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Novel 1-8-bridged chiral quinolones with activity against topoisomerase II: stereospecificity of the eukaryotic enzyme.

Froelich-Ammon SJ, McGuirk PR, Gootz TD, Jefson MR, Osheroff N
Antimicrob Agents Chemother. 1993 37 (4): 646-51

PMID: 8388196 · PMCID: PMC187729 · DOI:10.1128/aac.37.4.646

A series of novel C-7 quinolyl-substituted enantiomers of ofloxacin were used to determine the stereospecificity of topoisomerase II for the C-11 methyl group in tricyclic quinolones. In all cases, the S isomer was the most active compound against the eukaryotic enzyme. It was approximately 2.2-fold more potent than the R isomer at inhibiting the overall catalytic activity of topoisomerase II (as monitored by DNA relaxation assays). A markedly greater difference in quinolone activity was observed in enzyme-mediated DNA cleavage reactions. While the S enantiomer stimulated nucleic acid breakage approximately 3.5-fold, the R compound did not enhance and, in fact, decreased initial DNA cleavage levels by approximately 50%. The activity of the racemic mixture more closely resembled that of the R enantiomer. In competition experiments, the DNA cleavage-enhancing effects of the S isomer were attenuated by the R compound. Taken together, these latter results indicate that the R enantiomer is an antagonist of S isomer-promoted topoisomerase II-mediated DNA cleavage. Finally, the cytotoxic potential of quinolyl-substituted ofloxacin analogs correlated with the ability to stimulate enzyme-mediated DNA cleavage. Thus, stereochemistry appears to be a governing factor for the potential development of tricyclic quinolones as topoisomerase II-targeted drugs with antineoplastic activity.

MeSH Terms (11)

Animals Cells, Cultured Cell Survival DNA Drosophila melanogaster Escherichia coli Eukaryotic Cells Ofloxacin Quinolones Stereoisomerism Topoisomerase II Inhibitors

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