Discovery of Indoles as Potent and Selective Inhibitors of the Deacetylase SIRT1

Napper, Andrew D.; Hixon, Jeffrey; McDonagh, Thomas; Keavey, Kenneth; Pons, Jean‐François; Barker, Jonathan; Yau, Wei Tsung; Amouzegh, Patricia; Flegg, Adam; Hamelin, Estelle; Thomas, Russell J.; Kates, Michael J.; Jones, Stephen; Navia, Manuel A.; Saunders, Jeffrey O.; DiStefano, Peter S.; Curtis, Rory

doi:10.1021/jm050522v

Cited by 477 publications

(285 citation statements)

References 40 publications

(114 reference statements)

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“…The effect of fructose on nuclear sirtuin activity was also inhibited by the SIRT1 inhibitors EX-527, a specific SIRT1 inhibitor (Fig. 1J), and nicotinamide (Supplementary Figure 1A, see section on supplementary data given at the end of this article) at similar concentrations to those used in previous studies of SIRT1 activation (Napper et al 2005, Rodgers et al 2005. This indicated that the fructose-induced increase in nuclear sirtuin activity occurred as a result of increased SIRT1 activity.…”

Section: Fructose Induces Gluconeogenesis Through a Sirt1-dependent Msupporting

confidence: 68%

Fructose Induces Gluconeogenesis and Lipogenesis Through a Sirt1-Dependent Mechanism

Caton

Nayuni²,

Khan³

et al. 2011

Journal of Endocrinology

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Consumption of a fructose-rich diet leads to insulin resistance and dyslipidemia in part due to elevated gluconeogenesis and lipogenesis. SIRT1, an NAD C -dependent protein deacetylase, can induce gluconeogenesis and lipogenesis. The aim of this study was to determine whether fructose increased hepatic SIRT1, leading to induction of gluconeogenesis and lipogenesis. Rat hepatocytes were incubated with fructose (1-5 mM). SIRT1 protein, SIRT1 activity, and NAD C /NADH ratio were measured. The effects of SIRT1 inhibitors (EX-527 and nicotinamide) and activators (SIRT1 activator 3 and SRT1720) and the mitochondrial complex I inhibitor rotenone were examined on fructose-induced increases in gluconeogenesis and lipogenesis. Fructose increased SIRT1 protein, SIRT1 activity, and NAD C /NADH ratio. Fructose also induced gluconeogenesis, with increases in peroxisome proliferatoractivated receptor coactivator 1-alpha (PGC1a) and phosphoenolpyruvate carboxykinase (PEPCK; gene code Pck1) gene expression, PEPCK activity, and hepatocyte glucose production. In addition, levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) and acetyl-coA carboxylase (Acc) mRNA, and intracellular cholesterol were increased. Increases in gluconeogenesis, Hmgcr, Acc, and cholesterol were abolished by SIRT1 inhibitors and rotenone, while SIRT1 activators increased gluconeogenesis, Hmgcr, Acc, Pgc1b, and sterol regulatory element-binding protein 1c (Srebp1c) gene expression. In conclusion, fructose induces gluconeogenesis and lipogenesis through a SIRT1-dependent mechanism, suggesting that induction of hepatic SIRT1 could play a pivotal role in the metabolic changes observed in humans and animals consuming a fructose-rich diet. These results highlight the need for a greater understanding of the role of SIRT1 in metabolic regulation and indicate the potential for adverse effects of SIRT1 activators if used therapeutically.

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Section: Fructose Induces Gluconeogenesis Through a Sirt1-dependent Msupporting

confidence: 68%

Fructose Induces Gluconeogenesis and Lipogenesis Through a Sirt1-Dependent Mechanism

Caton

Nayuni²,

Khan³

et al. 2011

Journal of Endocrinology

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“…Ex-527 on the other hand, is much more specific for SIRT1, with IC50's of 98 nM, 19.6 mM, and 48.7 mM for SIRT1, SIRT2, and SIRT3. 14 We chose a top dose that would possibly inhibit all 3 SIRTs, 50 mM. Thus, through treatment with these additional 2 inhibitors, we should have a better idea of whether inhibiting more than one Sirtuin at a time will have a greater impact on melanoma cell growth and viability, or if using SIRT1 or SIRT2 inhibition individually would be a better treatment option.…”

Section: Introductionmentioning

confidence: 99%

Sirtuin deacetylases: A new target for melanoma management

et al. 2014

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y These authors contributed equally to this work.M elanoma continues to cause more deaths than any other skin cancer, necessitating the development of new avenues of treatment. One promising new opportunity comes in the form of mechanism-based therapeutic targets. We recently reported the overexpression and delocalization of the class III histone deacetylase SIRT1 in melanoma, and demonstrated that its small molecule inhibition via Tenovin-1 decreased cell growth and viability of melanoma cells, possibly by a p53 mediated induction of p21. Here, we support our data using additional SIRT inhibitors, viz. Sirtinol and Ex-527, which suggests possible benefits of concomitantly inhibiting more than one Sirtuin for an effective cancer management strategy. This "Extra View" paper also includes a discussion of our results in the context of similar recent and concurrent studies. Furthermore, we expand upon our findings in an analysis of new research that may link the cellular localization and growth effects of SIRT1 with the PI3K signaling pathway.

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“…7A). To further confirm that the SIRT1 pathway was involved in the enhanced exercise capacity of AC5 KO mice, AC5 KO mice were treated with EX527, a selective SIRT1 inhibitor (Napper et al ., 2005), which abolished the enhanced exercise capacity of AC5 KO mice (Fig. 7B).…”

Section: Resultsmentioning

confidence: 89%

Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

et al. 2015

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SummaryThe most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (β‐AR), and adenylyl cyclase (AC) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC5 disruption, that is, knock out (KO) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC5 KO. The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac‐ and skeletal muscle‐specific AC5 KO's, where exercise performance was no longer improved by the cardiac‐specific AC5 KO, but was by the skeletal muscle‐specific AC5 KO, and there was no difference in cardiac output during exercise in AC5 KO vs. WT. Mitochondrial biogenesis was a major mechanism mediating the enhanced exercise. SIRT1, FoxO3a, MEK, and the anti‐oxidant, MnSOD were upregulated in AC5 KO mice. The improved exercise in the AC5 KO was blocked with either a SIRT1 inhibitor, MEK inhibitor, or by mating the AC5 KO with MnSOD hetero KO mice, confirming the role of SIRT1, MEK, and oxidative stress mechanisms. The Caenorhabditis elegans worm AC5 ortholog, acy‐3 by RNAi, also improved fitness, mitochondrial function, antioxidant defense, and lifespan, attesting to the evolutionary conservation of this pathway. Thus, decreasing sympathetic signaling through loss of AC5 is not only a mechanism to improve exercise performance, but is also a mechanism to improve healthful aging, as exercise also protects against diabetes, obesity, and cardiovascular disease, which all limit healthful aging.

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Discovery of Indoles as Potent and Selective Inhibitors of the Deacetylase SIRT1

Cited by 477 publications

References 40 publications

Fructose Induces Gluconeogenesis and Lipogenesis Through a Sirt1-Dependent Mechanism

Fructose Induces Gluconeogenesis and Lipogenesis Through a Sirt1-Dependent Mechanism

Sirtuin deacetylases: A new target for melanoma management

Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

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