Quinol-containing ligands enable high superoxide dismutase activity by modulating coordination number, charge, oxidation states and stability of manganese complexes throughout redox cycling

Abstract

Reactivity assays previously suggested that two quinol-containing MRI contrast agent sensors for H₂O₂, [Mn(H₂qp1)(MeCN)]²⁺ and [Mn(H₄qp2)Br₂], could also catalytically degrade superoxide. Subsequently, [Zn(H₂qp1)(OTf)]⁺ was found to use the redox activity of the H₂qp1 ligand to catalyze the conversion of O₂˙⁻ to O₂ and H₂O₂, raising the possibility that the organic ligand, rather than the metal, could serve as the redox partner for O₂˙⁻ in the manganese chemistry. Here, we use stopped-flow kinetics and cryospray-ionization mass spectrometry (CSI-MS) analysis of the direct reactions between the manganese-containing contrast agents and O₂˙⁻ to confirm the activity and elucidate the catalytic mechanism. The obtained data are consistent with the operation of multiple parallel catalytic cycles, with both the quinol groups and manganese cycling through different oxidation states during the reactions with superoxide. The choice of ligand impacts the overall charges of the intermediates and allows us to visualize complementary sets of intermediates within the catalytic cycles using CSI-MS. With the diquinolic H₄qp2, we detect Mn(III)-superoxo intermediates with both reduced and oxidized forms of the ligand, a Mn(III)-hydroperoxo compound, and what is formally a Mn(IV)-oxo species with the monoquinolate/mono-para-quinone form of H₄qp2. With the monoquinolic H₂qp1, we observe a Mn(II)-superoxo ↔ Mn(III)-peroxo intermediate with the oxidized para-quinone form of the ligand. The observation of these species suggests inner-sphere mechanisms for O₂˙⁻ oxidation and reduction that include both the ligand and manganese as redox partners. The higher positive charges of the complexes with the reduced and oxidized forms of H₂qp1 compared to those with related forms of H₄qp2 result in higher catalytic activity (k_cat ∼ 10⁸ M⁻¹ s⁻¹ at pH 7.4) that rivals those of the most active superoxide dismutase (SOD) mimics. The manganese complex with H₂qp1 is markedly more stable in water than other highly active non-porphyrin-based and even some Mn(II) porphyrin-based SOD mimics.