Anti-cancer and immunomodulatory evaluation of new nicotinamide derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: in vitro and in silico studies.
Reda G YousefAlaa ElwanIbraheem M M GobaaraAhmed B M MehanyWagdy M EldehnaSouad A El-MetwallyBshra A AlsfoukEslam B ElkaeedAhmed M MetwalyIbrahim H EissaPublished in: Journal of enzyme inhibition and medicinal chemistry (2022)
New nicotinamide derivatives 6 , 7 , 10 , and 11 were designed and synthesised based on the essential features of the VEGFR-2 inhibitors. Compound 10 revealed the highest anti-proliferative activities with IC 50 values of 15.4 and 9.8 µM against HCT-116 and HepG2, respectively compared to sorafenib (IC 50 = 9.30 and 7.40 µM). Compound 7 owned promising cytotoxic activities with IC 50 values of 15.7 and 15.5 µM against the same cell lines, respectively. Subsequently, the VEGFR-2 inhibitory activities were assessed for the titled compounds to exhibit VEGFR-2 inhibition with sub-micromolar IC 50 values. Moreover, compound 7 induced the cell cycle cessation at the cycle at %G2-M and G0-G1phases, and induced apoptosis in the HCT-116. Compounds 7 and 10 reduced the levels of TNF- α by 81.6 and 84.5% as well as IL-6 by 88.4 and 60.9%, respectively, compared to dexamethasone (82.4 and 93.1%). In silico docking, molecular dynamics simulations, ADMET, and toxicity studies were carried out.
Keyphrases
- molecular dynamics simulations
- molecular docking
- cell cycle
- induced apoptosis
- endoplasmic reticulum stress
- oxidative stress
- vascular endothelial growth factor
- cell cycle arrest
- cell proliferation
- diabetic rats
- signaling pathway
- case control
- cell death
- rheumatoid arthritis
- high glucose
- pi k akt
- endothelial cells
- single cell
- drug induced
- human health