Cobalt(III) Complexes Containing Analogues of Bioactive Anticancer Compounds

Abstract

Since the discovery of cisplatin as a potent anticancer agent, transition metal complexes have played a significant role in the development of new anticancer compounds. The anticancer potential of cobalt complexes has been extensively studied over the last three decades, and much time has been devoted to understanding their mechanisms of action. After understanding the Co(III)/Co(II) reduction activation mechanism, several Co(III) complexes of bioactive anticancer agents have been investigated as potential hypoxia activated prodrugs. Furthermore, after the initial use of nitrogen mustard, several bioactive compounds and their analogues have been investigated as ligands to develop hypoxia activated Co(III) complexes. This thesis describes syntheses and characterisation of Co(III) complexes that have been designed using structural analogues of bioactive anticancer compounds. Chapter 1 gives an overview of the prodrug strategy in cancer therapy, prodrug design using a trigger and an effector unit, and different mechanisms for prodrug activation. Several examples of Co(III) complexes are given, which have been investigated as potential prodrugs to target tumour hypoxia. There are three different parts to this research. Chapters 2, 3 and 4 describe the syntheses and characterisation of Co(III) complexes designed using ligands, which are structural analogues of bioactive anticancer compounds. Chapter 2 describes syntheses of dipeptide analogues of bortezomib, a proteasome inhibitor that is currently being used for the treatment for multiple myeloma. The Co(III)-dipeptide complexes were also analysed for their possible use as hypoxia activated prodrugs in Chapter 2. Chapter 3 includes the continuation to the previous investigation by Ware et al. on Co(III)-cyclen complex using 8-hydroxyquinoline (8HQ) as a model cytotoxin. Efforts were made to establish a synthetic route to introduce a porphyrin derivative into prodrug design, with the aim of improving tumour cell targeting properties of the prodrug complex. Chapter 4 describes syntheses of two polypyridyl carboxamide ligands, PDPA and MID(AMP)2, and syntheses of their Co(III) complexes. PDPA and MID(AMP)2, are structural analogues of PMAH, Py3PH2, which are carboxamide ligands containing a similar metal-binding domain as bleomycins. The experimental procedures are detailed in Chapter 5.