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Design, Synthesis, and Biological Evaluation of Indolin-2-One-Matrine Derivatives as Potential VEGFR-2-Targeting
Ziyi Wang1, Yongquan Wei1, Zexu Xing2
1College of Chemistry and Chemical Engineering, Guangxi University, Nanning, China.
Abstract:
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.
Insights
Novel indolinone-matrine hybrids show potent anticancer activity. Compound J9 effectively targets VEGFR-2, inhibiting hepatocellular carcinoma growth with low toxicity, offering a promising new therapeutic strategy.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- VEGF/VEGFR-2 pathway inhibition is crucial for suppressing tumor angiogenesis.
- Existing VEGFR-2 tyrosine kinase inhibitors face challenges with resistance and systemic toxicity.
Purpose of the Study:
- To design and synthesize novel indolinone-matrine hybrids as potential anticancer agents.
- To evaluate the antiproliferative and mechanistic effects of these compounds against hepatocellular carcinoma (HCC).
Main Methods:
- Molecular hybridization strategy for compound synthesis.
- Antiproliferative assays against HCC cell lines (HepG-2, HuH7, MHCC97H).
- In vitro VEGFR-2 kinase inhibition assay, Western blot, cell cycle analysis, apoptosis assays, and molecular simulations.
Main Results:
- Compound J9 demonstrated potent antiproliferative activity against HCC cell lines with favorable selectivity over normal cells.
- J9 inhibited colony formation, migration, induced G1-phase arrest, and promoted apoptosis in HuH7 cells.
- J9 directly inhibited VEGFR-2 kinase activity in vitro and showed stable binding in simulations.
Conclusions:
- J9, a novel indolinone-matrine hybrid, exhibits significant antitumor potential via VEGFR-2 inhibition.
- J9 represents a promising lead compound for developing new hepatocellular carcinoma therapeutics.
