Discovery of 2-((4,6-dimethylpyrimidin-2-yl)thio)- N -phenylacetamide derivatives as new potent and selective human sirtuin 2 inhibitors

Interactions between sirtuins and fluorogenic small-molecule substrates offer insights into inhibitor design

“…[5][6][7] Especially, SIRT5 can highly efficiently hydrolyze acidic acyl modications such as succinylation, malonylation, and glutarylation, 3,8 whereas SIRT6 prefers long-chain fatty acyl groups such as myristoyl-lysine residues. 9,10 Due to their multifaceted catalytic activities on various substrate proteins (Table S1 †), sirtuins are pivotal regulators in various cellular processes, including transcription, genome stability, and energy metabolism, 1,2 and are involved in human pathologies such as diabetes, 11,12 cancer, [13][14][15][16] and neurodegeneration. 2,17 These features make sirtuins potentially attractive targets for drug discovery.…”

“…Thus, sirtuin modulators are sought as chemical tools and potential therapeutics. 14,[18][19][20] Current activity assays for the identication of new sirtuin modulators are based on quantitative analysis of substrates/ products via HPLC/CE, 21,22 uorescence resonance energy transfer (FRET)-based peptide substrates, 23 or uorogenic peptide substrates. 18,24,25 The latter has been most widely used and requires a trypsin-coupled assay in which the release of a uorophore, e.g.…”

Structure‐based discovery of new selective small‐molecule sirtuin 5 inhibitors

“…Finally, 20 hit compounds ( Figure 1) were selected for subsequent biochemical test; to the best of our knowledge, all of these compounds have not been reported as sirtuin inhibitors so far. The predicted binding modes of the selected compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) are shown in Figure 1. We observed that although these compounds may have different binding modes with SIRT5, all of them are likely to form hydrogen-bonding/electrostatic interactions with Tyr102 and Arg105 (Figure 1).…”

“…[6,8] Owing to the multifaceted activity on various substrate proteins, sirtuins are implicated in many biological processes such as metabolic regulation, transcriptional regulation, genome stability, and cell survival. [1,2,[11][12][13] SIRT5, which mainly localizes in the mitochondrial matrix and preferentially hydrolyzes acidic acyl modifications, was found to play a pivotal role in mitochondrial metabolism, for example, amino acid degradation, the tricarboxylic acid cycle, and fatty acid metabolism. [14,15] Park et al recently revealed that SIRT5 represses biochemical activity of, and cellular respiration through, pyruvate dehydrogenase complex (PDC) and succinate dehydrogenase (SDH) [14] ; dysregulated PDC or SDH activity is linked to type 2 diabetes and cancer.…”

Chemometric study of chromatographic and computational bioactivity parameters of diphenylacetamides

“…20 They are also used in veterinary and plant treatment because they have good antimicrobials 21 and insecticidal 22 activity. Recent researches have increasingly focused on the study of the possibility of their use as new anti-HIV drugs, 23 anticancer agents 24,25 or theranostics. 26 In most cases, the type and intensity of phenylacetamide activity are conditioned by the chemical nature of the substituent attached to the basic molecule.…”