Oxovanadium(IV) cyclam and bicyclam complexes: potential CXCR4 receptor antagonists.
Metal complexation can have a major influence on the antiviral and coreceptor 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)OH.1.5H(2)O show short V=O bonds (1.6093(19) and 1.599(3) A, respectively) with monodentate sulfate H-bonded to ring NH groups for 1, but a long V-Cl bond (2.650(12) A) for 2. The solid-state structures of 3 and 4 were compared to those of 1 and 2 using vanadium K-edge extended X-ray absorption fine structure (EXAFS) data. These suggested that complex 4 was oligomeric and contained bridging chlorido ligands. Electron paramagnetic resonance (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 microM for 3 and 0.1-0.3 microM for 4; in contrast the vanadyl cyclam complexes 1 and 2 were inactive. The factors that 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 alpha-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.
Ross
Allison
A
School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK.
Soares
Dinesh C
DC
Covelli
Danielle
D
Pannecouque
Christophe
C
Budd
Laura
L
Collins
Anna
A
Robertson
Neil
N
Parsons
Simon
S
De Clercq
Erik
E
Kennepohl
Pierre
P
Sadler
Peter J
PJ
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001596:Benzylamines; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D000080027:Cyclams; D004354:Drug Screening Assays, Antitumor; D015497:HIV-1 / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000737:chemistry*
D019380:Anti-HIV Agents; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D019718:Receptors, CXCR4; C075743:oxovanadium IV; C024560:cyclam; D014638:Vanadates; C088327:plerixafor