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

作者：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^*

来源：Chemistry - A European Journal, 2016, 22(36): 12916-12930.

DOI：10.1002/chem.201601468

• acetate binding
• copper
• CXCR4 chemokine receptor
• tetraazamacrocycles
• zinc

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.

• 出版日期2016-8-26
• 单位河北医科大学