Synthesis and Biological Activity of Fluorinated Analogues of the DAF-12 Receptor Antagonist 24-Hydroxy-4-cholen-3-one

Publication date: Available online 7 August 2019Source: SteroidsAuthor(s): Cristian R. Rodriguez, M. Celeste del Fueyo, Vanessa J. Santillán, M. Virginia Dansey, Adriana S. Veleiro, Olga A. Castro, Gerardo BurtonAbstractThe DAF-12 receptor is a ligand-activated transcription factor that in its ligand-bound form allows the expression of target genes needed to support the reproductive life cycle of the free-living nematode Caenorhabditis elegans, whereas unbound DAF-12 receptor leads to the developmentally arrested “dauer larvae”, specialized for survival and dispersal. The endogenous ligands of the DAF-12 receptor are 3-keto-cholestenoic acids dubbed dafachronic acids. In a previous publication we reported that oxysterols with a shorter side chain (C24) modulate the DAF-12 receptor activity either as partial agonists or, in the case of the C24 alcohol 24-hydroxy-4-cholen-3-one, as an antagonist both in vitro and in vivo. Preliminary structure-activity relationships suggested that this activity profile could be improved with more lipophilic and less acidic functional groups at the end of the side chain. Thus, we have now synthesized two fluorine containing analogues in which the C-24 hydroxyl was replaced by a difluoromethyl group (regarded as a “lipophilic hydroxyl”) or a difluoromethylidene group with similar lipophilicity but lacking the hydrogen bond donor capacity. Activity was evaluated in vitro using transactivation cell-based assays and in vivo by the effect on...
Source: Steroids - Category: Drugs & Pharmacology Source Type: research