Design, Synthesis, and Biological Evaluation of Indolin‐2‐One–Matrine Derivatives as Potential VEGFR‐2‐Targeting Agents for Hepatocellular Carcinoma

Inhibition of the VEGF/VEGFR‐2 pathway is a validated strategy to suppress tumor angiogenesis and progression; however, long‐term use of several VEGFR‐2 tyrosine kinase inhibitors is limited by resistance and systemic toxicity. Here, a series of novel indolinone–matrine hybrids were designed and synthesized via a molecular hybridization strategy. The antiproliferative activities were evaluated against human hepatocellular carcinoma (HCC) cell lines (HepG‐2, HuH7, and MHCC97H). Among them, J9 showed the most potent activity with IC 50 values of 5.81, 2.14, and 3.03 μM, respectively, and relatively low cytotoxicity toward HEK‐293 cells (IC 50 = 27.90 μM) and HL7702 cells (IC50 = 52.23 μM). In HuH7 cells, J9 significantly inhibited colony formation and migration, induced G1‐phase arrest, and promoted apoptosis in a dose‐dependent manner. Western blot analysis indicated that J9 treatment was associated with downregulation of VEGFR‐2 and activation of caspase‐dependent apoptosis (increased cleaved caspase‐3 and cleaved PARP). Moreover, J9 inhibited VEGFR‐2 kinase in vitro (IC 50 = 253.51 ± 1.21 nM), and docking/MD simulations suggested stable binding within the VEGFR‐2 ATP‐binding pocket. Collectively, J9 represents a promising matrine‐derived antitumor candidate with potential VEGFR‐2‐targeting activity.