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)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·CH3OH·1.5H2O 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 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 SO42− (from 1) and Cl− (from 2) ligands are readily substituted by water in solution, whereas these remain partially bound for the VIV 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 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 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.

金属配位对环状和双环状大环化合物环嗪的病毒抑制和共受体结合特性具有显著影响。本研究报道了钒氧环嗪复合物[V(IV)O(cyclam)SO4]（1）和[V(IV)O(cyclam)Cl]Cl（2），以及相应的苯基双环嗪硫酸盐（3）和氯化物（4）复合物的合成。1·1.33CH3OH和2·CH3OH·1.5H2O的X射线晶体结构显示出较短的V-O键（分别为1.6093(19)和1.599(3) Å），其中1的硫酸根以单齿形式与环上的NH基团形成氢键，而2则表现出较长的V-Cl键（2.650(12) Å）。3和4的固态结构通过与1和2的钒K边扩展X射线吸收精细结构（EXAFS）数据进行比较，表明复合物4为寡聚体，并含有桥连的氯化物配体。电子顺磁共振（EPR）研究表明，来自1的SO42−和来自2的Cl−配体在溶液中容易被水取代，而VIV苯基双环嗪复合物3和4中的这些配体则部分保持结合。钒氧苯基双环嗪复合物对HIV-1（IIIB）和HIV-2（ROD）菌株表现出高度活性，3的IC50值在1−5 μM之间，4的IC50值在0.1−0.3 μM之间；相比之下，钒氧环嗪复合物1和2则无活性。影响这些复合物活性的因素被进行了讨论。对钒氧环嗪与人类CXCR4共受体模型进行对接研究表明，钒与Asp171的羧酸基团配位可能伴随着与宏环的氢键结合以及与CXCR4骨架Trp195α碳氢原子的V-O···H吸引作用。此外，还存在与Trp195的疏水相互作用。环状构型和苯基连接体可能在决定双环嗪复合物更高活性方面发挥作用。