Novel quinoxaline-based VEGFR-2 inhibitors to halt angiogenesis

• Published in: Bioorganic chemistry 2023-10, Vol.139, p.106735-106735, Article 106735
• Main Authors: Ismail, Magda M.F., Shawer, Taghreed Z., Ibrahim, Rabab S., Allam, Rasha M., Ammar, Yousry A.
• Format: Article
• Language: English
• Subjects: Angiogenesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Cell Proliferation; Design; Doxorubicin - pharmacology; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular modeling; Molecular Structure; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Quinoxaline; Quinoxalines - pharmacology; Structure-Activity Relationship; Synthesis; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; VEGFR-2
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106735

[Display omitted] •Cytotoxicity of seventeen new quinoxaline derivatives was evaluated against MCF-7 and HCT-116 by MTT assay.•VEGFR2 kinase inhibitory activity and anti-angiogenic potential were evaluated for the most active hits.•Apoptosis studies and cell cycle analysis were evaluated for the most active derivative.•Docking of the most active compound in the active site of VEGFR2 kinase enzyme was done.•In silico assessment of all the library was performed. Vascular endothelial growth factor receptor-2 is a dynamic target for therapeutic intervention in various types of cancer. This study was aimed at exploring the VEGFR-2 inhibitory activity of a novel library of quinoxalin-2-one derivatives such as 3-furoquinoxaline carboxamides, 3-pyrazolylquinoxalines, and 3-pyridopyrimidyl-quinoxalines. Among them, 6c, 7a, and 7d-f produced remarkable cytotoxicity against HCT-116 (IC50′s 4.28–9.31 µM) and MCF-7 (IC50′s 3.57–7.57 µM) cell lines using the MTT assay and doxorubicin (DOX) as a reference standard. Interestingly, results of cytotoxicity towards the human fibroblast cell line WI38 revealed that these hits demonstrated higher selectivity indices towards both HCT-116 (SI 8.69–23.19) and MCF-7 (SI 9.48–27.80) than DOX, SI 0.72 and 0.90, respectively. Then, these hits were subjected to a mechanistic study; they showed direct inhibition of VEGFR-2. Impressively, compound 7f displayed 1.2 times the VEGFR-2 inhibitory activity of sorafenib. The antiangiogenic potential of 7f was proved via lowering the level of VEGF-A, than that of control. It as well, exhibited scratch closure percent of 61.8%, compared with 74.5% of control at 48 hrs, indicating the potential anti-migratory effect of the compound 7f. It significantly increased the expression of tumor suppressor gene (p53) on MCF-7 cells by almost 18 folds and upregulated the caspase-3 level by 10.7 folds, compared to the control. Cell cycle analysis revealed cell cycle arrest at G2/M together with a PreG increase which indicated apoptosis induction potential. Annexin V-FITC apoptosis results proposed the two modes of cell death (apoptosis and necrosis) as an inherent mechanism of cytotoxicity of compound 7f. Molecular docking further supported the mechanism showing the affinity of target compounds for VEGFR-2 active site. Moreover, physicochemical and drug-like properties were assessed from the ADME properties.