Novel pyrazolopyrimidine urea derivatives: Synthesis, antiproliferative activity, VEGFR-2 inhibition, and effects on the cell cycle profile
| Autor: | Asmaa E. Kassab, Yara El-Dash, Ehab M. Gedawy |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Cell cycle checkpoint
Pharmaceutical Science Antineoplastic Agents 01 natural sciences Pyrazolopyrimidine chemistry.chemical_compound Structure-Activity Relationship Cell Line Tumor Drug Discovery Humans Urea Fragmentation (cell biology) Cytotoxicity Protein Kinase Inhibitors Cell Proliferation chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Cell Cycle Cell cycle Vascular Endothelial Growth Factor Receptor-2 0104 chemical sciences Amino acid 010404 medicinal & biomolecular chemistry Pyrimidines chemistry Biochemistry Apoptosis Cancer cell Pyrazoles Drug Screening Assays Antitumor |
| Zdroj: | Archiv der PharmazieREFERENCES. 353(4) |
| ISSN: | 1521-4184 |
| Popis: | A series of novel diaryl urea pyrazolopyrimidine derivatives was designed and synthesized. All the synthesized compounds were evaluated for cytotoxic activity by the National Cancer Institute. A significant antiproliferative activity at a 10-µM dose was shown by four compounds (5c, 5e, 5g, and 5h), and they were accordingly evaluated at five concentrations. They showed a potent and broad-spectrum antiproliferative activity, with GI50 values between 0.553 and 3.80 µM and TGI values in the range of 2.17-100 µM. These four compounds potently inhibited the vascular endothelial growth factor receptor-2 (VEGFR-2) with IC50 values in the nanomolar range. Molecular docking attributed their potent VEGFR-2 inhibitory activity to their interactions with key amino acids in the VEGFR-2 active site. Their flow cytometric analysis showed that they exerted their cytotoxic activity by reduction of the cellular proliferation and by induction of cell cycle arrest at the G2/M phase. Additionally, they induced DNA degradation or fragmentation, confirming the role of apoptosis in the cancer cell death and cytotoxicity induced by these compounds. |
| Databáze: | OpenAIRE |
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