From Total Synthesis-Inspired Methodology to Anti-HIV therapy

Organic chemistry provides a bridge between the physical world of atoms, molecules and their reactions, and the biological sciences, with one area of particular importance being the development of new medicines. Many drugs are originally inspired by 'natural products' / molecules refined by Nature over millions of years, which can have potent, specific biological activity against human diseases. As such, natural products represent highly advanced starting points for pharmaceutical research; however, their development as drug leads can be hampered by low natural abundance. One solution (which avoids decimation of the natural habitat) is the artificial preparation, or 'total synthesis' of the natural product. Historically, this process can take many years, a timescale which cannot satisfy the requirements of automated pharmaceutical screening. However, the application of improved, efficient chemical methods which enable rapid and scalable syntheses of these natural medicines (and non-natural 'analogues' with improved efficacy), is now an aim that is within the grasp of the organic chemist. Natural products chemistry thus stands on the brink of being re-embraced by the pharmaceutical community; this proposal aims to show that the natural product target itself is just the beginning of what an organic chemist can deliver.Traditionally, organic chemistry can be divided into two schools of research. The development of new reactions, which is fundamental to improving the efficiency of chemical synthesis, investigates new ways to form bonds between atoms. Often there is no specific target, and researchers can resort to scouring a vast array of natural products for one which will showcase their methodology. By contrast, in the field of total synthesis of structurally challenging molecules (which provides the ultimate testing ground for methodology), chemists tend to use known methods to forge the most efficient path they are able to a given target. The challenge of synthesis itself usually dictates that the choice of reaction is one with precedent and reliability.This proposal seeks to reverse this accepted order of reaction development: Natural products are seen as the inspiration for new reactions, rather than an arbitrary setting. Biologically important targets will be selected, and provide the impetus for the invention of an efficient and appealing synthetic transformation. Following development in a general setting, this method will then be applied in the context it was intended / a total synthesis of the natural product and analogues. Two projects which demonstrate the potential for natural products to initiate the development of useful, general reactions with broad applicability are proposed: Cepacin A, a potent antibiotic which contains an intriguing unsaturation motif, is the inspiration for a novel synthesis of chiral allenes. Lancifodilactone G and rubriflordilactone A, which possess anti-HIV properties, are the basis for an innovative route to bi- or tricyclic molecules.My proposal also details a collaborative project towards new methods for HIV inhibition. A currently uninvestigated area of the HIV life cycle is the 'packaging' of viral RNA into new virus particles. Packaging is initiated by binding of the viral protein Gag to a region of the viral RNA called psi. It is known that psi, and a truncated analogue, are bound specifically by a region of Gag that contains amino acids with nucleophilic sidechains. We intend to design psi analogues containing an electrophilic site, which will bind to Gag and place this site in proximity to the nucleophilic sidechain amino acids, leading to the formation of a covalent bond, irreversible binding of Gag, and inhibition of packaging. This is an exciting and unexplored area of chemical biology which harnesses the expertise of both the organic chemist and the virologist, and could have implications for the design of inhibitors for other virus specific RNA-protein interactions.