Design, synthesis, and biological evaluation of novel ciprofloxacin derivatives as potential anticancer agents targeting topoisomerase II enzyme.

A series of novel ciprofloxacin (CP) derivatives substituted at the N-4 position with biologically active moieties were designed and synthesised. 14 compounds were 1.02- to 8.66-fold more potent than doxorubicin against T-24 cancer cells. Ten compounds were 1.2- to 7.1-fold more potent than doxorubicin against PC-3 cancer cells. The most potent compounds , , , , , and showed significant Topo II inhibitory activity (83-90% at 100 μM concentration). Compounds , , and were 1.01- to 2.32-fold more potent than doxorubicin. Compounds and induced apoptosis in T-24 (16.8- and 20.1-fold, respectively compared to control). This evidence was supported by an increase in the level of apoptotic caspase-3 (5.23- and 7.6-fold, sequentially). Both compounds arrested the cell cycle in the S phase in T-24 cancer cells while in PC-3 cancer cells the two compounds arrested the cell cycle in the G1 phase. Molecular docking simulations of compounds and into the Topo II active site rationalised their remarkable Topo II inhibitory activity.