Selectivity Activity against Mammalian Topoisomerase ii and Genetic Toxicity

Selectivity for DNA gyrase and topoisomerase IV over the related mammalian enzyme topoisomerase II is of course desirable for antibacterial therapy with quinolones. In the course of selectivity testing of the many quinolones synthesized to date, a number have been found to exhibit potent activity versus the mammalian enzyme; the potential for use of quinolone agents of this type as anticancer agents has been reviewed [127-129]. Certain structural features, most particularly those at N-1, C-7, and the 8-position, have been shown to increase activity versus topoisomerase II, which correlates with an increase in mammalian cytotoxicity and the potential for genetic toxicity [29]. In a general sense, molecular modifications that yield substantially heightened Gram-positive potency can also result in decreased selectivity for the gyrase enzyme [29]. Thus, C-7 pyrrolidines tend to show increased cytotoxicity over piperazines. Even more notable are the N-1 cyclopropyl and C-8 fluorine-, chlorine-, or methoxy-substituted quinolones. A number of studies [21] have shown that this pattern results in heightened cytotoxicity.

In several of the quinolones that have been developed, further structural manipulation has abrogated these structural tendencies, such that selective agents are generated despite the presence of the 8-substituted N-1 cyclopropyl pattern. In sparfloxacin, the two methyl groups on the piperazine ring are critical in this regard. Although sparfloxacin itself is inactive versus topoisomerase II, removal of both methyl groups results in a compound that is very potent against this enzyme. Interestingly, the cis stereochemistry of the methyl groups is also important: the trans isomer, where the methyl groups are on opposite sides of the piperazine ring, does interact with topoisomerase II [130]. The antibacterial activity of the trans dimethyl isomer, however, is unchanged from that of sparfloxacin itself [35].

In the case of sitafloxacin, modification of the N-1 cyclopropane was used in similar fashion. The analogue of sitafloxacin that bears an unsubsti-tuted cyclopropane at N-1 exhibited clastogenicity and was active against topoisomerase II. Sitafloxacin, however, displays an IC50 of >1600 |g/ml versus topoisomerase II and displays less than one-tenth the clastogenic activity of the des-fluoro analogue [131,132]. When examined against three stereoisomers bearing enantiomeric aminopyrrolidines and/or N-1 cyclopropanes, sitaflox-acin proved to be the least active against human placental topoisomerase II by as much as twofold [27]. Advancement of pazufloxacin into development was supported by its low cytotoxicity and minimal activity against topoisomerase II [133].

Thirteen marketed or late-stage quinolones that span all four generations were examined against both bacterial and mammalian topoisomerases. A good correlation was found between IC50s for inhibition of S. aureus topoisomerase IV and inhibition of E. coli DNA gyrase. Importantly, neither of the bacterial enzyme activities correlated with activity against HeLa cell topoisomerase II [28].

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