Switching between Inner- and Outer-Sphere PCET Mechanisms of Small-Molecule Activation: Superoxide Dismutation and Oxygen/Superoxide Reduction Reactivity Deriving from the Same Manganese Complex

Abstract

Readily exchangeable water molecules are commonly found in the active sites of oxidoreductases, yet the overwhelming majority of studies on small-molecule mimics of these enzymes entirely ignores the contribution of water to the reactivity. Studies of how these enzymes can continue to function in spite of the presence of highly oxidizing species are likewise limited. The mononuclear Mn complex with the potentially hexadentate ligand N-(2-hydroxy-5-methylbenzyl)-N,N',N'-tris(2-pyridinylmethyl)-1,2-ethanediamine (L) was previously found to act as both a HO-responsive MRI contrast agent and a mimic of superoxide dismutase (SOD). Here, we studied this complex in aqueous solutions at different pH values in order to determine its (i) acid-base equilibria, (ii) coordination equilibria, (iii) substitution lability and operative mechanisms for water exchange, (iv) redox behavior and ability to participate in proton-coupled electron transfer (PCET) reactions, (v) SOD activity and reductive activity toward both oxygen and superoxide, and (vi) mechanism for its transformation into the binuclear Mn complex with L-L and its hydroxylated derivatives. The conclusions drawn from potentiometric titrations, low-temperature mass spectrometry, temperature- and pressure-dependent O NMR spectroscopy, electrochemistry, stopped-flow kinetic analyses, and EPR measurements were supported by the structural characterization and quantum chemical analysis of proposed intermediate species. These comprehensive studies enabled us to determine how transiently bound water molecules impact the rate and mechanism of SOD catalysis. Metal-bound water molecules facilitate the PCET necessary for outer-sphere SOD activity. The absence of the water ligand, conversely, enables the inner-sphere reduction of both superoxide and dioxygen. The L complex maintains its SOD activity in the presence of OH and Mn-oxo species by channeling these oxidants toward the synthesis of a functionally equivalent binuclear Mn species.

Intracellular location matters: rationalization of the anti-inflammatory activity of a manganese(ii) superoxide dismutase mimic complex

“…Interestingly, the concentrations of À 1 and À 2 are similar at the mitochondria, which is recognized to be a fragile organelle to be protected under oxidative stress. This study is in line with other studies meant to better understand the bioactivity of SOD mimics, including studies on mechanisms of SOD mimics, [28][29][30] on the application of SOD mimics, 4,7,10,31,32 or on the distribution and speciation of these compounds. 13,18,33,34 The multimodal probe was synthesized with a pendant aldehyde moiety meant for conjugation with the ligand À L À 2 via a reductive amination coupling (ESI, † Section 5).…”

“…36 The SOD-like activity of À 1 was also investigated with a high excess of superoxide using a direct stopped-flow measurement combined with fast diode-array UV-vis detection. 30,37,41 The k cat value of 6.46 Â 10 6 M À1 s À1 in MOPS buffer (60 mM, ionic strength 150 mM, pH 7.8) is consistent with the k McCF , confirming that coupling with the probe does not change the intrinsic SOD activity of the SOD mimic.…”

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

“…We previously reported analogous studies for [Mn(Hptp1)(MeCN)] 2+ (1) and [Mn(H 4 qp2)Br 2 ] (3). 24,32 The new data enable us to fully compare the aqueous chemistries of 1, 2, and 3. Further, we determined catalytic rate constants for superoxide dismutation by 2 and 3 using the same techniques that were used for 1, again enabling the three to be compared.…”

“…The pH 7.4 )] + at pH 7.0-7.4, have higher aquation numbers (Table 2). 24,32 That the aquation number for 2 is lower than it is for 1 and 3 under similar conditions may suggest that the monoaqua species for 2 is thermodynamically favored to a lesser degree than the analogous species for the Hptp1 and H 4 qp2 ligands. Between pH 7.0 and 7.4, H 2 qp1 appears to be more strongly electron-donating than the other two ligands, as evident from its stronger chelating ability, vide supra.…”

“…23,24 The SOD activity of 1 was then conrmed using more quantitatively accurate stopped-ow kinetics measurements. 32 Comprehensive study of 1 revealed that in contrast to the majority of nonporphyrin-based manganese-containing SOD mimics, its SOD activity mainly proceeds through an outer-sphere pathway, with additional superoxide and oxygen reductase activity operating through an inner-sphere mechanism involving a Mn(IV)-oxo intermediate and the generation of OHc radicals. 32 As was observed with H 2 O 2 , these reactive species oxidatively couple the phenol groups of separate molecules to dimerize 1.…”