Synthesis And Biological Activity Of Benzimidazole Analogs As Sirtuin Enzyme Inhibitors
| dc.contributor.author | Yeong, Keng Yoon | |
| dc.date.accessioned | 2017-02-02T02:13:23Z | |
| dc.date.available | 2017-02-02T02:13:23Z | |
| dc.date.issued | 2016-07 | |
| dc.description.abstract | In the effort to search for potent sirtuin inhibitors, 90 benzimidazole analogs across 6 series were designed, synthesized and characterized. Compound 4h (ethyl 2-(4-(piperidin-1-yl)phenyl)-1H-benzo[d]imidazole-5-carboxylate)was identified to be the most potent sirtuin inhibitor in this project with a preference for sirtuin-2 (SIRT2) inhibition over SIRT1. Based on the profile of the compounds along with their demonstrated SIRT1/SIRT2 inhibitory activities, a structure-activity-relationship was deduced for the benzimidazole moeity. Remarkably, compound 4h exhibited potent growth inhibitory effect on colorectal cancer cell lines. Apart from colorectal cancer, it was also found to possess antiproliferative activity against leukemia and breast cancer cell lines. Molecular docking approach was used to rationalize the observed activity. The SIRT2 crystal homology model (PDB: 3ZGV) was found to be able to accommodate compound 4h in its active site, thus supporting the notion that 4h was indeed able to strongly inhibit the SIRT2 activity. However, the structure activity relationship of the compounds towards observed SIRT1 inhibition was unable to be completely rationalized using similar method.In light of the potential of compound 4h in combating cancer, some relevant physicochemical attributes of 4h such as water solubility, compoundstability andfluorescent properties were determined. Based on literature review, compound 4h is the first highly fluorescent sirtuin inhibitor reported so far. This is an added advantage as it could be useful in monitoring morphological as well as phenotype changes in cancer cells. In summary, the results reported in this thesis clearly demonstrated a significant correlation between sirtuin inhibition and cancer as 66.7% of the synthesized compounds with potent sirtuin inhibitory activity possessed antiproliferative effect against cancer cells. Furthermore, it provided a proof of concept that sirtuin enzymes are indeed targets of benzimidazole derivatives.Compounds with potent sirtuin inhibition and which demonstrated cyototoxic effect such as 4h are prime candidates for further modifications to enhance the activity and drug-like profiles as exploration of the benzimidazole scaffold may eventually yield useful compounds in cancer treatment.Although more research is needed to further elucidate the role of sirtuins in cancer, sirtuin inhibition remains a new and viable strategy in cancer therapy. | en_US |
| dc.identifier.uri | http://hdl.handle.net/123456789/3642 | |
| dc.subject | Synthesis and biological activity of benzimidazole analogs | en_US |
| dc.subject | as sirtuin enzyme inhibitors. | en_US |
| dc.title | Synthesis And Biological Activity Of Benzimidazole Analogs As Sirtuin Enzyme Inhibitors | en_US |
| dc.type | Thesis | en_US |
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