title: 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.
authors.affiliation: School of Chemistry, University of Edinburgh, Edinburgh, UK.
authors.forename: Allison
authors.initials: A
authors.lastname: Ross
authors.forename: Jong-Ha
authors.initials: JH
authors.lastname: Choi
authors.forename: Tina M
authors.initials: TM
authors.lastname: Hunter
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Moggach
authors.forename: Simon
authors.initials: S
authors.lastname: Parsons
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D003510:Cyclohexanes / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000737:chemistry; D008024:Ligands; D047028:Macrocyclic Compounds / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D003510:Cyclohexanes; D006571:Heterocyclic Compounds; D008024:Ligands; D047028:Macrocyclic Compounds; D009942:Organometallic Compounds; C024560:cyclam; C506365:Cyclohexane; D015032:Zinc