Discovery of Novel Pyrimidine Based Small Molecule Inhibitors as VEGFR-2 Inhibitors: Design, Synthesis, and
Sachin A Dhawale1,2, Santosh N Mokale1, Pratap S Dabhade1
1Department of Pharmaceutical Chemistry, Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Aurangabad, 431001, Maharashtra, India.
Background:
Receptor tyrosine kinases (RTKs) are potent oncoproteins in cancer that, when mutated or overexpressed, can cause uncontrolled growth of cells, angiogenesis, and metastasis, making them significant targets for cancer treatment. Vascular endothelial growth factor receptor 2 (VEGFR2), is a tyrosine kinase receptor that is produced in endothelial cells and is the most crucial regulator of angiogenic factors involved in tumor angiogenesis. So, a series of new substituted N-(4-((2-aminopyrimidin-5-yl)oxy)phenyl)-N-phenyl cyclopropane- 1,1-dicarboxamide derivatives as VEGFR-2 inhibitors have been designed and synthesized.
Methods:
Utilizing H-NMR, C13-NMR, and mass spectroscopy, the proposed derivatives were produced and assessed. HT-29 and COLO-205 cell lines were used for the cytotoxicity tests. The effective compound was investigated further for the Vegfr-2 kinase inhibition assay, cell cycle arrest, and apoptosis. A molecular docking examination was also carried out with the Maestro-12.5v of Schrodinger.
Results:
In comparison to the reference drug Cabozantinib (IC50 = 9.10 and 10.66 μM), compound SP2 revealed promising cytotoxic activity (IC50 = 4.07 and 4.98 μM) against HT-29 and COLO-205, respectively. The synthesized compound SP2 showed VEGFR-2 kinase inhibition activity with (IC50 = 6.82 μM) against the reference drug, Cabozantinib (IC50 = 0.045 μM). Moreover, compound SP2 strongly induced apoptosis by arresting the cell cycle in the G1 phase. The new compounds' potent VEGFR-2 inhibitory effect was noted with key amino acids Asp1044, and Glu883, and the hydrophobic interaction was also observed in the pocket of the VEGFR-2 active site by using a docking study.
Conclusion:
The results demonstrate that at the cellular and enzyme levels, the synthetic compounds SP2 are similarly effective as cabozantinib. The cell cycle and apoptosis data demonstrate the effectiveness of the suggested compounds. Based on the findings of docking studies, cytotoxic effects, in vitro VEGFR-2 inhibition, apoptosis, and cell cycle arrest, this research has given us identical or more effective VEGFR-2 inhibitors.
Insights
New cyclopropane-1,1-dicarboxamide derivatives were synthesized and show promising anti-cancer properties. Compound SP2 effectively inhibits vascular endothelial growth factor receptor 2 (VEGFR2), induces apoptosis, and arrests cell cycle, offering potential new cancer therapies.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Molecular Pharmacology
Background:
- Receptor tyrosine kinases (RTKs) are key drivers of cancer, promoting uncontrolled cell growth, angiogenesis, and metastasis.
- Vascular endothelial growth factor receptor 2 (VEGFR2) is a critical regulator of tumor angiogenesis and a significant therapeutic target.
- Novel VEGFR2 inhibitors are needed to combat cancer progression.
Purpose of the Study:
- To design and synthesize novel substituted N-(4-((2-aminopyrimidin-5-yl)oxy)phenyl)-N-phenyl cyclopropane-1,1-dicarboxamide derivatives.
- To evaluate the synthesized compounds as potential VEGFR2 inhibitors for cancer treatment.
- To investigate the mechanism of action of the most effective compounds.
Main Methods:
- Synthesis and structural characterization of novel cyclopropane-1,1-dicarboxamide derivatives using H-NMR, C13-NMR, and mass spectroscopy.
- Cytotoxicity assessment against HT-29 and COLO-205 cancer cell lines.
- In vitro VEGFR2 kinase inhibition assay, cell cycle analysis, apoptosis assays, and molecular docking studies.
Main Results:
- Compound SP2 exhibited potent cytotoxic activity against HT-29 (IC50 = 4.07 μM) and COLO-205 (IC50 = 4.98 μM), outperforming the reference drug Cabozantinib.
- SP2 demonstrated VEGFR2 kinase inhibition (IC50 = 6.82 μM) and induced significant apoptosis and G1 cell cycle arrest.
- Molecular docking revealed key interactions of SP2 with VEGFR2 active site residues (Asp1044, Glu883).
Conclusions:
- The synthesized cyclopropane-1,1-dicarboxamide derivatives, particularly SP2, show significant potential as VEGFR2 inhibitors.
- SP2 exhibits comparable efficacy to Cabozantinib at cellular and enzyme levels, inducing apoptosis and cell cycle arrest.
- These findings support the development of SP2 and related compounds as novel anti-cancer agents targeting VEGFR2.
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