Discovery of a potent and highly fluorescent sirtuin inhibitor

Yoon, Yeong Keng; Ali, Mohamed Ashraf; Wei, Ang Chee; Choon, Tan Soo; Shirazi, Amir Nasrolahi; Parang, Keykavous

doi:10.1039/c5md00307e

Cited by 21 publications

(26 citation statements)

References 30 publications

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“…All the ten evaluated compounds demonstrated relatively higher selectivity for SIRT2 over SIRT1 (Table ). The trend of the results is consistent with those observed previously for 1,2,5‐trisubstituted benzimidazole derivatives . Compounds 3–6 with functional groups other than a phenyl/pyridinyl ring at the R 2 were found to have poor activity.…”

Section: Resultssupporting

confidence: 90%

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Contrasting sirtuin and poly(ADP‐ribose)polymerase activities of selected 2,4,6‐trisubstituted benzimidazoles

Yoon

Tan

et al. 2017

Chem Biol Drug Des

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Both sirtuin and poly(ADP‐ribose)polymerase (PARP) family of enzymes utilize NAD+ as co‐substrate. Inhibitors of sirtuins and PARPs are important tools in drug discovery as they are reported to be linked to multiple diseases such as cancer. New potent sirtuin inhibitors (2,4,6‐trisubstituted benzimidazole) were discovered from reported PARP inhibitor scaffold. Interestingly, the synthesized compounds have contrasting sirtuin and PARP‐1 inhibitory activities. We showed that modification on benzimidazoles may alter their selectivity toward sirtuin or PARP‐1 enzymes. This offers an opportunity for further discovery and development of new promising sirtuin inhibitors. Molecular docking studies were carried out to aid the rationalization of these observations. Preliminary antiproliferative studies of selected compounds against nasopharyngeal cancer cells also showed relatively promising results.

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Section: Resultssupporting

confidence: 90%

“…Several notable classes of small molecule sirtuin inhibitors which have been identified so far includes indoles (EX‐527), α‐cyanopropenamide (AGK2), and tenovins (Tenovin‐6) . Recently, compounds based on the benzimidazole scaffold have been demonstrated to be potent sirtuin inhibitors …”

Section: Introductionmentioning

confidence: 99%

Contrasting sirtuin and poly(ADP‐ribose)polymerase activities of selected 2,4,6‐trisubstituted benzimidazoles

Yoon

Tan

et al. 2017

Chem Biol Drug Des

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“…Over the last decade, several small‐molecule sirtuin inhibitors were identified, including sirtinol, tenovin‐6, and cambinol . Among the newer inhibitors which have been identified recently, there are compounds bearing the benzimidazole scaffold . Furthering our initial findings, we hereby report on the synthesis of novel benzimidazoles with substitutional changes at the benzene terminus.…”

Section: Introductionmentioning

confidence: 76%

“…). From our previous results, compound 16 was shown to exhibit moderate SIRT2‐inhibitory activity (IC 50 = 26.85 μM) . Therefore, we were interested in investigating the effects on sirtuin inhibition after substituting the dimethylamino group at the ortho and meta positions on the benzene ring.…”

Section: Resultsmentioning

confidence: 99%

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Structural Modifications of Benzimidazoles via Multi‐Step Synthesis and Their Impact on Sirtuin‐Inhibitory Activity

Yoon

Choon

2015

Archiv der Pharmazie

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Benzimidazole derivatives have been shown to possess sirtuin-inhibitory activity. In the continuous search for potent sirtuin inhibitors, systematic changes on the terminal benzene ring were performed on previously identified benzimidazole-based sirtuin inhibitors, to further investigate their structure-activity relationships. It was demonstrated that the sirtuin activities of these novel compounds followed the trend where meta-substituted compounds possessed markedly weaker potency than ortho- and para-substituted compounds, with the exception of halogenated substituents. Molecular docking studies were carried out to rationalize these observations. Apart from this, the methods used to synthesize the interesting compounds are also discussed.

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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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Discovery of a potent and highly fluorescent sirtuin inhibitor

Abstract: Highly fluorescent sirtuin inhibitor was discovered to possess growth inhibitory effect against multiple cancer cell lines.

Cited by 21 publications

References 30 publications

Contrasting sirtuin and poly(ADP‐ribose)polymerase activities of selected 2,4,6‐trisubstituted benzimidazoles

Contrasting sirtuin and poly(ADP‐ribose)polymerase activities of selected 2,4,6‐trisubstituted benzimidazoles

Structural Modifications of Benzimidazoles via Multi‐Step Synthesis and Their Impact on Sirtuin‐Inhibitory Activity

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

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