Abstract
Human sirtuin 2 (SIRT2), a member of the sirtuin family, has been considered as a promising drug target in cancer, neurodegenerative diseases, type II diabetes, and bacterial infections. Thus, SIRT2 inhibitors have been involved in effective treatment strategies for related diseases. Using previously established fluorescence-based assays for SIRT2 activity tests, the authors screened their in-house database and identified a compound, 4-(5-((3-(quinolin-5-yl)ureido)methyl)furan-2-yl)benzoic acid (20), which displayed 63 ± 5% and 35 ± 3% inhibition against SIRT2 at 100 μM and 10 μM, respectively. The structure-activity relationship (SAR) analyses of a series of synthesized (5-phenylfuran-2-yl)methanamine derivatives led to the identification of a potent compound 25 with an IC50 value of 2.47 μM, which is more potent than AGK2 (IC50 = 17.75 μM). Meanwhile, 25 likely possesses better water solubility (cLogP = 1.63 and cLogS = −3.63). Finally, the molecular docking analyses indicated that 25 fitted well with the induced hydrophobic pocket of SIRT2.
Highlights
Histone deacetylases (HDACs) are enzymes that catalyze the removal of acyl groups from ε-N-acyl-lysine amino groups on histones and non-histone substrates
(5-phenylfuran-2-yl)methanamine derivatives led to the identification of a potent compound 25 with an IC50 value of 2.47 μM, which is more potent than AGK2 (IC50 = 17.75 μM)
sirtuin 2 (SIRT2), which is located in both cytoplasm and nucleus [8], mainly catalyzes deacetylation and defatty-acylation for a variety of protein substrates, including histones H3 and H4 [9,10], and nonhistone proteins α-tubulin [11], p53 [12], Foxo1 [13], p300 [14], NFκB [15], PAR3 and PRLR [16]
Summary
Histone deacetylases (HDACs) are enzymes that catalyze the removal of acyl groups from ε-N-acyl-lysine amino groups on histones and non-histone substrates. These have been identified and grouped into four classes [1,2,3]: Classes I, II, and IV HDACs are Zn2+ -dependent metalloproteases; class. III HDACs, namely sirtuins (SIRTs), use NAD+ as a cofactor for catalysis [4,5,6]. There are seven isotypes of sirtuins (SIRT1–7), which differ in their catalytic activity and subcellular localization [7]. Many studies revealed that the dysregulation of SIRT2 activity is a key factor contributing to the pathogenesis of cancer [24], neurodegenerative diseases [25,26], type II diabetes [27], and bacterial infections [21,23], which makes
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