Medicinal Inorganic Chemistry

该提案涵盖基础无机化学和作为三个独立项目基础的配位化学。最先进的研究包括设计和合成金属结合化合物(配体)，研究这些配体在溶液和固体中的金属结合过程，以及为检查其应用于下文列出的个别项目的潜力而量身定做的体外测试。1.多功能金属结合剂在阿尔茨海默病中的潜在应用-在这项研究中，我们致力于设计和合成不仅作为金属结合剂的分子，还包括其他功能，以对抗阿尔茨海默病的多因素性质。我们将探索两种支架的新化学：硫黄素-T(THT)，一种已知的淀粉样结合剂，以及去铁酮(DFP)，一种口服活性的双齿铁络合剂，已在欧洲获准临床使用。2.金属放射性同位素配位化学--新型、动力学速度快、热力学上合格的配位配体与金属离子的放射性同位素结合。使用我们的“pa”系列配体，人们正在发现新的放射性标记方法和化学方法，以及将所选择的放射性同位素引入这些分子以获得化学稳定实体的新的可靠、可重复、高产量和快速的方法，特别是Ga-68、In-111和稀土元素。3.金属抗菌剂-抗菌剂的潜在靶标是铁代谢-GA3+与Fe3+在化学上有许多相似之处，这使得生物系统很难区分这两种金属。镓不能进入铁代谢所必需的+3/+2氧化还原化学，这会导致微生物的细胞毒性。基于已报道的GA与已知抗生素之间的协同作用，我们将制备和研究(氟喹诺酮)类合成广谱抗生素的Ga(III)和Fe(III)配合物。为了在一个新的基础科学项目中验证这一假设，我们将研究这类新的镓(III)配位络合物的物理化学性质，特别强调稳定性。

This proposal covers basic inorganic chemistry and coordination chemistry underlying three separate projects. The state-of-the-art research undertaken involves design and synthesis of metal-binding compounds (ligands), studies of the metal-binding process of these ligands in the solution and solid states, and in vitro tests tailored to examine their potential for applications to the individual projects listed hereafter. 1. Multifunctional Metal-Binding Agents for the Potential Application in Alzheimer's Disease - In this research, much effort is undertaken to design and synthesize molecules that not only act as metal-binding agents but also include other functionalities to combat the multifactorial nature of this disease. We will explore new chemistry of two scaffolds: thioflavin-T (ThT), a known amyloid binder and deferiprone (DFP), the orally active bidentate iron chelator approved for clinical use in Europe. 2. Coordination Chemistry of Metallic Radioisotopes - New, kinetically fast and thermodynamically competent coordinating ligands to bind radioisotopes of metal ions are the focus. Using our "pa" family of ligands, new radiolabelling methods and chemistry are being discovered, as are new robust, reproducible, high-yielding and rapid methods for introducing the radioisotope of choice into these molecules to give chemically stable entities, with a particular focus on Ga-68, In-111 and lanthanides. 3. Metalloantimicrobials - A potential target for antimicrobials is iron metabolism - Ga3+ shares many chemical similarities with Fe3+, which makes it difficult for biological systems to distinguish between the two metals. The +3/+2 redox chemistry essential for the iron metabolism cannot be accessed for gallium, which leads to cellular toxicity for the microorganism. Building upon the reported synergism between Ga and known antibiotics, we will prepare and study Ga(III) and Fe(III) complexes of the (fluoro)quinolones, a class of synthetic broad-spectrum antibiotics. To test this hypothesis in a new basic science project, we will study the physicochemical properties of this novel class of gallium(III) coordination complexes with special emphasis on stability.