title: C(16)-C(22) oxygen-bridged analogues of ceDAF-12 and LXR ligands.
abstract: The DAF-12 receptor in nematodes and the Liver X Receptor (LXR) in mammals are structurally related transcription factors that play key roles in determining the life span of the organism. Both types of receptors are activated by oxysterols, cholesterol metabolites with oxidized side chains. Restricting the movement of the oxysterol side chain to certain orientations may have profound effects in the activity profile, however this has not been explored so far. In a first attempt to obtain analogues of natural ligands of DAF-12 and LXR with restricted side chain mobility we introduced a 16,22-oxygen bridge in 26-hydroxycholesterol, a cholestenoic acid and a dafachronic acid (5-7). Diosgenin was used as starting material, the key step to obtain the 16,22 epoxy functionality was the one pot formation and reduction of a cyclic hemiketal via the oxocarbenium ion using sodium cyanoborohydride. All new compounds were characterized by NMR and mass spectrometry and assayed as ceDAF-12 or LXR ligands in transactivation cell-based assays. The dafachronic acid analogue 7 behaved as a ceDAF-12 agonist.
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Ciudad de Buenos Aires, Argentina.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Del Fueyo
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Ciudad de Buenos Aires, Argentina.
authors.forename: M Virginia
authors.initials: MV
authors.lastname: Dansey
authors.affiliation: Departamento de Química Biológica and IFIBYNE (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Ciudad de Buenos Aires, Argentina.
authors.forename: Luciano S
authors.initials: LS
authors.lastname: Paolo
authors.affiliation: Departamento de Química Biológica and IFIBYNE (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Ciudad de Buenos Aires, Argentina.
authors.forename: Adalí
authors.initials: A
authors.lastname: Pecci
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Ciudad de Buenos Aires, Argentina.
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Veleiro
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Ciudad de Buenos Aires, Argentina. Electronic address: burton@qo.fcen.uba.ar.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Burton
mesh_terms: D000818:Animals; D002460:Cell Line; D002782:Cholestenes / Q000737:chemistry; D006224:Cricetinae; D057809:HEK293 Cells; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry*; D000071518:Liver X Receptors / Q000819:agonists* / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D000072376:Oxysterols / Q000737:chemistry
chemical_list: D002782:Cholestenes; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D000072376:Oxysterols; C533800:dafachronic acid
keywords: DAF-12 receptor; Dafachronic acid; Liver X Receptor; Oxocarbenium reduction; Oxysterols