Design and synthesis of novel mechanism-based inhibitors of IDO1

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-双加氧酶潜在的基于机理的抑制剂。这些酶在一系列疾病中具有重要意义，特别是由于观察到过度表达的肿瘤的高活性导致免疫抑制。新的、立体定义的底物衍生物和过渡态模拟物的合成将使人们能够更详细地研究酶的机制，化合物旨在捕获或拦截所提议的反应级联反应中的关键活性中间体，可能导致针对这些酶的新类药物的出现。目的和目的开发和应用合成路线/方法来制备一系列新型色氨酸类似物(博士生)。目的：研究所制备的化合物对吲哚胺2，3-双加氧酶的抑制活性及在肿瘤细胞模型(Celentyx)中的活性。使用在化合物上产生的数据来指导进一步的化学工具的设计，并开发和应用合成路线/方法来准备这些工具(博士生)。研究方法的新颖性这个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，吲哚胺2，3-双加氧酶是新兴免疫肿瘤学领域的关键目标。与EPSRC的战略和研究领域一致-EPSRC中的新研究在EPSRC的投资组合中，这项建议同时属于物理科学主题和医疗技术主题，横跨合成有机化学、化学生物学和生物化学的研究领域。英国合成有机化学是制药、精细化工和农化行业的基础，这些行业在英国具有很好的代表性。该项目将保持这一优势，提供一名训练有素的合成有机化学家，为进入化学工业或学术界做好准备。如果成功，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、先导化合物和最终可能的治疗方法-为患者带来重大好处，并为英国带来经济利益。所开发的合成方法学将对其他研究氨基酸、多肽或其他生物活性化合物的研究人员具有潜在的实用价值。制备的新型氨基酸模拟物将在其他环境下进行活性测试，例如通过礼来PD2和伯明翰内部抗生素屏幕进行测试。任何参与该项目的公司或合作者都是由Celentyx共同资助的，Celentyx是一家在免疫肿瘤学方面有积极研究兴趣的中小企业。

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.