Synthesis of novel arginine analogues as potential therapeutic agents to combat mesothelioma

在开发一种新的治疗药物时，有两个问题需要解决：1)如何使药物到达体内需要它的特定部位；2)它是否在目标部位起到我们想要的作用，并且没有不良副作用。这些要求非常具有挑战性，例如，你如何确保抗癌药物到达肿瘤，只杀死肿瘤细胞，而不是健康细胞？该项目解决了间皮瘤中的这些关键问题。人类恶性胸膜间皮瘤（MPM）是一种侵袭性（致命）肺癌，通常与石棉暴露有关。通常在初次接触后20-40年才出现症状，预期寿命为12-18个月。考虑到20世纪石棉的广泛使用和漫长的潜伏期，MPM病例继续上升也就不足为奇了。因此，迫切需要开发新的治疗方法来治疗MPM。精氨酸在各种肺癌的发展中是必不可少的。虽然大多数健康细胞能够产生自己的精氨酸，但大多数MPM肿瘤已经失去了基因ASS1的功能，该基因专门负责产生精氨酸。因此，MPM细胞已经失去了自身产生精氨酸的能力，而必须从血液中获得精氨酸。已经有研究表明，去除MPM肿瘤中的精氨酸会减缓它们的生长，并最终杀死它们：肺癌的“致命弱点”。该项目的总体目标是通过开发一系列双功能分子来解决MPM中药物传递和位点选择性的问题，旨在同时解决这两个问题。基本原理很简单：我们将使用精氨酸结构基序作为靶向系统，直接向肿瘤提供高效的抗癌药物，而不是剥夺肿瘤中的精氨酸。该项目将包括合成一个连接单元上的精氨酸衍生物库，然后是一个有毒分子，所有这些都是专门设计的，这样双功能分子的精氨酸部分将被依赖精氨酸的肿瘤迅速吸收，同时将一种（或多种）附着的抗癌药物直接输送到肿瘤的心脏。该项目还将包括对所制备的所有化合物进行生物学评价。

In developing a new therapeutic agent, there are two questions to address: i) how to get the drug to the specific site in the body where it is needed and ii) does it do what we want it to do at the target site and without undesirable side effects. These requirements are incredibly challenging e.g. how do you ensure that an anti-cancer drug reaches the tumour and only kills tumour cells and not healthy ones? This project addresses these key issues within mesothelioma.Human malignant pleural mesothelioma (MPM) is an aggressive (fatal) lung cancer which is always associated with asbestos exposure. Typically symptoms do not appear until 20-40 years after the original exposure, with life expectancy then 12-18 months. Given the widespread use of asbestos during the 20th century and this long latency period, it is no surprise that cases of MPM continue to rise. Therefore there is an urgent need to develop novel therapeutic approaches for the treatemnt of MPM.The amino acid arginine is essential in the development of various lung cancers. While most healthy cells are able to produce their own arginine, the majority of MPM tumours have lost the function of the gene ASS1, which is specifically responsible for the production of arginine. Thus MPM cells have lost the ability to produce arginine themselves and instead have to obtain it from the blood. It has already been shown that depriving MPM tumours of arginine slows their growth and eventually kills them: the 'achilles heel' of lung cancers.The overall aim of the project is to address the problems of drug delivery and site selectivity within MPM by developing a series of bifunctional molecules, designed to solve both problems simultaneously. The underlying principle is simple: rather than depriving a tumour of arginine, we will use the arginine structural motif as a targeting system to deliver a highly potent anti-cancer agent directly to the tumour. The project will involve the synthesis of a library of derivatives of arginine attached to a linker unit and then a toxic moeity, all specifically designed such that the arginine-portion of the bifunctional molecules will be rapidly absorbed by the arginine-dependant tumours, simultaneously delivering one (or more) attached anti-cancer agents directly to the heart of the tumour. The project will also involve the biological evaluation of all the compounds prepared.