Design and synthesis of novel mechanism-based inhibitors of IDO1

新型IDO1机制抑制剂的设计与合成

• 批准号: 1803829
• 金额: --
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1803829
• 关键词: Design; synthesis; novel; mechanism; based

The context of the researchThis project will examine the synthesis of novel tryptophan mimetic amino acids as potential mechanism-based inhibitors of indoleamine 2,3-dioxygenases. These enzymes are of significant interest in a range of diseases, in particular due to the observation of immunosuppression resulting from high activity in over-expressing tumours. The synthesis of novel, stereo-defined substrate derivatives and transition state mimics will allow more detailed study of the enzyme mechanism, with compounds designed to trap or intercept key reactive intermediates in the proposed reaction cascade, potentially leading to new classes of drugs targeting these enzymes. Aims and objectivesTo develop and apply synthetic routes/methods for the preparation of a range of novel tryptophan analogues (PhD student). To study the activity of the compounds prepared against isolated indoleamine 2,3-dioxygenases and in tumour cell models (Celentyx). To use the data generated on compounds to inform the design of further chemical tools, and to develop and apply synthetic routes/methods for the preparation of these tools (PhD student).Novelty of the research methodologyThis project will involve the development of new synthetic routes and methods. The compounds prepared will represent a wholly novel approach to inhibition of indoleamine 2,3-dioxygenases, a key target in the emerging field of immuno-oncology.Alignment to EPSRC's strategies and research areas - novel research within the EPSRC remitWithin the EPSRC portfolio, this proposal falls within both the Physical Sciences Theme and Healthcare Technologies Theme, straddling the research areas of Synthetic organic chemistry and Chemical biology and biological chemistry.Potential applications and benefitsUK synthetic organic chemistry underpins the pharmaceutical, fine chemical and agrochemical industries, which are well represented in the UK. This project will maintain this strength, delivering a highly trained synthetic organic chemist well placed to enter the chemical industry or academia. If successful, the novel class of indoleamine 2,3-dioxygenase inhibitors prepared will have utility as tool compounds, leads and ultimately potentially therapies - offering significant benefit to patients and accompanying economic benefit to the UK. The synthetic methodology developed will have potential utility for other researchers working on amino acids, peptides or other biologically active compounds. The novel amino acid mimics prepared will be tested for activity in other settings, e.g. through Lilly PD2 and in Birmingham's internal antibiotic screens. Any companies or collaborators involvedThe project is co-funded by Celentyx, an SME with active research interests in immuno-oncology.

研究背景本项目将研究新型色氨酸模拟氨基酸的合成，作为吲哚胺2，3-双加氧酶的潜在机制抑制剂。这些酶在一系列疾病中具有重要意义，特别是由于在过表达肿瘤中观察到高活性导致的免疫抑制。新型立体定向底物衍生物和过渡态模拟物的合成将允许对酶机制进行更详细的研究，其中化合物旨在捕获或拦截所提出的反应级联中的关键反应中间体，可能导致靶向这些酶的新型药物。目的和目标开发和应用合成路线/方法制备一系列新型色氨酸类似物（博士生）。研究制备的化合物对分离的吲哚胺2，3-双加氧酶和肿瘤细胞模型（Celentyx）的活性。利用化合物产生的数据为进一步的化学工具的设计提供信息，并开发和应用合成路线/方法来制备这些工具（博士生）。研究方法的新奇本项目将涉及新的合成路线和方法的开发。所制备的化合物将代表一种全新的方法来抑制吲哚胺2，3-双加氧酶，这是免疫肿瘤学新兴领域的一个关键靶点。与EPSRC的战略和研究领域保持一致-EPSRC内的新研究在EPSRC的投资组合中，该提案福尔斯属于物理科学主题和医疗保健技术主题，合成有机化学横跨合成有机化学、化学生物学和生物化学的研究领域。潜在的应用和效益英国合成有机化学是制药、精细化工和农用化学工业的基础，这些工业在英国有很好的代表性。该项目将保持这一优势，提供一个训练有素的合成有机化学家很好地进入化学工业或学术界。如果成功的话，所制备的新型吲哚胺2，3-双加氧酶抑制剂将作为工具化合物、先导物和最终潜在的治疗方法，为患者提供显著的益处，并为英国带来经济效益。开发的合成方法将对其他研究氨基酸，肽或其他生物活性化合物的研究人员具有潜在的实用性。制备的新型氨基酸模拟物将在其他环境中进行活性测试，例如通过礼来PD 2和伯明翰的内部抗生素筛选。该项目由Celentyx共同资助，Celentyx是一家对免疫肿瘤学有积极研究兴趣的中小企业。