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

Maples, RD, Cain, AN, Burke, BP, Silversides, JD, Mewis, RE, D'huys, T, Schols, D, Linder, DP, Archibald, SJ and Hubin, TJ (2016) Aspartate-Based CXCR4 Chemokine Receptor Binding of Cross-Bridged Tetraazamacrocyclic Copper(II) and Zinc(II) Complexes. Chemistry: A European Journal, 22 (36). pp. 12916-12930. ISSN 0947-6539

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Abstract

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 and Zn 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 acetate complexes and two new Zn 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 O)] coordination motif present in all of the Zn cross-bridged tetraazamacrocycle crystal structures, which differs from the chelating acetate [Zn(OAc)] structures of known unbridged and side-bridged tetraazamacrocyclic Zn -containing CXCR4 antagonists. 2+ 2+ 2+ 2+ + 2+ + 2+ 2

Item Type:	Article
Peer-reviewed:	Yes
Date Deposited:	08 Aug 2016 09:13
Publisher:	Wiley
Additional Information:	This is an Accepted Manuscript of an article which appeared in Chemistry, published by Wiley
Divisions:	Faculties > Science and Engineering
Subject terms:	Science & Technology, Physical Sciences, Chemistry, Multidisciplinary, Chemistry, acetate binding, copper, CXCR4 chemokine receptor, tetraazamacrocycles, zinc, TOPOLOGICALLY CONSTRAINED TETRAAZAMACROCYCLES, TRANSITION-METAL-COMPLEXES, RAY CRYSTAL-STRUCTURES, MANGANESE(II) COMPLEXES, COORDINATION CHEMISTRY, NICKEL(II) COMPLEXES, OXIDATION CATALYSIS, IN-VIVO, ANTAGONISTS, BICYCLAM, Copper, Zinc, Aspartic Acid, Receptors, CXCR4, Chelating Agents, Ligands, Crystallography, X-Ray, Protein Binding, Coordination Complexes, CXCR4 chemokine receptor, acetate binding, copper, tetraazamacrocycles, zinc, Aspartic Acid, Chelating Agents, Coordination Complexes, Copper, Crystallography, X-Ray, Ligands, Protein Binding, Receptors, CXCR4, Zinc, 03 Chemical Sciences, General Chemistry
URI:	https://e-space.mmu.ac.uk/id/eprint/617004
DOI:	https://doi.org/10.1002/chem.201601468
ISSN	0947-6539
e-ISSN	1521-3765

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