The presence of hypoxia in human tumours has been shown to drive key aspects of tumour progression as well as their resistance to therapy. This proposal brings together extensive experience with medicinal chemistry, free radical chemistry and pharmacology of tirapazamine analogues to design and evaluate the next generation of compounds of this class. By building on insights obtained through previous HRC-funded grants, new compounds are to be sought with improved potency against hypoxic cells and improved therapeutic activity in xenograft models. Lead compounds will be tested in vivo for anti-tumour activity (for applications with radiotherapy) and toxicology. The identification of these new drugs with increased potency, through an understanding of the radical mechanisms by which they act, will contribute to the development of new therapeutic agents that selectively and effectively target hypoxic tumour cells in patients. This new therapy will provide improved outcomes for patients with hypoxic tumours.