Targeting VEGFR-2 by new quinoxaline derivatives: Design, synthesis, antiproliferative assay, apoptosis induction, and in silico studies.
Nawaf A AlsaifHazem A MahdyA F M Motiur RahmanAhmad J ObaidullahHamad M AlkahtaniAbdullah M Al-HossainiAbdulrahman A Al-MehiziAlaa ElwanMohammed S TaghourPublished in: Archiv der Pharmazie (2021)
Twelve new triazolo[4,3-a]quinoxaline-based compounds are reported as anticancer agents with potential effects against vascular endothelial growth factor receptor-2 (VEGFR-2), using sorafenib as a reference molecule. With sorafenib as the positive control, the antiproliferative effects of the synthesized compounds against MCF-7 and HepG2 cells, as well as their VEGFR-2-inhibitory activities, were assessed. The most powerful VEGFR-2 inhibitor was compound 14a, which had an IC50 value of 3.2 nM, which is very close to that of sorafenib (IC50 = 3.12 nM). Furthermore, compounds 14c and 15d showed potential inhibitory activity against VEGFR-2, with IC50 values of 4.8 and 5.4 nM, respectively. Compound 14a caused apoptosis in HepG2 cells and stopped the cell cycle at the G2/M phase. In HepG2 cells, it also increased the levels of the proteases caspase-3 and caspase-9, as well as the Bax/Bcl-2 ratio. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) and toxicity experiments revealed that the synthesized agents had acceptable drug-likeness.
Keyphrases
- vascular endothelial growth factor
- cell cycle
- oxidative stress
- cell death
- induced apoptosis
- endoplasmic reticulum stress
- endothelial cells
- molecular docking
- photodynamic therapy
- cell cycle arrest
- cell proliferation
- human health
- emergency department
- high throughput
- risk assessment
- signaling pathway
- single cell
- pi k akt