1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies.
Mohamed HagrasMarwa A SalehRogy R Ezz EldinAbdelrahman A AbuelkhirEmad Gamil KhidrAhmed A El-HusseinyHesham A El-MahdyEslam B ElkaeedIbrahim H EissaPublished in: Journal of enzyme inhibition and medicinal chemistry (2022)
In the current work, some 1,3,4-oxadiazole-naphthalene hybrids were designed and synthesised as VEGFR-2 inhibitors. The synthesised compounds were evaluated in vitro for their antiproliferative activity against two human cancer cell lines namely, HepG-2 and MCF-7. Compounds that exhibited promising cytotoxicity ( 5 , 8 , 15 , 16 , 17 , and 18 ) were further evaluated for their VEGFR-2 inhibitory activities. Compound 5 showed good antiproliferative activity against both cell lines and inhibitory effect on VEGFR-2. Besides, it induced apoptosis by 22.86% compared to 0.51% in the control (HepG2) cells. This apoptotic effect was supported by a 5.61-fold increase in the level of caspase-3 compared to the control cells. Moreover, it arrested the HepG2 cell growth mostly at the Pre-G1 phase. Several in silico studies were performed including docking, ADMET, and toxicity studies to predict binding mode against VEGFR-2 and to anticipate pharmacokinetic, drug-likeness, and toxicity of the synthesised compounds.
Keyphrases
- induced apoptosis
- oxidative stress
- endoplasmic reticulum stress
- cell death
- vascular endothelial growth factor
- signaling pathway
- molecular docking
- endothelial cells
- case control
- emergency department
- cell proliferation
- molecular dynamics simulations
- anti inflammatory
- molecular dynamics
- risk assessment
- breast cancer cells
- binding protein
- papillary thyroid
- pi k akt
- human health