Sirtuin modulators: where are we now? A review of patents from 2015 to 2019

Mautone, Nicola; Zwergel, Clemens; Mai, Antonello; Rotili, Dante

doi:10.1080/13543776.2020.1749264

Cited by 44 publications

(34 citation statements)

References 95 publications

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“…According to these results, the chloro substitution at the 5‐position of the benzimidazole scaffold led to SIRT1 inhibition, whereas the nitro substitution at position 5 of the benzimidazole ring resulted in SIRT1 activation. Taking into account the fact that SIRT1 acts as a double‐edged sword in cancer, [ 7‐13 ] both agents could be beneficial for the management of cancer.…”

Section: Resultsmentioning

confidence: 99%

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A new series of benzoxazole‐based SIRT1 modulators for targeted therapy of non‐small‐cell lung cancer

Sever

Çiftçi

Altıntop

2020

Archiv der Pharmazie

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In an attempt to identify potential anticancer agents for non‐small‐cell lung cancer (NSCLC) targeting sirtuin 1 (SIRT1), the synthesis of a new series of benzoxazoles (3a – i) was carried out through a facile and versatile synthetic route. The compounds were evaluated for their cytotoxic effects on A549 human lung adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cells using the MTT assay. 2‐[(5‐Nitro‐1H‐benzimidazol‐2‐yl)thio]‐N‐(2‐methylbenzoxazol‐5‐yl)acetamide (3e) and 2‐[(5‐chloro‐1H‐benzimidazol‐2‐yl)thio]‐N‐(2‐methylbenzoxazol‐5‐yl)acetamide (3g) were the most potent and selective anticancer agents in this series against the A549 cell line, with IC50 values of 46.66 ± 11.54 and 55.00 ± 5.00 µM, respectively. The flow cytometry‐based apoptosis detection assay was performed to determine their effects on apoptosis in A549 cells. Both compounds induced apoptosis in a dose‐dependent manner. The effects of compounds 3e and 3g on SIRT1 activity were determined. On the basis of in vitro studies, it was observed that compound 3g caused a significant decrease in SIRT1 levels in a dose‐dependent manner, whereas compound 3e increased the SIRT1 levels. According to molecular docking studies, the substantial alteration in the type of action could be attributed to the difference between the interactions of compounds 3e and 3g with the same residues in the active site of SIRT1 (PDB code: 4IG9). On the basis of in silico ADME (absorption, distribution, metabolism, and excretion) studies, these compounds are predicted to possess favorable ADME profiles. According to the in vitro and in silico studies, compounds 3e and 3g, small‐molecule SIRT1 modulators, were identified as potential orally bioavailable anticancer agents for the targeted therapy of NSCLC.

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Section: Resultsmentioning

confidence: 99%

“…The modulation of SIRT1 activity by small‐molecule activators or inhibitors stands out as a promising strategy for the management of many types of cancer including NSCLC. [ 7‐13 ]…”

Section: Introductionmentioning

confidence: 99%

A new series of benzoxazole‐based SIRT1 modulators for targeted therapy of non‐small‐cell lung cancer

Sever

Çiftçi

Altıntop

2020

Archiv der Pharmazie

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“…Despite the clear involvement of sirtuins in PD, there is a distinct lack of clinical trials investigating their modulation for treatment of neurodegeneration (Bonkowski and Sinclair, 2016;Mautone et al, 2020). This is largely due to a lack of isoform specific inhibitors and activators and the need to target specific cells to avoid unintended effects.…”

Section: Sirtuinsmentioning

confidence: 99%

“…This is largely due to a lack of isoform specific inhibitors and activators and the need to target specific cells to avoid unintended effects. Resolution of current controversies and a greater understanding of the tissue-specific functions, as well as the complexity and interconnectedness of sirtuin interaction and activity networks is required to optimally target these molecules (Dang, 2014;Mautone et al, 2020;Wang et al, 2020).…”

Section: Sirtuinsmentioning

confidence: 99%

Targeting Mitochondrial Impairment in Parkinson's Disease: Challenges and Opportunities

Prasuhn

Davis

Kumar

2021

Front. Cell Dev. Biol.

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The underlying pathophysiology of Parkinson's disease is complex, but mitochondrial dysfunction has an established and prominent role. This is supported by an already large and rapidly growing body of evidence showing that the role of mitochondrial (dys)function is central and multifaceted. However, there are clear gaps in knowledge, including the dilemma of explaining why inherited mitochondriopathies do not usually present with parkinsonian symptoms. Many aspects of mitochondrial function are potential therapeutic targets, including reactive oxygen species production, mitophagy, mitochondrial biogenesis, mitochondrial dynamics and trafficking, mitochondrial metal ion homeostasis, sirtuins, and endoplasmic reticulum links with mitochondria. Potential therapeutic strategies may also incorporate exercise, microRNAs, mitochondrial transplantation, stem cell therapies, and photobiomodulation. Despite multiple studies adopting numerous treatment strategies, clinical trials to date have generally failed to show benefit. To overcome this hurdle, more accurate biomarkers of mitochondrial dysfunction are required to detect subtle beneficial effects. Furthermore, selecting study participants early in the disease course, studying them for suitable durations, and stratifying them according to genetic and neuroimaging findings may increase the likelihood of successful clinical trials. Moreover, treatments involving combined approaches will likely better address the complexity of mitochondrial dysfunction in Parkinson's disease. Therefore, selecting the right patients, at the right time, and using targeted combination treatments, may offer the best chance for development of an effective novel therapy targeting mitochondrial dysfunction in Parkinson's disease.

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“…Given the critical roles of SIRT6 in a variety of human diseases including cancer, diabetes, inflammation, hepatic diseases, neurodegenerative disorders, renal injury, and retinal dysfunction and viral infections, regulating the activity of SIRT6 using small modulators may offer therapeutic benefits for blocking the initiation and progression of these diseases 288,289 . Small molecules targeting a well‐defined target have been reported to indirectly act on SIRT6 by regulating its expression or modulating SIRT6‐mediated signaling pathways, 290–295 exemplified by the DPP‐4 inhibitor Sitagliptin, which inhibits vascular inflammation by upregulating SIRT6 expression 155 .…”

Section: Sirt6 Modulatorsmentioning

confidence: 99%

Emerging roles of SIRT6 in human diseases and its modulators

Liu

Chen

Liu

et al. 2020

Medicinal Research Reviews

103

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The biological functions of sirtuin 6 (SIRT6; e.g., deacetylation, defatty‐acylation, and mono‐ADP‐ribosylation) play a pivotal role in regulating lifespan and several fundamental processes controlling aging such as DNA repair, gene expression, and telomeric maintenance. Over the past decades, the aberration of SIRT6 has been extensively observed in diverse life‐threatening human diseases. In this comprehensive review, we summarize the critical roles of SIRT6 in the onset and progression of human diseases including cancer, inflammation, diabetes, steatohepatitis, arthritis, cardiovascular diseases, neurodegenerative diseases, viral infections, renal and corneal injuries, as well as the elucidation of the related signaling pathways. Moreover, we discuss the advances in the development of small molecule SIRT6 modulators including activators and inhibitors as well as their pharmacological profiles toward potential therapeutics for SIRT6‐mediated diseases.

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Sirtuin modulators: where are we now? A review of patents from 2015 to 2019

Cited by 44 publications

References 95 publications

A new series of benzoxazole‐based SIRT1 modulators for targeted therapy of non‐small‐cell lung cancer

A new series of benzoxazole‐based SIRT1 modulators for targeted therapy of non‐small‐cell lung cancer

Targeting Mitochondrial Impairment in Parkinson's Disease: Challenges and Opportunities

Emerging roles of SIRT6 in human diseases and its modulators

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