Rational discovery of second generation anti-cancer ligands

Abstract

Recently, a novel series of Pyrrolo-1,5-BenzOXazepine (PBOX) compounds have shown apoptotic activity upon numerous cancer cell lines. Importantly, they have been suggested as potential antineoplastic agents in particular for the treatment of Leukaemia chemotherapeutic resistant. This thesis combines in silico and in vitro screening technologies for the discovery and mechanistic elucidation of a second generation of PBOX compounds. It is wished to scaffold hop away from the original chemotype due to an adverse in vitro profile. Cancer medicinal chemistry space is examined to focus the virtual screens towards relevant regions of chemical space and enhanced the success of chemotype switching. To overcome the inherent difficulties of working with active analogues set of actives, this work also aims to rationalise the PBOX tubulin interaction so as to guide biochemical research on the understanding and description of PBOX anti-cancer mechanism of action. Finally, a High Content Screening (HCS) platform was employed to determine a Structure Activity Relationship (SAR) for this group o f compounds, validate the in silico work and assess the bio-activities of novel molecules based on the PBOX pharmacophore..