Synthesis and evaluation of benzoylbenzofurans and isoflavone derivatives as sirtuin 1 inhibitors with antiproliferative effects on cancer cells
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Authors
Selepe, Mamoalosi A.
Kunyane, Phaladi
Seboletswe, Pule
Nair, Shankari
Cele, Nosipho
Engelbrecht, Monique
Joubert, Daniel Francois
Vandevoorde, Charlot
Singh, Parvesh
Sonopo, Molahlehi S.
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Publisher
Elsevier
Abstract
Isoflavone derivatives were prepared from benzoylbenzofuran precursors. The synthesized compounds were analyzed by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy, as well as high-resolution mass spectrometry (HRMS) to confirm their structures. The benzoylbenzofuran and isoflavone analogues were evaluated for inhibition of sirtuin 1 (SIRT1) and cell proliferation in MDA-MB-231 triple-negative breast cancer (TNBC) cells. Several isoflavone and benzoylbenzofuran derivatives exhibited potent antiproliferative effects against the MDA-MB-231 cancer cell line. Most of the isoflavone derivatives attenuated SIRT1 activity to below 50%. The most active compounds were the isoflavone quinones 38, 39, and 40, at IC50 values of 5.58 ± 0.373, 1.62 ± 0.0720, and 7.24 ± 0.823 μM, respectively. Importantly, the most active compound, 6-methoxy-4′,6′-dimethylisoflavone-2′,5′-quinone (39) displayed SIRT1 inhibitory activity comparable to that of the reference compound, suramin. The in silico docking simulations in the active site of SIRT1 further substantiated the experimental results and explored the binding orientations of potent compounds in the active site of the target.
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Keywords
High-resolution mass spectrometry (HRMS), Benzoylbenzofurans, Isoflavones, Sirtuin 1 (SIRT1), MDA-MB-231, Nuclear magnetic resonance (NMR), Triple-negative breast cancer (TNBC)
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Citation
Selepe, M.A., Kunyane, P., Seboletswe, P. et al. 2022, 'Synthesis and evaluation of benzoylbenzofurans and isoflavone derivatives as sirtuin 1 inhibitors with antiproliferative effects on cancer cells', Bioorganic Chemistry, vol. 128, art. 106101, pp. 1-9, doi : 10.1016/j.bioorg.2022.106101.