Synthesis of indole inhibitors of silent information regulator 1 (SIRT1), and their evaluation as cytotoxic agents

Laaroussi, Hanna; Ding, Ying; Teng, Yuou; Deschamps, P; Vidal, Michel; Yu, Peng; Broussy, Sylvain

doi:10.1016/j.ejmech.2020.112561

Cited by 11 publications

(9 citation statements)

References 47 publications

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“…25 Over the past years, different SIRT inhibitors have been found among various classes of compounds. 7,[26][27][28][29][30][31][32] Downregulating activity towards HDACs class III was identified in 2-anilinobenzamides (nicotinamide analogues), 33 some acetyl lysine mimics, 26 azomethines based on 2-hydroxy-1naphthaldehyde (sirtinol, JGB1714 and others analogues), 34,35 thioureas (cambinol, tenovin-6), 36,37 and thiobarbituric acid 5-ylidene derivatives, 38 bis(indolyl)maleinimides, 34 5-benzylidene-2-phenyl-1,3-dioxane-4,6-diones 39 and indole derivatives, 40,41 naphtho[2,1-b]pyrane-3ones (splitomicin and analogues), 42 thieno[3,2-d]pyrimidine-6-carboxamides, 43 2-substituted nicotinic acid ethyl esters, 44 dihydro-1,4-benzoxazine carboxamides, 45 1,5-dihydro-1H-pyrano[2,3-d]pyrimidine-2,4(3H)-diones, 46 dihydropyrano[2,3-c]pyrazole, 47 2-arylamino-3-cyanopyridines, 48 3-heteroarylmethylene isoindolin-1-ones, 49 1,8-dioxo-octahydroxanthenes, 50 highly ionized naphthylurea suramin, 51 and various substances from natural sources (amurensin G) 52 or modified natural products such as steroids. 35 Most of these compounds have been evaluated using enzymatic and cell-based assays.…”

Section: Paper Synopenmentioning

confidence: 99%

Discovery of Novel N-Acylhydrazone Derivatives as Potent Inhibitors of Sirtuin-1

Lipson,

Yaremenko,

Vakula

et al. 2024

SynOpen

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SIRT1 enzyme is a key family member of Silent Information Regulators (Sirtuins), which catalyze the deacetylation of proteins. Therefore, developing new SIRT1 inhibitors has potential application in treating cancer disease and age-related metabolic disorders. In this study, we synthesized a series of N-acylhydrazone (NAH) derivatives and performed high-throughput screening of their inhibitory activity against the recombinant SIRT1 protein by a luminescent assay. Using in silico screening, we identified a new NAH derivative that features both selectivity and a high binding affinity towards the active pocket of SIRT1 that are comparable to known inhibitors such as Ex527 and Sirtinol. Such high binding affinity makes the new derivatives promising alternatives to the available inhibitors and holds promise for developing better-targeted drugs against SIRT1 activity.

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Section: Paper Synopenmentioning

confidence: 99%

Discovery of Novel N-Acylhydrazone Derivatives as Potent Inhibitors of Sirtuin-1

Lipson,

Yaremenko,

Vakula

et al. 2024

SynOpen

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“…Tripeptide linked to heterocyclic nuclei [117] Furopyridine derivatives [118] Indole compounds (strictly related to EX-527) [119] Benzylidene-dioxane compounds [120] Pyridine derivatives [121,122] Tryptophan conjugates [77] Pyrano [2,3-d ]pyrimidinone derivatives [123] Variable five-membered ring derivatives [81] Thienopyrimidone derivatives [74] 1,8-dioxo-octahydroxanthene derivatives [76]…”

Section: Sirt1ismentioning

confidence: 99%

Recent Advances in the Discovery of SIRT1/2 Inhibitors via Computational Methods: A Perspective

Scarano,

Brullo,

Musumeci

et al. 2024

Pharmaceuticals

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Sirtuins (SIRTs) are classified as class III histone deacetylases (HDACs), a family of enzymes that catalyze the removal of acetyl groups from the ε-N-acetyl lysine residues of histone proteins, thus counteracting the activity performed by histone acetyltransferares (HATs). Based on their involvement in different biological pathways, ranging from transcription to metabolism and genome stability, SIRT dysregulation was investigated in many diseases, such as cancer, neurodegenerative disorders, diabetes, and cardiovascular and autoimmune diseases. The elucidation of a consistent number of SIRT–ligand complexes helped to steer the identification of novel and more selective modulators. Due to the high diversity and quantity of the structural data thus far available, we reviewed some of the different ligands and structure-based methods that have recently been used to identify new promising SIRT1/2 modulators. The present review is structured into two sections: the first includes a comprehensive perspective of the successful computational approaches related to the discovery of SIRT1/2 inhibitors (SIRTIs); the second section deals with the most interesting SIRTIs that have recently appeared in the literature (from 2017). The data reported here are collected from different databases (SciFinder, Web of Science, Scopus, Google Scholar, and PubMed) using “SIRT”, “sirtuin”, and “sirtuin inhibitors” as keywords.

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“…Compound 3g , designed by Laaroussi and colleagues, proved to be an SIRT-1 and SIRT-2 inhibitor with cytotoxic effects on leukemia, colorectal, lung and breast cancer cell lines [ 198 ].…”

Section: Sirtuins As Targets In Different Pathologiesmentioning

confidence: 99%

Virtual Screening in the Identification of Sirtuins’ Activity Modulators

et al. 2022

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Sirtuins are NAD+-dependent deac(et)ylases with different subcellular localization. The sirtuins’ family is composed of seven members, named SIRT-1 to SIRT-7. Their substrates include histones and also an increasing number of different proteins. Sirtuins regulate a wide range of different processes, ranging from transcription to metabolism to genome stability. Thus, their dysregulation has been related to the pathogenesis of different diseases. In this review, we discussed the pharmacological approaches based on sirtuins’ modulators (both inhibitors and activators) that have been attempted in in vitro and/or in in vivo experimental settings, to highlight the therapeutic potential of targeting one/more specific sirtuin isoform(s) in cancer, neurodegenerative disorders and type 2 diabetes. Extensive research has already been performed to identify SIRT-1 and -2 modulators, while compounds targeting the other sirtuins have been less studied so far. Beside sections dedicated to each sirtuin, in the present review we also included sections dedicated to pan-sirtuins’ and to parasitic sirtuins’ modulators. A special focus is dedicated to the sirtuins’ modulators identified by the use of virtual screening.

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Synthesis of indole inhibitors of silent information regulator 1 (SIRT1), and their evaluation as cytotoxic agents

Cited by 11 publications

References 47 publications

Discovery of Novel N-Acylhydrazone Derivatives as Potent Inhibitors of Sirtuin-1

Discovery of Novel N-Acylhydrazone Derivatives as Potent Inhibitors of Sirtuin-1

Recent Advances in the Discovery of SIRT1/2 Inhibitors via Computational Methods: A Perspective

Virtual Screening in the Identification of Sirtuins’ Activity Modulators

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