CXCR4 chemokine receptor antagonists: nickel(II) complexes of configurationally restricted macrocycles.
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).
Department of Chemistry, The University of Hull, Cottingham Road, Hull, UK HU6 7RX.
Rachel
R
Smith
Dana
D
Huskens
Dirk
D
Daelemans
Ryan E
RE
Mewis
Courtney D
CD
Garcia
Amy N
AN
Cain
TaRynn N Carder
TN
Freeman
Christophe
C
Pannecouque
Erik
E
De Clercq
Dominique
D
Schols
Timothy J
TJ
Hubin
Stephen J
SJ
Archibald
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D056831:Coordination Complexes / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D009532:Nickel / Q000737:chemistry*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; D056831:Coordination Complexes; D047028:Macrocyclic Compounds; D019718:Receptors, CXCR4; D009532:Nickel