Development and investigation of thiazolidinedione and pyrazoline compounds as antiangiogenic weapons targeting VEGFR-2

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Deregulation of angiogenesis is a hallmark of cancer, making it a critical therapeutic target.
• Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is a key mediator of angiogenesis.
• Targeting VEGFR-2 offers a promising strategy for anti-cancer drug development.

Purpose of the Study:

• To synthesize and evaluate novel compounds as inhibitors of VEGFR-2.
• To assess the antiangiogenic potential of these compounds in vitro and in vivo.
• To elucidate the mechanism of action of the most potent inhibitors.

Main Methods:

• Synthesis of 29 novel compounds designed as VEGFR-2 inhibitors.
• In vitro assays using Human Umbilical Vein Endothelial Cells (HUVECs) to assess antiangiogenic activity (IC50, migration, capillary tube formation).
• In vivo antiangiogenic testing using the Chorioallantoic Membrane (CAM) assay.
• Molecular docking studies to investigate binding interactions with VEGFR-2.

Main Results:

• Compounds B1, PB11, and PB16 exhibited submicromolar IC50 values against HUVECs.
• B1, B2, and PB16 significantly reduced HUVEC migration and capillary tube formation.
• Potent VEGFR-2 inhibition was observed in the nanomolar range for B1 (200 nM), B2 (500 nM), and PB16 (600 nM).
• B1 and PB16 demonstrated efficacy in suppressing neovascularization in the CAM assay.
• Docking studies revealed that B1 and PB16 bind to the ATP site and an allosteric pocket of VEGFR-2.

Conclusions:

• The novel compounds effectively target VEGFR-2.
• Compounds B1 and PB16 possess significant in vitro and in vivo antiangiogenic properties.
• These compounds represent potential therapeutic agents for cancer treatment by inhibiting angiogenesis.