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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.

Authors

Rachel Smith

Dana Huskens

Dirk Daelemans

Ryan E. Mewis

Courtney D. Garcia

Amy N. Cain

TaRynn N. Carder Freeman

Christophe Pannecouque

Erik De Clercq

Dominique Schols

Timothy J. Hubin



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