Second- and higher-order structural changes of DNA induced by antitumor-active tetrazolato-bridged dinuclear platinum(II) complexes with different types of 5-substituent

Abstract

Here, we used circular dichroism (CD) and fluorescence microscopy (FM) to examine the interactions of a series of antitumor-active tetrazolato-bridged dinuclear platinum(II) complexes, [{cis-Pt(NH3)2}2(μ-OH)(μ-5-R-tetrazolato-N2,N3)]n+ (R=CH3 (1), C6H5 (2), CH2COOCH2CH3 (3), CH2COO− (4), n=2 (1–3) or 1 (4)), which are derivatives of [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)]2+ (5-H-Y), with DNA to elucidate the influence of these interactions on the secondary or higher-order structure of DNA and reveal the mechanism of action. The CD study showed that three derivatives, 1–3, with a double-positive charge altered the secondary structures of calf thymus DNA but that 4, the only complex with a single positive charge, induced almost no change, implying that the B- to C-form conformational change is influenced by ionic attraction. Unexpectedly, single-molecule observations with FM revealed that 4 changed the higher-order structure of T4 DNA into the compact-globule state most efficiently, at the lowest concentration, which was nearly equal to that of 5-H-Y. These contradictory results suggest that secondary structural changes are not necessarily linked to higher-order ones, and that the non-coordinative interaction could be divided into two distinct interactions: (1) ionic attraction and (2) hydrogen bonding and/or van der Waals contact. The relationship between diffusion-controlled non-coordinative DNA interactions and cytotoxicities is also discussed.