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Aspartate-Based CXCR4 Chemokine Receptor Binding of Cross-Bridged Tetraazamacrocyclic Copper(II) and Zinc(II) Complexes

Maples, Randall D.; Cain, Amy N.; Burke, Benjamin P.; Silversides, Jon D.; Mewis, Ryan E.; D'huys, Thomas; Schols, Dominique; Linder, Douglas P.; Archibald, Stephen J.; Hubin, Timothy J.


Randall D. Maples

Amy N. Cain

Benjamin P. Burke

Jon D. Silversides

Ryan E. Mewis

Thomas D'huys

Dominique Schols

Douglas P. Linder

Timothy J. Hubin


© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim The CXCR4 chemokine receptor is implicated in a number of diseases including HIV infection and cancer development and metastasis. Previous studies have demonstrated that configurationally restricted bis-tetraazamacrocyclic metal complexes are high-affinity CXCR4 antagonists. Here, we present the synthesis of Cu 2+ and Zn 2+ acetate complexes of six cross-bridged tetraazamacrocycles to mimic their coordination interaction with the aspartate side chains known to bind them to CXCR4. X-ray crystal structures for three new Cu 2+ acetate complexes and two new Zn 2+ acetate complexes demonstrate metal-ion-dependent differences in the mode of binding the acetate ligand concomitantly with the requisite cis-V-configured cross-bridged tetraazamacrocyle. Concurrent density functional theory molecular modelling studies produced an energetic rationale for the unexpected [Zn(OAc)(H 2 O)] + coordination motif present in all of the Zn 2+ cross-bridged tetraazamacrocycle crystal structures, which differs from the chelating acetate [Zn(OAc)] + structures of known unbridged and side-bridged tetraazamacrocyclic Zn 2+ -containing CXCR4 antagonists.


Maples, R. D., Cain, A. N., Burke, B. P., Silversides, J. D., Mewis, R. E., D'huys, T., …Hubin, T. J. (2016). Aspartate-Based CXCR4 Chemokine Receptor Binding of Cross-Bridged Tetraazamacrocyclic Copper(II) and Zinc(II) Complexes. Chemistry: a European journal, 22(36), 12916-12930.

Journal Article Type Article
Acceptance Date Mar 29, 2016
Online Publication Date Jul 26, 2016
Publication Date Aug 26, 2016
Deposit Date Oct 26, 2018
Journal Chemistry - A European Journal
Print ISSN 0947-6539
Electronic ISSN 1521-3765
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 22
Issue 36
Pages 12916-12930
Keywords Acetate binding; Copper; CXCR4 chemokine receptor; Tetraazamacrocycles; Zinc
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