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Targeting VEGFR-2 with piperazine bridged indolin-2-one derivatives
Merve Zengin1, Reem K Arafa2, Tuba Tüylü Küçükkılınç3
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkiye.
Bioorganic Chemistry
|March 5, 2026
Summary
New indolin-2-one derivatives show potent inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), a key target in cancer angiogenesis. Some compounds exhibit significant breast cancer cell cytotoxicity, offering potential as novel cancer therapies.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is crucial for tumor angiogenesis and a significant therapeutic target in cancer treatment.
- Developing novel inhibitors targeting VEGFR-2 is essential for advancing cancer therapy.
Purpose of the Study:
- To synthesize and evaluate novel 6-substituted-3-(4-(4-(substitutedphenyl/benzyl)piperazin-1-yl)benzylidene) indolin-2-one derivatives as potential VEGFR-2 inhibitors and anticancer agents.
- To assess the cytotoxic activity of these derivatives against breast cancer cell lines and normal breast epithelial cells.
Main Methods:
- Synthesis of indolin-2-one derivatives (compounds 2-24) with structural confirmation using IR, NMR, and HRMS.
- In vitro evaluation of VEGFR-2 inhibition and cytotoxicity assays against MCF-7, MDA-MB-231, and MCF-10A cell lines.
- Mechanistic studies including cell cycle analysis, apoptosis induction, and reactive oxygen species (ROS) generation for promising compounds.
Main Results:
- Several synthesized derivatives demonstrated strong VEGFR-2 inhibition, with potencies comparable to or exceeding sorafenib.
- Five derivatives (4, 7, 9, 10, 12) showed superior cytotoxicity against MCF-7 breast cancer cells compared to doxorubicin.
- Compounds exhibited moderate activity against MDA-MB-231 cells and no significant toxicity against normal MCF-10A cells.
- Mechanistic studies on compound 10 revealed G0/G1 phase arrest, apoptosis induction, and increased ROS generation.
Conclusions:
- The synthesized indolin-2-one derivatives represent a promising class of compounds with significant VEGFR-2 inhibitory and anticancer activities.
- Compound 10, in particular, shows potential as a selective and effective lead compound for breast cancer therapy due to its mechanism of action.
- Further investigation is warranted to explore the therapeutic potential of these novel compounds in breast cancer treatment.
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