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

TY - JOUR

T1 - Aspartate-Based CXCR4 Chemokine Receptor Binding of Cross-Bridged Tetraazamacrocyclic Copper(II) and Zinc(II) Complexes

AU - Maples, Randall D.

AU - Cain, Amy N.

AU - Burke, Benjamin P.

AU - Silversides, Jon D.

AU - Mewis, Ryan E.

AU - D'huys, Thomas

AU - Schols, Dominique

AU - Linder, Douglas P.

AU - Archibald, Stephen J.

AU - Hubin, Timothy J.

N1 - Publisher Copyright: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

PY - 2016/8/26

Y1 - 2016/8/26

N2 - 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 Cu2+and Zn2+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 Cu2+acetate complexes and two new Zn2+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)(H2O)]+coordination motif present in all of the Zn2+cross-bridged tetraazamacrocycle crystal structures, which differs from the chelating acetate [Zn(OAc)]+structures of known unbridged and side-bridged tetraazamacrocyclic Zn2+-containing CXCR4 antagonists.

AB - 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 Cu2+and Zn2+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 Cu2+acetate complexes and two new Zn2+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)(H2O)]+coordination motif present in all of the Zn2+cross-bridged tetraazamacrocycle crystal structures, which differs from the chelating acetate [Zn(OAc)]+structures of known unbridged and side-bridged tetraazamacrocyclic Zn2+-containing CXCR4 antagonists.

KW - acetate binding

KW - copper

KW - CXCR4 chemokine receptor

KW - tetraazamacrocycles

KW - zinc

UR - http://www.scopus.com/inward/record.url?scp=84979787897&partnerID=8YFLogxK

U2 - 10.1002/chem.201601468

DO - 10.1002/chem.201601468

M3 - Article

C2 - 27458983

AN - SCOPUS:84979787897

SN - 0947-6539

VL - 22

SP - 12916

EP - 12930

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

IS - 36

ER -