Zinc(ii) complexes of constrained antiviral macrocycles

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 (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.

1,8-bis(2-hydroxy-3,5-di-tert-butylbenzyl)-4,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane

“…Subsequently, complexes of these ligands have potential to be utilised for medical imaging and therapy, such as anti-HIV drugs [1][2][3][4], magnetic resonance imaging (MRI) contrast agents [5] and positron emission tomography (PET) theranostic compounds [6][7][8][9]. The strong affinity that these ligands have for important metal ions, such as copper(II), has seen them becoming increasingly used in the formation of sensors for either environmental analysis or cellular studies [10][11][12].…”

Syntheses, crystal structures, and spectroscopic properties of copper(II) complexes with 3,14-diethyl-2,6,13,17-tetraazatricyclo(16.4.0.07,12)docosane

“…With cytotoxic concentrations of 4100 mmol L À1 , they showed high activity and low levels of toxicity to cells [23]. In our study, we introduced two methyl or ethyl substitutions on the macrocycle for steric hindrance, which may provide interesting electronic effect as well as applications in medicine [17][18][19][20][21][22][23][24]. The anionic species also play important roles in chemistry, medicine, catalysis, molecular assembly, and in biology, yet their binding characteristics have not received much recognition [25,26].…”

“…More recently, we found that L 1 and [Zn(L 1 )(OAc) 2 ] Á 0.5H 2 O were active toward viral strains HIV-1 (IIIB) and HIV-2 (ROD). With cytotoxic concentrations of 4100 mmol L À1 , they showed high activity and low levels of toxicity to cells [23]. In our study, we introduced two methyl or ethyl substitutions on the macrocycle for steric hindrance, which may provide interesting electronic effect as well as applications in medicine [17][18][19][20][21][22][23][24].…”

Molecular Interactions of a,e‐cis‐1,4‐cyclohexanedicarboxylate (chdc) and e,e‐trans‐1,4‐chdc Ions toward Macrocyclic Zinc(II) Complexes

“…1,[3][4][5] It has been well understood that the carboxylate groups of the CXCR4 coreceptor play a crucial role in recognizing cyclam moieties of AMD 3100. 6 The molecular recognition between zinc(II) macrocycles and aspartates is realized by a strong Zn O covalent bond as well as hydrogen bonds between N-H group of the macrocycle and noncoordinating oxygen atom of the carboxylate group.…”