Probing key coordination interactions: configurationally restricted metal activated CXCR4 antagonists.
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.
McRobbie
Graeme
G
Department of Chemistry, The University of Hull, Cottingham Road, Hull, UK HU6 7RX.
Valks
Gina C
GC
Empson
Christopher J
CJ
Khan
Abid
A
Silversides
Jon D
JD
Pannecouque
Christophe
C
De Clercq
Erik
E
Fiddy
Steven G
SG
Bridgeman
Adam J
AJ
Young
Nigel A
NA
Archibald
Stephen J
SJ
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*
D019380:Anti-HIV Agents; D015335:Molecular Probes; D019718:Receptors, CXCR4