Novel 1-8-bridged chiral quinolones with activity against topoisomerase II: stereospecificity of the eukaryotic enzyme.
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.
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
S J
SJ
Froelich-Ammon
P R
PR
McGuirk
T D
TD
Gootz
M R
MR
Jefson
N
N
Osheroff
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004331:Drosophila melanogaster; D004926:Escherichia coli / Q000201:enzymology; D005057:Eukaryotic Cells / Q000201:enzymology; D015242:Ofloxacin / Q000031:analogs & derivatives / Q000138:chemical synthesis; D015363:Quinolones / Q000494:pharmacology*; D013237:Stereoisomerism; D059005:Topoisomerase II Inhibitors
D015363:Quinolones; D059005:Topoisomerase II Inhibitors; D004247:DNA; D015242:Ofloxacin