFA salt, from Aniba sp.; ophiobolin C from fermentation extracts of fungi Mollisia sp.; and 19,20-epoxycytochalasin Q from Xylaria sp. Formation of the TFA salt of anibamine is plausibly an artifact of the isolation. The identity of the natural counterion is unknown. Anibamine.TFA competed for the binding of 125I-gp120 to human CCR5 with an IC50 of 1 microM. Ophiobolin C and 19,20-epoxycytochalasin Q exhibited binding IC50) values of 40 and 60 microM, respectively.