Structures and Mechanisms of Reactive Metal Centres: Metal-based Drugs and Bioinorganic Catalysts

我们的研究正在开发基于金属的抗癌化合物和新型生物无机催化剂。为了探索这些体系中的结构-活性关系，我们使用光谱方法的组合来表征顺磁性金属中心、中间体和自由基物种。这些机理研究指导着我们设计和合成活性金属络合物和新的反应体系。 (I)基于Ru的化疗药物在临床研究中显示出巨大的前景。我们正在开发新的Ru(III)抗癌化合物，目标是与白蛋白相互作用，选择性地将其输送到癌细胞。利用磁共振波谱方法，我们正在研究蛋白质介导的细胞间运输以及这些化合物在细胞环境中的命运。 (2)在体内还原Ru(III)络合物可以激活它们与生物分子进行配体交换。我们正在制备氧化还原活性配体的配合物，其还原电位可以通过体内的水和生物分子配体交换来调节。这些化合物通过产生活化的Ru(II)物种和活性氧物种，针对肿瘤的低氧、还原环境进行选择性激活。 (3)仅由阳离子和阴离子组成的溶剂体系为生物催化提供了独特的环境。我们正在使用与细胞色素c等血红素蛋白生物相容的“离子液体”来开发选择性氧化和羟化的新体系。机理研究指导我们设计新的催化剂，并洞察溶剂效应对金属蛋白化学的影响。 (Iv)我们正在开发仿生卟啉和非血红素铁催化剂，使用离子液体作为金属酶活性部位的蛋白质环境的非生物替代品。对反应性和反应中间体的研究使我们能够确定离子液体如何影响催化机理。这项工作旨在开发新的催化系统，其效用是由离子液体的可调溶剂环境定制的。

Our research is developing metal-based anticancer compounds and novel bioinorganic catalysts. To probe structure-activity relationships in these systems, we use a combination of spectroscopic methods to characterize paramagnetic metal centres, intermediates, and radical species. These mechanistic studies are leading our design and synthesis of reactive metal complexes and new reaction systems. (i) Ruthenium-based chemotherapeutics have shown great promise in clinical studies. We are developing new Ru(III) anticancer compounds that target interactions with albumin for selective delivery to cancer cells. Using magnetic resonance spectroscopic methods, we are studying protein mediated intercellular transport and the fate of these compounds in cellular environments. (ii) Reduction of Ru(III) complexes in vivo can activate them towards ligand exchange with biomolecules. We are preparing complexes with redox-active ligands, whose reduction potentials can be tuned by aqueous and biomolecule ligand exchange in vivo. These compounds target the hypoxic, reducing environment of tumours for selective activation, both by production of activated Ru(II) species and reactive oxygen species. (iii) Solvent systems that are comprised only of cations and anions provide unique environments for biocatalysis. We are using biocompatible "ionic liquids" with heme proteins such as cytochrome c to develop new systems for selective oxidations and hydroxylations. Mechanistic studies guide our design of new catalysts and provide insight into the influence of solvent effects on the chemistry of metalloproteins. (iv) We are developing biomimetic porphyrin and non-heme iron catalysts, using ionic liquids to act as non-biological substitutes for the protein environment at the active sites of metalloenzymes. Studies of reactivity and reaction intermediates allow us to determine how the ionic liquids influence catalytic mechanisms. This work seeks to develop new catalytic systems whose utility is tailored by the tunable solvent environment of ionic liquids.