Steroidal and Triterpenoidal Fungal Metabolites as Ligands of Liver X Receptors

Abstract

Cholesterol homeostasis is tightly controlled process that involves a variety of regulators including liver X receptors (LXR). Agonists of LXR are expected to increase cholesterol efflux, lower LDL, and raise HDL levels. Screening of a natural product library of microbial extracts using a LXR-scintillation proximity assay (SPA) binding assay and bioassay-guided fractionation of a number of fungal extracts led to the isolation of five ergostane and a cycloartane derivative. These compounds exhibited IC 50 value ranging 0.5ϳ9 m M in the binding assay for a-receptor and a number of these showed in vitro agonist activity in the coactivator association assays but lacked the cell based LXR activation. The isolation and LXR activity of these compounds are described.

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…Another cholesterol-derived molecule, follicular fluid Nuclear Receptors and Their Selective Modulators meiosis activating sterol, is also a potent activator of LXRa. Desmosterol, 6a-hydroxylated bile acids, and various compounds derived from plants and fungi are also potent activators of LXR (Song et al, 2000;Huang et al, 2005;Jayasuriya et al, 2005;Ondeyka et al, 2005;Yang et al, 2006). LXR is widely known to be targeted by two nonsteroidal synthetic agonists: T0901317 [N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide] and GW3965 [2-[3-[3-[[2-chloro-3-(trifluoromethyl)phenyl]methyl-(2,2-diphenylethyl)amino]propoxy]phenyl]acetic acid] (Fig.…”

Antineoplastic 31-Norcycloartanones from Solanum cernuum Vell

“…Later these authors reported the identification of its C-4 epimer . Cycloeucalenone has also been described as produced from fungus source (Ondeyka et al, 2005) and from Tinospora crispa (Menispermaceae) (Kongkathip et al, 2002). In this last work 1 was tested as cardiac contractile agent.…”

Natural Ligands for Nuclear Receptors: Biology and Potential Therapeutic Applications

“…(7) displayed non selective binding affinity with IC 50 values of 0.5 and 1.0 μM, respectively, for LXR and , thus pointing toward the positive effect on selectivity played by the presence of the methyl group at C-24 and/or the lack of the C-29 methyl group. However, this compound was not an agonist at 10 μM against either of the two receptors and was not effective in the transactivation assays [252].…”