Applied Electrochemistry Group, FOCAS Institute, Technological University Dublin, Camden Row, Dublin 8, D08 CKP1 Dublin, Ireland.
Department of Chemistry, University of Oxford, Oxford OX1 3TA, UK.
Molecules. 2022 Jan 19;27(3):645. doi: 10.3390/molecules27030645.
Several classes of copper complexes are known to induce oxidative DNA damage that mediates cell death. These compounds are potentially useful anticancer agents and detailed investigation can reveal the mode of DNA interaction, binding strength, and type of oxidative lesion formed. We recently reported the development of a DNA electrochemical biosensor employed to quantify the DNA cleavage activity of the well-studied [Cu(phen)] chemical nuclease. However, to validate the broader compatibility of this sensor for use with more diverse-and biologically compatible-copper complexes, and to probe its use from a drug discovery perspective, analysis involving new compound libraries is required. Here, we report on the DNA binding and quantitative cleavage activity of the [Cu(TPMA)(,)] class (where TPMA = tris-2-pyridylmethylamine) using a DNA electrochemical biosensor. TPMA is a tripodal copper caging ligand, while , represents a bidentate planar phenanthrene ligand capable of enhancing DNA interactions through intercalation. All complexes exhibited electroactivity and interact with DNA through partial (or semi-) intercalation but predominantly through electrostatic attraction. Although TPMA provides excellent solution stability, the bulky ligand enforces a non-planar geometry on the complex, which sterically impedes full interaction. [Cu(TPMA)(phen)] and [Cu(TPMA)(DPQ)] cleaved 39% and 48% of the DNA strands from the biosensor surface, respectively, while complexes [Cu(TPMA)(bipy)] and [Cu(TPMA)(PD)] exhibit comparatively moderate nuclease efficacy (ca. 26%). Comparing the nuclease activities of [Cu(TPMA)(phen)] and [Cu(phen)] (ca. 23%) confirms the presence of TPMA significantly enhances chemical nuclease activity. Therefore, the use of this DNA electrochemical biosensor is compatible with copper(II) polypyridyl complexes and reveals TPMA complexes as a promising class of DNA damaging agent with tuneable activity due to coordinated ancillary phenanthrene ligands.
已知几类铜配合物可诱导介导细胞死亡的氧化 DNA 损伤。这些化合物具有潜在的抗癌作用，深入研究可以揭示 DNA 相互作用、结合强度和形成的氧化损伤类型。我们最近报道了一种 DNA 电化学生物传感器的开发，该传感器用于定量研究[Cu(phen)]化学核酸酶的 DNA 切割活性。然而，为了验证该传感器更广泛地适用于更多不同的、生物相容的铜配合物，并从药物发现的角度探讨其用途，需要进行涉及新化合物库的分析。在这里，我们报告了使用 DNA 电化学生物传感器研究[Cu(TPMA)(,)]类（其中 TPMA = 三（2-吡啶基甲基）胺）的 DNA 结合和定量切割活性。TPMA 是一种三足铜笼状配体，而 代表一种双齿平面菲咯啉配体，能够通过嵌入增强 DNA 相互作用。所有配合物均表现出电化学活性，并通过部分（或半）嵌入与 DNA 相互作用，但主要通过静电吸引。虽然 TPMA 提供了出色的溶液稳定性，但庞大的配体使配合物具有非平面几何形状，从而阻碍了其完全相互作用。[Cu(TPMA)(phen)]和[Cu(TPMA)(DPQ)]分别从生物传感器表面切割了 39%和 48%的 DNA 链，而配合物[Cu(TPMA)(bipy)]和[Cu(TPMA)(PD)]的核酸酶效能相对适中（约 26%）。比较[Cu(TPMA)(phen)]和[Cu(phen)]的核酸酶活性（约 23%）证实了 TPMA 的存在显著增强了化学核酸酶的活性。因此，该 DNA 电化学生物传感器与铜（II）多吡啶配合物兼容，并揭示了 TPMA 配合物是一种很有前途的 DNA 损伤剂类别，其活性可通过配位的菲咯啉配体进行调节。
