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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 IC50s 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.

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S1421 Staurosporine (STS) Staurosporine (STS) is a potent PKC inhibitor for PKCα, PKCγ and PKCη with IC50 of 2 nM, 5 nM and 4 nM, less potent to PKCδ (20 nM), PKCε (73 nM) and little active to PKCζ (1086 nM) in cell-free assays. Also shows inhibitory activities on other kinases, such as PKA, PKG, S6K, CaMKII, etc. Phase 3.

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