Studies towards the total synthesis of an anti-HIV natural product

该项目属于EPSRC合成有机化学研究领域。在过去的二十年中，Newman等人进行了一系列全面的综述，记录了天然产物在医学上作为治疗剂的使用。他们的发现表明，尽管组合药物化学正在兴起，但天然产物（及其衍生物和类似物）在发现用于开发人类疾病药物的先导物方面发挥着重要作用。因此，继续研究迄今未开发的天然产物的生物活性和合成对新药的发展至关重要。从放线菌ununalis链霉菌中提取的天然产物ununaphenol由Andersen等人于2015年首次报道，他们证明了ununaphenol可以抑制体外HIV-1复制，而不会伴随宿主t细胞的细胞毒性。对市场上销售的抗逆转录病毒疗法因地那韦、依非韦伦或雷替格拉韦耐药的HIV毒株也观察到类似的效果。由于这些药物在对抗艾滋病毒方面具有不同的作用机制，因此，吲哚酚对这些耐药病毒的功效表明，天然产物具有不同的作用机制。然而，这一机制的阐明，阻碍了低量的ununaphenol分离。ununaphenol与enediyne抗生素ununalamycin结构相似，ununalamycin本身被认为是ununaphenol的生物合成前体。虽然uncalamycin已经有几篇报道，包括Nicolaou等人的全合成，但除了关于uncalamycin的分离论文外，还没有关于uncalamycin的报道。本课题组之前的工作研究了利用氨基酸衍生的催化剂来构建含氮的叔酚核。我们还开发了一个天然产物的简化模型系统，以探索可能适用于其制备的关键合成变换。本项目的主要目的是完成第一次全合成吲哚酚。新的催化剂将被研究，以使更有效地制备氮基核心，而在模型系统上开发的合成转化将用于修改该核心，以获得天然产物。一旦合成完成，将针对分离报告中进行的进一步生物测试，以便更好地了解其抗艾滋病毒活性和作为治疗艾滋病毒先导化合物的潜力。希望核心的催化结构将使ununaphenol的类似物多样化，与原始天然产物相比，可能显示出更好的治疗性能。

This project falls within the EPSRC Synthetic Organic Chemistry research areaOver the last two decades, a series of comprehensive reviews by Newman et al have documented the use of natural products as therapeutic agents in medicine. Their findings reveal that, despite the rise of combinatorial medicinal chemistry, natural products (and their derivatives and analogues) play a major role in the discovery of leads for the development of drugs for human diseases. As such, continued research into the biological activity and synthesis of hitherto unexplored natural products remains crucial to the advancement of new medicines.The natural product unciaphenol, extracted from the actinomycete Streptomyces uncialis, was first reported by Andersen et al in 2015, who demonstrated that unciaphenol inhibits in vitro HIV-1 replication without concomitant cytotoxicity to host T-cells. Similar effects were also observed against strains of HIV resistant to the marketed anti-retroviral therapies indinavir, efavirenz or raltegravir. Since these drugs have different mechanisms of action in combatting HIV, the efficacy of unciaphenol against these drug-resistant viruses indicates a distinct mechanism of action for the natural product. Elucidation of this mechanism was, however, hindered by the low quantity of unciaphenol isolated.Unciaphenol bears close structural similarities to the enediyne antibiotic uncialamycin, itself considered a biosynthetic precursor to unciaphenol. While uncialamycin has been the subject of several reports, including its total synthesis by Nicolaou et al, there are no reports beyond the isolation paper concerning unciaphenol. Previous work in our group has investigated the use of an amino acid-derived catalyst in order to construct the nitrogen-bearing core of unciaphenol. We have also developed a simplified model system of the natural product in order to probe key synthetic transformations which may be applicable to its preparation.The principal aim of this project is to complete the first total synthesis of unciaphenol. New catalysts will be investigated to enable a more efficient preparation of the nitrogen-based core, while the synthetic transformations developed on the model system will be used to modify this core to give the natural product. Once the synthesis has been accomplished, biological testing further to that performed in the isolation report will be targeted in order to better understand its anti-HIV activity and potential as a lead compound for treatment of HIV. It is hoped that the catalytic construction of the core will enable diversification to analogues of unciaphenol which may display improved therapeutic properties compared to those of the original natural product.