title: 27-Nor-Δ(4)-dafachronic acid is a synthetic ligand of Caenorhabditis elegans DAF-12 receptor.
abstract: 27-Nor-Δ(4)-dafachronic acid was prepared in nine steps and 14% overall yield by two sequential 2-carbon homologations from 20β-carboxyaldehyde-4-pregnen-3-one. Its activity was evaluated in vivo, where it rescued the Mig phenotype of daf-9(rh50) Caenorhabditis elegans mutants and restored their normal resistance to oxidative stress. 27-Nor-Δ(4)-dafachronic acid was also able to directly bind and activate DAF-12 in a transactivation cell-based luciferase reporter assay, although it was less active than the corresponding 25R-and 25S dafachronic acids. The binding mode of the 27-Nor steroid was studied by molecular dynamics using a homology model of the CeDAF-12 receptor.
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 Buenos Aires, Argentina.
authors.forename: Gisela A
authors.initials: GA
authors.lastname: Samaja
authors.forename: Olga
authors.initials: O
authors.lastname: Castro
authors.forename: Lautaro D
authors.initials: LD
authors.lastname: Alvarez
authors.forename: María V
authors.initials: MV
authors.lastname: Dansey
authors.forename: Daiana S
authors.initials: DS
authors.lastname: Escudero
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Veleiro
authors.forename: Adalí
authors.initials: A
authors.lastname: Pecci
authors.forename: Gerardo
authors.initials: G
authors.lastname: Burton
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000737:chemistry*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism*; D002782:Cholestenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D029742:Caenorhabditis elegans Proteins; D002782:Cholestenes; C410905:DAF-12 protein, C elegans; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; C533799:delta4-dafachronic acid