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Title: Proteins and nucleic acids as targets for titanium(IV)
Author: Guo, Maolin
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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TiIV compounds have pronounced anticancer, antiviral and antibacterial activities, and titanocene dichloride (TDC) is currently on phase II clinical trials as an anticancer drug. However, the biological chemistry and mechanisms of action of TiIV are poorly understood. Proteins and nucleic acids are expected to be biological targets for TiIV. Human transferrin (hTF) is a bilobal serum glycoprotein (80 kDa) which transports FeIII to cells via receptor-mediated endocytosis. A structurally similar periplasmic iron binding protein (FBP, 34 kDa) is present in some pathogenic bacteria and is required for virulence. In this thesis, the aqueous coordination chemistry of TiIV with the phenolate ligand N,N'-ethylene-bis-(o-hydroxyphenylglycine)(H4ehpg) was investigated as a model for Ti-hTF (or FBP) interactions. TiIV forms 7-coordinae monomer (rac) and dimer (meso) complexes with H4ehpg (rac + meso) with novel stereo-selectivity. 1H and 31P NMR studies show that TDC binds selectivity to H4ehpg at neutral pH, but preferentially to adenosine triphosphate (APT) at pH values below 5; TiIV transfers from TiIV-ehpg to ATP at acidic pH values. The interactions of TDC with hTF and that of Ti2-hTF with ATP have characteristics which could allow transferrin to act as a mediator for titanium delivery to tumour cells. TDC reacts rapidly with apo-hTF under extra-cellular conditions and binds in the specific FeIII sites with release of the Cp and Cl ligands. TiIV is readily released from Ti2-hTF at endosomal pH (ca 5.0) and in the presence of ATP. Ti2hTF competes effectively for cell uptake of 59Fe-hTF into BeWo cancer cells. TDC binds strongly to the phosphate group of nucleotides in aqueous solution and TiIV binds to the phosphodiester groups of nucleotides in the less polar solvent N,N-dimethylformamide. This behaviour contrasts with that of the anticancer drug cisplatin which binds mainly to N-sites of nucleobases, and may account for the intracellular localisation behaviour of TiIV drugs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available