Abstract
Four novel 3-Aryl -1-(pyridin-4-yl)benzo[4,5]imidazo[1,2-d][1,2,4]- triazin-4(3H)-ones derivatives (C1 to C4) have been designed, synthesized, and evaluated for their anticancer activity. The structure of compounds was characterized by IR,1H NMR, 13C NMR and high-resolution mass (HRMS). The crystal structures of C1, C2 and C4 were previously determined by single-crystal X-ray analysis.
The results from docking experiments with EGFR suggested the binding of the compounds at the active site of EGFR. The new compounds exhibited different levels of cytotoxicity against HCC1937 and MCF7 breast cancer cells. Results of the MTT assay identified C3 as the most cytotoxic of the series against both MCF7 and HCC1937 breast cancer cell lines with IC50 values of 36.4 and 48.2 µM, respectively. In addition to its ability to inhibit cell growth and colony formation ability, C3 also inhibited breast cancer cell migration. Western blotting results showed that C3 treatment inhibited EGFR signaling and induced cell cycle arrest and apoptosis as indicated by the low level of p-EGFR and p-AKT and the increasing levels of p53, p21 and cleaved PARP. Our work represents a promising starting point for the development of a new series of compounds targeting cancer cells.
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Acknowledgments
Bassam Abu Thaher would like to thank by the Palestinian Research Council (Ramallah) for funding and Alexander von Humboldt Foundation (AvH) for funding his short visit, in 2022.
Funding
This work was supported by Palestinian Research Council (Ramallah) and Alexander von Humboldt Foundation (AvH) for funding his short visit, in 2022.
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B.A, B.Q and R.M prepared the compounds. C.J and H.D supervised the chemical design and synthesis. I. A and K.W performed the modeling. S.I wrote the main manuscript and supervised the biological work.S.kh, I.A, A.M, and A. I performed biological experiments. All authors reviewed the manuscript. The authors declare that all data were generated in-house and that no paper mill was used
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Thaher, B.A., Al-Masri, I., Wahedy, K. et al. Synthesis and bioassay of 3-Aryl -1-(pyridin-4-yl)benzo[4,5]imidazo[1,2-d][1,2,4]- triazin-4(3H)-ones as anti-cancer agents. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1797–1810 (2023). https://doi.org/10.1007/s00210-023-02433-5
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DOI: https://doi.org/10.1007/s00210-023-02433-5