Interaction of metal complexes with DNA and proteins: towards a new generation of therapeutic and imaging agents

寻找具有治疗作用的新化学物质是一个漫长而昂贵的过程，需要不断寻找化学多样性。虽然有机化合物在这方面已经得到了广泛的研究，但对金属络合物的治疗特性知之甚少。尽管顺铂等金属药物在癌症治疗中取得了巨大的成功，在核磁共振成像(MRI)中也获得了Gd配合物的成功，但药物无机化学在制药行业和一般药物化学界中的关注相对较少。然而，金属中心的结构和电子的多样性为药物的合理设计提供了独特的机会来探索化学多样性。此外，金属通常具有诱人的光学和磁性，非常适合开发用于生物成像的分子探针。本项目旨在开发新型金属络合物作为潜在的抗癌药物。特别是，我们的目标是开发能够选择性地与特定类型的DNA相互作用的复合体(称为四链DNA，它近年来越来越多地与人类基因组中的调节过程有关，并已成为抗癌药物开发的新的和独特的靶点)。为了实现所开发化合物的全部治疗潜力，将研究它们与与运输和传递相关的蛋白质的相互作用。除了开发的化合物的潜在治疗特性(对一系列受益者具有明显的影响)外，我们还将致力于开发分子探针，用于更好地了解小分子和四链DNA之间的相互作用。含金属化合物长期以来一直被制药业和药物化学界忽视。然而，它们独特的结构和功能特性为开发新的治疗剂和成像工具提供了独特的机会。该项目的愿景是展示与四链DNA相互作用的金属络合物，可以成为开发抗癌药物的极佳候选者，也是生物成像的独特探针。

The search for new chemicals that have therapeutic properties is a lengthy and costly process that continuously looks for chemical diversity. While organic compounds have been extensively studied in this context far less is known about the therapeutic properties of metal complexes. In spite of the great success of some metallo-pharmaceuticals such as cis-platin in cancer therapy, and gadolinium complexes in Magnetic Resonance Imaging (MRI), medicinal inorganic chemistry has received comparatively very little attention from the pharmaceutical industry and in general from the medicinal chemistry community. However, the structural and electronic versatility of metal centres provide a unique opportunity to explore chemical diversity for the rational design of drugs. Furthermore, metals often have attractive optical and magnetic properties that are ideally suited for the development of molecular probes for bio-imaging. The project herein presented aims at developing novel metal complexes as potential anticancer drugs. In particular, we will aim to develop complexes that can selectively interact with a specific type of DNA (named quadruplex DNA which in recent years has been increasingly associated with regulatory processes in the human genome and has emerged as a novel and distinctive target for the development of anticancer drugs). To realize the full therapeutic potential of the compounds developed, their interactions with proteins relevant to transport and delivery will be studied. Besides the potential therapeutic properties of the compounds developed (with the obvious implications to a range of beneficiaries) we will also aim to develop molecular probes that can be used to gain a better understanding of the interaction of small molecules and quadruplex DNA.Metal-containing compounds have been overlooked for a long time by the pharmaceutical industry and medicinal chemistry community. However, their distinctive structural and functional properties provide a unique opportunity for the development of new therapeutic agents and imaging tools. The vision of this project is to demonstrate that metal complexes that interact with quadruplex DNA, can be excellent candidates for the development of anticancer drugs and also unique probes for bio-imaging.