Synthetic approaches to medicinally relevant Euphorbia diterpenes

该项目属于EPSRC合成有机化学研究领域。天然产物（及其类似物和衍生物）作为治疗剂的流行已被Newman等人在过去二十年的一系列综合综述中广泛记录。他们的分析表明，尽管组合药物化学的兴起，这些分子在临床阶段仍然占据主导地位。在抗感染和抗癌类别中，天然产品及其衍生产品占我们小分子治疗武器库的50%以上。然而，由于高度的分子复杂性，合成被认为是过于冗长和低效的，不能被认为是药物化学的一个有效分支。现代天然产物合成正朝着一种范式发展，在这种范式中，达到一种中间体或一系列密切相关的中间体的策略是实现的，然后是各种天然产物及其类似物的多样化。大戟属植物的成员产生一系列复杂的萜类天然产物，具有广泛的结构基序和生物活性。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。大戟二萜在麻疯烷类中是通过不同的氧化、不饱和和关键位置的酯化状态来区分的。这种模块化结构的多样性使得这类天然产物非常适合于发散合成方法，其中开发了一种达到复杂中间体的稳健策略，允许随后选择性衍生各种天然产物和非天然类似物。peplanin A和euphodendroidin D分别从peplplus和euphodendroides中分离出来，是麻疯素类的成员，并显示出对道霉素在癌细胞中的p糖蛋白（P-gp）外排的有效抑制；每一种药物的有效性都是目前临床金标准环孢素的两倍。这种有效的活性，以及在整个麻风树类中发现的广泛的P-gp外排泵抑制，表明这些天然产物及其衍生物可能是对抗多药耐药的有力工具。衍生化工作将以Corea等人在2003年进行的麻风烷二萜的构效关系研究为指导。因此，我们之前已经在我们提议的合成pepluanin A和euphodendroidin d的后期中间体中开发了功能路线。这个项目的目的是通过精炼和完成这些拟议的合成来巩固先前的工作，然后在大戟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.