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Title: Chemistry of antiviral cyclam complexes
Author: Liang, Xiangyang
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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In order to elucidate the mechanism of action of AMD3100 and aid the design of more effective drugs, I synthesised AMD3100 and 15N-labelled cyclam, and their Zn(II), Cd(II) (NMR-active 111Cd) complexes. AMD3100 was synthesised efficiently by an extension of the mono N-alkylation procedure using phosphoryl-protected cyclam. 1D and 2D 1H, 13C and 15N NMR studies revealed that Zn cyclam complexes exist as three configurations I aqueous solution: trans-I, trans-III and cis-V. Crystal structures of [Zn(cyclam)(H2O)2(OAc)2 and [Zn(cyclam)(phthalate)]n (CH3OH)2n were obtained and indicate that Zn cyclam complexes adopt the most stable conformation trans-III in which six membered-rings are in the chair conformation and five membered-rings are in the gauche conformation. However, the trans-III configuration, which is the most stable conformation for small metal ions, is no longer stable for large metals, e.g. Cd(II), and only the configurations trans-I and cis-V were detected using 1H, 13C, 15N and 111Cd NMR spectroscopy for chloride and perchlorate Cd cyclam complexes in solution. The Cd cyclam perchlorate complex was shown to fix atmospheric CO2 and [Cd3(cyclam)3(CO3)](ClO4)4.3H2O was crystallised. This complex shows bidentate CO32- coordination to three Cd cyclam units and adopts a cis-I configuration in the crystals, the first example for unsubstituted cyclam complexes. The 3J(1H,1H) and 3J(1H, 111Cd) coupling constants were determined and used to derive structural information using a Karplus relationship. The six-membered rings adopt the chair conformation in solution as in the solid state, and the five-membered rings adopt eclipsed conformations in solution for the trans-I configuration. 1D and 2D 1H, 13C and 13N NMR studies also revealed that the cyclam rings of Zn bicyclam AMD3100 adopt three configurations, trans-I, trans-III and cis-V, in aqueous solution. Anions were found to affect the distribution of the three configurations in solution. The cis-V configuration predominates for Zn (bi)cyclam complexes in the presence in water. Titrations of Zn (bi)cyclam complexes with acetate also confirmed that carboxylates readily increase the proportion of the cis-V configuration. The carboxylate groups of two aspartate residues, Asp171 and Asp262, in the target protein CXCR4 are potential binding sites for Zn (bi)cyclam. Therefore, the cis-V configuration may be important for the anti-HIV activity of (bi)cyclam complexes. The interaction between the model target protein lysozyme and Zn­2bicyclam4+ was confirmed by ESI-MS and attempts were made to cocrystallise lysozyme with Zn2bicyclam4+.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available