DNA conformation and repair of polymeric natural DNA damaged by antitumor azolato-bridged dinuclear PtII complex

Design of new antitumor Pt drugs is currently also focused on those new Pt complexes which form on DNA major adducts that can hardly be removed by DNA repair systems. An attempt of this kind has already been done by designing and synthesizing new antitumor azolato-bridged dinuclear PtII complexes, such as [{cis-Pt(NH3)2}2(μ-OH)(μ-pyrazolate)]2+ (AMPZ). This new PtII complex exhibits markedly higher toxic effects in some tumor cell lines than conventional mononuclear cisplatin. The primary objective in the present study was to further delineate differences in the interactions of AMPZ and cisplatin with natural, high-molecular-mass DNA using a combination of biochemical and molecular biophysics techniques. The results demonstrate for the first time that little conformational distortions induced by AMPZ in highly polymeric DNA with a random nucleotide sequence represent a structural motif recognizable by DNA repair systems less efficiently than distortions induced by cisplatin. Thus, DNA adducts of azolato-bridged dinuclear PtII complexes can escape repair mechanisms more easily than those of cisplatin, which may potentiate antitumor effects of these new metallodrugs in cancer cells.

The results demonstrate for the first time that little conformational distortions induced by an antitumor azolato-bridged dinuclear PtII complex, [{cis-Pt(NH3)2}2(μ-OH)(μ-pyrazolate)]2+, in highly polymeric DNA with a random nucleotide sequence represent structural motif recognizable by DNA repair systems less efficiently than distortions induced by cisplatin.Figure optionsDownload as PowerPoint slideHighlights
► Biophysical and biochemical characterization of natural DNA modified by azolato-bridged dinuclear PtII complex.
► Azolato-bridged dinuclear PtII complex distorts natural DNA only weakly.
► DNA adducts produced by this PtII complex are poor substrates for DNA repair.
► This potentiates toxic effects of this new generation metallodrug in cancer cells.