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

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.

Automated summary

In this study, a series of pyrazoline derivatives bearing 3,4,5-trimethoxy phenyl and thiophene moieties were synthesized and evaluated as tubulin polymerization inhibitors. The top hit compound, 3q, showed potent anti-proliferation activity on cancer cell lines and comparable efficacy with less toxicity than the positive control Colchicine. Further investigations indicated the potential for improving tubulin polymerization inhibition and introducing VEGFR2 inhibition through ring transposition.