Macrocyclic receptors for the recognition of biologically relevant substrates

合成化学家有独特的机会来创造纳米级的试剂，这些试剂与生物世界连接，检测和揭示细胞中的事件，并提供对重要过程的洞察。在此背景下，我们的研究项目主要集中在两类用于检测重要DNA折叠和DNA损伤的合成试剂上：(i)鸟嘌呤四联体是参与癌症发生、增殖和侵袭的重要核酸折叠。只要干扰剂在细胞中找到目标，就有可能阻止这些事件的发生。为了实现这一目标，我们正在研究中心有金属离子的大环配体。这些药物应该选择特定的鸟嘌呤四联体，并为研究癌症相关事件的调节提供新的工具。在我们可以选择的所有金属中，我们对镧系元素感到兴奋，因为它们应该允许这些试剂在到达目标时“点亮”。这对于在细胞中定位这些因子和信号事件非常有用。将探索一种软技术，以便在温和条件下分析细胞和组织。与诱变剂反应产生的DNA加合物在癌症出现之前形成。我们想知道如何检测这些早期事件。受天然酶的启发，我们提出了由金属离子组织的人工口袋，可以容纳加合物。我们将探索它们识别癌症相关DNA损伤的三个主要家族的能力，并确定哪些特征对损伤识别最重要。这项工作将由8名学生进行，他们将在技术方面（合成、光谱学、显微镜、生化、生物物理学研究）和领导方面（协作工作、融入国际网络）接受指导。研究成果将惠及跨学科的受众，从生物化学家和生物物理学家（A、C部分）到从事非线性光学研究的物理学家（B部分）和合成化学家（所有部分）。发光和/或电化学传感器也有望应用于工业。

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.