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Previously, we found that linear quinol-containing ligands could allow manganese complexes to act as functional mimics of superoxide dismutase (SOD). The redox activity of the quinol enables even Zn(ii) complexes with these ligands to catalyze superoxide degradation. As we were investigating the abilities of manganese and iron complexes with 1,8-bis(2,5-dihydroxybenzyl)-1,4,8,11-tetraazacyclotetradecane (H 4 qp4) to act as redox-responsive contrast agents for magnetic resonance imaging (MRI), we found evidence that they could also catalyze the dismutation of H 2 O 2 . Here, we investigate the antioxidant behavior of Mn(ii), Fe(ii), and Zn(ii) complexes with H 4 qp4. Although the H 4 qp4 complexes are relatively poor mimetics of SOD, with only the manganese complex displaying above-baseline catalysis, all three display extremely potent catalase activity. The ability of the Zn(ii) complex to catalyze the degradation of H 2 O 2 demonstrates that the use of a redox-active ligand can enable redox-inactive metals to catalyze the decomposition of reactive oxygen species (ROS) besides superoxide. The results also demonstrate that the ligand framework can tune antioxidant activity towards specific ROS., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

In the current work, we demonstrate ligand design concepts that significantly improve the superoxide dismutase (SOD) activity of a zinc complex; the catalysis is enhanced when two quinol groups are present in the polydentate ligand. We investigate the mechanism through which the quinols influence the catalysis and determine the impact of entirely removing a chelating group from the original hexadentate ligand. Our results suggest that SOD mimicry with these compounds requires a ligand that coordinates Zn(II) strongly in both its oxidized and reduced forms and that the activity proceeds through Zn(II)-semiquinone complexes. The complex with two quinols displays greatly enhanced catalytic ability, with the activity improving by as much as 450% over a related complex with a single quinol. In the reduced form of the diquinol complex, one quinol appears to coordinate to the zinc much more weakly than the other. We believe that superoxide can more readily displace this portion of the ligand, facilitating its coordination to the metal center and thereby hastening the SOD reactivity. Despite the presence of two redox-active groups that may communicate through intramolecular hydrogen bonding and redox tautomerism, only one quinol undergoes two-electron oxidation to a para -quinone during the catalysis. After the formation of the para -quinone, the remaining quinol deprotonates and binds tightly to the metal, ensuring that the complex remains intact in its oxidized state, thereby maintaining its catalytic ability. The Zn(II) complex with the diquinol ligand is highly unusual for a SOD mimic in that it performs more efficiently in phosphate solution.

A highly water- and air-stable Fe(II) complex with the quinol-containing macrocyclic ligand H 4 qp4 reacts with H 2 O 2 to yield Fe(III) complexes with less highly chelating forms of the ligand that have either one or two para-quinones. The reaction increases the T 1 -weighted relaxivity over four-fold, enabling the complex to detect H 2 O 2 using clinical MRI technology. The iron-containing sensor differs from its recently characterized manganese analog, which also detects H 2 O 2 , in that it is the oxidation of the metal center, rather than the ligand, that primarily enhances the relaxivity., (© 2022 Wiley-VCH GmbH.)

In this review, we focus on the preclinical development and study of coordination complexes that act as magnetic resonance imaging (MRI) contrast agent sensors for hydrogen peroxide. Redox-responsive probes have been developed that provide signals that can be detected through traditional T 1 -weighted 1 H, 19 F, and Chemical Exchange Saturation Transfer MRI. The sensors can also be classified with respect to whether the change in the signal corresponds to the oxidation of the metal ion or the organic ligand., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Previously prepared Mn(II)- and quinol-containing magnetic resonance imaging (MRI) contrast agent sensors for H 2 O 2 relied on linear polydentate ligands to keep the redox-activatable quinols in close proximity to the manganese. Although these provide positive T 1 -weighted relaxivity responses to H 2 O 2 that result from oxidation of the quinol groups to p -quinones, these reactions weaken the binding affinity of the ligands, promoting dissociation of Mn(II) from the contrast agent in aqueous solution. Here, we report a new ligand, 1,8-bis(2,5-dihydroxybenzyl)-1,4,8,11-tetraazacyclotetradecane, that consists of two quinols covalently tethered to a cyclam macrocycle. The macrocycle provides stronger thermodynamic and kinetic barriers for metal-ion dissociation in both the reduced and oxidized forms of the ligand. The Mn(II) complex reacts with H 2 O 2 to produce a more highly aquated Mn(II) species that exhibits a 130% greater r 1 , quadrupling the percentile response of our next best sensor. With a large excess of H 2 O 2 , there is a noticeable induction period before quinol oxidation and r 1 enhancement occurs. Further investigation reveals that, under such conditions, catalase activity initially outcompetes ligand oxidation, with the latter occurring only after most of the H 2 O 2 has been depleted.