Effects of novel fluoroquinolones on the catalytic activities of eukaryotic topoisomerase II: Influence of the C-8 fluorine group.
A previous study (M.J. Robinson, B.A. Martin, T.D. Gootz, P.R. McGuirk, M. Moynihan, J.A. Sutcliffe, and N. Osheroff, J. Biol. Chem. 266:14585-14592, 1991) demonstrated that novel 6,8-difluoroquinolones were potent effectors of eukaryotic topoisomerase II. To determine the contribution of the C-8 fluorine to drug potency, we compared the effects of CP-115,955 [6-fluoro-7-(4-hydroxyphenyl)-1-cyclopropyl-4-quinolone-3-carboxylic acid] on the enzymatic activities of Drosophila melanogaster topoisomerase II with those of CP-115,953 (the 6,8-difluoro parent compound of CP-115,955). Removal of the C-8 fluoro group decreased the ability of the quinolone to enhance enzyme-mediated DNA cleavage approximately 2.5-fold. Like its difluorinated counterpart, CP-115,955 increased the levels of cleavage intermediates without impairing the DNA religation reaction of the enzyme. Removal of the C-8 fluorine reduced the ability of the quinolone to inhibit topoisomerase II-catalyzed DNA relaxation. In addition, the cytotoxicity of CP-115,955 towards Chinese hamster ovary cells was decreased compared with that of CP-115,953. These results demonstrate that the C-8 fluorine increases the potency of quinolone derivatives against eukaryotic topoisomerase II and mammalian cells. Further comparisons of CP-115,955 with CP-115,953 and CP-67,804 (the N-1 ethyl-substituted derivative of the difluoro parent compound) indicate that the two intrinsic activities of quinolone-based drugs towards topoisomerase II (i.e., enhancement of DNA cleavage and inhibition of catalytic strand passage) can be differentially influenced by alteration of ring substituents. Finally, correlations between the biochemical and cytological activities of these drugs suggest that the ability to inhibit catalytic strand passage enhances the cytotoxic potential of quinolones towards eukaryotic cells.
Robinson
M J
MJ
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146.
Martin
B A
BA
Gootz
T D
TD
McGuirk
P R
PR
Osheroff
N
N
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D004247:DNA / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000235:genetics; D004587:Electrophoresis, Agar Gel; D024841:Fluoroquinolones; D066298:In Vitro Techniques; D015363:Quinolones / Q000494:pharmacology*
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D015363:Quinolones; C070116:CP 115953; C076132:CP 115955; D004247:DNA; D004250:DNA Topoisomerases, Type II