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

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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.