info:eu-repo/semantics/article
Synthesis and Biological Activity of Fluorinated Analogues of the DAF-12 Receptor Antagonist 24-Hydroxy-4-cholen-3-one
Fecha
2019-07Registro en:
Rodriguez, Cristian Ramon; del Fueyo, Maria Celeste; Santillan, Vanessa; Dansey, Maria Virginia; Veleiro, Adriana Silvia; et al.; Synthesis and Biological Activity of Fluorinated Analogues of the DAF-12 Receptor Antagonist 24-Hydroxy-4-cholen-3-one; Elsevier Science Inc; Steroids; 151; 7-2019; 1-7
0039-128X
CONICET Digital
CONICET
Autor
Rodriguez, Cristian Ramon
del Fueyo, Maria Celeste
Santillan, Vanessa
Dansey, Maria Virginia
Veleiro, Adriana Silvia
Castro, Olga Alejandra
Burton, Gerardo
Resumen
The 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 the development of wild-type C. elegans. The 24-difluoromethyl analogue retained the antagonist activity in vitro, being completely devoid of agonist activity and exhibited improved activity in vivo. The difluoromethylidene showed a slight antagonist tendency in vitro (statistically not significant), in the concentration range tested and was weakly active in vivo. None of the compounds were toxic, as treated worms recovered to normal development, when transferred to fresh media without added steroids.