Configurations of Nickel-Cyclam Antiviral Complexes and Protein Recognition

Nickel(II)–xylylbicyclam is a potent anti‐HIV agent and binds strongly to the CXCR4 co‐receptor. We have investigated configurational equilibria of NiII–cyclam derivatives, since these are important for receptor recognition. Crystallographic studies show that both trans and cis configurations are readily formed: [Ni(cyclam)(OAc)2]⋅H2O adopts the trans‐III configuration with axial monodentate acetates, as does [Ni(benzylcyclam)(NO3)2] with axial nitrate ligands, whereas [Ni(benzylcyclam)(OAc)](OAc)⋅2 H2O has an unusual folded cis‐V configuration with NiII coordination to bidentate acetate. UV/Vis and NMR studies show that the octahedral trans‐III configuration slowly converts to square‐planar trans‐I in aqueous solution. For NiII–xylylbicyclam, a mixture of cis‐V and trans‐I configurations was detected in solution. X‐ray diffraction studies showed that crystals of lysozyme soaked in NiII–cyclam or NiII2–xylylbicyclam contain two major binding sites, one involving NiII coordination to Asp101 and hydrophobic interactions between the cyclam ring and Trp62 and Trp63, and the second hydrophobic interactions with Trp123. For NiII–cyclam bound to Asp101, the cis‐V configuration predominates. Protein recognition: The configurations adopted by antiviral nickel–(bi)cyclam complexes are important for specific recognition of the membrane co‐receptor protein CXCR4. We show that axial ligands such as acetate and nitrate can have dramatic effects on nickel–cyclam configurations both in the solid state and in solution.