We have previously synthesised the piperazino side-bridged cyclam chelator 1, and studied its copper(II) and zinc(II) complexes., X-ray structural data revealed a trans-II macrocyclic configuration with the metal ion displaced from the plane of the macrocyclic nitrogen donors. NMR data showed that the zinc(II) complex adopts this single configuration in aqueous solution. Chelator 2 is a novel monomacrocyclic compound with a single primary amino group in the position of the second macrocyclic group. It was thought that this may provide a H-bonding interaction with second aspartate/glutamate residue on binding to the protein. The third cyclam based compound 3 incorporates two rings at meta positions on the central phenyl ring. This shortens the distance between the two metal centres on complex formation. Nickel(II) complexes were formed and their interaction with the CXCR4 chemokine receptor probed through cellular signalling and anti-viral assays.
Tetraazamacrocyclic complexes of transition metals provide useful units for incorporating multiple coordination interactions into a single protein binding molecule. They can be designed with available sites for protein interactions with donor atom containing amino acid side chains or have labile ligands such as H2O allowing facile exchange. Three configurationally restricted nickel(II) cyclam complexes with either one or two macrocyclic rings were synthesised and their ability to abrogate the CXCR4 chemokine receptor signalling process was assessed (IC50 = 8320, 194 and 14 nM). Analogues were characterised crystallographically to determine the geometric parameters of acetate binding as a model for aspartate. The most active nickel(II) compound was tested in several anti-HIV assays against representative viral strains showing highly potent EC50 values down to 13 nM against CXCR4 using viruses with no observed cellular cytotoxicity (CC50 > 125 μM).
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Nickel incorporation into the cyclam molecules produced C-functionalized nickel catalysts with stereochemical integrity maintained throughout the synthesis.