Synthesis and biological evaluation of 6-fluoro-3-phenyl-7-piperazinyl quinolone derivatives as potential topoisomerase I inhibitors

• Some of our compounds demonstrate potent Top I inhibitory activity as Camptothecin.
• 18f and 18g show comparable ability as Camptothecin in Top I inhibitory activity and cellular inhibitory activity.
• 18f and 18g impair the cell cycle progression in the s phase.
• 18f and 18g represent more safety compared with hydroxycamptothecin.

The design and synthesis of a new series of 6-fluoro-3-phenyl-7-piperazinyl quinolone derivatives, built on the structure of 1-ethyl-3-(6-nitrobenzoxazol-2-yl)-6,8-difluoro-7-(3-methylpiperazin-1-yl)-4(1H)-quinolone, are described. These compounds provide new scaffold for the discovery of Topoisomerase I (Top I) inhibitors and target based assay showed that they can obviously inhibited Top I at 100 μM. The in vitro anti-proliferative activity of these new compounds was evaluated against A549, Hela, BGC-823, and HepG2 cell lines. Compounds 18a-g showed potent inhibitory activity against the growth of those cancer cell lines. The most positive compounds 18f and 18g demonstrated as potent as camptothecin in Top I inhibition assay and MTT assay. Compounds 18f and 18g led to an obvious increase in the percentage of S phase of the cells in 24 h. The in vivo data showed that 18f and 18g inhibited tumor growth with the inhibitory rate of 29.25% and 42.75% at 20 mg/kg, respectively. The data suggested the therapeutic potential for further development.

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