Pyrazoline derivatives as tubulin polymerization inhibitors with one hit for Vascular Endothelial Growth Factor Receptor 2 inhibition

• Published in: Bioorganic chemistry 2021-09, Vol.114, p.105134, Article 105134
• Main Authors: Yang, Bing, Zhou, Jiahua, Wang, Fa, Hu, Xiao-Wei, Shi, Yujun
• Format: Article
• Language: English
• Subjects: Anti-tumor; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Dual inhibition; Humans; Mitotic catastrophe; Molecular Structure; Polymerization - drug effects; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazoline; Structure-Activity Relationship; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tubulin polymerization inhibitor; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105134

[Display omitted] •A novel series of pyrazoline derivatives developed as tubulin polymerization inhibitors.•Structurally design to check the possibility of the transposition.•The top hit 3q showed inhibitory activity for both tubulin and VEGFR2.•The docking simulation visualized the possible binding patterns of 3q into tubulin and VEGFR2. In this work, to check the effect of the transposition of the rings in typical patterns, a series of pyrazoline derivatives 3a-3t bearing the characteristic 3,4,5-trimethoxy phenyl and thiophene moieties were synthesized and evaluated as tubulin polymerization inhibitors. Basically, as the concise output of our design, a majority of the synthesized compounds showed potency in inhibiting the tubulin polymerization. The top hit, 3q, exhibited potent anti-proliferation activity on cancer cell lines. It was comparable on tubulin-polymerization inhibition with the positive control Colchicine but lower toxic. The VEGFR2 inhibitory potency was introduced occasionally. The flow cytometry assay confirmed the apoptotic procedure and the confocal imaging revealed the tubulin-microtubule dynamics pattern. The anti-cancer mechanism of 3q was similar to Colchicine but not exactly the same on forming multi-polar spindles. The docking simulation visualized the possible binding patterns of 3q into tubulin and VEGFR2, respectively. The results inferred that further investigations on the transposition of the rings might lead to the improvement of tubulin polymerization inhibitory activity and the steadily introduction of the VEGFR2 inhibition.