Illudine, a novel potent trypanocidal natural product; optimisation of simplified analogues, investigating its mode of action and elucidation of its p

寄生原生动物布鲁氏锥虫、克氏锥虫和利什曼原虫是“被忽视”的热带病：非洲昏睡病、恰加斯病和利什曼病的病原体。这些疾病共同影响着数百万人，占世界传染病负担的很大比例。目前的药物治疗严重不足，存在毒性、现场管理困难、成本和新出现的耐药性等问题。如果要根除/控制这些疾病，迫切需要确定新的治疗靶点，以便将先导化合物开发成安全、廉价和易于施用的药物；到2020年成为世卫组织的优先事项。天然产物是生物在进化过程中产生次生代谢产物，增强生物在其生存环境中的生存能力和竞争力。这些化学实体通常是复杂的，结构多样的，并且已经通过它们的本质进行了生物学验证，使它们成为候选药物的理想起点。从历史上看，天然产物已被证明是药物发现先导化合物的丰富资源，1981年至2011年期间，几乎50%的批准药物本身就是天然产物或其衍生物。天然产物和天然产物样支架，以及伴随它们的典型复杂性和多样性，在合成文库中被大大低估，主要是因为它们具有挑战性的合成和巨大的结构修改难度。然而，研究表明，更大的复杂性和立体中心的结合与化合物从发现到临床试验并最终成为药物的过渡存在显著的正相关关系。利用天然产物的灵感，因为它们的结构和功能多样性，以及生物验证是提高生物活性和可利用性概率的有益方法。Smith小组先前对NIH天然产物收集（120个分离化合物）进行了筛选，以对抗所有三种寄生虫，并提出了几种在低nM范围内具有EC50的高效化合物，对哺乳动物细胞具有高选择性。其中一个靶点是富马青霉素，这是Florence和Smith小组研究的主题，以优化简化靶点的SAR并确定其在布鲁氏杆菌中的蛋白靶点。另一个有效的天然产物是Illudine M，这是一种对克氏锥虫的Ec50为6.67 nM的四萜化合物。已经研究了它的合成，以及几种自然变体。https://pubs.acs.org/doi/pdf/10.1021/acs.joc.0c01301This将是这个学生的主要课题，进行illumine和一些简化的类似物的合成，允许随后对寄生虫进行测试，以获得一些SAR和初始表型。将合适的片段添加到优化的简化类似物中，允许交联和亲和纯化以识别蛋白质目标。如果时间允许，作为备份，将研究其他几种有效的锥虫天然产物命中，包括几种环肽类似物。

The parasitic protozoa Trypanosoma brucei, Trypanosoma cruzi, and Leishmania speciesare the causative agents of the "neglected" tropical diseases: African sleeping sickness,Chagas' disease and leishmaniasis. Collectively, these diseases affect millions of peopleand represent a huge percentage of the world's communicable disease burden. Currentdrug treatments are woefully inadequate, having problems of toxicity, difficult administration in the field, cost and emerging resistance. There is an urgent need for identification of novel therapeutic targets, allowing development of lead compounds into safe, cheap, and easy to administer drugs if these diseases are to be eradicated/controlled; a WHO priority by 2020.Natural products arise from the evolution of organisms to produce secondary metabolites, which enhance the survival and competitiveness of the organism in its habitat. These chemical entities are often complex, structurally diverse, and already biologically validated by their very nature making them ideal starting points for drug candidates. Historically, natural products have proved to be a bountiful resource of lead compounds in drug discovery, with almost 50% of all approved drugs between 1981 and 2011 being natural products themselves or derivatives thereof. Natural products and natural product-like scaffolds, and the typical complexity and diversity that accompanies them, are vastly underrepresented in synthetic libraries, mainly due to their challenging synthesis and enormous difficulty of structural modifications. It has, however, been shown that there is significant positive correlation of greater complexity and incorporation of stereogenic centres, with the transitioning of compounds from discovery, through clinical trials and eventually to drugs. Utilising the inspiration of natural products, for their structural and functional diversity, and biological validation is a beneficial approach for increasing probability of both biological activity and availability.The Smith group have previously undertaken a screen of NIH Natural Products Collection (120isolated compounds) against all three parasites and came up with several highly potent compounds with EC50 in the low nM range with high selectivity versus mammalian cells.One of these targets was Fumagillin, which has been the subject of research in the Florence and Smith groups to optimize the SAR of simplified targets and identify its protein target(s) in T. brucei.Another potent natural product identified in this screen is Illudine M, a sequiterpene with an Ec50 against T. cruzi of 6.67 nM. The synthesis of which has been studied, along with several natural variants. https://pubs.acs.org/doi/pdf/10.1021/acs.joc.0c01301This will be the main topic of this studentship to undertake the synthesis of illudine and some simplified analogues allowing subsequent testing against the parasites to obtain some SAR and initial phenotyping. Suitable moieties will be added to the optimized simplified analogues allowing cross-linking and affinity purifications to identify protein targets.If time allows and as a backup several other potent trypanocidal natural product hits will investigated including several cyclopeptide analogues.