Oxovanadium(IV) cyclam and bicyclam complexes: potential CXCR4 receptor antagonists

Abstract

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.

Figure 1

ORTEP (30% probability thermal ellipsoids) views of the sulfato complex 1 (left), and the chlorido complex 2 (right).

Figure 2

R-space (non-phase shift corrected) with calculated fits EXAFS data for (a) [V^IVO(cyclam)SO₄)] 1, (b) [(V^IVO)₂(xylylbicyclam)(SO₄)₂] 3, (c) [V^IVO(cyclam)Cl]⁺ 2, and (d) [(V^IVO)₂(xylylbicyclam)(Cl₂)]²⁺ 4. Key: black line, R-space; red line, R-space fit.

Figure 3

Normalized solid-state XANES spectra of the pre-edge region of the four vanadyl compounds. Top: [V^IVO(cyclam)SO₄)] 1 (⋯·), [(V^IVO)₂(xylylbicyclam(SO₄)₂] 3 (—). Bottom: [V^IVO(cyclam)Cl]⁺ 2 (⋯·), [(V^IVO)₂(xylylbicyclam(Cl)] ⁺ 4 (—). The arrow indicates the slight increase in energy of the pre-edge feature when moving from vanadyl cyclam to bicyclam for both the Cl and SO₄ compounds.

Figure 4

EPR spectra of sulfato oxovanadium(IV) cyclam 1. (a) In water at 298 K (the aqua complex, see Table 3). (b) In frozen methanol at 77 K (sulfato complex).

Figure 5

EPR solution spectra at 298 K of oxovanadium(IV) bicyclam complexes [(VO)₂(bicyclam)X₂] where X = solvent, sulfate or chloride. (a) Aqua complex, (b) sulfato complex 3, and (c) chloride complex, 4. The spectra clearly show two different environments for vanadium for both the sulfato and chlorido complexes. The chlorido complex in particular shows significant overlapping signals and may be due to different ring configurations in solution, or replacement of one chlorido ligand by H₂O.

Figure 6

EPR spectra of oxovanadium(IV) bicyclam complexes [(VO)₂(bicyclam)X₂], where X = (a) sulfate (complex 3) and (b) chloride (complex 4), as frozen methanolic solutions at 77 K. Hyperfine couplings (A^‖, z-axis) are seen for two sets of signals from complex 4 (A1 and A2) and one set of signals from complex 3 (A1). These signals cannot all be attributed to the solvent-exchanged complex [(VO)₂(bicyclam)X₂] where X = methanol, as only one set of signals would be seen and both complexes would give rise to signals with the same A and g values. It seems likely that only one V center of the bicyclam complexes undergoes exchange.

Figure 7

Molecular model of {V^IVO(cyclam)} bound to the co-receptor CXCR4, based on the trans-III configuration of [V^IVO(cyclam)SO₄] 1 found in its X-ray structure. (a) Model 1 (left), vanadyl cyclam forms a coordinative bond (2.14 Å) and other H-bonds with Asp171. A weak V=O⋯H (2.3 Å) attraction is also seen between the α-carbon proton from Trp195 and the vanadyl oxygen atom. (b) Model 2 (right), lacks the coordination bond to the carboxylate of Asp171 (V⋯O 3.4 Å).

Chart 1

Configurations of metallocyclams and structures of cyclam, xylylbicyclam and complexes 1-4. AMD3100 is the octahydrochloride salt (xylylbicyclam.8HCl).