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

Smith, Rachel; Huskens, Dana; Daelemans, Dirk; Mewis, Ryan E.; Garcia, Courtney D.; Cain, Amy N.; Freeman, TaRynn N. Carder; Pannecouque, Christophe; Clercq, Erik De; Schols, Dominique; Hubin, Timothy J.; Archibald, Stephen J.

Abstract

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). © 2013 The Royal Society of Chemistry.

Citation

Smith, R., Huskens, D., Daelemans, D., Mewis, R. E., Garcia, C. D., Cain, A. N., Freeman, T. N. C., Pannecouque, C., Clercq, E. D., Schols, D., Hubin, T. J., & Archibald, S. J. (2012). CXCR4 chemokine receptor antagonists: nickel(II) complexes of configurationally restricted macrocycles. Dalton Transactions : an international journal of inorganic chemistry, 41(37), 11369-11377. https://doi.org/10.1039/c2dt31137b

• Journal Article Type: Article
• Acceptance Date: Jul 11, 2012
• Online Publication Date: Jul 16, 2012
• Publication Date: Dec 1, 2012
• Deposit Date: Nov 13, 2014
• Publicly Available Date: Nov 13, 2014
• Journal: Dalton transactions
• Print ISSN: 1477-9226
• Electronic ISSN: 1477-9234
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 41
• Issue: 37
• Pages: 11369-11377
• DOI: https://doi.org/10.1039/c2dt31137b
• Keywords: REF 2014 submission, CXCR4 chemokine receptor antagonists, Nickel(II) complexes
• Public URL: https://hull-repository.worktribe.com/output/470715
• Publisher URL: http://pubs.rsc.org/en/Content/ArticleLanding/2012/DT/c2dt31137b#!divAbstract
• Additional Information: Copy of article published in: Dalton transactions, 2012, v.41, issue 37
• Contract Date: Nov 13, 2014