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.
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Research Article|
December 12 2014
Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle
María V. Dansey;
María V. Dansey
*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
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Lautaro D. Alvarez;
Lautaro D. 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
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Gisela Samaja;
Gisela Samaja
†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
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Daiana S. Escudero;
Daiana S. Escudero
‡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
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Adriana S. Veleiro;
Adriana S. Veleiro
†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
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Adalí Pecci;
Adalí Pecci
*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
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Olga A. Castro;
Olga A. Castro
1
‡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
1Correspondence may be addressed to either of these authors (email ocastro@qb.fcen.uba.ar or burton@qo.fcen.uba.ar).
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Gerardo Burton
Gerardo Burton
1
†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
1Correspondence may be addressed to either of these authors (email ocastro@qb.fcen.uba.ar or burton@qo.fcen.uba.ar).
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Publisher: Portland Press Ltd
Received:
July 03 2014
Revision Received:
August 27 2014
Accepted:
November 06 2014
Accepted Manuscript online:
November 06 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2015 Biochemical Society
2015
Biochem J (2015) 465 (1): 175–184.
Article history
Received:
July 03 2014
Revision Received:
August 27 2014
Accepted:
November 06 2014
Accepted Manuscript online:
November 06 2014
Citation
María V. Dansey, Lautaro D. Alvarez, Gisela Samaja, Daiana S. Escudero, Adriana S. Veleiro, Adalí Pecci, Olga A. Castro, Gerardo Burton; Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle. Biochem J 1 January 2015; 465 (1): 175–184. doi: https://doi.org/10.1042/BJ20140833
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