title: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka 513-8670, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Uemura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Takaji
authors.initials: T
authors.lastname: Sato
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Mino
authors.forename: Masahiko
authors.initials: M
authors.lastname: Chikuma
authors.forename: Seiji
authors.initials: S
authors.lastname: Komeda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D010984:Platinum / Q000737:chemistry*; D013777:Tetrazoles / Q000737:chemistry* / Q000494:pharmacology; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D013777:Tetrazoles; D014867:Water; D010984:Platinum; D004247:DNA; C427203:calf thymus DNA
keywords: Cancer; Circular dichroism; DNA interaction; Dinuclear Pt complexes; Fluorescence microscopy; Tetrazole