VEGFR-2 inhibiting effect and molecular modeling of newly synthesized coumarin derivatives as anti-breast cancer agents
Autor: | Eman Y. Ahmed, Mohamed F. El-Mansy, Nehad A. Abdel Latif, Omaima M. Abdelhafez, Weam S. Elserwy |
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Rok vydání: | 2019 |
Předmět: |
Models
Molecular Cell Survival Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Breast Neoplasms 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Drug Discovery medicine Staurosporine Humans Cytotoxicity Molecular Biology Protein Kinase Inhibitors ADME Cell Proliferation Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Cell growth Chemistry Organic Chemistry Cell Cycle Coumarin Vascular Endothelial Growth Factor Receptor-2 In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry MCF-7 PC-3 Cells MCF-7 Cells Molecular Medicine Female Kinase binding Drug Screening Assays Antitumor medicine.drug |
Zdroj: | Bioorganicmedicinal chemistry. 28(5) |
ISSN: | 1464-3391 |
Popis: | Twenty five newly synthesized coumarin scaffold based derivatives were assayed for their in vitro anticancer activity against MCF-7 breast and PC-3 prostate cancer cell lines and were further assessed for their in vitro VEGFR-2 kinase inhibitory activity. The in vitro cytotoxic studies revealed that most of the synthesized compounds possessed very promising cytotoxicity against MCF-7, particularly; compounds 4a (IC50 = 1.24 µM) and 3d (IC50 = 1.65 µM) exhibited exceptional activities superior to the positive control staurosporine (IC50 = 8.81 µM). Similarly, the majority of the compounds exhibited higher antiproliferative activities compared to the reference standard with IC50 values ranging from 2.07 to 8.68 µM. The two cytotoxic derivatives 4a and 3d were selected to evaluate their inhibitory potencies against VEGFR-2 kinase. Remarkably, compound 4a, exhibited significant IC50 of 0.36 µM comparable to staurosporine (IC50; 0.33 µM). Moreover, it was capable of inducing preG1 apoptosis, cell growth arrest at G2/M phase and activating caspase-9. On the other hand, insignificant cytotoxic activity was observed for all compounds towards PC-3 cell line. Molecular docking study was carried out for the most active anti-VEGFR-2 derivative 4a, which demonstrated the ability of the tested compound to interact with the key amino acids in the target VEGFR-2 kinase binding site. Additionally, the ADME parameters and physicochemical properties of compound 4a were examined in silico. |
Databáze: | OpenAIRE |
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