Synthesis of new -ferulic acid derivatives as potential anticancer agents and VEGFR-2 inhibitors.

VEGFR-2 signaling is the primary driver of angiogenesis, a process essential for tumor development and metastasis. Although -ferulic acid (TFA), a naturally occurring polyphenol, has demonstrated anticancer and antiangiogenic potential, its low solubility and rapid metabolism limit its therapeutic application. To overcome these drawbacks, seven novel TFA derivatives with chemically masked hydroxyl (-OH) groups were designed and synthesized, aiming to improve their metabolic stability and pharmacokinetic properties. This study evaluates their safety in normal WI-38 fibroblasts and anticancer efficacy in HepG2, Hep3B, and Huh7 hepatocellular carcinoma (HCC) cells. Compound 4e emerged as the lead candidate, demonstrating exceptional cytotoxicity against HCC cells (HepG2: IC = 1.8 μg mL; Huh7: IC = 6.7 μg mL, and Hep3B: IC = 7.1 μg mL) with 23-fold greater potency than TFA and 2-fold superiority to doxorubicin while maintaining minimal toxicity in WI-38 fibroblasts. Further mechanistic studies revealed that 4e significantly modulates key cancer-associated biomarkers in HepG2 lysates, including the downregulation of AFP (α-fetoprotein), BCL-2, MCL-1, and γ-carboxyprothrombin, accompanied by the upregulation of pro-apoptotic caspase-3 and the tumor suppressor P53. The compound also exhibited good inhibitory activity against VEGFR-2, with its binding interaction further supported by molecular docking studies. These findings suggest that compound 4e is a promising anticancer candidate worthy of further therapeutic development research.