Natural products represent the backbone of clinically used antitumour agents and are also widely used in areas such as antibacterials and antivirals. Classical total synthesis of natural products is time consuming and usually not atom economical. From a medicinal chemistry point of view, it does not allow the rapid synthesis of analogue structure in order to establish structure activity relationships for compounds and it is not generally amenable to automation.

In this project, we will extend our previous work on cyclic peptide natural products and their analogues such as chlorofusin(ref i) and TANDEM (ref ii and iii) and apply similar methodology to compounds that have potent biological activity. The project will require the solution phase synthesis of monomers that are amenable to Fmoc chemistry but are based upon unnatural amino acids, along with solid phase peptide chemistry. Ultimately, there will also be elements of biological assay development and application.

The aim of the project is to use solid phase synthesis to design routes to complex natural products and to generate analogues for biological assay in a parallel fashion.

(i) Woon, E. C. Y; Arcieri, M.; Wilderspin, A. F.; Malkinson, J. P. ; Searcey M. Solid phase synthesis of chlorofusin analogues. J. Org. Chem. 2007, 72, 5146-5151
(ii) Dawson, S.; Malkinson, J. P.; Paumier, D.; Searcey, M. Bisintercalator natural products with potential therapeutic applications. Isolation, structure determination, synthetic and biological studies. Nat. Prod. Rep. 2007, 24, 109-126.
(iii) Malkinson, J. P.; Anim, M. K.; Zloh, M; Searcey M.; Hampshire, A. J.; Fox, K. R.; Efficient Solid-Phase-Based Total Synthesis of the Bisintercalator TANDEM  J. Org. Chem. 2005, 70, 7654-7661.