Binding of Cu(II) complexes of oxicam NSAIDs to alternating AT and homopolymeric AT sequences: differential response to variation in backbone structure

Abstract

Besides their principal functions as painkillers and anti-inflammatory agents, drugs belonging to the nonsteroidal anti-inflammatory drug (NSAID) group also have anticancer properties. Cu(II) complexes of these drugs enhance the anticancer effect. How they exert this effect is not clear. As a possible molecular mechanism, our group has already shown that the Cu(II) complexes of two oxicam NSAIDs with anticancer properties, viz. piroxicam and meloxicam, can directly bind to the DNA backbone. AT stretches are abundant in the eukaryotic genome. These stretches are more accessible to binding of different ligands, resulting in expression of different functions. AT stretches containing both alternating base pairs and homopolymeric bases in individual strands show subtle differences in backbone structures. It is therefore of interest to see how the Cu(II)–NSAID complexes respond to such differences in backbone structure. Binding studies of these complexes with alternating polydA–dT and homopolymeric polydA–polydT have been conducted using UV–vis absorption titration studies, UV melting studies and circular dichroism spectroscopy. Competitive binding with the standard intercalator ethidium bromide and the minor groove binder 4′,6-diamidino-2-phenylindole was monitored using fluorescence to identify the possible binding mode. Our results show that Cu(II)–NSAID complexes are highly sensitive to the subtle differences in backbone structures of polydA–dT and polydA–polydT and respond to them by exhibiting different binding properties, such as binding constants, effect on duplex stability and binding modes. Both complexes have a similar binding mode with polydA–dT, which is intercalative, but for polydA–polydT, the results point to a mixed mode of binding.