Configurationally Restricted Bismacrocyclic CXCR4 Receptor Antagonists

Abstract

A zinc(II) containing configurationally restricted analogue of bismacrocyclic cyclam-type CXCR4 chemokine receptor antagonists has been synthesized and shown to adopt only one configuration in solution. The single crystal X-ray structure reveals favorable binding to acetate via a bidentate chelation that can be related to the proposed interaction with aspartate on the receptor protein surface. The zinc(II) complex is highly active against HIV infection in vitro. AMD3100 (the octa HCl salt of 1-1′-[1,4-phenylenebis-(methylene)]-bis(1,4,8,11-tetraazacyclotetradecane)), Figure 1c, is a drug that interacts with a cell surface protein (CXCR4) via hydrogen bonding interactions or more effectively as the metal complex via coordinate bonds with aspartate residues. 1 On metal complex formation, the tetra-aza macrocyclic rings in AMD3100 show multiple configurations in solution. 2 Configurationally fixed analogues would have the advantage of presenting only one configuration in solution for coordinate bond formation on binding to the protein. Our study aims to produce a series of configurationally fixed complexes and show the key importance of the coordination interaction for drug binding. We also wish to validate the general strategy of configurational fixing as a route to improve the activity of metal-containing drugs.The CXCR4 chemokine receptor is a seven-helix transmembrane G-protein coupled receptor with multiple critical functions in both normal and pathological physiology. It is a member of the family of 18 recognized chemokine receptors and has a sole natural ligand (CXCL12). 3 Synthetic small molecule antagonists exist, including AMD3100, and have been shown to have both a high binding specificity and an effective inhibitory action against a number of disease states. 4,5 For example, in vitro assays show that AMD3100 inhibits infection by the human immunodeficiency virus (HIV-1 and HIV-2) at micromolar concentrations. 6 It has been demonstrated that formation of metal complexes and aza-macrocyclic ring configuration may have major effects on AMD3100-protein interactions. 1,2,[7][8][9] In particular, it has been suggested that zinc(II) could play a key role in the biological activity of the bicyclam derivatives. 10,11 In an attempt to rationalize the effects of cyclam configuration and to produce new specific antagonists for CXCR4, we have successfully synthesized a configurationally fixed bismacrocyclic compound and its zinc(II) complex. The solution and solid-state properties of the zinc(II) complex were investigated via high field NMR (800 MHz) and X-ray crystallography. The inhibitory effect on infection by HIV-1 and HIV-2 in MT-4 cells is also presented for both the chelator, 4 ((5-5′-[1,4-phenylenebis(methylene)]-bis (1,5,8,12-tetraazabicyclo[10.2.2]hexadecane)), and the complex Zn 2 4(OAc) 4 .There are six possible configurations that a cyclam ring can adopt on complexation to a metal ion, as defined by Bosnich and co-workers and shown in Figure 1b, where trans-III is generally the most thermodyn...

Azamacrocyclic Metal Complexes as CXCR4 Antagonists

“…[14,36] However, herein we focus on novel nonpeptidic low-molecular-weight CXCR4 antagonists. To date, AMD3100 (1), [20,22] Dpa-Zn complex (2), [37] KRH-1636, [27] and other compounds [31][32][33][34][35] have been developed in this and other laboratories as low-molecularweight nonpeptidic CXCR4 antagonists. The present study reports structure-activity relationship studies based on the combination of common structural motifs, such as xylene scaffolds and cationic moieties that are present in the aforementioned compounds.…”

Binding of zinc(II) macrocycles toward carboxylate ligands

“…In this context, we have previously prepared and structurally characterized several macrocyclic zinc(II) complexes in order to elucidate the selective recognition of macrocyclic zinc(II) complexes by carboxylate ligands [8][9][10]. Nevertheless, only a handful of structurally characterized examples of such complexes are known at present [7][8][9][10][11][12]. As an extension of our investigations on expanding the examples of carboxylato zinc(II) macrocycles, we investigated the reactions of Zn(L)(NO 3 ) 2 (1) and sodium fumarate.…”

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

“…Within the past decade, these macrocycles have become important structural moieties for a variety of diagnostic and therapeutic pharmaceutical agents (21). Our group has been actively involved in the synthesis of these macrocyclic polyamines and their metal complexes and demonstrated their activities against HIV through CXCR4 inhibition (22)(23)(24)(25)(26)(27). We have recently employed the metal coordination approach to prepare a series of metal complexes using cross-bridged and side-bridged tetraazamacrocyclic ligands and have shown that both the ligands and their metal complexes are effective antimalarial agents (22,28).…”

“…1) for their activities against S. mansoni in vitro and in vivo and present here our findings on their antischistosomal activity. Seven of these 26 compounds (compounds 8, 9, 15 to 17, 20, and 21) are newly described in this report, and for the other compounds, either their antiviral or antimalarial activities have been described previously or they have been submitted elsewhere for synthetic method development and/or to report their antiviral or antimalarial activities (21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”