Zinc(Ii) Complexes Of Constrained Antiviral Macrocycles

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.