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 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.

Acetate as a model for aspartate-based CXCR4 chemokine receptor binding of cobalt and nickel complexes of cross-bridged tetraazamacrocycles

“…16,17 We have taken advantage of these properties by designing bis-linked cross-bridged tetraazamacrocycle metal complexes (Fig. 2) that have remarkably efficient binding 16,[18][19][20] to the aspartate side chains of the CXCR4 chemokine receptor, a trans-membrane receptor important to the fusion process of the HIV virus to leukocytes, 17 the metastasis of cancer cells, 21 and other biological processes. 22 Most relevant to this work, we have shown that a dinickel complex, the meta analogue of ligand 7 (Fig.…”

“…Because of the significant challenges in production of X-ray quality bis-linked tetraazamacrocycle complex crystals, 18,23 single-macrocycle transition metal complexes are often used as models. 16,[18][19][20]23 To provide the most accurate model for our bis-macrocycle antagonists, which are linked through a xylene linker, we have synthesised a number of monobenzyl and dibenzyl 4 pendant arm containing cross-bridged tetraazamacrocycles (Fig. 3).…”

Discovery of Antischistosomal Drug Leads Based on Tetraazamacrocyclic Derivatives and Their Metal Complexes

“…The synthesis of some of the cross-bridged tetraazamacrocycle mono-and bisligands, precursors, and complexes (compounds 1 to 18) was conducted on the basis of methods described in the literature (29,33,34,39 Archibald, submitted for publication). The mono-and bisquinoline derivatives of macrocyclic polyamines (compounds 19 to 26) were synthesized and purified by chromatography and/or solvent crystallization according to the methods that we described earlier (22,30) and were recovered in moderate to good yields.…”

Iron(III) Complexes with Cross‐Bridged Cyclams: Synthesis and Use in Alcohol and Water Oxidation Catalysis

“…Macrocyclic polyamines deserve great interest as ligands for transition metal ions. Cross‐bridged cyclams ( L‐R,R′ in Figure a) represent an excellent instance of the class, as their cleft‐like structure allows the lone pairs of the four nitrogen atoms to converge, thus becoming suitable to chelate a metal ion (Figure b).…”

“…Cross bridged cyclam ligands have been first investigated by Weisman, who reported a detailed synthesis of the dimethyl species L‐Me,Me Busch and co‐workers used both the dimethyl and dibenzyl L‐Bn,Bn ligands to coordinate mid‐late transition metals, getting complexes useful for different applications: manganese compounds were largely discussed in patent literature as bleach catalysts, while copper complexes found application in radiopharmaceutical and medical fields …”