Novel curcumin-based analogues as potential VEGFR2 inhibitors with promising metallic loading nanoparticles: synthesis, biological evaluation, and molecular modelling investigation.

VEGFR2 inhibition has been established as a therapeutic approach for managing cancer. A series of curcumin-based analogues were designed, synthesized, and screened for their anticancer activity against MCF-7 and HepG-2 cell lines and WISH normal cells. Compounds 4b, 4d, 4e, and 4f showed potent cytotoxicity against MCF-7 with IC₅₀ values of 0.49, 0.14, 0.01, and 0.32 μM, respectively, compared to curcumin (IC₅₀ = 13.8 μM) and sorafenib (IC₅₀ = 2.13 μM). Interestingly, compound 4e, the most active compound, exhibited potent VEGFR2 inhibition with an IC₅₀ value of 11.6 nM (96.5% inhibition) compared to sorafenib with an IC₅₀ value of 30 nM (94.8% inhibition). Additionally, compound 4e significantly induced apoptotic cell death in MCF-7 cells by 41.1% compared to a control group (0.8%), halting cell division during the G2/M phase by 39.8% compared to the control (21.7%). Molecular docking-coupled dynamics simulations highlighted the bias of the VEGFR2 pocket towards compound 4e compared to other synthesized compounds. Predicting superior binding affinities and relevant interactions with the pocket's key residues recapitulated in vitro findings towards higher inhibition activity for compound 4e. Furthermore, compound 4e with adequate pharmacokinetic and drug-likeness profiles in terms of ADME and safety characteristics can serve as a promising clinical candidate for future lead optimization and development. Notably, 4e-Fe₂O₃-humic acid NPs exhibited potent cytotoxicity with IC₅₀ values of 2.41 and 13.4 ng mL^-1 against MCF-7 and HepG-2 cell lines, respectively. Hence, compound 4e and its Fe₂O₃-humic acid-NPs could be further developed as promising anti-breast cancer agents.