Complexes between fluoroquinolones and calf thymus DNA: binding mode and photochemical reactivity

Abstract

The binding of the highly photocarcinogenic and phototoxic fluoroquinolones (FQs) lomefloxacin (LOM) and enoxacin (ENX) to calf thymus DNA (ct-DNA), as well as the photoreactivity of the FQs-ct-DNA complexes, have been investigated at neutral pH through the combination of several spectroscopic techniques. Both the nature and efficiency of the binding are markedly dependent on the buffer concentration. In 10⁻³ M phosphate buffer the interaction with ct-DNA seems to involve mainly the cationic form of both FQs, which bind to the helix with different efficiency. The overall results are consistent with a binding mode characterized by a close proximity of the chromophores to the DNA bases. An increase of one order of magnitude of the buffer concentration induces a displacement of the molecules from the DNA interior, leading to significant decrease of the association constants. The formation of external complexes involving mainly the zwitterionic forms and characterized by similar binding efficiency for both FQs appears highly probable under these experimental conditions. In this overall scenario, the positively charged piperazinyl ring of both molecules is thought to act as a pivot, going from one binding mode to another. The FQs-DNA complexes reveal a remarkably different photoreactivity. The LOM-ct-DNA complex is characterized by a photodefluorination yield similar to that observed for the free molecule whereas the ENX-ct-DNA complex is basically unphotoreactive. A rationale for these effects is provided. The relation of the overall results to the adverse side reaction photoinduced by these drugs is also commented upon briefly.