Under water control: A cascade approach to the pseudolaric acid anti-tumour agents

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In the constant battle against disease, we look to nature for inspiration in the design of new therapeutics. Biologically-active, naturally-occuring molecules often have unique, complex molecular architectures that have evolved over millennia to interact selectively with biological systems. We call these naturally-occuring molecules 'natural products'. With these wonderfully intricate structures comes a major scientific challenge: if we can't isolate what we need from nature, as is often the case, can we synthesise these substances efficiently from scratch in the laboratory?In this project, we will develop new reactions that will allow us to build natural products called the pseudolaric acids very quickly and efficiently. The pseudolaric acids have challenging structures and the potential to inspire ground-breaking, anti-tumour drugs. One member of this family, pseudolaric acid B, has been shown to circumvent the problems of resistance from which many anti-tumour drugs suffer, thus the natural product is active against multi-drug resistant cancers. For example, pseudolaric acid B has been shown to be active against a liver cancer that is resistant to treatment by the famous anti-cancer agent Taxol.Our approach to the pseudolaric acids will involve new 'cascade' reactions that allow simple starting materials to cascade through to complex molecules in just one reaction flask, using just one reagent. Cascade reactions make great economic sense as they extract high value from a chemical reaction, saving steps and therefore time, chemical resources, and minimising waste generation. The cascades that we will develop will also allow us to control the shape, or stereochemistry, of the molecule under construction. The cascade reactions will be triggered by supplying electrons to the starting materials. The electron-transfer processes will be facilitated by the water present in the reaction flask thus we say the reactions are 'under water control'.Improvements in the way we build molecules are urgently needed and are eagerly sought. The new, selective chemical reactions that result from our studies will allow chemists to streamline routes when building molecules in the future, thus saving precious resources. The preliminary results from our laboratory on the discovery of new organic reactions mediated by electron-transfer means that we are uniquely placed to meet this challenge. Obtaining analogues of the biologically-important natural product pseudolaric acid B is a significant and timely problem. While pseudolaric acid B has been shown to bind to a new site on tubulin and to be active against multi-drug resistant cancers, the link between the structure of the molecule and its anti-tumour activity is not understood. Our concise approach to the molecular skeleton of the pseudolaric acids will allow us to make changes to the structure and thus to prepare 'unnatural products' related to the pseudolaric acids. The biological testing of these analogues will give us a unique insight into how the molecule exerts its important biological effect. Ultimately, our studies may lead to new drugs and to improvements in the quality of life, worldwide.