Configurations of Nickel–Cyclam Antiviral Complexes and Protein Recognition

Abstract

Nickel(II)–xylylbicyclam is a potent anti‐HIV agent and binds strongly to the CXCR4 co‐receptor. We have investigated configurational equilibria of Ni^II–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 Ni^II 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 Ni^II–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 Ni^II–cyclam or Ni^II₂–xylylbicyclam contain two major binding sites, one involving Ni^II coordination to Asp101 and hydrophobic interactions between the cyclam ring and Trp62 and Trp63, and the second hydrophobic interactions with Trp123. For Ni^II–cyclam bound to Asp101, the cis‐V configuration predominates.