Hou Ming-Hon, Wang Andrew H-J
Institute of Biological Chemistry, Academia Sinica Taipei, 115 Taiwan.
Nucleic Acids Res. 2005 Mar 1;33(4):1352-61. doi: 10.1093/nar/gki276. Print 2005.
Mith (mithramycin) forms a 2:1 stoichiometry drug-metal complex through the chelation with Fe(II) ion as studied using circular dichroism spectroscopy. The binding affinity between Mith and Fe(II) is much greater than other divalent metal ions, including Mg(II), Zn(II), Co(II), Ni(II) and Mn(II). The [(Mith)2-Fe(II)] complex binds to DNA and induces a conformational change of DNA. Kinetic analysis of surface plasmon resonance studies revealed that the [(Mith)2-Fe(II)] complex binds to DNA duplex with higher affinity compared with the [(Mith)2-Mg(II)] complex. A molecular model of the Mith-DNA-Metal(II) complex is presented. DNA-break assay showed that the [(Mith)2-Fe(II)] complex was capable of promoting the one-strand cleavage of plasmid DNA in the presence of hydrogen peroxide. Intracellular Fe(II) assays and fluorescence microscopy studies using K562 indicated that this dimer complex maintains its structural integrity and permeates into the inside of K562 cells, respectively. The [(Mith)2-Fe(II)] complex exhibited higher cytotoxicity than the drug alone in some cancer cell lines, probably related to its higher DNA-binding and cleavage activity. Evidences obtained in this study suggest that the biological effects caused by the [(Mith)2-Fe(II)] complex may be further explored in the future.
丝裂霉素（mithramycin）通过与Fe(II)离子螯合形成化学计量比为2:1的药物-金属络合物，这是利用圆二色光谱法进行的研究。丝裂霉素与Fe(II)之间的结合亲和力远大于其他二价金属离子，包括Mg(II)、Zn(II)、Co(II)、Ni(II)和Mn(II)。[(丝裂霉素)2-Fe(II)]络合物与DNA结合并诱导DNA构象变化。表面等离子体共振研究的动力学分析表明，[(丝裂霉素)2-Fe(II)]络合物与DNA双链的结合亲和力高于[(丝裂霉素)2-Mg(II)]络合物。本文给出了丝裂霉素-DNA-金属(II)络合物的分子模型。DNA断裂试验表明，[(丝裂霉素)2-Fe(II)]络合物在过氧化氢存在下能够促进质粒DNA的单链切割。使用K562细胞进行的细胞内Fe(II)测定和荧光显微镜研究表明，这种二聚体络合物分别保持其结构完整性并渗透到K562细胞内部。在某些癌细胞系中，[(丝裂霉素)2-Fe(II)]络合物比单独的药物表现出更高的细胞毒性，这可能与其更高的DNA结合和切割活性有关。本研究获得的证据表明，[(丝裂霉素)2-Fe(II)]络合物引起的生物学效应未来可能会得到进一步探索。
Zotero 插件
