Pancreatic cancer drug discovery based upon (+)-grandifloracin

Abstract

Approximately 1 in 70 people in the UK will be diagnosed with pancreatic cancer during their lifetime and there are currently no effective drugs to treat the disease. Anti-austerity agents - compounds capable of removing a cancer cells’ ability to tolerate nutrient deprivation – provide one possibility for future chemotherapeutics in this area. (+)-Grandifloracin (GF) is one such agent and is, therefore, an exciting lead for anti-austerity drug discovery against PANC-1 cells.

The initial aim of this project was to explore the potential of GF through the production of a range of structural analogues based upon variation of the ester R-group within the molecule. A series of analogues exploring electronic and steric parameters was designed and synthesised. This aim was further broadened through the design of amide and thioester containing R-groups. A selection of GF analogues was then assessed for their biological activity against PANC-1 cells with the most active compound, shown below, discovered to have increased its activity by an order of magnitude when compared to the parent compound.

Through the course of this work a number of unusual structural rearrangement products were also discovered. Some of which contained novel 3D architectures and were only accessed via novel synthetic methodologies also discovered during this project. The two most structurally unusual compounds are shown below.

Date of Award	3 Apr 2019
Original language	English
Awarding Institution	University of Bath
Supervisor	Lorenzo Caggiano (Supervisor) & Simon Lewis (Supervisor)