Chemistry Cascades: Synthesis of prostratin analogues for evaluation against HIV

In the field of healthcare, there are few greater challenges than the continuing fight against HIV and AIDS. In this war, we look to nature for inspiration in the design of new therapeutics as natural products often have complex molecular architectures that have evolved over millennia to act as selective ligands for biological targets. For example, naturally occuring phorbol esters are amongst the most potent of tumour promoters and have proved useful 'small molecule' tools for the study of carcinogenesis and the development of methods for its prevention. The discovery that natural compounds related to phorbol, such as the non-tumour promoting natural product prostratin, are active against latent HIV is the most exciting recent development in the biology of this compound class. In fact, prostratin promises a major advance in approaches to deplete viral reservoirs and has caused significant excitement in recent years. Latent HIV viral reservoirs persist after treatment of HIV-infected patients using current therapies, thus preventing elimination of the virus. Prostratin functions by flushing 'hibernating' HIV out of resting T-cells so that antiretroviral drugs can attack.Unfortunately, the levels of prostratin found in the source plants is very low and limited access to the natural product has slowed its development as a therapeutic agent. This poses the question: if we can't isolate what we need from nature, can we synthesise these substances efficiently in the laboratory? Unfortunately, natural products related to phorbol are very difficult to prepare using the current state-of-the-art synthetic tools. In fact, the only reported synthesis of phorbol took 52 chemical steps! The only attempt to prepare prostratin to date has started from the scarce natural product phorbol. Not only is this an unsatisfactory solution to the supply problem, but a 'top-down' synthesis such as this does not facilitate fundamental changes to the interior of the molecule and we learn little about the effect of modifying the natural product's core structure. The development of an efficient synthesis of prostratin from scratch is a timely challenge and will address the issue of supply and will allow the preparation of analogues of prostratin that are urgently needed but are currently unobtainable.In this project we will develop selective reactions in which simple starting materials 'cascade' through to complex molecules in a single step, using a single reagent. Not only will the cascade reactions grant us rapid access to the targets but they will also allow us to control the shape, or stereochemistry, of the molecule under construction. The new synthetic tools developed will allow us to carry out the first synthesis of prostratin and analogues of the natural product that will prove valuable weapons in the fight against HIV and AIDS. In addition, the new synthetic methods we create will allow chemists to streamline routes when designing syntheses in the future, thus shortening processes and minimising waste. Such improvements in the way we build molecules are urgently needed by the scientific community.

Who will benefit from this research and why? The impact on health - In the field of healthcare, there are few greater challenges than the fight against HIV and AIDS. According to the AIDS research alliance, prostratin is potentially capable of eliminating HIV reservoirs and curing AIDS . Our work on prostratin analogues will benefit members of the international research community working in the field of HIV and AIDS in pharmaceutical, biotech and biopharmaceutical companies, improving economic competitiveness and aiding wealth creation. The timescale for industrial impact will be relatively short, with benefits arising 2-3 years after the completion of this project. New prostratins will lead to improvements in the quality of life and health of individuals worldwide. The impact on chemical production - Synthesis underpins the work of a broad cross-section of industrial scientists in chemistry, biology, medicine and materials, by providing access to the molecules they need. New, selective transformations and cascade reactions will therefore be valuable tools for synthetic chemists in their day-to-day work in industrial labs and plants. More specific beneficiaries include the pharmaceutical, biotech, biopharmaceutical and agrochemical industries. The synthetic technology developed during our studies will allow chemists to streamline routes when designing future syntheses, thus shortening processes and minimising waste. The impact on the 'people pipeline' - Breakthroughs in industrial research require skilled synthetic chemists. The project will provide a unique training in multi-step asymmetric synthesis, reaction development, mechanism, target synthesis and structure elucidation. In addition, the PDRA will liaise with biological groups and initiate the evaluation of prostratin analogues. Organisation, critical and creative thinking and the use of IT are crucial in modern research and the PDRA will also be trained in these transferable skills. Finally, the PDRA will receive instruction in the preparation of posters and lectures for dissemination activities that are important for achieving impact quickly. How will we maximize the Impact of our research? Exploitation - Results of commercial significance will be protected with help from UMIP (The University of Manchester Intellectual Property Limited). In collaboration with UMIP, we expect to patent the prostratin analogues prepared during the project and the synthetic routes that render them accessible for the first time. Furthermore, we expect prostratin analogues with accompanying biological preliminary data to be an attractive package for sale or licensing to pharmaceutical and biotech companies. Communications - After protection of IP, findings will be published in high impact factor journals. Dissemination to a wider scientifically literate community will be achieved through articles in science magazines. In addition, results will be disseminated by the PDRA and PI at national and international conferences and by the PI in invited talks at companies. Engagement with beneficiaries - The PI has ongoing collaborations with industrial teams (Schering Plough, SAFC-Hitech, ACAL Energy, AstraZeneca, GlaxoSmithKline, Pfizer) in addition to past collaborations (Novartis, Syngenta, Avecia, Celltech, OSI pharmaceuticals) and consultancies (PZ Cussons). A Knowledge Transfer Fellow, jointly funded by ACAL Energy and the Knowledge Transfer Account at Manchester, has recently completed his studies aimed at implanting the group's synthetic expertise into the company. In addition, the first AstraZeneca Fellow has joined the PI's group on secondment. Through these regular interactions with industrial teams, the group's new synthetic methods will be shared - and valuable feedback received - thus ensuring effective knowledge transfer. Importantly, this project will also lead to the creation of new links with industrialists, particularly those working in the field of HIV.