The development of flow-assisted synthetic methodologies as tools for drug discovery

Abstract

Our research group has a keen interest in drug discovery through the exploration of new biologically active products that display potential for anticancer or antibacterial use. Additionally, we aim to develop and optimise flow chemistry methodologies that allow access to these products in a rapid and improved manner. This thesis is presented as a series of four publications; Paper I details the SAR of structurally diverse cantharidin-based scaffold that show good growth inhibition potential of cancer cell lines. Using flow chemistry techniques, Paper II reports the improved synthesis of the most potent products from Paper I under optimised conditions. Additionally, further derivatisation of the product was carried out using flow hydrogenation and a robust method optimised to effect chemoselective hydrogenation of a single olefin bond over the other. Further, a streamlined approach to hydrogenate dual olefin bonds with a degree of stereoselectivity. Additionally, our group is interested in cyclic peptides capable of preventing quorum sensing between bacterial cells and thus acting as a potential antibacterial through the reduction of bacterial virulence. Paper III describes the use of flow chemistry techniques for the systematic optimisation of reaction parameters used to synthesise linear peptide sequences on solid-phase. This technique was then used to synthesise the linear sequence of potential quorum sensing peptides and other biologically relevant peptides. Further, Paper IV adds to the overall goal of continuous flow solid-phase peptide synthesis by focusing on the initial resin loading step. With the combined protocols and total continuous flow sloid phase peptide synthesis method was created. Collectively, the four articles represent a step forward and contribute to the field of flow chemistry, and drug discovery through the use of flow assisted methodologies.

Date of Award	2020
Original language	English