New series of fluoroquinolone derivatives as potential anticancer Agents: Design, Synthesis, in vitro biological Evaluation, and Topoisomerase II Inhibition

Abstract

A series of fluoroquinolone analogs (II, IIIa-g) derived from Ciprofloxacin hydrazide were designed, and synthesized. The NCI-60 Human Tumor Cell Line Screening assay indicated that compounds II, IIIb, and IIIf are the most potent among the series and were further selected for five-dose evaluation, where they exhibited potent cytotoxicity with mean GI50 values of 3.30, 2.45, and 9.06 µM, respectively, where they reduced the cell proliferation of most of the tested cell lines with IC50 values significantly lower than the reference drug Etoposide. A selectivity study demonstrated the high selective cytotoxicity of IIIf towards cancerous cells over normal mammalian Vero cells, presenting it as a potent and selective antitumor agent. Cell cycle analysis revealed that treatment with II, IIIb, or IIIf induced cell cycle arrest at the G2/M phase in MCF-7 cells. Topoisomerase II enzyme inhibition assay showed that the three tested compounds are potent topo II inhibitors where compound II (IC50 = 51.66 µM) displayed more potent inhibitory activity compared to the well-known topo II inhibitor Etoposide (IC50 = 58.96 µM), while compounds IIIb and IIIf showed comparable activity to the reference drug. Molecular modeling study suggested that the topoisomerase inhibitory activity may be attributed to the binding to the Merbarone binding site and chelation with Mg2+