Synthetic approaches to medicinally relevant Euphorbia diterpenes

该项目福尔斯属于EPSRC合成有机化学研究领域。纽曼等人在过去二十年的综合系列综述中广泛记录了天然产物（及其类似物和衍生物）作为治疗剂的流行情况。他们的分析表明，尽管组合药物化学的兴起，这些分子仍然是临床阶段的主导者。在抗感染和抗癌类别中，天然产品及其后代占我们小分子治疗药物库的50%以上。然而，由于高度的分子复杂性，合成可能被认为太冗长和低效而不能被认为是药物化学的有效分支。现代天然产物的合成正朝着先合成一个或一系列密切相关的中间体，然后再合成多种天然产物及其类似物的方向发展，大戟属植物产生了一系列复杂的萜类天然产物，其结构和生物活性具有多样性。这些分子及其非天然类似物的复杂性和治疗潜力使它们成为诱人的合成靶标。大戟属二萜在麻风树烷类中通过在关键位置的各种氧化、不饱和和酯化状态而彼此区分。这种模块化结构多样性使得这类天然产物非常适合于不同的合成方法，其中开发了用于获得复杂中间体的稳健策略，其允许随后选择性衍生为各种天然产物和非天然类似物。peplus和E.树枝状花序分别是麻风树烷类的成员，并且显示出对癌细胞中柔红霉素的P-糖蛋白（P-gp）流出的有效抑制;每一种都是目前临床金标准环孢菌素的大约两倍有效。这种有效的活性，沿着广泛的P-gp外排泵抑制，在整个jatrophane类中发现，表明这些天然产物及其衍生物可能是对抗多药耐药性的有力工具。2003年Corea等人对麻风树烷型二萜化合物的构效关系进行了研究，为衍生化工作提供了指导。因此，我们已经开发了合成pepluanin A和euphodendroidin D的后期中间体的功能路线。该项目的目的是通过改进和完成这些建议的合成来巩固先前的工作，然后在大戟属二萜类中寻找其他目标。

This project falls within the EPSRC Synthetic Organic Chemistry research area.The prevalence of natural products (and analogues and derivatives thereof) as therapeutic agents has been extensively documented by Newman et al. in a comprehensive series of reviews over the last two decades. Their analyses reveal that these molecules remain dominant players on the clinical stage, despite the rise of combinatorial medicinal chemistry. In both the anti-infective and anti-cancer categories, natural products and their descendants constitute over 50% of our small molecule therapeutic arsenal. However, due to high degrees of molecular complexity, syntheses can be considered to be too lengthy and inefficient to be considered as an effective branch of medicinal chemistry. Modern natural product synthesis is moving towards a paradigm wherein a strategy to reach an intermediate or series of closely related intermediates is achieved, and then diversification to various natural products and analogues thereof follows.The members of the Euphorbia genus of plants produce an array of complex terpenoid natural products, which feature a vast diversity of structural motifs and biological activities. The complexity and therapeutic potential of these molecules, and non-natural analogues thereof, make them alluring synthetic targets. Euphorbia diterpenes within the jatrophane class are differentiated from one another by various oxidation, unsaturation, and esterification states at key positions. Such modular structural diversity renders this class of natural product well-suited to a divergent synthetic approach, wherein a robust strategy for reaching complex intermediates is developed which allows for subsequent selective derivatisation to various natural products and non-natural analogues.Pepluanin A and euphodendroidin D, isolated from E. peplus and E. dendroides respectively, are members of the jatrophane class and show potent inhibition of the P-glycoprotein (P-gp) efflux of daunomycin in cancer cells; each is approximately twice as effective as the current clinical gold-standard, cyclosporin. This potent activity, along with the broad P-gp efflux pump inhibition found throughout the jatrophane class, suggests that these natural products and their derivatives might be powerful tools with which to combat multidrug resistance. The derivatisation effort would be guided by the structure-activity relationship studies of the jatrophane diterpenes undertaken by Corea et al. in 2003.As such, we have previously developed functional routes to late-stage intermediates in our proposed syntheses of pepluanin A and euphodendroidin D. The aim of this project is to consolidate prior work by refining and completing these proposed syntheses, and then to strike out for other targets within the Euphorbia diterpene class.