Synthetic DAF-12 modulators with potential use in controlling nematodes life cycle

DANSEY, MARÍA V.; ALVAREZ, LAUTARO D.; SAMAJA, GISELA; ESCUDERO, DAIANA S.; VELEIRO, ADRIANA S.; PECCI, ADALÍ; CASTRO, OLGA A.; BURTON, GERARDO

BIOCHEMICAL JOURNAL

PORTLAND PRESS LTD

Año: 2015 vol. 465 p. 175 - 184

0264-6021

Dafachronic acids (DAs) are 3-keto colestenoic acids bearing a carboxylic acid moiety at the end of the steroid side chain. These compounds interact with the DAF-12 receptor, a ligand dependent transcription factor that acts as a molecular switch mediating the choice between arrest at diapause or progression to reproductive development and adult lifespan in different nematodes. Recently, we reported that the 27-nor-D4-DA, was able to directly activate DAF-12 in a transactivation cell-based luciferase assay and rescued the Mig phenotype of daf-9(rh50) C. elegans mutants. Here, to further investigate the relationship between the structure of the steroid side chain and the DAF-12 activity, we evaluated the in vitro and in vivo activity of D4-DA analogues with modified side chains using transactivation cell based assays and daf-9(dh6) C. elegans mutants. Our results revealed that introduction of a 24,25 double bond on the cholestenoic acid side chain did not affect DAF-12 activity while shortening the side chain lowered the activity. Most interestingly, the C24 alcohol 24-hydroxy-4-cholen-3-one (6) was an antagonist of the DAF-12 receptor both in vitro and in vivo.