Design, synthesis and molecular modeling of new quinazolin-4(3H)-one based VEGFR-2 kinase inhibitors for potential anticancer evaluation
| Autor: | Maged Mohammed Saleh Al Ward, Ahmed B.M. Mehany, Mohamed El-Zahabi, Reda R. Mabrouk, Abdallah E. Abdallah, Sally I. Eissa |
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| Rok vydání: | 2021 |
| Předmět: |
Cell Survival
Protein Conformation Thio Antineoplastic Agents 01 natural sciences Biochemistry Gene Expression Regulation Enzymologic Cell Line Tumor Cytochrome P-450 CYP2D6 Inhibitors Drug Discovery Humans Molecular Biology Cell Proliferation Molecular Structure 010405 organic chemistry Chemistry Cell growth Kinase Organic Chemistry Vascular Endothelial Growth Factor Receptor-2 In vitro 0104 chemical sciences Gene Expression Regulation Neoplastic Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Cytochrome P-450 CYP2D6 Apoptosis Docking (molecular) Cell culture Drug Design Drug Screening Assays Antitumor Tyrosine kinase |
| Zdroj: | Bioorganic Chemistry. 109:104695 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2021.104695 |
| Popis: | Globally cancer is the second leading cause of death. So that this work is an attempt to develop new effective anti-cancer agents. In line with pharmacophoric features of VEGFR-2 kinase inhibitors, new nineteen quinazolin-4-one derivatives were designed, synthesized and biologically evaluated for their potential anticancer activity. All target compounds were evaluated in vitro for VEGFR-2 tyrosine kinase inhibition. Then, nine compounds of best results were further investigated by in vitro assay against three human cancer cell lines, namely HepG2, PC3 and MCF. N’-{2-](3-Ethyl-6-nitro-4-oxo-3,4-dihydroquinazoline-2-yl)thio[acetyl}benzohydrazide (36) was found to be the most potent candidate as it showed IC50 = 4.6 ± 0.06 µM against VEGFR-2 kinase. It also exhibited IC50 = 17.23 ± 1.5, 26.10 ± 2.2 and 30.85 ± 2.3 µg/mL against HepG2, PC3 and MCF, respectively. At the same time it showed IC50 = 145.93 ± 1.1 µg/mL against the normal human lung fibroblasts cell line (WI-38), indicating good selectivity index. Further investigation into HepG2 cell cycle showed the ability of compound 36 to induce apoptosis and arrest cell growth at G2/M phase. Moreover, docking studies demonstrated the ability of compound 36 to bind VEGFR-2 in a correct manner making three essential hydrogen bonds with the key residues Glu885, Asp1046 and Cys919. In sum, this work suggests that compound 36 can serve as a lead for development of effective anticancer agents targeting VEGFR-2. |
| Databáze: | OpenAIRE |
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