S -Alkylated quinazolin-4(3 H )-ones as dual EGFR/VEGFR-2 kinases inhibitors: design, synthesis, anticancer evaluation and docking study.
Samar S TawfikAbdelrahman HamdiAhmed R AliAbdullah A ElgazarHamed W El-ShafeyAdel S El-AzabAhmed H BakheitMohamed M HefnawyHazem A GhabourAlaa A-M Abdel-AzizPublished in: RSC advances (2024)
Dual targeting by a single molecule has emerged as a promising strategy for fighting cancer. In this study, a new set of 2-thioquinazolin-4(3 H )-ones as potential anti-cancer surrogates endowed with dual EGFR/VEGFR-2 kinases inhibitory activities were synthesized. The anti-tumor potency of the newly synthesized candidates 4-27 was evaluated against a panel of four cancer cell lines. The prepared candidates 4-27 showed comparable activity to that of the standard drug sorafenib. For instance, compound 4 (IC 50 = 1.50-5.86 μM) and compound 20 (IC 50 = 4.42-6.39 μM) displayed superior potencies against all cell lines compared to sorafenib (IC 50 = 5.47-7.26 μM). Dual EGFR/VEGFR-2 inhibitory activities of the most active analogues (4, 11, and 20) were investigated. Compound 4 showed comparable EGFR/VEGFR-2 inhibitory activity to the used control drugs. Flow cytometric analysis indicates that the most potent analogue 4 stopped the cell cycle at the G1 phase and induced 46.53% total apoptosis in HCT-116 cells that was much more powerful than the untreated cells with 2.15% apoptosis. Molecular docking and dynamic simulations of 4, 11, and 20 with EGFR and VEGFR-2 were performed to examine the binding mode and interaction within the enzyme binding pockets.
Keyphrases
- cell cycle arrest
- small cell lung cancer
- epidermal growth factor receptor
- molecular docking
- tyrosine kinase
- cell cycle
- single molecule
- cell death
- induced apoptosis
- vascular endothelial growth factor
- endoplasmic reticulum stress
- pi k akt
- papillary thyroid
- oxidative stress
- cell proliferation
- molecular dynamics
- atomic force microscopy
- squamous cell
- squamous cell carcinoma
- signaling pathway
- risk assessment
- young adults
- high glucose
- transcription factor
- childhood cancer
- binding protein
- cancer therapy
- high resolution
- drug delivery
- high speed