Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities

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

doi:10.1016/j.bmc.2013.12.029

Cited by 49 publications

(31 citation statements)

References 29 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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“…. In addition to that, cell cytotoxicity assays also showed good antitumor activity against two different cancer cell lines MCF-7 and MDA-MB-468, derived from breast cancer [57]. SAR study was also done to know the contribution of different functional groups in activity as shown in Fig.…”

Section: CDmentioning

confidence: 98%

Structure activity relationship (SAR) study of benzimidazole scaffold for different biological activities: A mini-review

Yadav

Ganguly

2015

European Journal of Medicinal Chemistry

339

141

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“…In the field of medicinal chemistry, benzimidazole represents a highly privileged scaffold and has been copiously explored as an anti-proliferative agent targeting different breast cancer cells [14,15,16,17,18,19,20,21]. Surveying the literature revealed that different benzimidazole-based scaffolds were developed with significant activity toward the TNBC MDA-MB-468 cells in the anticancer drug screening program of the U.S. National Cancer Institute (NCI), according to their applied protocol against full NCI 60 human cell lines panel (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Crystal Study, and Anti-Proliferative Activity of Some 2-Benzimidazolylthioacetophenones towards Triple-Negative Breast Cancer MDA-MB-468 Cells as Apoptosis-Inducing Agents

Abdel‐Aziz

Eldehna

Ghabbour

et al. 2016

IJMS

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On account of its poor prognosis and deficiency of therapeutic stratifications, triple negative breast cancer continues to form the causative platform of an incommensurate number of breast cancer deaths. Aiming at the development of potent anticancer agents as a continuum of our previous efforts, a novel series of 2-((benzimidazol-2-yl)thio)-1-arylethan-1-ones 5a–w was synthesized and evaluated for its anti-proliferative activity towards triple negative breast cancer (TNBC) MDA-MB-468 cells. Compound 5k was the most active analog against MDA-MB-468 (IC50 = 19.90 ± 1.37 µM), with 2.1-fold increased activity compared to 5-fluorouracil (IC50 = 41.26 ± 3.77 µM). Compound 5k was able to induce apoptosis in MDA-MB-468, as evidenced by the marked boosting in the percentage of florecsein isothiocyanate annexin V (Annexin V–FITC)-positive apoptotic cells (upper right (UR) + lower right (LR)) by 2.8-fold in comparison to control accompanied by significant increase in the proportion of cells at pre-G1 (the first gap phase) by 8.13-fold in the cell-cycle analysis. Moreover, a quantitative structure activity relationship (QSAR) model was established to investigate the structural requirements orchestrating the anti-proliferative activity. Finally, we established a theoretical kinetic study.

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Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities

Cited by 49 publications

References 29 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

Structure activity relationship (SAR) study of benzimidazole scaffold for different biological activities: A mini-review

Synthesis, Crystal Study, and Anti-Proliferative Activity of Some 2-Benzimidazolylthioacetophenones towards Triple-Negative Breast Cancer MDA-MB-468 Cells as Apoptosis-Inducing Agents

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