Abstract:
This thesis describes the synthesis, characterisation and biological evaluation of cobalt(III) complexes which have been designed as hypoxia selective cytotoxins (HSCs).
Chapter One describes the rationale behind the design and synthesis of metal-based HSCs, including their proposed mode of action, in comparison to the modes of action of other metal-based anti-cancer agents, and of organic HSCs. The synthesis and biological activities of the lead compounds in the class of metal-based HSCs, a series of cobalt(III)-acac-nitrogen mustard complexes, (acac=pentane-2,4-dionato) are also discussed.
Chapter Two details the synthesis of cobalt(III)-aliphatic nitrogen mustard complexes, and their non-toxic alkyl-substituted diamine analogues, which incorporate the tropolonato ancillary ligand, and cobalt(III)-diamine complexes with the 5-bromotropolonato ancillary ligand. The characterisation, biological testing and electrochemical behaviour of these complexes are also discussed, and the X-ray crystal structure analysis of [Co(trop)2(BEE)]ClO4(BEE=N,N'-diethylethylenediamine) is presented.
Chapter Three describes the synthesis of cobalt(III)-aliphatic nitrogen mustard complexes with dithiocarbamato ligands, using the novel dinuclear precursor [Co2(R2dtc)5]BF4 (R2dtc=dialkydithiocarbamato). In addition, the synthesis of the first cobalt(III) complexes of the aromatic mustard ligand OPDM (OPDM=4-[N,N-bis-(2-chloroethyl)amino]-1,2-diaminobenzene) are discussed. These compounds undergo a base-catalysed oxidation to the OPDMI complexes (OPDMI=4-[N,N-bis-(2-chloroethyl)amino]-1,2-diiminocyclohexa-3,5-diene) which contain a coordinated diimine mustard ligand. The characterisation, biological evaluation and electrochemical behaviour of the aliphatic and aromatic mustard complexes are discussed.
Chapter Four describes efforts which were directed towards the synthesis of higher denticity mustard complexes in a template fashion from [Co(u-EDDA)(BCE)]PF6 (u-EDDA=ethylenediamine-N,N-diacetato). The synthesis and characterisation of the precursor [Co(u-EDDA)(BCE)]PF6 (BCE=N,N'-di(2-chloroethyl)ethylenediamine) and its analogue [Co(u-EDDA)(BEE)]PF6 are discussed, in addition to the reactivity of the former complex.
Chapter Five Discusses the synthesis of cobalt(III)-Schiff base complexes with bidentate nitrogen mustard ligands and their diamine analogues. The X-ray crystal structure analyses of two Schiff base complexes, [Co(happen)(BEE)]ClO4 and [Co(acacen)(BCE)]ClO4 are presented.
Chapter Six describes experimental and instrumental methods and details the syntheses of the new compounds.
