Endeavor toward Redox-Responsive Transition Metal Contrast Agents Based on the Cross-Bridge Cyclam Platform

We present the synthesis and characterization of a series of Mn(III), Co(III), and Ni(II) complexes with cross-bridge cyclam derivatives (CB-cyclam = 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane) containing acetamide or acetic acid pendant arms. The X-ray structures of [Ni(CB-TE2AM)]Cl₂·2H₂O and [Mn(CB-TE1AM)(OH)](PF₆)₂ evidence the octahedral coordination of the ligands around the Ni(II) and Mn(III) metal ions, with a terminal hydroxide ligand being coordinated to Mn(III). Cyclic voltammetry studies on solutions of the [Mn(CB-TE1AM)(OH)]²⁺ and [Mn(CB-TE1A)(OH)]⁺ complexes (0.15 M NaCl) show an intricate redox behavior with waves due to the Mn^III/Mn^IV and Mn^II/Mn^III pairs. The Co(III) and Ni(II) complexes with CB-TE2A and CB-TE2AM show quasi-reversible features due to the Co^III/Co^II or Ni^II/Ni^III pairs. The [Co(CB-TE2AM)]³⁺ complex is readily reduced by dithionite in aqueous solution, as evidenced by ¹H NMR studies, but does not react with ascorbate. The [Mn(CB-TE1A)(OH)]⁺ complex is however reduced very quickly by ascorbate following a simple kinetic scheme (k₀ = k₁[AH^-], where [AH^-] is the ascorbate concentration and k₁ = 628 ± 7 M^-1 s^-1). The reduction of the Mn(III) complex to Mn(II) by ascorbate provokes complex dissociation, as demonstrated by ¹H nuclear magnetic relaxation dispersion studies. The [Ni(CB-TE2AM)]²⁺ complex shows significant chemical exchange saturation transfer effects upon saturation of the amide proton signals at 71 and 3 ppm with respect to the bulk water signal.