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

该项目福尔斯属于EPSRC合成有机化学研究领域。在过去的二十年里，纽曼等人的一系列综合评论记录了天然产物在医学中作为治疗剂的用途。他们的研究结果表明，尽管组合药物化学的兴起，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线索方面发挥着重要作用。因此，对迄今尚未开发的天然产物的生物活性和合成的持续研究对于新药的发展仍然至关重要。天然产物unciaphenol是从放线菌链霉菌uncialis中提取的，由Andersen等人于2015年首次报道，他们证明unciaphenol抑制体外HIV-1复制，而不伴随对宿主T细胞的细胞毒性。对市售抗逆转录病毒疗法茚地那韦、依法韦仑或雷特格韦耐药的艾滋病毒株也观察到类似的效果。由于这些药物在对抗HIV方面具有不同的作用机制，因此unciaphenol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。Unciaphenol与烯二炔类抗生素uncialamycin（uncialamycin）具有密切的结构相似性，后者本身被认为是unciaphenol的生物合成前体。虽然uncialamycin已成为几个报告的主题，包括Nicolaou等人的全合成，但除分离论文外，没有关于unciaphenol的报告。我们小组以前的工作已经研究了使用氨基酸衍生的催化剂来构建unciaphenol的含氮核心。我们还开发了一个简化的天然产物模型系统，以探索可能适用于其制备的关键合成转化。本项目的主要目标是完成unciaphenol的首次全合成。将研究新的催化剂，以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饰该核心以得到天然产物。一旦合成完成，将针对分离报告中进行的进一步生物学测试，以更好地了解其抗艾滋病毒活性和作为治疗艾滋病毒的先导化合物的潜力。希望核心的催化构建将使unciaphenol类似物多样化，与原始天然产物相比，unciaphenol类似物可显示出改善的治疗性质。

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.