Design, synthesis and bioevaluation of 2,7-diaryl-pyrazolo[1,5-a]pyrimidines as tubulin polymerization inhibitors

Two series of 2,7-diaryl-pyrazolo[1,5-a]pyrimidines as tubulin polymerization inhibitors were designed to restrict bioactive configuration of (E,Z)-vinylogous CA-4. All of the target compounds were synthesized and then evaluated for their in vitro antiproliferative activities against three cancer cell lines (MCF-7, SGC-7901 and A549). Among them, 6d exhibited the most potent antiproliferative activity against the MCF-7 with IC50 value of 0.047 mu M. Moreover, 6d significantly inhibited tubulin polymerization, disrupted microtubule networks, arrested cell cycle at G2/M phase, induced apoptosis and hindered cancer cell migration. Colchicine competition assay and molecular docking studies suggested that 6d could interact with tubulin by binding to the colchicine site.

Automated summary

The newly designed compound 6d showed significant antiproliferative activity against MCF-7 cancer cells, inhibiting cancer cell growth and migration through multiple pathways.