Komeda Seiji, Yoneyama Hiroki, Uemura Masako, Muramatsu Akira, Okamoto Naoto, Konishi Hiroaki, Takahashi Hiroyuki, Takagi Akimitsu, Fukuda Wakao, Imanaka Tadayuki, Kanbe Toshio, Harusawa Shinya, Yoshikawa Yuko, Yoshikawa Kenichi
Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science , Suzuka, Mie 513-8670, Japan.
Faculty of Pharmaceutical Sciences, Osaka University of Pharmaceutical Sciences , Takatsuki, Osaka 569-1094, Japan.
Inorg Chem. 2017 Jan 17;56(2):802-811. doi: 10.1021/acs.inorgchem.6b02239. Epub 2017 Jan 3.
Derivatives of the highly antitumor-active compound [{cis-Pt(NH)}(μ-OH)(μ-tetrazolato-N2,N3)] (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(NH)}(μ-OH)(μ-5-R-tetrazolato-N2,N3)], where R is (CH)CH and 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.
具有高度抗肿瘤活性的化合物[{顺式-Pt(NH)}(μ-OH)(μ-四唑-N2,N3)]（5-H-Y）是一种四唑桥联双核铂（II）配合物，通过在四唑环的C5位取代直链烷基链部分制备了其衍生物。衍生物的通式为[{顺式-Pt(NH)}(μ-OH)(μ-5-R-四唑-N2,N3)]，其中R为(CH)CH且n = 0至8（配合物1-9）。配合物1-4在NCI-H460人非小细胞肺癌细胞中的细胞毒性随烷基链长度增加而降低，而配合物5-9的细胞毒性随烷基链长度增加而增加。也就是说，发现配合物1-9的体外细胞毒性与烷基链长度呈U形关联。这种U形关联归因于细胞内积累程度。尽管圆二色光谱测量表明配合物1-9在DNA二级结构中诱导了相当的构象变化，但如通过荧光显微镜的单DNA测量所揭示的，四唑桥联配合物诱导了不同程度的DNA压缩，其也与烷基链长度呈U形关联，这与细胞毒性观察到的关联相匹配。配合物7-9具有足够长的烷基链，赋予配合物类似表面活性剂的性质，其诱导DNA压缩的效率比5-H-Y或亚精胺高20倍或1000倍。透射电子显微镜的单DNA测量表明配合物8形成了大的球形自组装结构，其以极高的效率诱导DNA压缩。该结果表明这些结构可能在由具有较长烷基链的配合物诱导的DNA压缩中起作用。用直链烷基链进行衍生化产生了一系列具有独特细胞积累和DNA构象变化谱的配合物，是开发下一代铂基抗癌药物的潜在有用手段。此外，这些配合物诱导DNA压缩的显著高能力及其高细胞内积累强调了其作用机制与铂基抗癌药物的差异。
