New 5-aryl-1H-imidazoles display in vitro antitumor activity against apoptosis-resistant cancer models, including melanomas, through mitochondrial targeting
(2013) Journal of Medicinal Chemistry — Vol. 56, p. 6626-6637 (2013)
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- Abstract
- Various cancer types including melanomas remain associated with a dismal prognosis due, at least partly, to their innate resistance to pro-apoptotic stimuli. As imidazole derivatives display a wide range of bioactivities, we designed and synthesized 40 aryl-imidazoles to investigate their in vitro growth inhibitory activity in cancer cell lines known to present various levels of resistance to pro-apoptotic stimuli. The IC50 in vitro growth inhibitory concentration of these compounds ranged from >100µM to single digit µM. Among the most active compounds, 2i displayed similar in vitro growth inhibition in cancer cells independently of the cells’ levels of resistance to pro-apoptotic stimuli, and was found to be cytostatic in melanoma cell lines. Compound 2i was then tested by the National Cancer Institute Human Tumor Cell Line Anti-Cancer Drug Screen, and the NCI COMPARE algorithm did not reveal any correlation between its growth inhibition profiles with the NCI database compound profiles. The use of transcriptomically characterized melanoma models then enabled us to highlight mitochondrial targeting by 2i. This hypothesis was further confirmed by reactive oxygen production measurement and oxygen consumption analysis.
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Mathieu, V., Van Den Berge, E., Ceusters, J., Konopka, T., Cops, A., Bruyère, C., Pirker, C., Tran, T.-V., Kiss, R., Robiette, R., Berger, W., Serteyn, D., & et al. (2013). New 5-aryl-1H-imidazoles display in vitro antitumor activity against apoptosis-resistant cancer models, including melanomas, through mitochondrial targeting. Journal of Medicinal Chemistry, 56, 6626-6637. https://doi.org/10.1021/jm400287v (Original work published 2013)