Angiokinase inhibition of VEGFR-2, PDGFR and FGFR and cell growth inhibition in lung cancer: Design, synthesis, biological evaluation and molecular docking of novel azaheterocyclic coumarin derivatives

The present work represents the design and synthesis of some azaheterocyclic coumarin derivatives which are evaluated as anti-lung Cancer agents. Ten out of the twenty azaheterocyclic compounds showed superior activity than the standard drug staurosporine against non-small cell lung Cancer (A549). Representing the four different azaheterocyclic series, compounds 4a, 5d, 6e, and 7d, which demonstrated IC_50s of 2.38, 2.39, 1.05 and 3.98 µM, respectively, each exhibiting the best cytotoxicity in its group, were selected for further assessment of their toxicity on normal lung cells (WI-38). Compound 4a was selected for further investigations because it remarkably revealed less cytotoxicity (IC₅₀ = 53.76 µM) than 7d (IC₅₀ = 19.95 µM) on (WI-38) compared to staurosporine (IC₅₀ = 24.41 µM). 4a was assessed for its ability to inhibit the angiokinases VEGFR-2, PDGFR, FGFR and the growth factor EGFR, remarkably it showed better VEGFR-2, PDGFR, FGFR inhibition than the reference drugs used and exhibited as well noticeable EGFR inhibition. Going further, 4a was capable of arresting the cell cycle at pre-G1 phase and S phase and inducing Apoptosis. Moreover, the capability of the target 4a to interact with the key Amino acids of VEGFR-2 binding site was detected by molecular docking. Finally, the in silico physicochemical properties of 4a were studied.

Angiogenesis; Apoptosis; Azaheterocyclic coumarin derivatives; Cell cycle inhibition; Lung cancer; Molecular modeling; Pharmacokinetics.