Zinc(ii) complexes of constrained antiviral macrocycles

摘要

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 (III _B) (IC _(50) values of 10.51 ± 0.23 and 3.50 ± 0.33 μM, respectively), and HIV-2 (ROD) (IC _(50) values of 133.78 ± 14.10 and >110.67 μM, respectively). 2D [~1H, ~(13)C] and [~1H, ~(15)N] NMR spectroscopic studies suggested that the types of configurational isomers present in solution depend on the axial ligand.