Concise Syntheses of the Meroterpenoids: Facilitating the Discovery of New Classes of Pharmaceuticals

癌症和传染病是英国和全球相当大的发病率和死亡率的原因。这两种疾病的耐药性特别令人担忧，因为当患者对可用的治疗没有反应时，预后往往很差。例如，在英国和美国最常见的癌症是乳腺癌。美国国家癌症研究所公布了美国癌症的统计数据，2015年乳腺癌新发病例估计为234，190例，其中40，700例死亡[http：//www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf]。英国癌症研究中心还公布了英国的统计数据，2011年有331,487例新诊断的癌症，其中乳腺癌、前列腺癌、肺癌和肠癌占一半以上。在同一篇文章中，作者报告了2011年50，285例新发乳腺癌病例和11，716例乳腺癌死亡[http：//www.cancerresearchuk.org/health-professional/cancer-appropriatics#heading-Zero]。包括乳腺癌在内的许多癌症患者对治疗期间使用的药物产生耐药性。例如，他莫昔芬耐药发生在约25%的接受治疗的患者中。他莫昔芬是乳腺组织中雌激素受体的拮抗剂，并且是在乳腺癌治疗中相当重要的药物。在感染性疾病领域，细菌对常见抗生素的耐药性在一般媒体中被广泛报道，具有临床表现如坏死性筋膜炎（食肉病）的万古霉素耐药性肠球菌或甲氧西林耐药性金黄色葡萄球菌感染的令人痛心的报道。患者群体中耐药性的出现是发现和开发治疗癌症和细菌感染等疾病的新药的主要驱动力。2014年，Vertex公司的科学家[http：//pubs.acs.org/doi/abs/10.1021/jm500941m]报告说，天然产物再次非常适合通过化学转化进行研究和衍生，以制备新的生物活性化合物，用于测定和优化，作为明天的抗癌剂和抗生素。在这篇文章中，他们报告说，从1981年1月到2010年12月，在1073种新药中，有540种是天然产品、天然产品的衍生物或结构上与天然产品相关（生物启发），但通过化学合成制成。作为实例，作者描述了天然产物先导物对于多西紫杉醇（其是用于治疗多种癌症的紫杉醇的衍生物）和伊沙匹隆（其是用于治疗紫杉醇抗性癌症的埃博霉素B的类似物）以及许多其它实例的重要性。这项研究计划的重点是设计和开发四种新的化学转化，这些化学转化是在帝国理工学院发明的，用于合成一类天然产物，即meroterpenoids。部分萜类化合物是结构多样的系列，以作为抗生素和抗癌剂等的不同生物活性而闻名。通常，这些化合物具有活性，但其本身的活性不足以成为药物。在制药术语中，它们是命中而不是引线。为了使复杂的天然产物如类萜化合物的合成是实用的，合成路线必须是短的，并且适合于由生物测定结果和计算机辅助药物设计指导的平行合成，以产生药物先导物。帝国团队现在拥有必要的合成工具来进行结构活性研究，并将基于meroterpenoids的新药发现带到触手可及的地方。在这项研究中，新的帝国化学反应将与其他转化一起使用，包括选择性氧化和环化反应（形成额外的环），以打开meroterpenoids的领域，以合理的药物化学和药物发现。

Cancer and infectious disease are the cause of very considerable morbidity and mortality in the UK and globally. Resistance with both diseases is of particular concern since, when a patient does not respond to available therapies, the prognosis is often grim. For example, the most common cancer in the UK and USA is breast cancer. The National Cancer Institute has published statistics for cancer in the USA numbers of new cases on breast cancer there in 2015 has been estimated to be 234,190 with 40,700 deaths [http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf]. Cancer Research UK also publishes statistics for the UK with 331,487 new diagnoses of cancer in 2011 with cancers of the breast, prostate, lung and bowel accounting for over half that number. In the same article, the authors reported 50,285 new cases of breast cancer and 11,716 deaths from breast cancer in 2011 [http://www.cancerresearchuk.org/health-professional/cancer-statistics#heading-Zero]. Patients with many cancers including breast cancer develop resistance to the medicines used during treatment. For example, Tamoxifen resistance occurs in about 25% of patients undergoing treatment. Tamoxifen is an antagonist of the estrogen receptor in breast tissue and is a drug of considerable importance in breast cancer therapy. In the area of infectious disease, bacterial resistance to common antibiotics is widely reported in the general press with harrowing accounts of Vancomycin Resistant Enterococci or Methicillin-resistant Staphylococcus aureus infections with clinical manifestations such as Necrotizing fasciitis (flesh eating disease). The emergence of resistance amongst cohorts of patients is a major driver for the discovery and development of new medicines to treat cancer and bacterial infections amongst other diseases.In 2014, scientists in the Vertex company [http://pubs.acs.org/doi/abs/10.1021/jm500941m] reported that natural products are again very appropriate to study and derivatise by chemical transformations in order to prepare new bioactive compounds for assay and optimization as the anti-cancer agents and antibiotics of tomorrow. In this article, they reported that from January 1981 to December 2010, 540 out of 1073 of the new drugs introduced were either natural products, derivatives of natural products or were structurally related to natural products (bioinspired) but made by chemical synthesis. By way of examples, the authors described the importance of natural product leads for Docetaxel, which is a derivative of paclitaxel used to treat diverse cancers, and Ixabepilone, which is an analogue of epothilone B used to treat taxol-resistant cancers, amongst many other examples. The focus of this research proposal is the design and development of four new chemical transformations, which have been invented at Imperial College, for the synthesis of a class of natural products, the meroterpenoids. The meroterpenoids are a structurally diverse series noted for diverse bioactivities as antibiotics and as anti-cancer agents, etc. In general, these compounds are active but insufficiently active to be drugs in their own right. In pharmaceutical terminology they are hits not leads. In order for the synthesis of a complex natural product such as a meroterpenoids to be practical, it is necessary that the synthetic route is short and amenable to parallel synthesis directed by bioassay results and computer assisted drug design to produce pharmaceutical leads. The Imperial team now has the necessary synthetic tools to make structure activity studies and bring new drug discovery based on the meroterpenoids within reach. In the research, the new Imperial chemical reactions will be employed with other transformations including selective oxidation and cyclisation reactions (forming additional rings) to open up the area of the meroterpenoids to rational medicinal chemistry and drug discovery.