Sanchez-Cano, Carlos (2009)
Ph.D. thesis, University of Birmingham.
The work described herein concerns the effect on the anticancer activity and the ability to reach their possible intracellular targets of certain steroidal metallodrugs and metallosupramolecular cylinders. Chapter 1 surveys the background to the project, surveying different DNA-binding modes, explaining their importance in the anticancer properties of metallodrugs and showing an overview of the different strategies used for enhanced delivery of these metallodrugs. In Chapter 2 the synthesis of new steroidal DNA covalent-binding platinum(II) complexes together with techniques to purify previously synthesised steroidal complexes are presented. Their cytotoxicity, cellular uptake and biomolecular interaction are investigated, showing that the coupling of the steroid confers activity to otherwise inactive complexes, modifying their DNA binding mode and cellular uptake and distribution. Chapter 3 explores the coupling of similar steroidal delivery vectors to non-covalent metallodrugs, presenting simple synthetic pathways to create such complexes in a single step. Their anticancer activity and DNA-binding affinity are investigated: surprisingly showing that this coupling has negative effects. In Chapter 4 the cytoxicity and cellular behaviour of metallosupramolecular cylinders are studied. It is shown that these complexes can cross the cellular membrane, concentrating in the nuclei where they can interact with cellular DNA.
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