靶向富集细胞核的环金属化钌配合物合成及其抗肿瘤机制研究

DNA is an important material of organisms. It not only plays an important role in the normal life activities such as biological growth, development and reproduction, but also is closly related with the exception of life such as cancer, and has been one of the excellent targets in anticancer drugs development. This project is constructing cyclometalated Ru complexes that target the cell nucleus; Combined with the spectroscopy, biochemistry, biophysics and molecular biology, we will study the specific form and acting way of DNA damage caused by ruthenium complexes as transcription inhibitors. From the cell level, the DNA damage of signal transduction, and the relationship between the activation of cancer cells signal regulating apoptosis kinase and downstream events will be investigated, the relationship between the ruthenium complexes inhibit transcription, damage DNA and induce the apoptosis will be discussed, and the chemical small molecular probe with specific regulation function to the action of relevant signal molecules will be looked for. For those ruthenium complexes with obvious tumor proliferation inhibitory activity in naked mice animal model experiment, we will evaluate their drugs effectiveness from living level. We hope the results to be of value in further setting up the new metal complexes drug design thought, as well as looking for high efficiency, low toxicity of a new generation of inorganic cancer drugs.

DNA是生物体的重要组成物质。不仅在生物的生长，发育和繁殖等正常生命活动中起着重要的作用，与致癌等生命的异常情况也密切相关，是抗肿瘤药物研究的一个重要靶标。本项目拟通过环金属化结构修饰，构建靶向富集细胞核的钌配合物。结合波谱学、生物化学、生物物理和分子生物学方法，研究钌配合物抑制转录而引起DNA损伤的具体形式和作用途径等；从细胞水平上研究DNA损伤信号的转导、对肿瘤细胞中凋亡信号调节激酶的激活及下游事件的关系，探讨钌配合物抑制转录、损伤DNA并诱导细胞凋亡的作用机制，寻找对相关信号分子有特异性调控作用的化学小分子探针；对有明显抑制肿瘤增殖作用的钌配合物开展裸鼠动物模型实验，从活体水平上评价其药物有效性。这方面的研究对建立新的金属配合物药物设计思想，寻找高效、低毒的新一代无机抗癌药物有着重要意义。

DNA是生物体的重要组成物质。不仅在生物的生长，发育和繁殖等正常生命活动中起着重要的作用，与致癌等生命的异常情况也密切相关，是抗肿瘤药物研究的一个重要靶标。本项目通过环金属化结构修饰，构建靶向富集细胞核的钌配合物。结合波谱学、生物化学、生物物理和分子生物学方法，研究钌配合物抑制转录而引起DNA损伤的具体形式和作用途径等；从细胞水平上研究DNA损伤信号的转导、对肿瘤细胞中凋亡信号调节激酶的激活及下游事件的关系，探讨钌配合物抑制转录、损伤DNA并诱导细胞凋亡的作用机制，寻找对相关信号分子有特异性调控作用的化学小分子探针；对有明显抑制肿瘤增殖作用的钌配合物开展裸鼠动物模型实验，从活体水平上评价其药物有效性。累计发表SCI论文58篇，所有论文中主持者均为通讯者；申请中国发明专利2项。