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Aspartate‐Based CXCR4 Chemokine Receptor Binding of Cross‐Bridged Tetraazamacrocyclic Copper(II) and Zinc(II) Complexes
Author(s) -
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.
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201601468
Subject(s) - zinc , chemistry , metal , copper , ligand (biochemistry) , chelation , cxcr4 , chemokine receptor , stereochemistry , receptor , crystallography , chemokine , biochemistry , inorganic chemistry , organic chemistry
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.