The Kellett Group at Dublin City University (DCU), have developed a new copper-based compound that can selectively bind to and damage DNA. This research contributes to the ongoing search for innovative approaches to targeting genetic material, which could have applications in cancer research. Using a versatile chemical method known as click chemistry, the team has created a highly efficient system for designing and optimising new DNA-interacting molecules.

The compound, Cu₂-BPL-C6, belongs to a class of molecules known as artificial metallo-nucleases (AMNs). These are synthetic compounds designed to mimic the function of natural enzymes that cut DNA. In living organisms, enzymes called nucleases help repair, copy, or break down DNA. Artificial metallo-nucleases achieve similar effects using metal ions, which can generate highly reactive species capable of cleaving DNA strands. Scientists are exploring these compounds as potential tools for studying DNA, developing new therapies, and even targeting cancer cells.

Click chemistry is a simple and highly reliable approach used by chemists to quickly and efficiently connect molecular building blocks, much like snapping pieces of a puzzle together. This method allows scientists to create complex molecules in a controlled and predictable way, making it a valuable tool for designing new drugs and biomolecules. Using click chemistry, the DCU researchers were able to precisely construct Cu₂-BPL-C6 to enhance its DNA-targeting properties.

Cu₂-BPL-C6 is a dinuclear copper complex designed to induce oxidative DNA damage through two redox-active copper centres linked by a flexible aliphatic spacer. The research team has shown that the compound exhibits site-specific DNA recognition with low micromolar activity, preferentially binding to AT-rich DNA sequences.

The binding properties of Cu₂-BPL-C6 were characterised using molecular and biophysical techniques, including circular dichroism spectroscopy, agarose gel electrophoresis, and fluorescence quenching assays. Its oxidative cleavage mechanism was further investigated through in vitro studies involving spin-trapping antioxidants and free radical scavengers, and was shown to damage DNA extracted from peripheral mononuclear blood cells.

A copper-free version of the compound was tested in collaboration with the National Cancer Institute (NCI-60) screening programme against a panel of cancer cell lines. The results revealed selective activity against melanoma, breast, colon, and non-small cell lung cancers. In conjunction with this screening, a further study using cancer cell lines demonstrated that the presence of copper(II) ions sensitises lethality in MDA-MB-468, a triple-negative breast cancer cell line.

The study highlights the potential of Cu₂-BPL-C6 as a DNA-targeting agent and demonstrates the advantages of click chemistry in the design and optimisation of new metallo-nucleases. The application of this approach in synthetic chemistry is expected to expand, providing new opportunities for the development of DNA-targeted therapeutics.

“This latest work shows another leap forward for the SSPC in the development of advanced therapeutics. Here, the Kellett group demonstrated very elegant and efficient synthesis of copper-based drugs to target DNA in cancer cells. We keep pushing forward as a transdisciplinary Centre, co-developing drug synthesis, formulation and process engineering platforms to translate a broad range of advanced modalities including these promising copper-based drugs into sustainable patient-centred medicines.” Professor Damien Thompson

Link to paper in Nucleic Acids Research:
Design and in vitro anticancer assessment of a click chemistry-derived dinuclear copper artificial metallo-nuclease | Nucleic Acids Research | Oxford Academic
Simon Poole, Obed Akwasi Aning, Vickie McKee, Thomas Catley, Aaraby Yoheswaran Nielsen, Helge Thisgaard, Pegah Johansson, Georgia Menounou, Joseph Hennessy, Creina Slator, Alex Gibney, Alice Pyne, Bríonna McGorman, Fredrik Westerlund, Andrew Kellett