Mapping the DNA Damaging Effects of Polypyridyl Copper Complexes with DNA Electrochemical Biosensors
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 report...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/3/645 |
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| author | Anna Banasiak Nicolò Zuin Fantoni Andrew Kellett John Colleran |
| author_facet | Anna Banasiak Nicolò Zuin Fantoni Andrew Kellett John Colleran |
| author_sort | Anna Banasiak |
| collection | DOAJ |
| description | 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)<sub>2</sub>]<sup>2+</sup> 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)(<i>N</i>,<i>N</i>)]<sup>2+</sup> class (where TPMA = tris-2-pyridylmethylamine) using a DNA electrochemical biosensor. TPMA is a tripodal copper caging ligand, while <i>N</i>,<i>N</i> 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)]<sup>2+</sup> and [Cu(TPMA)(DPQ)]<sup>2+</sup> cleaved 39% and 48% of the DNA strands from the biosensor surface, respectively, while complexes [Cu(TPMA)(bipy)]<sup>2+</sup> and [Cu(TPMA)(PD)]<sup>2+</sup> exhibit comparatively moderate nuclease efficacy (ca. 26%). Comparing the nuclease activities of [Cu(TPMA)(phen)] <sup>2+</sup> and [Cu(phen)<sub>2</sub>]<sup>2+</sup> (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. |
| first_indexed | 2024-03-09T23:30:35Z |
| format | Article |
| id | doaj.art-c30a3729a667435b8e53e91629a9954f |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T23:30:35Z |
| publishDate | 2022-01-01 |
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| spelling | doaj.art-c30a3729a667435b8e53e91629a9954f2023-11-23T17:10:06ZengMDPI AGMolecules1420-30492022-01-0127364510.3390/molecules27030645Mapping the DNA Damaging Effects of Polypyridyl Copper Complexes with DNA Electrochemical BiosensorsAnna Banasiak0Nicolò Zuin Fantoni1Andrew Kellett2John Colleran3Applied Electrochemistry Group, FOCAS Institute, Technological University Dublin, Camden Row, Dublin 8, D08 CKP1 Dublin, IrelandDepartment of Chemistry, University of Oxford, Oxford OX1 3TA, UKSchool of Chemical Sciences and National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, D09 NR58 Dublin, IrelandApplied Electrochemistry Group, FOCAS Institute, Technological University Dublin, Camden Row, Dublin 8, D08 CKP1 Dublin, IrelandSeveral 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)<sub>2</sub>]<sup>2+</sup> 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)(<i>N</i>,<i>N</i>)]<sup>2+</sup> class (where TPMA = tris-2-pyridylmethylamine) using a DNA electrochemical biosensor. TPMA is a tripodal copper caging ligand, while <i>N</i>,<i>N</i> 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)]<sup>2+</sup> and [Cu(TPMA)(DPQ)]<sup>2+</sup> cleaved 39% and 48% of the DNA strands from the biosensor surface, respectively, while complexes [Cu(TPMA)(bipy)]<sup>2+</sup> and [Cu(TPMA)(PD)]<sup>2+</sup> exhibit comparatively moderate nuclease efficacy (ca. 26%). Comparing the nuclease activities of [Cu(TPMA)(phen)] <sup>2+</sup> and [Cu(phen)<sub>2</sub>]<sup>2+</sup> (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.https://www.mdpi.com/1420-3049/27/3/645DNA biosensorchemical nucleasesDNA-drug interactioncopper complexesmetallodrugs |
| spellingShingle | Anna Banasiak Nicolò Zuin Fantoni Andrew Kellett John Colleran Mapping the DNA Damaging Effects of Polypyridyl Copper Complexes with DNA Electrochemical Biosensors Molecules DNA biosensor chemical nucleases DNA-drug interaction copper complexes metallodrugs |
| title | Mapping the DNA Damaging Effects of Polypyridyl Copper Complexes with DNA Electrochemical Biosensors |
| title_full | Mapping the DNA Damaging Effects of Polypyridyl Copper Complexes with DNA Electrochemical Biosensors |
| title_fullStr | Mapping the DNA Damaging Effects of Polypyridyl Copper Complexes with DNA Electrochemical Biosensors |
| title_full_unstemmed | Mapping the DNA Damaging Effects of Polypyridyl Copper Complexes with DNA Electrochemical Biosensors |
| title_short | Mapping the DNA Damaging Effects of Polypyridyl Copper Complexes with DNA Electrochemical Biosensors |
| title_sort | mapping the dna damaging effects of polypyridyl copper complexes with dna electrochemical biosensors |
| topic | DNA biosensor chemical nucleases DNA-drug interaction copper complexes metallodrugs |
| url | https://www.mdpi.com/1420-3049/27/3/645 |
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