Zinc(II) complexes of constrained antiviral macrocycles

Allison Ross, Jong-Ha Choi, Tina M. Hunter, Christophe Pannecouque, Stephen A. Moggach, Simon Parsons, Erik De Clercq, Peter J. Sadler

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Abstract

The configurations of metallocyclams are of interest in relation to protein recognition and anti-HIV activity. We have synthesised four novel zinc(II) complexes with hexyl-Me-2-cyclam (HMC; 3,14-dimethyl-2,6,13,17-tetraazatricyclo(16.4.0.0(7,12))docosane), 1, and naphthyl-hexyl-Me-2-cyclam (NHMC; 2,13-bis(1-naphthylmethyl)-5,16-dimethyl-2,6,13,17-tetraazatricyclo(16.4.0.0(7,12))docosane), 2, as ligands. X-ray crystallographic data for Zn(II)-HMC diacetate, 3 show that zinc is six-coordinate in a distorted octahedral environment bound to four equatorial N atoms from the macrocycle and two axial acetato O atoms. The 14-membered metallo-macrocycle adopts a trans-III (RRSS) configuration with two six-membered rings in chair forms and two five-membered rings in gauche forms. In the chlorido Zn(II)-HMC complex 5, zinc appears to be 5-coordinate with square-pyramidal geometry. Interestingly, the chlorido Zn(II)-NHMC complex 6 crystallised in a trans-I configuration containing 4-coordinate tetrahedral zinc bound to three cyclam ring N atoms, a possible model for intermediates formed during the uptake and release of metals by cyclams. The ligand 1 and the zinc complex 3 were active towards viral strains HIV-1 (IIIB) (IC50 values of 10.51 +/- 0.23 and 3.50 +/- 0.33 mu M, respectively), and HIV-2 (ROD) (IC50 values of 133.78 +/- 14.10 and >110.67 mu M, respectively). 2D [H-1, C-13] and [H-1, N-15] NMR spectroscopic studies suggested that the types of configurational isomers present in solution depend on the axial ligand.

Original languageEnglish
Pages (from-to)6408-6418
Number of pages11
JournalDalton Transactions
Volume41
Issue number21
DOIs
Publication statusPublished - 2012
Externally publishedYes

Cite this

Ross, A., Choi, J-H., Hunter, T. M., Pannecouque, C., Moggach, S. A., Parsons, S., ... Sadler, P. J. (2012). Zinc(II) complexes of constrained antiviral macrocycles. Dalton Transactions, 41(21), 6408-6418. https://doi.org/10.1039/c2dt30140g