The anticancer and EGFR-TK/CDK-9 dual inhibitory potentials of new synthetic pyranopyrazole and pyrazolone derivatives: X-ray crystallography, in vitro, and in silico mechanistic investigations

Musa, Arafa; Ihmaid, Saleh K.; Hughes, David L.; Said, Musa A.; Abulkhair, Hamada S.; El-Ghorab, Ahmed H.; Abdelgawad, Mohamed A.; Shalaby, Khaled; Shaker, Mohamed E.; Alharbi, Khalid Saad; Alotaibi, Nasser Hadal; Kays, Deborah L.; Taylor, Laurence J.; Parambi, Della Grace Thomas; Alzarea, Sami I.; Al-Karmalawy, Ahmed A.; Ahmed, Hany E.A.; El-Agrody, Ahmed M.

Abstract

Treatment options for the management of breast cancer are still inadequate. This inadequacy is attributed to the lack of effective targeted medications, often resulting in the recurrence of metastatic disorders. Cumulative evidence suggests that epidermal growth factor receptor (EGFR-TK) and cyclin-dependent kinases-9 (CDK-9) overexpression correlates with worse overall survival in breast cancer patients. Pyranopyrazole and pyrazolone are privileged options for the development of anticancer agents. Inspired by this proven scientific fact, we report here the synthesis of two new series of suggested anticancer molecules incorporating both heterocycles together with their characterization by IR, 1H NMR, 13C NMR, 13C NMR-DEPT, and X-ray diffraction methods. An attempt to get the pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3H-pyrazol-3-one instead. This unexpected result was confirmed by X-ray crystallographic analysis. All newly synthesized compounds were assessed for their anti-proliferative activity against two different human breast cancer cells, and the obtained results were compared with the reference drug Staurosporine. The target compounds revealed variable cytotoxicity with IC50 at a low micromolar range with superior selectivity indices. Target enzyme EGFR-TK and CDK-9 assays showed that compounds 22 and 23 effectively inhibited both biological targets with IC50 values of 0.143 and 0.121 µM, respectively. Molecular docking experiments and molecular dynamics simulation were also conducted to further rationalize the in vitro obtained results.

Citation

Musa, A., Ihmaid, S. K., Hughes, D. L., Said, M. A., Abulkhair, H. S., El-Ghorab, A. H., Abdelgawad, M. A., Shalaby, K., Shaker, M. E., Alharbi, K. S., Alotaibi, N. H., Kays, D. L., Taylor, L. J., Parambi, D. G. T., Alzarea, S. I., Al-Karmalawy, A. A., Ahmed, H. E., & El-Agrody, A. M. (2023). The anticancer and EGFR-TK/CDK-9 dual inhibitory potentials of new synthetic pyranopyrazole and pyrazolone derivatives: X-ray crystallography, in vitro, and in silico mechanistic investigations. Journal of Biomolecular Structure and Dynamics, 41(21), 12411-12425. https://doi.org/10.1080/07391102.2023.2167000

• Journal Article Type: Article
• Acceptance Date: Jan 3, 2023
• Online Publication Date: Jan 20, 2023
• Publication Date: Jan 20, 2023
• Deposit Date: May 2, 2023
• Publicly Available Date: Jan 21, 2024
• Journal: Journal of Biomolecular Structure and Dynamics
• Print ISSN: 0739-1102
• Electronic ISSN: 1538-0254
• Publisher: Taylor and Francis
• Peer Reviewed: Peer Reviewed
• Volume: 41
• Issue: 21
• Pages: 12411-12425
• DOI: https://doi.org/10.1080/07391102.2023.2167000
• Keywords: Crystal structure; Phenylpyrazole; Pyrazolone; EGFR-TK; CDK-9; Anticancer; Molecular dynamics
• Public URL: https://nottingham-repository.worktribe.com/output/16230803
• Publisher URL: https://www.tandfonline.com/doi/full/10.1080/07391102.2023.2167000