Bio-evaluation of the 2-nitrochalcones as potential anti-lung cancer agents, inducers of apoptosis and inhibitors of protein kinase (VEGFR-2)

Abstract

A series of the 2-nitrochalcones 3a–3k was synthesized and evaluated for cytotoxicity against the human lung adenocarcinoma (A549) and human embryonic kidney (HEK293-T) cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The 3-(4-fluorophenyl) 3c and the 3-(4-(1,1,2,2-tetrafluoroethoxy)phenyl derivative 3k induced early (25–29%) and late (48–60%) apoptosis of A549 cells as determined by the Annexin V-FITC/PI method. The 3-(4-fluorophenyl) 3c, 3-(4-methoxyphenyl) 3h, 3-(2,3,4-trimethoxyphenyl) 3j and the 3-(4-(1,1,2,2-tetrafluoroethoxy)phenyl derivative 3k were also found to exhibit significant inhibitory activity against vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase compared to staurosporine (0.035 ± 0.002 µM) or nintedanib (IC50 = 0.021 ± 0.001 µM) with IC50 values of 31.49 ± 0.02, 39.95 ± 0.17, 36.90 ± 0.16 and 29.10 ± 0.16 µM, respectively. Molecular docking studies were also conducted on 3c and 3k as representative models to recognize the hypothetical binding motif of the title compounds within the active site of VEGFR-2.

Design, Synthesis, and Molecular Docking of Novel Miscellaneous Chalcones as p38α Mitogen‐Activated Protein Kinase Inhibitors

“…[25] Concerning the nitro chalcones, an increase in the interactions with the protein residues in the VEGFR-2 active site was detected when the nitro group was present in the α,β-unsaturated carbonyl system. [26] Some pyrazole chalcones were reported to be effective against HELA and MCF-7 cancer cells, [27] whereas pyrazole-based chalcones 7 and 8 were effective against leukaemia cell lines. [28,29] Chalcones can suppress cancer cells through a variety of methods, including tubulin inhibition, [30] cyclin-dependent kinase (CDK(, [31] vascular endothelial growth factor receptor-2 (VEGFR-2), [32] epidermal growth factor receptor (EGFR), [33] glycogen synthase kinase 3 beta (GSK3β), [34] and mitogen-activated protein kinase (MAPK), [35] which is a common serine and threonine protein kinase found in eukaryotes, [36] and is critical for conveying extracellular stimuli into cells and inducing biological responses that can impact cell proliferation, differentiation, apoptosis, inflammation, and other processes.…”