Bioorganic & Medicinal Chemistry Letters 2014-01-01

Evaluation of benzoic acid derivatives as sirtuin inhibitors.

Yi-Pei Chen, Chad C Catbagan, Jeannette T Bowler, Trevor Gokey, Natalie D M Goodwin, Anton B Guliaev, Weiming Wu, Taro Amagata

Index: Bioorg. Med. Chem. Lett. 24(1) , 349-52, (2014)

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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. Copyright © 2013 Elsevier Ltd. All rights reserved.