Anticancer therapies from renewable sources

Well over 50% of anti-cancer drugs take their inspiration from molecules that were isolated from Nature (so called Natural Products). During this PhD project you will explore the preparation of anticancer natural products from renewable starting materials. Depending upon your scientific background and previous lab experience, we can offer a selection of specific targets that could be accessed using a blend of synthetic chemistry and synthetic biology. Possible molecular targets are the taxanes (e.g. Taxol), glycosyldiglycerides and/or homoharringtonine (HHT), which represent three distinct structural types (and biosynthetic origins), and display their anti-cancer activity by three different mechanisms (microtubule stabilisation, translation initiation inhibition, translation elongation inhibition). These molecules can all be extracted from plant species, but sustainable/renewable routes for their large scale production are required. During this PhD we will explore preparing these materials synthetically from simpler renewable precursor building blocks, and/or we can exploit protein overexpression techniques to produce them in a host organism (or a combination of the two).
Taxanes: Previous work in our laboratory has shown that taxadiene, the key precursor to Taxol, can be prepared in two different ways using either synthetic chemistry or synthetic biology. In the synthetic chemistry approach, we synthesised taxadiene from the simpler renewable terpene farnesol, and using synthetic biology we were able to overexpresss taxadiene synthase in tomato plants that then produced taxadiene instead of the usual carotenoid pigments. During this PhD project we want to advance this science to explore further steps along the pathway to Taxol, and this will involve exploration of chemical and/or biological oxidation of the hydrocarbon taxadiene scaffold.

Glycosyldiglycerides: Previous work in our laboratory has shown that certain glycosyldiglycerides can be extracted from plant species, and that they show novel anti-cancer activity. Specifically, these molecules are newly discovered selective inhibitors of protein translation, and they have shown efficacy in vivo. These molecules have a modular construction (sugar-glycerol linker-lipid sidechain) and they are readily prepared in the laboratory. During this PhD we plan to synthesise a wide variety of analogues of these molecules to explore their structure/activity relationship. Furthermore, we will also examine methods to improve their drug-like properties.

Homoharringtonine (HHT): Previous work in our laboratory has resulted in the synthesis of the alkaloid core of HHT. This alkaloid core is called cephalotaxine and it is also produced by the same Japanese Plum Yew tree that produces HHT, and the structures only differ by the presence/absence of an ester side chain. During this project, we will examine the use of biotransformations to attach the ester side chain to cephalotaxine to produce HHT. This will require you to first synthesise the required side chain carboxylic acid, and then explore the use of enzymes for the key biocatalytic esterification reaction.

References to learn more:
1. Howat, S., Park, B., Oh, I. S., Jin, Y-W., Lee, E-K., & Loake, G. J. Paclitaxel: biosynthesis,
production and future prospects. New Biotechnology, 2014, 31, 242-245.
doi:10.1016/j.nbt.2014.02.010
2. Bhat, M., Robichaud, N., Hulea, L. et al. Targeting the translation machinery in cancer. Nat
Rev Drug Discov 2015, 14, 261-278 doi:10.1038/nrd4505