Quercetin based derivatives as sirtuin inhibitors

Heger, Vladimír; Tyni, Jonna; Hunyadi, Attila; Horáková, Ľubica; Lahtela‐Kakkonen, Maija; Rahnasto-Rilla, Minna

doi:10.1016/j.biopha.2019.01.035

Cited by 41 publications

(37 citation statements)

References 45 publications

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“…Other data indicate that resveratrol activates both the PGC1α/SIRT1/AMPK axis and DNMTs, with beneficial effects for cancer prevention and treatment [268]. Similar results have been reported for quercetin [269] and EVOO polyphenols; the latter were shown to activate the Sirt1 path, with possible relevance for AD prevention/treatment [40]. Furthermore, studies performed on esophageal, oral, skin, regulatory T-cells, lung, breast, and prostate cancer cells reported alterations induced by bioactive compounds from green tea, including EGCG, on DNMT activity in studies performed on esophageal, oral, skin, regulatory T-cells, lung, breast, and prostate cancer cells [270].…”

Section: Dna Methylationsupporting

confidence: 73%

Healthy Effects of Plant Polyphenols: Molecular Mechanisms

Leri

Scuto

Ontario

et al. 2020

IJMS

311

213

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The increasing extension in life expectancy of human beings in developed countries is accompanied by a progressively greater rate of degenerative diseases associated with lifestyle and aging, most of which are still waiting for effective, not merely symptomatic, therapies. Accordingly, at present, the recommendations aimed at reducing the prevalence of these conditions in the population are limited to a safer lifestyle including physical/mental exercise, a reduced caloric intake, and a proper diet in a convivial environment. The claimed health benefits of the Mediterranean and Asian diets have been confirmed in many clinical trials and epidemiological surveys. These diets are characterized by several features, including low meat consumption, the intake of oils instead of fats as lipid sources, moderate amounts of red wine, and significant amounts of fresh fruit and vegetables. In particular, the latter have attracted popular and scientific attention for their content, though in reduced amounts, of a number of molecules increasingly investigated for their healthy properties. Among the latter, plant polyphenols have raised remarkable interest in the scientific community; in fact, several clinical trials have confirmed that many health benefits of the Mediterranean/Asian diets can be traced back to the presence of significant amounts of these molecules, even though, in some cases, contradictory results have been reported, which highlights the need for further investigation. In light of the results of these trials, recent research has sought to provide information on the biochemical, molecular, epigenetic, and cell biology modifications by plant polyphenols in cell, organismal, animal, and human models of cancer, metabolic, and neurodegenerative pathologies, notably Alzheimer’s and Parkinson disease. The findings reported in the last decade are starting to help to decipher the complex relations between plant polyphenols and cell homeostatic systems including metabolic and redox equilibrium, proteostasis, and the inflammatory response, establishing an increasingly solid molecular basis for the healthy effects of these molecules. Taken together, the data currently available, though still incomplete, are providing a rationale for the possible use of natural polyphenols, or their molecular scaffolds, as nutraceuticals to contrast aging and to combat many associated pathologies.

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Section: Dna Methylationsupporting

confidence: 73%

Healthy Effects of Plant Polyphenols: Molecular Mechanisms

Leri

Scuto

Ontario

et al. 2020

IJMS

311

213

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“…They might be the explanation why the deacetylase activity of Sirt6 is weak in vitro yet significant in vivo 7 . Furthermore, quercetin inhibits other Sirtuin isoforms with low potency and more potent derivatives appear to exist also for these isoforms 36 and might contribute to physiological effects of the compound family.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives

You

Zheng

Weiss

et al. 2019

Sci Rep

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Mammalian Sirtuin 6 (Sirt6) is an NAD+-dependent protein deacylase regulating metabolism and chromatin homeostasis. Sirt6 activation protects against metabolic and aging-related diseases, and Sirt6 inhibition is considered a cancer therapy. Available Sirt6 modulators show insufficient potency and specificity, and even partially contradictory Sirt6 effects were reported for the plant flavone quercetin. To understand Sirt6 modulation by quercetin-based compounds, we analysed their binding and activity effects on Sirt6 and other Sirtuin isoforms and solved crystal structures of compound complexes with Sirt6 and Sirt2. We find that quercetin activates Sirt6 via the isoform-specific binding site for pyrrolo[1,2-a]quinoxalines. Its inhibitory effect on other isoforms is based on an alternative binding site at the active site entrance. Based on these insights, we identified isoquercetin as a ligand that can discriminate both sites and thus activates Sirt6 with increased specificity. Furthermore, we find that quercetin derivatives that inhibit rather than activate Sirt6 exploit the same general Sirt6 binding site as the activators, identifying it as a versatile allosteric site for Sirt6 modulation. Our results thus provide a structural basis for Sirtuin effects of quercetin-related compounds and helpful insights for Sirt6-targeted drug development.

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“…Polyphenols, such as quercetin and luteolin at higher concentrations activate Sirt6, whereas inhibit at lower levels. Thus polyphenols modulate Sirt6 activity in a concentration dependent manner (Rahnasto-Rilla et al, 2016;Rahnasto-Rilla et al, 2018;Heger et al, 2019). Cyanidin, another polyphenol, is a potent activator of Sirt6 producing 5-15 folds increase in Sirt6 activity compared to other polyphenols (Rahnasto-Rilla et al, 2018).…”

Section: Sirt6 Modulatorsmentioning

confidence: 99%

Sirt6 Deacetylase: A Potential Key Regulator in the Prevention of Obesity, Diabetes and Neurodegenerative Disease

et al. 2020

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Sirtuins, NAD + dependent proteins belonging to class III histone deacetylases, are involved in regulating numerous cellular processes including cellular stress, insulin resistance, inflammation, mitochondrial biogenesis, chromatin silencing, cell cycle regulation, transcription, and apoptosis. Of the seven mammalian sirtuins present in humans, Sirt6 is an essential nuclear sirtuin. Until recently, Sirt6 was thought to regulate chromatin silencing, but new research indicates its role in aging, diabetes, cardiovascular disease, lipid metabolism, neurodegenerative diseases, and cancer. Various murine models demonstrate that Sirt6 activation is beneficial in alleviating many disease conditions and increasing lifespan, showing that Sirt6 is a critical therapeutic target in the treatment of various disease conditions in humans. Sirt6 also regulates the pathogenesis of multiple diseases by acting on histone proteins and non-histone proteins. Endogenous and non-endogenous modulators regulate both activation and inhibition of Sirt6. Few Sirt6 specific non-endogenous modulators have been identified. Hence the identification of Sirt6 specific modulators may have potential therapeutic roles in the diseases described above. In this review, we describe the development of Sirt6, the role it plays in the human condition, the functional role and therapeutic importance in disease processes, and specific modulators and molecular mechanism of Sirt6 in the regulation of metabolic homeostasis, cardiovascular disease, aging, and neurodegenerative disease.

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Quercetin based derivatives as sirtuin inhibitors

Cited by 41 publications

References 45 publications

Healthy Effects of Plant Polyphenols: Molecular Mechanisms

Healthy Effects of Plant Polyphenols: Molecular Mechanisms

Structural basis for the activation and inhibition of Sirtuin 6 by quercetin and its derivatives

Sirt6 Deacetylase: A Potential Key Regulator in the Prevention of Obesity, Diabetes and Neurodegenerative Disease

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