The anticancer drug temozolomide (TMZ), has been in the clinic for treating brain tumours for nearly 30 years. Despite its “Blockbuster” status, no other compounds of this class have reached clinical trial. The mechanism of action of TMZ means the range of tumour types able to respond to TMZ is significantly compromised. New analogues with promising in vitro activity have exhibited problems with solubility and distribution in vivo. This project takes two approaches to resolving these difficulties. The first phase is developing a preliminary study that has identified that improve water solubility and control prodrug activation kinetics. The second phase is more ambitious and proposes confirming and exploiting new knowledge about the mechanism of the released active drug. This has allowed us to design a specific metabolic switch so that the active drug form can only be generated in tumour tissue.
In this project, the candidate will initially focus on the synthesis and crystal structures of new TMZ and MTZ analogues with improved water solubility. Subsequently, the aims of the project are to explore the prodrug activation mechanism of compounds, provided by collaborators at the University of Nottingham, and synthesis and evaluation of new Bradford compounds.