Interaction of new dinuclear platinum complexes effective to cisplatin-resistant tumor cell lines with DNA.

对顺铂耐药肿瘤细胞系有效的新型双核铂配合物与 DNA 的相互作用。

• 批准号: 13672265
• 负责人: CHIKUMA Masahiko
• 金额: $ 2.3万
• 依托单位: Osaka University of Pharmaceutical Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672265/
• 关键词: cisplatin; platinum complexes; dinuclear complexes; electrostatic interaction; DNA; drug resistance; antitumor agents; apoptosis; 金属錯体; 核酸塩基

Cisplatin is one of the most widely used anticancer agents. A current challenge in platinum bioinorganic chemistry is to design effective anticancer agents overcoming cisplatin resistance, based on the detailed knowledge of apoptosis attributable to DNA lesion by platinum binding. The purpose of this research project is to elucidate the differences of the interaction mode of some new dinuclear platinum complexes and that of cisplatin.The following results have been obtained.(1)New dinuclear platinum complexes with hydroxo-and pyrazolato-bridges were prepared and they induced apoptosis in the wild-type L 1210 and its cisplatin resistant cell lines.(2)Proton-assist square-planar platinum(II) substitution reaction in the dinuclear complexes was analyzed kinetically in the presence of sodium chloride.(3)Uptake of platinum atom by tumor cells was investigated by atomic absorption spectrometry, and intracellular platinum level was higher in the dinuclear complexes than in cisplatin.(4)Since the dinuclear complexes showed not only coordination binding with DNA but also non-covalent interactions, the DNA binding mode of dinuclear complexes is different from that of cisplatin. Effectiveness of the dinuclear complexes to the cisplatin resistant tumor cells seems to be attributed to this different binding mode with DNA.This research promises to lead to the development of new generation of anticancer agents overcoming cisplatin resistance.

顺铂是使用最广泛的抗癌药之一。铂生物有机化学的当前挑战是设计有效克服顺铂耐药性的有效抗癌药，基于铂结合归因于DNA病变的细胞凋亡的详细知识。该研究项目的目的是阐明某些新的双核铂络合物和顺铂的相互作用模式的差异。（1）制备了羟基和吡az骨和吡az骨的新核铂综合体。在存在氯化钠的情况下，在动力学上分析了在双核复合物中的平面 - 平面铂（II）。（3）通过肿瘤细胞吸收铂原子，通过原子吸收光谱法受到原子的吸收光谱法的含量，并且仅在二核素中均与二核复合物相比，在二核铂中的结合均高（4）。但也非共价相互作用，双核复合物的DNA结合模式与顺铂不同。双核复合物对顺铂抗性肿瘤细胞的有效性似乎归因于这种不同的结合模式。这项研究有望导致新一代抗癌剂克服了顺铂的耐药性。

项目成果

Seiji Komeda, Ganna V.Kalayda, Martin Lutz, Anthony L.Spek, Yasuyuki Yamanaka, Takaji Sato, Masahiko Chikuma, Jan Reedijk: "New isomeric azine-bridged dinuclear platinum(II) complexes circumvent cross-resistance to cisplatin."J.Med.Chem.. 46(7). 1210-1219

Seiji Komeda、Ganna V.Kalayda、Martin Lutz、Anthony L.Spek、Yasuyuki Yamanaka、Takaji Sato、Masahiko Chikuma、Jan Reedijk：“新型异构吖嗪桥双核铂 (II) 配合物可避免对顺铂的交叉耐药性。”

Ganna V.Kalayda: "Synthesis, structure and biological activity of azine-bridged dinuclear platinum (II) complexes-A new lass of anticancer compounds."Euro.J.Inorg.Chem.. 2003. 4347-4355 (2003)

Ganna V.Kalayda：“吖嗪桥双核铂 (II) 配合物的合成、结构和生物活性——一类新的抗癌化合物。”Euro.J.Inorg.Chem.. 2003. 4347-4355 (2003)

Seiji Komeda: "A novel isomerization on interaction of antitumor-active azole-bridged dinuclear platinum(II) complexes with 9-ethylguanine. Platinum(II) atom migration from N2 to N3 on 1,2,3-triazole"Journal of American Chemical Society. 124(accepted)(Web

Seiji Komeda：“抗肿瘤活性唑桥双核铂 (II) 配合物与 9-乙基鸟嘌呤相互作用的新型异构化。铂 (II) 原子在 1,2,3-三唑上从 N2 迁移到 N3”美国化学杂志

Masahiko Chikuma: "Preparation and characterization of a sulfonated dibenzoylmethane immobilized anion-exchange resin"Analytical Sciences. 17・Suppl.. 713-715 (2001)

Masahiko Chikuma：“磺化二苯甲酰甲烷固定化阴离子交换树脂的制备和表征”Analytical Sciences 17・Suppl.. 713-715 (2001)

Seiji Komeda: "A novel isomerization on interaction of antitumor-active azole-bridges dinuclear platinum(II) complexes with 9-etylguanine. Platinum(II) atom migration from N2 to N3 on 1,2,3-triazole"Journal of American Chemical Society. 124・17. 4738-4746

Seiji Komeda：“抗肿瘤活性唑桥双核铂 (II) 配合物与 9-乙基鸟嘌呤相互作用的新型异构化。铂 (II) 原子在 1,2,3-三唑上从 N2 迁移到 N3”美国化学杂志社会124・17。