Evaluation of benzoic acid derivatives as sirtuin inhibitors.
Bioorg Med Chem Lett
; 24(1): 349-52, 2014 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-24269123
ABSTRACT
Employing a genetically modified yeast strain as a screening tool, 4-dimethylaminobenzoic acid (5) was isolated from the marine sediment-derived Streptomyces sp. CP27-53 as a weak yeast sirtuin (Sir2p) inhibitor. Using this compound as a scaffold, a series of disubstituted benzene derivatives were evaluated to elucidate the structure activity relationships for Sir2p inhibition. The results suggested that 4-alkyl or 4-alkylaminobenzoic acid is the key structure motif for Sir2p inhibitory activity. The most potent Sir2p inhibitor, 4-tert-butylbenzoic acid (20), among the tested compounds in this study turned out to be a weak but selective SIRT1 inhibitor. The calculated binding free energies between the selected compounds and the catalytic domain of SIRT1 were well correlated to their measured SIRT1 inhibitory activities.
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MEDLINE
Assunto principal:
Streptomyces
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Benzoatos
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Proteínas Reguladoras de Informação Silenciosa de Saccharomyces cerevisiae
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Sirtuína 2
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Inibidores de Histona Desacetilases
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article