Ti<sup>IV</sup> 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 Ti<sup>IV</sup> are poorly understood. Proteins and nucleic acids are expected to be biological targets for Ti<sup>IV</sup>. Human transferrin (hTF) is a bilobal serum glycoprotein (80 kDa) which transports Fe<sup>III</sup> to cells <i>via</i> 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 Ti<sup>IV</sup> with the phenolate ligand <i>N,N'-</i>ethylene-bis-(<i>o</i>-hydroxyphenylglycine)(H<sub>4</sub>ehpg) was investigated as a model for Ti-hTF (or FBP) interactions. Ti<sup>IV</sup> forms 7-coordinae monomer (<i>rac</i>) and dimer (<i>meso</i>) complexes with H<sub>4</sub>ehpg (<i>rac + meso</i>) with novel stereo-selectivity. <sup>1</sup>H and <sup>31</sup>P NMR studies show that TDC binds selectivity to H<sub>4</sub>ehpg at neutral pH, but preferentially to adenosine triphosphate (APT) at pH values below 5; Ti<sup>IV </sup>transfers from Ti<sup>IV</sup>-ehpg to ATP at acidic pH values. The interactions of TDC with hTF and that of Ti<sub>2</sub>-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 Fe<sup>III</sup> sites with release of the Cp and Cl ligands. Ti<sup>IV</sup> is readily released from Ti<sub>2</sub>-hTF at endosomal pH (ca 5.0) and in the presence of ATP. Ti<sub>2</sub>hTF competes effectively for cell uptake of <sup>59</sup>Fe-hTF into BeWo cancer cells. TDC binds strongly to the phosphate group of nucleotides in aqueous solution and Ti<sup>IV</sup> binds to the phosphodiester groups of nucleotides in the less polar solvent <i>N,N</i>-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 Ti<sup>IV</sup> drugs.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:651886 |
| Date | January 2000 |
| Creators | Guo, Maolin |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/13967 |
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