Issue 43, 2007

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 EC50 = 0.026 μM against HIV-1) than the non-constrained dicopper(II) 1,1′-[1,4-phenylenebis(methylene)]-bis(1,4,8,11-tetraazacyclotetradecane) (average EC50 = 0.047 μM against HIV-1) although it is an order of magnitude less active than the configurationally restricted dizinc(II) complex.

Graphical abstract: Probing key coordination interactions: configurationally restricted metal activated CXCR4 antagonists

Supplementary files

Article information

Article type
Paper
Submitted
17 Apr 2007
Accepted
15 Jun 2007
First published
02 Oct 2007

Dalton Trans., 2007, 5008-5018

Probing key coordination interactions: configurationally restricted metal activated CXCR4 antagonists

G. McRobbie, G. C. Valks, C. J. Empson, A. Khan, J. D. Silversides, C. Pannecouque, E. De Clercq, S. G. Fiddy, A. J. Bridgeman, N. A. Young and S. J. Archibald, Dalton Trans., 2007, 5008 DOI: 10.1039/B705800D

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