27-Nor-?4-dafachronic acid is a synthetic ligand of Caenorhabditis elegans DAF-12 receptor

Article

Authorship

Samaja, Gisela Anabel ; Castro, Olga Alejandra ; ALVAREZ, LAUTARO DAMIAN ; DANSEY, MARIA VIRGINIA ; Escudero, Daiana Sabrina ; Veleiro, Adriana Silvia ; PECCI, ADALI ; Burton, Gerardo

Date

2013

Publishing House and Editing Place

Elsevier

Magazine

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 23 (pp. 2893-2896) Elsevier

Summary Information provided by the agent in SIGEVA

27-Nor-?4-dafachronic acid was prepared in nine steps and 14% overall yield by two sequential 2-carbon homologations from 20?-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-?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 ... 27-Nor-?4-dafachronic acid was prepared in nine steps and 14% overall yield by two sequential 2-carbon homologations from 20?-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-?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.