Chemistry Cascades: Synthesis of prostratin analogues for evaluation against HIV

Professor David Procter was recently awarded an EPSRC grant: 'Chemistry Cascades: Synthesis of prostratin analogues for evaluation against HIV' (£297,875). This research project which aims to develop an efficient method to synthesis prostratin, will start in November 2010.

In the field of healthcare, there are few greater challenges than the continuing fight against HIV and AIDS. Biologically active natural products often have complex molecular architectures that have evolved over millennia to act as selective ligands for biological targets and provide a source of inspiration for the design of new therapeutic weapons in this fight. The recent discovery that compounds related to the tumour-promoter phorbol, such as prostratin, are non-tumour promoting natural products that are active against latent HIV is the most exciting recent development in the biology of this compound class. Latent HIV viral reservoirs persist after treatment of AIDS patients using current therapies, thus preventing elimination of the virus. Prostratin therefore promises a major advance in approaches to deplete viral reservoirs and has caused significant excitement in recent years.

 

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The levels of prostratin found in source plants are 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 'topdown' 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.

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