title: Probing key coordination interactions: configurationally restricted metal activated CXCR4 antagonists.
abstract: The syntheses of configurationally restricted mono- and bis-macrocyclic copper(II) perchlorate complexes (copper(II) 5-benzyl-1,5,8,12-tetraazabicyclo[10.2.2]hexadecane and dicopper(II) 5,5'-[1,4-phenylenebis(methylene)]-bis(1,5,8,12-tetraazabicyclo[10.2.2]hexadecane)) are reported and the X-ray structure of the copper(II) mono-macrocyclic complex has been determined. EXAFS studies on the bis-macrocyclic species in aqueous solution show that the copper coordination spheres are essentially identical to the solid state structure, and do not vary in the presence of 20 equivalents of sodium acetate per metal centre. DFT calculations were carried out at the BP86/TZP level to determine the nature of potential binding interactions with CXCR4 aspartate residues. The alkylated single macrocyclic compound was modelled with an acetate included to represent the aspartate residue, demonstrating that the predicted macrocycle configuration has the lowest energy and the acetate interaction is effectively monodentate giving a distorted trigonal bipyramidal geometry at the copper centre. In vitro anti-HIV infection assays show that the configurationally restricted dicopper(II) complex is more active (average EC(50) = 0.026 microM against HIV-1) than the non-constrained dicopper(II) 1,1'-[1,4-phenylenebis(methylene)]-bis(1,4,8,11-tetraazacyclotetradecane) (average EC(50) = 0.047 microM against HIV-1) although it is an order of magnitude less active than the configurationally restricted dizinc(II) complex.
authors.affiliation: Department of Chemistry, The University of Hull, Cottingham Road, Hull, UK HU6 7RX.
authors.forename: Graeme
authors.initials: G
authors.lastname: McRobbie
authors.forename: Gina C
authors.initials: GC
authors.lastname: Valks
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Empson
authors.forename: Abid
authors.initials: A
authors.lastname: Khan
authors.forename: Jon D
authors.initials: JD
authors.lastname: Silversides
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Steven G
authors.initials: SG
authors.lastname: Fiddy
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bridgeman
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Young
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Archibald
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D015335:Molecular Probes; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
chemical_list: D019380:Anti-HIV Agents; D015335:Molecular Probes; D019718:Receptors, CXCR4