DNA-BINDING STUDIES AND INFLUENCE ON THE ACTIVITY OF DNA TOPOISOMERASES OF BIS-NETROPSINS - DIFFERENT EFFECTS OF ANALOGS CONTAINING CIS ANDTRANS ETHYLENE LINKERS

Binding to DNA and synthetic duplex polymers of two bifunctional netro psins and effects on supercoiled plasmid DNA as well as their inhibito ry potency on DNA topoisomerases have been investigated. Characteristi c differences were found in the DNA binding properties of the two bis- netropsins containing a cis and trans tether as reflected by CD, therm al melting and sedimentation measurements. CD results indicate, that t he bis-netropsins interact with DNA by a two-step binding mode dependi ng on the ligand concentration. The trans bis-netropsin may form stabl e complexes with different DNA's at high salt concentration, whereas f or cis bis-netropsin DNA complexes the second binding step is complete ly abolished. The variations in the DNA binding ability of trans and c is bis-netropsin show a close relationship to the differences observed in their inhibitory effects on DNA topoisomerases. It appeared that t rans bis-netropsin more strongly blocks topoisomerase activity than th e cis isomer and represents the most potent inhibitor of DNA gyrase. D ifferences in the DNA binding ability of the bis-netropsins and their inhibitory potency on topoisomerase activity are explained in terms of a bidentate and monodentate binding mode of the trans and cis isomer, respectively.