Multiple Recognition of DNA by dinuclear platinum complexes with effective cell growth inhibition in cisplatin resistant cell lines

双核铂配合物对 DNA 的多重识别，有效抑制顺铂耐药细胞系的细胞生长

• 批准号: 20590045
• 负责人: CHIKUMA Masahiko
• 金额: $ 3.16万
• 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: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20590045/
• 关键词: 核酸; 抗がん剤; 物理系薬学; 分子認識; 複核白金錯体; 白金錯体; シスプラチン; 複核錯体; 非共有結合性相互作用

Both mechanisms of anti-tumor activity and cellular resistance to platinum complexes are believed to be related with coordination binding mode of platinum complexes with DNA. Polynuclear complexes are expected to interact variously with DNA and to have different mechanism of action from that of mononuclear complexes such as cisplatin, one of the most effective anti-tumor agents. In an attempt to search for more active platinum complexes and to overcome cisplatin resistance, we have developed a dinuclear platinum(II) cation complex, [{cis-Pt(NH_3)_2}_2(μ-pyrazolato) (μ-OH)](NO_3)_2 (AMPZ) and its derivatives using pyrazole analogues as bridging ligands. These platinum complexes were effective to cisplatin-resistant tumor cell lines. AMPZ was found to interact covalently and non-covalently with DNA. In this study we focused to non-covalent binding mode of AMPZ with DNA and investigated with various methods.The non-covalent binding mode of AMPZ with DNA has been found to an electrostatic interaction. It remains to be elucidated whether the anti-tumor activity of AMPZ is attributed to the non-covalent binding of AMPZ with DNA or not.

铂配合物的抗肿瘤活性和细胞耐药机制均与铂配合物与DNA的配位结合方式有关。多核复合物与DNA的相互作用方式多样，作用机制不同于单核复合物，如顺铂，是最有效的抗肿瘤药物之一。为了寻找活性更高的铂配合物和克服顺铂的耐药性，我们合成了一种双核铂（II）阳离子配合物[{cis-Pt（NH_3）_2}_2（μ-pyrazolato）（μ-OH）]（NO_3）_2（AMPZ）及其以吡唑类似物为桥连配体的衍生物。这些铂配合物对顺铂耐药的肿瘤细胞系有效。AMPZ被发现与DNA共价和非共价相互作用。本研究主要针对AMPZ与DNA的非共价结合模式，采用多种方法进行了研究，发现AMPZ与DNA的非共价结合模式为静电作用。AMPZ的抗肿瘤活性是否与DNA的非共价结合有关尚有待进一步研究。

项目成果

アゾラト架橋白金(II)二核錯体とDNAの相互作用様式に関する研究

氮桥铂(II)双核配合物与DNA相互作用模式的研究

• 发表时间: 2011
• 作者: 植村雅子;藤澤豊;飯田靖彦;森井孫俊;桜井弘;千熊正彦;米田誠治
• 通讯作者: 米田誠治

X-ray crystallographic studies on DNA adduct formation by the anticancer-active polynuclear Pt(II)complexes

抗癌活性多核 Pt(II) 配合物形成 DNA 加合物的 X 射线晶体学研究

• 发表时间: 2009
• 作者: Komeda;S.;Odani;A.;Chikuma;M.;Farrell;N.P.;Williams;L.D.
• 通讯作者: L.D.

白金錯体化合物およびその利用

铂络合物及其用途

• 发表时间: 2010

A Tetrazolato-Bridged Dinuclear Platinum(II) Complex Exhibits Markedly High in vivo Antitumor Activity against Pancreatic Cancer

• DOI: 10.1002/cmdc.201100141
• 发表时间: 2011-06-06
• 期刊: CHEMMEDCHEM
• 影响因子: 3.4
• 作者: Komeda, Seiji;Lin, Yuh-Ling;Chikuma, Masahiko
• 通讯作者: Chikuma, Masahiko

制がん活性を有する白金(II)複核錯体と核酸との相互作用

具有抗癌活性的铂(II)双核配合物与核酸之间的相互作用

• 发表时间: 2010
• 作者: 米田誠治;Yuh-Ling Lin;鈴木俊宏;植村雅子;Nicholas P.Farrell;Loren D.Williams;小谷明;千熊正彦
• 通讯作者: 千熊正彦