Macrocyclic receptors for the recognition of biologically relevant substrates

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Synthetic chemists have unique opportunities to create nanoscopic agents that interface with the biological world, detect and reveal events in cells, and provide insight into vital processes. In this context, our research program focuses on two types of synthetic agents for the detection of important DNA folds and DNA damage: (i) Guanine quadruplexes are important nucleic acid folds that are involved in cancer inception, proliferation and invasion. It is possible to prevent these events with interfering agents, provided they find their target in the cell. To achieve this goal, we are investigating macrocyclic ligands bearing a metal ion in their center. Such agents should select specific guanine quadruplexes and provide new tools to study the regulation of cancer-related events. Among all the metals we can choose from, we are excited by lanthanides as they should allow these agents to 'light-up' upon reaching their target. This is very useful to localize these agents and signal events in cells. A soft technology will be explored to facilitate the analysis of cells and tissues under mild conditions. (ii) DNA adducts generated by reaction with mutagens form before cancer appears. We want to understand how to detect these early events. Inspired by natural enzymes, we propose artificial pockets organized by metal ions where the adducts could fit. We will explore their capacity to recognize three main families of cancer-relevant DNA damage, and determine which features are most important for damage recognition. The work will be carried out by eight students who will be mentored on technical grounds (synthesis, spectroscopies, microscopies, biochemical, biophysical studies) and leadership grounds (collaborative work, integration within an international network). Research outcomes will benefit an interdisciplinary audience, from Biochemists and Biophysicists (parts A,C) to Physicists working on non-linear optics (Part B) and synthetic Chemists (all parts). Translation to industry is also anticipated with luminescent and/or electrochemical sensors.