The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.
Discovery of Indoles as Potent and Selective Inhibitors of the Deacetylase SIRT1
Open accessAbstract
High-throughput screening against the human sirtuin SIRT1 led to the discovery of a series of indoles as potent inhibitors that are selective for SIRT1 over other deacetylases and NAD-processing enzymes. The most potent compounds described herein inhibit SIRT1 with IC50 values of 60-100 nM, representing a 500-fold improvement over previously reported SIRT inhibitors. Preparation of enantiomerically pure indole derivatives allowed for their characterization in vitro and in vivo. Kinetic analyses suggest that these inhibitors bind after the release of nicotinamide from the enzyme and prevent the release of deacetylated peptide and O-acetyl-ADP-ribose, the products of enzyme-catalyzed deacetylation. These SIRT1 inhibitors are low molecular weight, cell-permeable, orally bioavailable, and metabolically stable. These compounds provide chemical tools to study the biology of SIRT1 and to explore therapeutic uses for SIRT1 inhibitors.
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Citations
Cites
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
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Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
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Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase
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Increased Nuclear NAD Biosynthesis and SIRT1 Activation Prevent Axonal Degeneration
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Cited by
Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes
Milne, J. C., Lambert, P. D., Schenk, S., Carney, D. P., Smith, J. J., Gagne, D. J., Jin, L., Boss, O., Perni, R. B., Vu, C. B., et al. (2007) · Nature · doi:10.1038/nature06261 · Cited by 1,707
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270
Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy
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SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1
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Self-citationSirtuin activators and inhibitors: Promises, achievements, and challenges
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“N-alkylated thiobabiturates are assumed to exploit, with a certain specificity, SIRT5’s acylLys pocket (Maurer et al., 2012).”
BackgroundInfluentialSirtuin functions and modulation: from chemistry to the clinic
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Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation
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Cross‐Talk between Aging and Cancer: The Epigenetic Language
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Sirtuin catalysis and regulation
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Protective effects and mechanisms of sirtuins in the nervous system
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Inhibition of Nicotinamide Phosphoribosyltransferase
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Sirtuins, a key regulator of ageing and age-related neurodegenerative diseases
Bhatt, V., & Tiwari, A. K. (2023) · International Journal of Neuroscience · doi:10.1080/00207454.2022.2057849 · Cited by 28
Metadata
- Authors
- Napper, A. D., Hixon, J., McDonagh, T., Keavey, K., Pons, J.-F., Barker, J., Yau, W. T., Amouzegh, P., Flegg, A., Hamelin, E., Thomas, R. J., Kates, M., Jones, S., Navia, M. A., Saunders, J. O., DiStefano, P. S., & Curtis, R.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2005-11-09
- Volume
- 48
- Issue
- 25
- Pages
- 8045-8054
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W1990931780
- Cited by
- 523
- References
- 5
- FWCI
- 5.64
- Type
- journal article
- Language
- en
- Open access
- green
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