Bio-inorganic chemistry of manganese and titanium
MetadataShow full item record
A wide range of metals are transported in the body by the protein transferrin, including both essential metal ions and probably also metals used in therapeutic agents. The metal binding sites on transferrin contain tyrosine, histidine and aspartate ligands. This thesis is concerned with studies of the essential metal ion manganese, and with titanium, which is used in anticancer agents. In order to aid the characterisation of Mn(III) and Ti(IV) transferrins, the Mn(III) and Ti(IV) complexes with the model ligand ethylenebis[(a-hydroxyphenyl)glycine](H₄EHPG) have been studied. The Mn(III) complexes rac-Na[Mn(EHPG)].3H₂0 (1) and rac,mesoNa[Mn(EHPG)].H₂0 (2), have been prepared and their X-ray crystal structures determined. Complex 1 contains N(S,S)C(R,R) configurations at the N and C stereogenic centres, whilst in the unit cell of complex 2 there are two independent molecules, 2a (mesa) and 2b (rac), with N(R,R)C(S,R) and N(R,R)C(S,S) configurations, respectively. Enantiomers of each complex are also present. The Mn(III) centres have Jahn-Teller-distorted octahedral geometry, with two long bonds and four short bonds. ¹H NMR spectra of these high-spin d⁴ paramagnetic complexes are reported. These complexes give rise to similar ligand (phenolate)-tometal charge-transfer bands as Mn(III)-transferrin. Dissociation of Mn(III) from EHPG occurs below pH 3.4. The Ti(IV) complex of rac-[Ti(EHPG)(H₂0)].1113H₂0 (3) has also been prepared and the X-ray crystal structure determined. All previously-reported crystalline racEHPG metal complexes contain N(S,S)C(R,R), or N(R,R)C(S,S) isomers, whereas 3 unexpectedly contains the N(S,S)C(S,S) and N(R,R)C(R,R) forms. 2D NMR studies indicate that 3 has a similar structure in solution to that in the solid state. A ligand (phenolate)-to-metal charge transfer band was observed at 386 nm, similar to that seen for Ti(IV)-transferrin. Ti(IV)EHPG was stable at pH values down to 1, however, the complex decomposed above pH 7. Mn(III)-transferrin complexes were prepared by air oxidation of Mn(II) in the presence of transferrin. The oxidation state of manganese bound to transferrin was Abstract confirmed by K edge EXAFS. Analysis of the EXAFS data revealed that the metal centre is also Jahn-Teller distorted but with four long bonds and two short bonds, i.e. an inverse distortion to that seen in the Mn(III)EHPG model complexes. Attempts to prepare other Mn(III) complexes which might be suitable for studies of Mn transfer to proteins are described and include cyclam and bicyclam as ligands. The crystal structure of [Mn(cyclam)Ch]Cl₂H₂0 was determined, and contained two long axial Mn-Cl bonds of 2.5249 Å. This complex was shown by electronic absorption spectroscopy to undergo a complicated series of reactions in aqueous solution. K edge EXAFS measurements suggested that at least one Cl ligand dissociated from the complex in aqueous solution. The hydrolysis was shown to be inhibited by the presence of fluoride.