title: Aspartate-Based CXCR4 Chemokine Receptor Binding of Cross-Bridged Tetraazamacrocyclic Copper(II) and Zinc(II) Complexes.
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(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)(H2 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.
authors.affiliation: Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK, 73096, USA.
authors.forename: Randall D
authors.initials: RD
authors.lastname: Maples
authors.affiliation: Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK, 73096, USA.
authors.forename: Amy N
authors.initials: AN
authors.lastname: Cain
authors.affiliation: Department of Chemistry and Positron Emission Tomography Research Centre, University of Hull, Hull, HU6 7RX, UK.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Burke
authors.affiliation: Department of Chemistry and Positron Emission Tomography Research Centre, University of Hull, Hull, HU6 7RX, UK.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Silversides
authors.affiliation: Department of Chemistry and Positron Emission Tomography Research Centre, University of Hull, Hull, HU6 7RX, UK.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Mewis
authors.affiliation: Rega Institute for Medical Research, KU Leuven, 3000, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: D'huys
authors.affiliation: Rega Institute for Medical Research, KU Leuven, 3000, Leuven, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.affiliation: Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK, 73096, USA.
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Linder
authors.affiliation: Department of Chemistry and Positron Emission Tomography Research Centre, University of Hull, Hull, HU6 7RX, UK. S.J.Archibald@Hull.ac.uk.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Archibald
authors.affiliation: Department of Chemistry and Physics, Southwestern Oklahoma State University, Weatherford, OK, 73096, USA. Tim.Hubin@swosu.edu.
authors.forename: Timothy J
authors.identifier: http://orcid.org/0000-0003-2277-1191
authors.initials: TJ
authors.lastname: Hubin
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry*; D002614:Chelating Agents / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D008024:Ligands; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000737:chemistry* / Q000378:metabolism; D015032:Zinc / Q000737:chemistry*
chemical_list: D002614:Chelating Agents; D056831:Coordination Complexes; D008024:Ligands; D019718:Receptors, CXCR4; D001224:Aspartic Acid; D003300:Copper; D015032:Zinc
keywords: CXCR4 chemokine receptor; acetate binding; copper; tetraazamacrocycles; zinc