New quinoxaline-based VEGFR-2 inhibitors: design, synthesis, and antiproliferative evaluation with in silico docking, ADMET, toxicity, and DFT studies.
Mohammed M AlanaziHazem ElkadyNawaf A AlsaifAhmad J ObaidullahHamad M Al KahtaniManal M AlanaziMadhawi A AlharbiIbrahim H EissaMohammed A DahabPublished in: RSC advances (2021)
A new series of 3-methylquinoxaline-based derivatives having the same essential pharmacophoric features as VEGFR-2 inhibitors have been synthesized and evaluated for their antiproliferative activities against two human cancer cell lines, MCF-7 and HepG-2. Compounds 15b and 17b demonstrated a significant antiproliferative effect with IC 50 ranging from 2.3 to 5.8 μM. An enzymatic assay was carried out for all the tested candidates against VEGFR-2. Compound 17b was the most potent VEGFR-2 inhibitor (IC 50 = 2.7 nM). Mechanistic investigation including cell cycle arrest and apoptosis was performed for compound 17b against HepG-2 cells, and the results revealed that 17b induced cell apoptosis and arrested cell cycle in the G2/M phase. Moreover, apoptosis analyses were conducted for compound 17b to evaluate its apoptotic potential. The results showed upregulation in caspase-3 and caspase-9 levels, and improving the Bax/Bcl-2 ratio by more than 10-fold. Docking studies were performed to determine the possible interaction with the VEGFR-2 active site. Further docking studies were carried out for compound 17b against cytochrome P450 to present such compounds as non-inhibitors. In silico ADMET, toxicity, and physico-chemical properties revealed that most of the synthesized members have acceptable values of drug-likeness. Finally, DFT studies were carried out to calculate the thermodynamic, molecular orbital and electrostatic potential properties.
Keyphrases
- cell death
- cell cycle arrest
- molecular docking
- molecular dynamics simulations
- cell cycle
- oxidative stress
- vascular endothelial growth factor
- case control
- molecular dynamics
- cell proliferation
- pi k akt
- protein protein
- induced apoptosis
- endoplasmic reticulum stress
- endothelial cells
- density functional theory
- single cell
- signaling pathway
- diabetic rats
- high throughput
- risk assessment
- squamous cell carcinoma
- hydrogen peroxide
- poor prognosis
- nitric oxide
- human health
- young adults
- induced pluripotent stem cells
- pluripotent stem cells