Synthesis of novel small conjugate molecules as potential therapeutic agents to combat mesothelioma

新型小共轭分子的合成作为对抗间皮瘤的潜在治疗剂

• 批准号: 2748285
• 金额: --
• 依托单位: University of Surrey
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2748285
• 关键词: Synthesis; novel; small; conjugate; molecules

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-like mimics (based around a guanidine skeleton) attached to a linker unit and then a toxic moeity, all specifically designed such that the guanidine-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.

在开发新的治疗剂时，有两个问题需要解决：i）如何将药物输送到体内需要的特定部位；ii）它是否能在目标部位发挥我们想要的作用，并且不会产生不良副作用。这些要求非常具有挑战性，例如如何确保抗癌药物到达肿瘤并仅杀死肿瘤细胞而不杀死健康细胞？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，始终与石棉暴露有关。通常，最初接触后 20-40 年才会出现症状，预期寿命为 12-18 个月。鉴于石棉在 20 世纪的广泛使用和漫长的潜伏期，MPM 病例持续增加也就不足为奇了。因此，迫切需要开发新的治疗方法来治疗MPM。氨基酸精氨酸在各种肺癌的发生发展中至关重要。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 ASS1 基因的功能，该基因专门负责精氨酸的产生。因此，MPM 细胞失去了自身产生精氨酸的能力，而必须从血液中获取精氨酸。已经表明，剥夺 MPM 肿瘤的精氨酸会减慢其生长并最终杀死它们：这是肺癌的“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 中的药物输送和位点选择性问题，旨在同时解决这两个问题。基本原理很简单：我们不会剥夺肿瘤中的精氨酸，而是使用精氨酸结构基序作为靶向系统，将高效抗癌剂直接递送至肿瘤。该项目将涉及合成精氨酸样模拟物（基于胍骨架）的衍生物库，这些衍生物连接到连接单元，然后连接到有毒部分，所有这些都经过专门设计，使得双功能分子的胍部分将被精氨酸依赖性肿瘤快速吸收，同时将一种（或多种）连接的抗癌药物直接递送到肿瘤细胞。 肿瘤的心脏。该项目还将涉及对所有制备的化合物进行生物学评价。