Medicinal Inorganic Chemistry

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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.