New quinoline and isatin derivatives as apoptotic VEGFR-2 inhibitors: design, synthesis, anti-proliferative activity, docking, ADMET, toxicity, and MD simulation studies.
Eslam B ElkaeedMohammed S TaghourHazem A MahdyWagdy M EldehnaNehal M El-DeebAhmed M KenawyBshra A AlsfoukMohammed A DahabAhmed M MetwalyIbrahim H EissaMohamed A El-ZahabiPublished in: Journal of enzyme inhibition and medicinal chemistry (2022)
New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects of these compounds were estimated against A549, Caco-2, HepG2, and MDA-MB-231. Compounds 13 and 14 showed comparable activities with doxorubicin against the Caco-2 cells. These compounds strongly inhibited VEGFR-2 kinase activity. The cytotoxic activities were evaluated against Vero cells. Compound 7 showed the highest value of safety and selectivity. Cell migration assay displayed the ability of compound 7 to prevent healing and migration abilities in the cancer cells. Furthermore, compound 7 induced apoptosis in Caco-2 through the expressive down-regulation of the apoptotic genes, Bcl2, Bcl-xl, and Survivin, and the upregulation of the TGF gene. Molecular docking against VEGFR-2 emerged the interactions of the synthesised compounds in a similar way to sorafenib. Additionally, seven molecular dynamics simulations studies were applied and confirmed the stability of compound 13 in the active pocket of VEGFR-2 over 100 ns.
Keyphrases
- molecular docking
- induced apoptosis
- molecular dynamics simulations
- endoplasmic reticulum stress
- signaling pathway
- oxidative stress
- vascular endothelial growth factor
- cell migration
- cell death
- cell cycle arrest
- molecular dynamics
- genome wide
- high throughput
- cell proliferation
- drug delivery
- poor prognosis
- small molecule
- anti inflammatory
- transforming growth factor
- long non coding rna
- endothelial cells
- genome wide analysis
- protein protein