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Polypyridyl-Based Copper Phenanthrene Complexes: Combining Stability with Enhanced DNA Recognition
Nicoló Zuin Fantoni1,2, Zara Molphy1,3, Sinéad O'Carroll1
1School of Chemical Sciences and National Institute for Cellular, Biotechnology, Dublin City University, Glasnevin, Dublin, 9, Ireland.
Chemistry (Weinheim an Der Bergstrasse, Germany)
|June 11, 2020
Summary
New copper(II) artificial metallo-nucleases (AMNs) show potent DNA damaging and anticancer properties. The most effective compound, Cu-DPA-DPPZ, targets pancreatic cancer cells, outperforming the drug oxaliplatin.
Area of Science:
- Inorganic Chemistry
- Bioinorganic Chemistry
- Medicinal Chemistry
Background:
- Artificial metallo-nucleases (AMNs) are engineered catalysts with DNA cleavage capabilities.
- Copper complexes offer potential for developing novel therapeutic agents due to their redox activity.
- Developing targeted cancer therapies remains a critical challenge, particularly for pancreatic cancer.
Purpose of the Study:
- To synthesize and characterize novel copper(II) artificial metallo-nucleases (AMNs).
- To evaluate the DNA damaging properties and in-vitro cytotoxicity of these AMNs against human pancreatic cancer cells.
- To investigate the structure-activity relationships governing DNA binding and recognition.
Main Methods:
- Synthesis and characterization of copper(II) complexes incorporating di-(2-pycolyl)amine (DPA) and phenanthrene derivatives (Phen, DPQ, DPPZ).
- Structural and electronic characterization using X-ray crystallography, cw-EPR, HYSCORE, and Davies ENDOR spectroscopies.
- In-vitro assessment of DNA binding affinity (Kapp), DNA cleavage assays, and cytotoxicity studies against human pancreatic cancer cell lines.
Main Results:
- The synthesized Cu-DPA-N,N' complexes exhibited enhanced solution stability and DNA recognition.
- DNA binding affinity increased with the planarity of the phenanthrene unit, with Cu-DPA-DPPZ showing the highest affinity.
- Cu-DPA-DPPZ effectively recognized the minor groove of G-C rich DNA sequences and induced oxidative DNA damage.
- Cu-DPA-DPPZ demonstrated significant in-vitro anticancer activity against human pancreatic cancer cells, exceeding that of oxaliplatin.
Conclusions:
- Copper(II) AMNs, particularly Cu-DPA-DPPZ, are effective DNA-damaging agents.
- The DPA ligand and planar phenanthrene unit are crucial for enhanced DNA binding and stability.
- Cu-DPA-DPPZ exhibits promising therapeutic potential as an anticancer agent for pancreatic cancer, warranting further investigation.
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