PLACEMENT OF ALKYL SUBSTITUENTS ON THE C-7 PIPERAZINE RING OF FLUOROQUINOLONES - DRAMATIC DIFFERENTIAL-EFFECTS ON MAMMALIAN TOPOISOMERASE-II AND DNA GYRASE

Several substituted analogs of hylpiperazinyl)-6,8-difluoro-5-amino-1- cyclopropyl quinolone were prepared and tested in a DNA cleavage assay with calf thymus topoisomerase II. Positioning of the methyl groups o n the C-7 piperazine ring influenced potency against the mammalian enz yme; the cis-3,5-dimethyl configuration did not stimulate cleavage at drug concentrations less than or equal to 2,000 muM, while the trans c onfiguration was active at drug levels as low as 36 muM. Removal of th e cis-methyl groups produced a compound that was only sixfold less pot ent than the antitumor agent etoposide in stimulating enzyme-mediated DNA cleavage. The cis- and trans-methyl substitutions on the piperazin e that conferred potency against the mammalian type II enzyme had litt le effect on bacterial DNA gyrase cleavage activity, suggesting that a n asymmetric barrier exists with the mammalian enzyme which influences productive quinolone interaction, favoring the less bulky trans-3,5-d imethylpiperazine substituent at C-7.