Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle.
Dafachronic acids (DAs) are 3-keto cholestenoic 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-Δ4-DA was able to directly activate DAF-12 in a transactivation cell-based luciferase assay and rescued the Mig phenotype of daf-9(rh50) Caenorhabditis elegans mutants. In the present paper, to investigate further the relationship between the structure of the steroid side chain and DAF-12 activity, we evaluated the in vitro and in vivo activity of Δ4-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, whereas 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.
*Departamento de Química Biológica and IFIBYNE (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Buenos Aires, Argentina.
María V
MV
Dansey
†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.
Lautaro D
LD
Alvarez
†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.
Gisela
G
Samaja
‡Departamento de Química Biológica and IQUIBICEN (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Buenos Aires, Argentina.
Daiana S
DS
Escudero
†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.
Adriana S
AS
Veleiro
*Departamento de Química Biológica and IFIBYNE (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Buenos Aires, Argentina.
Adalí
A
Pecci
‡Departamento de Química Biológica and IQUIBICEN (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Buenos Aires, Argentina.
Olga A
OA
Castro
†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.
Gerardo
G
Burton
D000483:Alleles; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002782:Cholestenes / Q000737:chemistry / Q000494:pharmacology*; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects*; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D002782:Cholestenes; C410905:DAF-12 protein, C elegans; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; C533800:dafachronic acid