When the ‘CO-releasing molecule-3’, CORM-3 (Ru(CO)3Cl(glycinate)), is dissolved in water it forms a range of ruthenium complexes. These are taken up by cells and bind to intracellular ligands, notably thiols such as cysteine and glutathione, where the Ru(II) reaches high intracellular concentrations. Here, we show that the Ru(II) ion also binds to DNA, at exposed guanosine N7 positions. It therefore has a similar cellular target to the anticancer drug cisplatin, but not identical, because Ru(II) shows no evidence of forming intramolecular crossbridges in the DNA. The reaction is slow, and with excess Ru, intermolecular DNA crossbridges are formed. The addition of CORM-3 to human colorectal cancer cells leads to strand breaks in the DNA, as assessed by the alkaline comet assay. DNA damage is inhibited by growth media containing amino acids, which bind to extracellular Ru and prevent its entry into cells. We conclude that the cytotoxicity of Ru(II) is different from that of platinum, making it a promising development target for cancer therapeutics.

中文翻译：

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CORM-3 通过与 DNA 结合的 Ru(II) 诱导 DNA 损伤

当“释放 CO 的分子 3”、CORM-3 (Ru(CO)3Cl(甘氨酸盐)) 溶解在水中时，它会形成一系列钌络合物。这些被细胞吸收并与细胞内配体结合，特别是硫醇，如半胱氨酸和谷胱甘肽，其中 Ru(II) 达到高细胞内浓度。在这里，我们展示了 Ru(II) 离子也在暴露的鸟苷 N7 位置与 DNA 结合。因此，它具有与抗癌药物顺铂相似的细胞靶点，但不相同，因为 Ru(II) 没有显示在 DNA 中形成分子内交叉桥的证据。反应缓慢，过量的钌会形成分子间 DNA 交桥。通过碱性彗星试验评估，将 CORM-3 添加到人类结肠直肠癌细胞中会导致 DNA 链断裂。DNA损伤被含有氨基酸的生长培养基抑制，与细胞外Ru结合并阻止其进入细胞。我们得出结论，Ru(II) 的细胞毒性不同于铂，使其成为癌症治疗的有希望的发展目标。