New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies.

Publisher: Taylor & Francis Country of Publication: England NLM ID: 101150203 Publication Model: Print Cited Medium: Internet ISSN: 1475-6374 (Electronic) Linking ISSN: 14756366 NLM ISO Abbreviation: J Enzyme Inhib Med Chem Subsets: MEDLINE

Original Publication: Basingstoke, UK : Taylor & Francis, c2002-

Drug Design*; Antineoplastic Agents/*pharmacology ; Apoptosis/*drug effects ; Benzoxazoles/*pharmacology ; Protein Kinase Inhibitors/*pharmacology ; Vascular Endothelial Growth Factor Receptor-2/*antagonists & inhibitors; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Benzoxazoles/chemical synthesis ; Benzoxazoles/chemistry ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Structure-Activity Relationship ; Vascular Endothelial Growth Factor Receptor-2/metabolism

A new series of benzoxazole derivatives were designed and synthesised to have the main essential pharmacophoric features of VEGFR-2 inhibitors. Cytotoxic activities were evaluated for all derivatives against two human cancer cell lines, MCF-7 and HepG2. Also, the effect of the most cytotoxic derivatives on VEGFR-2 protein concentration was assessed by ELISA. Compounds 14o , 14l , and 14b showed the highest activities with VEGFR-2 protein concentrations of 586.3, 636.2, and 705.7 pg/ml, respectively. Additionally, the anti-angiogenic property of compound 14b against human umbilical vascular endothelial cell (HUVEC) was performed using a wound healing migration assay. Compound 14b reduced proliferation and migratory potential of HUVEC cells. Furthermore, compound 14b was subjected to further biological investigations including cell cycle and apoptosis analyses. Compound 14b arrested the HepG2 cell growth at the Pre-G1 phase and induced apoptosis by 16.52%, compared to 0.67% in the control (HepG2) cells. The effect of apoptosis was buttressed by a 4.8-fold increase in caspase-3 level compared to the control cells. Besides, different in silico docking studies were also performed to get better insights into the possible binding mode of the target compounds with VEGFR-2 active sites.

Erratum in: J Enzyme Inhib Med Chem. 2022 Dec;37(1):514. doi: 10.1080/14756366.2022.2024999. (PMID: 34986713)

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Keywords: Anti-proliferative; VEGFR-2 inhibitors; apoptosis; benzoxazole

0 (Antineoplastic Agents)
0 (Benzoxazoles)
0 (Protein Kinase Inhibitors)
EC 2.7.10.1 (KDR protein, human)
EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)

Date Created: 20211228 Date Completed: 20220302 Latest Revision: 20240820

20240820

PMC8725875

10.1080/14756366.2021.2015343

34961427