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

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+