Macrocyclic receptors for the recognition of biologically relevant substrates

合成化学家拥有独特的机会来创造与生物世界对接的纳米试剂，检测和揭示细胞中的事件，并提供对重要过程的洞察。在这种背景下，我们的研究计划集中在两种类型的合成试剂上，用于检测重要的DNA折叠和DNA损伤：(I)鸟嘌呤四链是重要的核酸折叠，参与癌症的发生、增殖和侵袭。只要干扰剂在细胞内找到靶点，就有可能防止这些事件发生。为了实现这一目标，我们正在研究中心含有金属离子的大环配体。这类药物应该选择特定的鸟嘌呤四链，并提供新的工具来研究癌症相关事件的调节。在我们可以选择的所有金属中，我们对镧系元素感到兴奋，因为它们应该会让这些试剂在到达目标时‘点燃’。这对于定位这些代理并向细胞中的事件发送信号非常有用。将探索一种软技术，以便于在温和的条件下对细胞和组织进行分析。(Ii)在癌症出现之前，通过与诱变剂反应而产生的DNA加合物。我们想了解如何发现这些早期事件。受天然酶的启发，我们提出了由金属离子组织的人工口袋，其中加合物可以容纳。我们将探索它们识别与癌症相关的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。这项工作将由八名学生进行，他们将在技术基础(合成、光谱、显微镜、生化、生物物理研究)和领导基础(合作工作、融入国际网络)方面得到指导。研究成果将使跨学科的受众受益，从生物化学家和生物物理学家(A、C部分)到从事非线性光学工作的物理学家(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转化为工业。

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.