Non-Benzenoid Fluorophores to Enable New Imaging Modalities

新药的开发是实现现代文明所享有的预期寿命和生活质量提高的核心。传统的民间疗法是通过反复试验发现的，而现代药物的开发依赖于对任何特定疾病发生的生物过程有深入的了解。这一知识使人们能够在了解新药实际工作原理的情况下，专门设计新药。为了了解疾病或健康细胞中可能发生的复杂和相互关联的细胞过程，科学家们广泛使用了所谓的“生物成像”技术。获取生物样本图像的最直接的方法是使用你可能在生物教室里找到的那种光学显微镜。然而，仅仅通过观察这样的图像是不可能识别细胞中可能存在的各种物质的。取而代之的是，科学家使用“荧光探针”--这种分子会发出特定的颜色，但只有在它们被设计用来探测的特定物质存在的情况下才会发光。使用这种荧光探针，我们可以确定一种物质是否存在，存在多少，它确切地出现在细胞内的哪里，以及它可能存在多长时间。例如，可以对一种名为淀粉样β蛋白的蛋白质进行成像的荧光探针已经表明，它在阿尔茨海默病中起着关键作用；其他荧光探针已经揭示了各种蛋白质在癌症中扮演的关键角色。荧光探针分子由一个“受体”部分(其目的是检测特定物质)和一个“荧光团”(其工作是发出显微镜将检测到的彩色光)组成。目前，已经开发了大量不同的受体来检测多种不同的物质。另一方面，当涉及到选择荧光团时，实际上没有那么多可供选择的。具体地说，大约有十几种著名的荧光团，每一种都有自己的优缺点。因此，迫切需要发现和开发与现有荧光分子不同的新的荧光分子，因为这将克服目前生物成像中的许多限制。我们建议开发基于一种名为天青烯的分子的新荧光分子。它的名字来源于西班牙语单词“蓝色”，因为它色彩鲜艳，而且也是荧光的。一些天青烯存在于自然界中，是某些蘑菇和珊瑚呈现蓝色的原因。天青烯的荧光特性将使我们能够开发以新的方式工作的荧光团(例如，同时发射多种颜色的光)，因此将能够通过成像到目前为止难以研究的物质为我们提供有价值的新信息。从长远来看，我们希望我们正在开发的这些新工具将使人们能够更深入地了解疾病的机制，从而能够开发出造福社会的新药。

The development of new medicines has been central to realising the increases in life expectancy and quality of life enjoyed by modern civilization. Whereas traditional folk remedies were discovered by trial and error, modern drug development relies on having a deep understanding of the biological processes that occur for any given disease. This knowledge allows new medicines to be specifically designed with an understanding of how they actually work.In order to gain this understanding of the complex and interrelated cellular processes that can occur in either diseased or healthy cells, scientists have made extensive use of so-called "bio-imaging" techniques. The most straightforward way to acquire an image of a biological sample is to use an optical microscope of the type you might find in a biology classroom. However, It is not possible to identify the various substances that may be present in a cell just by looking at such an image. Instead, scientists make use of "fluorescent probes" - molecules that will glow a particular colour, but only in the presence of a particular substance they have been designed to detect. Using such fluorescent probes allows us to determine whether or not a substance is present, how much of it is present, where exactly within cells it occurs, and for how long it may be present. For example, fluorescent probes that allow the imaging of a protein called amyloid-beta have shown it plays a crucial role in Alzheimer's disease; other fluorescent probes have revealed the key role played by various proteins in cancer.Fluorescent probe molecules consist of a "receptor" part (whose purpose is to detect a particular substance), joined to a "fluorophore" (whose job is to emit the coloured light the microscope will detect). Currently a great number of different receptors have been developed to detect many different substances. On the other hand, when it comes to choosing a fluorophore, there are actually not that many to choose from. Specifically there are about a dozen well-known fluorophores, each with its own advantages and disadvantages. As such, there is a pressing need to discover and develop new fluorophores with different characteristics to the ones we already have, as this will allow many current limitations in bio-imaging to be overcome.We propose to develop new fluorophores based on a molecule called "azulene". The name comes from the Spanish word "azul" (="blue"), as it is highly coloured and is also fluorescent. Some azulenes occur in nature and are responsible for the blue colour of certain mushrooms and corals. The fluorescence properties of azulene will enable us to develop fluorophores that work in new ways (e.g. by emitting more than one colour of light simultaneously) and so will be able to give us valuable new information through imaging substances that have been difficult to study up to now. Longer term, it is our aspiration that these new tools we are developing will allow greater insights into disease mechanisms, hence enabling the development of new medicines for the benefit of society.