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Evaluation of benzoic acid derivatives as sirtuin inhibitors.

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.

SUBMITTER: Chen YP

PROVIDER: S-EPMC3909564 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Evaluation of benzoic acid derivatives as sirtuin inhibitors.

Chen Yi-Pei YP Catbagan Chad C CC Bowler Jeannette T JT Gokey Trevor T Goodwin Natalie D M ND Guliaev Anton B AB Wu Weiming W Amagata Taro T

Bioorganic & medicinal chemistry letters 20131112 1

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 ...[more]

PMID: 24269123

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