Antiproliferative and Antiangiogenic Properties of New VEGFR-2-targeting 2-thioxobenzo[ g ]quinazoline Derivatives (In Vitro)

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-12, Vol.25 (24), p.5944
• Main Authors: Abuelizz, Hatem A, Marzouk, Mohamed, Bakheit, Ahmed H, Awad, Hanem M, Soltan, Maha M, Naglah, Ahmed M, Al-Salahi, Rashad
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Angiogenesis Inhibitors - pharmacology; Antiangiogenics; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferatives; Apoptosis; Apoptosis - drug effects; benzoquinazolines; Binding sites; Breast; Cancer; Cell adhesion & migration; Cell cycle; Cell Cycle - drug effects; Cell Proliferation - drug effects; Chemistry; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA fragmentation; Doxorubicin; Flow cytometry; Fluorescence; Fluorescence microscopy; Fragmentation; Hep G2 Cells; Hepatocytes; HepG2; Humans; Iodides; MCF-7; MCF-7 Cells; Molecular Docking Simulation; Molecular Structure; MTT assay; Pharmaceutical sciences; Propidium iodide; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Structure-Activity Relationship; Tumor cell lines; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vascular endothelial growth factor receptors; VEGFR-2
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25245944

A series of 3-ethyl(methyl)-2-thioxo-2,3-dihydrobenzo[ ]quinazolines ( - ) were synthesized, characterized, and evaluated in vitro for their antiangiogenesis VEGFR-2-targeting, antiproliferative, and antiapoptotic activities against breast MCF-7 and liver HepG2 cells. Flow cytometry was used to determine cancer-cell cycle distributions, and apoptosis was detected using annexin-V-FITC (V) and propidium iodide (PI) dyes. Fluorescence microscopy, in combination with Hoechst staining was used to detect DNA fragmentation. Most of the tested benzo[ ]quinazolines demonstrated promising activity (IC = 8.8 ± 0.5-10.9 ± 0.9 μM) and (IC = 26.0 ± 2.5-40.4 ± 4.1 μM) against MCF-7 and HepG2, respectively. Doxorubicin was used as a reference drug. Compounds - showed the highest activity against both cancer cell lines. Differential effects were detected by cell-cycle analysis, indicating similarities in the actions of and against both MCF7 and HepG2, involving the targeting of G1 and S phases, respectively. Compound showed similar indices against both cells, indicating that its cytotoxicity toward the examined cancer cells could be unselective. Interestingly, and showed the highest apoptosis (30.76% and 25.30%, respectively) against MCF-7. The DNA fragmentation results agreed well with the apoptosis detected by flow cytometry. In terms of antiangiogenesis activity, as derived from VEGFR-2 inhibition, and were comparable to sorafenib and effected 1.5- and 1.4-fold inhibition relative to the standard sorafenib. A docking study was conducted to investigate the interaction between the synthesized benzo[ ]quinazolines and the ATP-binding site within the catalytic domain of VEGFR-2.