Oxovanadium(IV) Cyclam and Bicyclam Complexes: Potential CXCR4 Receptor Antagonists

摘要

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)SO4] (>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 >1·1.33CH3OH and >2·CH3OH1.5H2O 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 SO4^2- (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 (IIIB) and HIV-2 (ROD) strains with IC50 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 co-receptor 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.