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.
Arafa MusaSaleh K IhmaidDavid L HughesMusa A SaidHamada S AbulkhairAhmed H El-GhorabMohamed Abdelwahab AbdelgawadKhaled ShalabyMohamed E ShakerKhalid Saad AlharbiNasser Hadal AlotaibiDeborah L KaysLaurence J TaylorDella Grace Thomas ParambiSami I AlzareaAhmed Ali Al-KarmalawyHany E A AhmedAhmed M El-AgrodyPublished in: Journal of biomolecular structure & dynamics (2023)
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, 1 H NMR, 13 C NMR, 13 C NMR-DEPT, and X-ray diffraction methods. An attempt to get the pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3 H -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 IC 50 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 IC 50 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.Communicated by Ramaswamy H. Sarma.
Keyphrases
- epidermal growth factor receptor
- molecular docking
- high resolution
- molecular dynamics simulations
- cell cycle
- tyrosine kinase
- advanced non small cell lung cancer
- small cell lung cancer
- magnetic resonance
- solid state
- dual energy
- cell proliferation
- breast cancer cells
- electron microscopy
- endothelial cells
- squamous cell carcinoma
- mass spectrometry
- free survival
- transcription factor
- computed tomography
- high throughput
- magnetic resonance imaging
- signaling pathway
- induced pluripotent stem cells
- cancer therapy
- adverse drug
- drug induced
- contrast enhanced