Abstract:
Cancer is a leading cause of death. Current therapies to combat this devastating
disease include surgery, radiotherapy and chemotherapy. The efficacy of the latter two
approaches is limited by hypoxic (oxygen-deficient) regions found in solid tumours. This
thesis describes the development of two classes of cobalt(lll)- and chromium(lll)-based
chemotherapeutic agents that are designed to exploit hypoxia for therapeutic effect.
Chopters 2, 3, ond 4 discuss the synthesis and characterisation of cobolt(lll) complexes
designed to selectively release diffusible cytotoxins in the hypoxic regions of tumours
upon bioreduction. This prodrug class is entitled hypoxia-activated prodrugs of diffusible
cytotoxins (HPDCs). Chapter 2 describes attempts to coordinate novel diamine-based nitrogen mustard cytotoxins to cobalt(lll). The difficulties experienced in the synthesis of
bis(pentane-2,4-dionato) cobalt(lll) complexes of non-cytotoxic analogues of the candidate nitrogen mustard ligands highlight the importance of steric and stability considerations in HPDC design. Chapter 3 details efforts to devise a general synthetic route for the preparation of mixed ligand cobolt(lll) complexes containing the nitrogen mustard ligand N,N-bis(2-chloroethyl)-1,2-ethanediamine (dce). The reaction of tris-
bidentate ligand complexes with dce, or its non-cytotoxic analogue N,N-diethyl-1,2-
ethanediomine (dee), led to the successful one-step synthesis of corresponding bis-oxalato and bis-carbonato complexes. This synthetic approach was subsequently utilised in Chapter 4 for the preparation of dce-based prodrugs containing a variety of 3-substituted-pentane-2,4-dionato ancillary ligands.
