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Title: Chemistry of antiviral metallomacrocycles
Author: Hunter, Tina M.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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In order to elucidate the mechanism of action of AMD3100, 1 synthesised several metal-cyclam complexes, metal complexes of xylyl-bicyclam, AMD3329 and its component macrocycle, and their metal complexes. Xylyl-bicyclam was synthesised, and complexed with palladium, nickel, copper and cobalt. 1D and 2D 1H, 13C and 15N NMR studies revealed that [Pd2(xylyl-bicyclam)](OAc)4 exists as one major configuration in aqueous solution, the trans-III configuration. The addition of acetate to this solution did not induce any configurational change. NMR studies on [Ni2(xylyl-bicyclam)](OAc)4 showed it to be a mixture of paramagnetic and diamagnetic species in solution. Visible spectroscopy showed the main configuration to be square-planar. Two trans configurations of [Co2(xylyl-bicyclam)Cl4]Cl2 were identified using 1D and 2D 1H, 13C and 15N NMR spectroscopy. Upon addition of acetate to this complex, configurational changes occur, eventually to give one trans configuration. Mass spectrometry on this product showed it to be [Co2(xylyl-bicyclam)(OAc)4](OAc)2. AMD 3329 and its component macrocycle were synthesised, and complexed with Cd(II), using NMR-active enriched 111Cd. Using 1D and 2D 1H, 13C, 15N and 111Cd NMR spectroscopy, these novel metallomacrocycles were fully characterised, and two configurations were found in solution for both the 111Cd-macrocycle and the analogous AMD 3329 complex. The monomer was also complexed with Zn(III), and NMR studies showed it to exist also in two configurations in solution. Addition of excess acetate to the Zn(II) complex did not induce any configurational change in the macrocyclic framework. The interaction between Cu(II)-cyclam, Ni(II)-cyclam and Cu(II)2-xylyl-bicyclam and lysozyme was studied. NMR spectroscopy revealed binding sites in lysozyme involving tryptophan residues. Solid-state x-ray crystallographic studies on the copper complexes showed the presence of two distinct binding sites. Polar and non-polar interactions were established in the protein recognition of the metallomacrocycles, including H-bonding between the cyclam ring and protein carboxylate groups, and hydrophobic stacking interactions. These studies provide the first direct demonstration of the mode of interaction between metal cyclams and proteins and the relevance to binding to the CXCR43 protein is discussed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available