CXCR4 chemokine receptor antagonists: nickel(II) complexes of configurationally restricted macrocycles

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 via donor atom-containing amino acid side chains or labile ligands,...

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Bibliographic Details
Published in:	Dalton transactions : an international journal of inorganic chemistry Vol. 41; no. 37; p. 11369
Main Authors:	Smith, Rachel, Huskens, Dana, Daelemans, Dirk, Mewis, Ryan E, Garcia, Courtney D, Cain, Amy N, Freeman, TaRynn N Carder, Pannecouque, Christophe, De Clercq, Erik, Schols, Dominique, Hubin, Timothy J, Archibald, Stephen J
Format:	Journal Article
Language:	English
Published:	England 01-01-2012
Subjects:	Antiviral Agents - chemistry Antiviral Agents - pharmacology Cell Line Coordination Complexes - chemistry Crystallography, X-Ray HIV-1 - drug effects Humans Inhibitory Concentration 50 Macrocyclic Compounds - chemistry Macrocyclic Compounds - pharmacology Models, Molecular Nickel - chemistry Receptors, CXCR4 - antagonists & inhibitors
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Summary:	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 via donor atom-containing amino acid side chains or labile ligands, such as H(2)O, 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 (IC(50) = 8320, 194 and 14 nM). Analogues were characterised crystallographically to determine the geometric parameters of the 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 EC(50) values down to 13 nM against CXCR4 using viruses, with no observed cytotoxicity (CC(50) > 125 μM).
ISSN:	1477-9234
DOI:	10.1039/c2dt31137b