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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 [(1)H, (13)C] and [(1)H, (15)N] NMR spectroscopic studies suggested that the types of configurational isomers present in solution depend on the axial ligand.

Metal complexation can have a major influence on the antiviral and co-receptor binding properties of cyclam and bicyclam macrocycles. We report the synthesis of the vanadyl cyclam complexes [V (IV) O(cyclam)SO 4 ] (1) and [V (IV) O(cyclam)Cl]Cl -(2), and the analogous xylylbicyclam sulfato (3) and chlorido (4) complexes. The X-ray crystal structures of 1·1.33CH 3 OH and 2·CH 3 OH1.5H 2 O show short V=O bonds (1.6093(19) and 1.599(3) Å, respectively) with monodentate sulfate H-bonded to ring NH groups for 1, but a long V-Cl bond (2.650(12) Å) for 2. The solid-state structures of 3 and 4 were compared to those of 1 and 2 using vanadium K-edge EXAFS data. These suggested that complex 4 was oligomeric and contained bridging chlorido ligands. EPR studies suggested that the SO 4 2-(from 1) and Cl -(from 2) ligands are readily substituted by water in solution, whereas these remain partially bound for the V IV xylylbicyclam complexes 3 and 4. The vanadyl xylylbicyclam complexes were highly active against HIV-1 (III B ) and HIV-2 (ROD) strains with IC 50 values in the range 1-5 μM for 3 and 0.1-0.3 μM for 4; in contrast the vanadyl cyclam complexes 1 and 2 were inactive. The factors which contribute to the activity of these complexes are discussed. Studies of vanadyl cyclam docked into a model of the human CXCR4 coreceptor revealed that the coordination of vanadium to the carboxylate of Asp171 may be accompanied by H-bonding to the macrocycle and an attractive V=O··H interaction involving the backbone Trp195 α-carbon proton of CXCR4. In addition, hydrophobic interactions with Trp195 are present. Both ring configuration and the xylyl linker may play roles in determining the higher activity of the bicyclam complexes.

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