Development of novel furan-based VEGFR-2 inhibitors and apoptotic inducers for colorectal cancer.

AIMS: This study aimed to synthesize and evaluate novel furan derivatives as potential anticancer agents targeting colon cancer through VEGFR-2 inhibition and apoptosis induction.

MATERIALS AND

METHODS

The cytotoxic activity of the synthesized compounds was assessed against human fibroblast (HSF) and colon cancer cell lines (HCT-116, Caco-2, and HT-29) using the MTT assay. VEGFR-2 inhibitory activity was determined in vitro, and immunocytochemistry was employed to evaluate VEGFR-2 expression. Apoptosis, cell cycle arrest, and migration inhibition were analyzed in Caco-2 cells. Molecular docking, molecular dynamics (MD) simulations, Density Functional Theory (DFT), and ADMET analyses were conducted to assess binding affinity, stability, and safety profiles.

RESULTS

Compound 6 exhibited potent cytotoxicity against HT-29 (IC50 = 22.39 μM) and strong VEGFR-2 inhibition (IC50 = 0.28 ± 0.42 μM), comparable to sorafenib. It suppressed VEGFR-2 expression, induced G2/M cell cycle arrest, and promoted early and late apoptosis in 97% of treated Caco-2 cells. Upregulation of Bax and caspase-3, along with downregulation of Bcl-2, confirmed intrinsic apoptotic activation. Computational analyses supported compound 6's stability and drug-likeness.

CONCLUSIONS

Compound 6 is a promising lead furan derivative with potent, selective anticancer activity against colon cancer via VEGFR-2 inhibition and apoptosis induction. Further, in vivo evaluation is warranted.