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Design, Synthesis, and Evaluation of Benzoxazole-linked Pyrazole Hybrids as VEGFR-2-targeted Antiproliferative Agents
Elif Deniz1, Furkan Ozan Çöven2, Ali Ergüç3
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Van Yuzuncu Yil University, Van, Türkiye.
Abstract:
In this study, a series of benzoxazole-linked pyrazole compounds (20a-t) were synthesized and tested for their antiproliferative activity. Their effects on lung cancer (A549) and normal lung (CCD-34Lu) cell lines were evaluated using the MTT assay. Among them, compounds 20m and o showed strong antiproliferative effects, with IC50 values of 7.64 and 15.82 µM, respectively, and selectivity indices of 2.84 and 1.95 in favor of cancer cells. ELISA tests demonstrated that both compounds statistically significantly reduced VEGFR-2 protein levels by 24.8 and 28.7% at their respective IC50 values, indicating potential antiangiogenic properties. Molecular docking studies supported these findings by showing favorable binding of 20m and o to the VEGFR-2 receptor, with binding energies of -7.33 kcal/mol and -7.22 kcal/mol, respectively. Overall, compounds 20m and o stand out as promising candidates for further development as anticancer drugs.
Insights
New benzoxazole-linked pyrazole compounds show significant antiproliferative effects against lung cancer cells. Compounds 20m and o also demonstrated potential antiangiogenic properties by reducing VEGFR-2 protein levels.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Lung cancer remains a leading cause of cancer-related mortality worldwide.
- Development of novel therapeutic agents with improved efficacy and selectivity is crucial.
- Targeting angiogenesis, a key process in tumor growth and metastasis, is a promising strategy.
Purpose of the Study:
- To synthesize and evaluate the antiproliferative activity of novel benzoxazole-linked pyrazole compounds against lung cancer.
- To investigate the potential antiangiogenic effects of the synthesized compounds by assessing their impact on VEGFR-2.
- To explore the molecular interactions of lead compounds with the VEGFR-2 receptor through molecular docking.
Main Methods:
- Synthesis of a series of 20 benzoxazole-linked pyrazole compounds (20a-t).
- Antiproliferative activity assessed using the MTT assay on A549 (lung cancer) and CCD-34Lu (normal lung) cell lines.
- VEGFR-2 protein levels quantified using ELISA; molecular docking performed against the VEGFR-2 receptor.
Main Results:
- Compounds 20m and 20o exhibited potent antiproliferative effects against A549 cells, with IC50 values of 7.64 µM and 15.82 µM, respectively.
- Compounds 20m and 20o displayed selectivity indices of 2.84 and 1.95, favoring cancer cells.
- ELISA revealed significant reductions in VEGFR-2 protein levels (24.8% for 20m, 28.7% for 20o) at IC50 concentrations.
- Molecular docking studies indicated favorable binding affinities for compounds 20m (-7.33 kcal/mol) and 20o (-7.22 kcal/mol) to the VEGFR-2 receptor.
Conclusions:
- Benzoxazole-linked pyrazole derivatives, particularly compounds 20m and 20o, possess significant antiproliferative activity against lung cancer cells.
- These compounds demonstrate potential antiangiogenic properties through the inhibition of VEGFR-2 protein expression.
- Compounds 20m and 20o represent promising lead candidates for further preclinical development as novel anticancer therapeutics.
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