Synthesis And Biological Activity Of Benzimidazole Analogs As Sirtuin Enzyme Inhibitors

Yeong, Keng Yoon (2016) Synthesis And Biological Activity Of Benzimidazole Analogs As Sirtuin Enzyme Inhibitors. PhD thesis, Universiti Sains Malaysia.

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    Abstract

    Bagi mencari perencat enzim sirtuin yang poten, 90 analog benzimidazol telah berjaya direka.Kaedah sintesis yang digunakan dalam projek ini mengambilkira langkah-langkah yang lestari.Sebatian4h (ethyl 2-(4-(piperidin-1-yl)phenyl)-1H-benzo[d]imidazole-5-carboxylate)merupakanperencat enzim sirtuin yang paling baik dalam projek ini. Ia didapati merencat sirtuin-2 (SIRT2) lebih baik daripada sirtuin-1 (SIRT1). Daripada profil sebatian dengan aktiviti perencatan SIRT1/SIRT2, perhubungan struktur dengan aktiviti boleh disimpulkan.Juga menarik perhatian ialah kemampuan sebatian4h untuk mengekang pertumbuhan sel kanser kolorektal. Selain daripada itu, ia juga mempunyai keupayaan untuk mencegah pertumbuhan sel kanser leukemia dan payudara. Pemodelan komputer turut digunakan untuk memberi penjelasan yang wajar terhadapkeputusan aktiviti yang diperolehi. Sebatian4h didapati boleh didokkan kedalam tapak aktif enzim SIRT2 dengan menggunakan struktur kristal (PDB: 3ZGV). 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.

    Item Type: Thesis (PhD)
    Subjects: R Medicine > R Medicine (General) > R735-854 Medical education. Medical schools. Research
    Divisions: Institut Penyelidikan Perubatan Molekul (Institute for Research in Molecular Medicine INFORMM) > Thesis
    Depositing User: Mr Noorazilan Noordin
    Date Deposited: 08 Mar 2017 12:24
    Last Modified: 05 Apr 2017 14:12
    URI: http://eprints.usm.my/id/eprint/32341

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