title: 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.
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA.
authors.forename: Yi-Pei
authors.initials: YP
authors.lastname: Chen
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA.
authors.forename: Chad C
authors.initials: CC
authors.lastname: Catbagan
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA.
authors.forename: Jeannette T
authors.initials: JT
authors.lastname: Bowler
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Gokey
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA.
authors.forename: Natalie D M
authors.initials: ND
authors.lastname: Goodwin
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA.
authors.forename: Anton B
authors.initials: AB
authors.lastname: Guliaev
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA. Electronic address: amagata@sfsu.edu.
authors.forename: Taro
authors.initials: T
authors.lastname: Amagata
mesh_terms: D001565:Benzoates / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015394:Molecular Structure; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000037:antagonists & inhibitors*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D013302:Streptomyces / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D001565:Benzoates; D056572:Histone Deacetylase Inhibitors; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2
keywords: 4-Dimethylaminobenzoic acid; 4-tert-Butylbenzoic acid; Class III HDAC inhibitor; Marine-derived Streptomyces sp.; Sirtuin