title: Specific Conformational Change in Giant DNA Caused by Anticancer Tetrazolato-Bridged Dinuclear Platinum(II) Complexes: Middle-Length Alkyl Substituents Exhibit Minimum Effect.
abstract: Derivatives of the highly antitumor-active compound [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)]2+(5-H-Y), which is a tetrazolato-bridged dinuclear platinum(II) complex, were prepared by substituting a linear alkyl chain moiety at C5 of the tetrazolate ring. The general formula for the derivatives is [{cis-Pt(NH3)2}2(μ-OH)(μ-5-R-tetrazolato-N2,N3)]2+, where R is (CH2)nCH3and n = 0 to 8 (complexes 1-9). The cytotoxicity of complexes 1-4 in NCI-H460 human non-small-cell lung cancer cells decreased with increasing alkyl chain length, and those of complexes 5-9 increased with increasing alkyl chain length. That is, the in vitro cytotoxicity of complexes 1-9 was found to have a U-shaped association with alkyl chain length. This U-shaped association is attributable to the degree of intracellular accumulation. Although circular dichroism spectroscopic measurement indicated that complexes 1-9 induced comparable conformational changes in the secondary structure of DNA, the tetrazolato-bridged complexes induced different degrees of DNA compaction as revealed by a single DNA measurement with fluorescence microsopy, which also had a U-shaped association with alkyl chain length that matched the association observed for cytotoxicity. Complexes 7-9, which had alkyl chains long enough to confer surfactant-like properties to the complex, induced DNA compaction 20 or 1000 times more efficiently than 5-H-Y or spermidine. A single DNA measurement with transmission electron microscopy revealed that complex 8 formed large spherical self-assembled structures that induced DNA compaction with extremely high efficiency. This result suggests that these structures may play a role in the DNA compaction that was induced by the complexes with the longer alkyl chains. The derivatization with a linear alkyl chain produced a series of complexes with unique cellular accumulation and DNA conformational change profiles and a potentially useful means of developing next-generation platinum-based anticancer drugs. In addition, the markedly high ability of these complexes to induce DNA compaction and their high intracellular accumulation emphasized the difference in mechanism of action from platinum-based anticancer drugs.
authors.affiliation: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science , Suzuka, Mie 513-8670, Japan.
authors.forename: Seiji
authors.identifier: http://orcid.org/0000-0001-5532-3251
authors.initials: S
authors.lastname: Komeda
authors.affiliation: Faculty of Pharmaceutical Sciences, Osaka University of Pharmaceutical Sciences , Takatsuki, Osaka 569-1094, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoneyama
authors.affiliation: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science , Suzuka, Mie 513-8670, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Uemura
authors.affiliation: Faculty of Life and Medical Sciences, Doshisha University , Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Muramatsu
authors.affiliation: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science , Suzuka, Mie 513-8670, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: Yakult Central Institute , Yakult Honsha Co., Ltd., Kunitachi, Tokyo 186-8650, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Konishi
authors.affiliation: Pharmaceutical Research and Development Department, Yakult Honsha Co., Ltd. , Chuo, Tokyo 104-0061, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Yakult Central Institute , Yakult Honsha Co., Ltd., Kunitachi, Tokyo 186-8650, Japan.
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Takagi
authors.affiliation: Department of Biotechnology, College of Life Sciences, Ritsumeikan University , Kusatsu, Shiga 525-8577, Japan.
authors.forename: Wakao
authors.initials: W
authors.lastname: Fukuda
authors.affiliation: Department of Biotechnology, College of Life Sciences, Ritsumeikan University , Kusatsu, Shiga 525-8577, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Imanaka
authors.affiliation: Laboratory of Medical Mycology, Research Institute for Disease Mechanism and Control, School of Medicine, Nagoya University , Nagoya 464-0064, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kanbe
authors.affiliation: Faculty of Pharmaceutical Sciences, Osaka University of Pharmaceutical Sciences , Takatsuki, Osaka 569-1094, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Harusawa
authors.affiliation: Faculty of Life and Medical Sciences, Doshisha University , Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yoshikawa
authors.affiliation: Faculty of Life and Medical Sciences, Doshisha University , Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Kenichi
authors.identifier: http://orcid.org/0000-0002-2751-7136
authors.initials: K
authors.lastname: Yoshikawa
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013095:Spermidine / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D013501:Surface-Active Agents; D013777:Tetrazoles; D004247:DNA; D002945:Cisplatin; D013095:Spermidine