A study into the synthesis of potential radiation-activated prodrugs of cobalt(III) targeting tumour hypoxia in cancer therapy

Abstract

Radiotherapy has been a mainstream therapeutic method of cancer treatment for decades. Advances in the technology have allowed ionising radiation to be given with precision and accuracy. The widespread prescription of radiotherapy to cancer patients implies that even minor improvements in the treatment method can result in large number of successful prognoses. This thesis describes the syntheses and characterisation of cobalt(III) complexes that have been designed to counter the limitations of radiotherapy under hypoxic (low oxygen concentration) cell environments. Chapter I addresses the cause of tumour hypoxia and its impact on radiotherapy. It then describes how hypoxia can be exploited as a condition for prodrug activation and how products from the radiolysis of water can be utilised in the activation process. Examples of compounds prepared in previous studies from this laboratory and compounds reported in the literature are presented to demonstrate the prodrug concept. The design criteria for radiation activated prodrugs (RAPs) are discussed and the rationale behind the selection of each component presented. Chapters II, III, and IV describe the syntheses and characterisation of three generations of Cobalt(III) complexes designed as potential candidates for RAPs. The three generations of complexes differ by the macrocyclic ancillary ligands used. Chapter II discusses complexes of cyclen based ligands. Chapter III presents complexes containing cross-bridged macrocycles of cyclen or cyclam. Chapter IV investigates the novel complexes from 2,6-dioxocyclen and 5,12-dioxocyclam which incorporate amidate donor groups. The synthetic approach and difficulties encountered are discussed and resolutions presented. Preliminary evaluations for the first and the second generation prodrugs are outlined at the end of their respective chapters. Chapter V contains an overview of the syntheses covered in this thesis. The impacts of various features incorporated onto the macrocycle are compiled into tables, allowing comparisons to be drawn on the suitability of these complexes as RAP. Experimental procedures are detailed in Chapter VI.