CXCR4 chemokine receptor antagonists: nickel(ii) complexes of configurationally restricted macrocycles

Abstract

Tetraazamacrocyclic complexes of transition metals provide useful units for incorporating multiple coordination interactions into a single protein binding molecule. They can be designed with available sites for protein interactions via donor atom-containing amino acid side chains or labile ligands, such as H(2)O, allowing facile exchange. Three configurationally restricted nickel(II) cyclam complexes with either one or two macrocyclic rings were synthesised and their ability to abrogate the CXCR4 chemokine receptor signalling process was assessed (IC(50) = 8320, 194 and 14 nM). Analogues were characterised crystallographically to determine the geometric parameters of the acetate binding as a model for aspartate. The most active nickel(II) compound was tested in several anti-HIV assays against representative viral strains showing highly potent EC(50) values down to 13 nM against CXCR4 using viruses, with no observed cytotoxicity (CC(50) > 125 μM).

1,8-bis(2-hydroxy-3,5-di-tert-butylbenzyl)-4,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane

“…Subsequently, complexes of these ligands have potential to be utilised for medical imaging and therapy, such as anti-HIV drugs [1][2][3][4], magnetic resonance imaging (MRI) contrast agents [5] and positron emission tomography (PET) theranostic compounds [6][7][8][9]. The strong affinity that these ligands have for important metal ions, such as copper(II), has seen them becoming increasingly used in the formation of sensors for either environmental analysis or cellular studies [10][11][12].…”

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

“…Additional examples of the cross‐bridged architecture leading to the M(OAc)(H 2 O) structural unit can be found in the crystal structures of [Ni 1 (OAc)(H 2 O)] + and [Ni 5 (OAc)(H 2 O)] + , which we have recently published . In these structures, very similar six‐coordinate geometries to the cross‐bridged Zn 2+ structures discussed above are present, with monodentate acetate ligands hydrogen bonded to aqua ligands that complete pseudo‐octahedral structures.…”

“…AMD3100, and the high potency CXCR4 antagonists that we have developed are bismacrocyclic with an aryl (xylyl) linker. Our previously collected data indicates that monomacrocyclic compounds will also have affinity for the receptor, but this will be lower than for the bismacrocyclic derivatives.…”

Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands

“…Complexes Mn( L1 )Cl 2 , Fe( L1 )Cl 2 , Mn( L2 )Cl 2 and Fe( L1 )Cl 2 were synthesized 45,58 and complex [Ni( L1 )OAc]PF 6 was synthesized according to the literature procedure. 59 …”