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 IC50 values of 5.81, 2.14, and 3.03 μM, respectively, and relatively low cytotoxicity toward HEK-293 cells (IC50 = 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 (IC50 = 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.