Benzoxazole derivatives as new VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, and antiproliferative evaluation.
Mohammed S TaghourHazem A MahdyMaher H GomaaAhmed AglanMahmoud Gomaa EldeibAlaa ElwanMohammed A DahabEslam B ElkaeedAisha A AlsfoukMohamed M KhalifaIbrahim H EissaHazem ElkadyPublished in: Journal of enzyme inhibition and medicinal chemistry (2022)
In this study, a set of novel benzoxazole derivatives were designed, synthesised, and biologically evaluated as potential VEGFR-2 inhibitors. Five compounds ( 12d , 12f , 12i , 12l , and 13a ) displayed high growth inhibitory activities against HepG2 and MCF-7 cell lines and were further investigated for their VEGFR-2 inhibitory activities. The most potent anti-proliferative member 12 l ( IC 50 = 10.50 μM and 15.21 μM against HepG2 and MCF-7, respectively ) had the most promising VEGFR-2 inhibitory activity (IC 50 = 97.38 nM). A further biological evaluation revealed that compound 12l could arrest the HepG2 cell growth mainly at the Pre-G1 and G1 phases. Furthermore, compound 12l could induce apoptosis in HepG2 cells by 35.13%. likely, compound 12l exhibited a significant elevation in caspase-3 level (2.98-fold) and BAX (3.40-fold), and a significant reduction in Bcl-2 level (2.12-fold). Finally, docking studies indicated that 12l exhibited interactions with the key amino acids in a similar way to sorafenib.
Keyphrases
- vascular endothelial growth factor
- cell death
- endoplasmic reticulum stress
- oxidative stress
- cell cycle arrest
- induced apoptosis
- breast cancer cells
- amino acid
- case control
- photodynamic therapy
- molecular dynamics
- molecular dynamics simulations
- single cell
- mass spectrometry
- high resolution
- atomic force microscopy
- human health