Medicinal Inorganic Chemistry

该提案涵盖了三个独立项目的基础无机化学和配位化学。所进行的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状态下的金属结合过程，以及量身定制的体外测试，以检查它们在下文列出的各个项目中的应用潜力。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，人们花了很多精力来设计和合成分子，这些分子不仅可以作为金属结合剂，还包括其他功能，以对抗这种疾病的多因素性质。我们将探索两种支架的新化学成分：硫黄素- t (ThT)，一种已知的淀粉样蛋白粘合剂和去铁素（DFP），一种在欧洲被批准临床使用的口服活性双齿铁螯合剂。金属放射性同位素的配位化学——与金属离子的放射性同位素结合的新的、动力学快速和热力学胜任的配位配体是焦点。利用我们的“pa”配体家族，人们正在发现新的放射性标记方法和化学方法，以及新的强大、可重复、高产和快速的方法，将放射性同位素选择引入这些分子中，以获得化学稳定的实体，特别是Ga-68、In-111和镧系元素。3. 金属抗菌剂-抗菌剂的潜在目标是铁代谢- Ga3+与Fe3+具有许多化学相似性，这使得生物系统难以区分这两种金属。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，我们将制备和研究一类合成广谱抗生素（氟）喹诺酮类药物的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，我们将研究这类新型镓（III）配位配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.