Stratingh Institute for Chemistry , University of Groningen , Nijenborgh 4 , 9747 AG Groningen , The Netherlands.
Department of Pathology and Medical Biology , University of Groningen, University Medical Center Groningen , Hanzeplein 1 , 9713 GZ Groningen , The Netherlands.
Inorg Chem. 2018 Jul 2;57(13):7748-7756. doi: 10.1021/acs.inorgchem.8b00714. Epub 2018 Jun 19.
Metal coordination complexes can display interesting biological activity, as illustrated by the bleomycins (BLMs), a family of natural antibiotics that when coordinated to a redox-active metal ion, show antitumor activity. Yet, which metal ion is required for the activity in cells is still subject to debate. In this study, we described how different metal ions affect the intracellular behavior and activity of the synthetic BLM-mimic N, N-bis(2-pyridylmethyl)- N-bis(2-pyridyl)methylamine (N4Py). Our study shows that a mixture of iron(II), copper(II), and zinc(II) complexes can be generated when N4Py is added to cell cultures but that the metal ion can also be exchanged by other metal ions present in cells. Moreover, the combination of chemical data, together with the performed biological experiments, shows that the active complex causing oxidative damage to cells is the Fe-N4Py complex and not per se the metal complex that was initially added to the cell culture medium. Finally, it is proposed that the high activity observed upon the addition of the free N4Py ligand is the result of a combination of scavenging of biologically relevant metals and oxidative damage caused by the iron(II) complex.
金属配合物可以表现出有趣的生物活性，例如博来霉素（BLMs），这是一类天然抗生素，当与氧化还原活性金属离子配位时，表现出抗肿瘤活性。然而，对于细胞中哪种金属离子是必需的，仍存在争议。在这项研究中，我们描述了不同的金属离子如何影响合成 BLM 类似物 N，N-双（2-吡啶甲基）-N，N-双（2-吡啶基）甲基胺（N4Py）的细胞内行为和活性。我们的研究表明，当 N4Py 被添加到细胞培养物中时，可以产生铁(II)、铜(II)和锌(II)配合物的混合物，但金属离子也可以被细胞中存在的其他金属离子交换。此外，化学数据的组合以及进行的生物学实验表明，导致细胞氧化损伤的活性配合物是 Fe-N4Py 配合物，而不是最初添加到细胞培养基中的金属配合物。最后，提出在添加游离 N4Py 配体时观察到的高活性是生物相关金属的清除和铁(II)配合物引起的氧化损伤的综合结果。
