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Superoxide dismutase activity enabled by a redox-active ligand rather than metal

Nature Chemistry volume 10, pages 1207–1212 (2018)Cite this article

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Abstract

Reactive oxygen species are integral to many physiological processes. Although their roles are still being elucidated, they seem to be linked to a variety of disorders and may represent promising drug targets. Mimics of superoxide dismutases, which catalyse the decomposition of O2•− to H2O2 and O2, have traditionally used redox-active metals, which are toxic outside of a tightly coordinating ligand. Purely organic antioxidants have also been investigated but generally require stoichiometric, rather than catalytic, doses. Here, we show that a complex of the redox-inactive metal zinc(ii) with a hexadentate ligand containing a redox-active quinol can catalytically degrade superoxide, as demonstrated by both reactivity assays and stopped-flow kinetics studies of direct reactions with O2•− and the zinc(ii) complex. The observed superoxide dismutase catalysis has an important advantage over previously reported work in that it is hastened, rather than impeded, by the presence of phosphate, the concentration of which is high under physiological conditions.

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Fig. 1: Structures of complex 2 obtained from solid-state and aqueous measurements.
Fig. 2: Assays of the antioxidant capabilities of 2.
Fig. 3: Kinetic traces of superoxide decomposition.
Fig. 4: Possible mechanistic pathway for the reduction/oxidation of O2•− by 2.

Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition nos. CCDC 1830122 ([ZnH2qtp1](MeCN)](OTf)2, 3), 1830123 ([Zn(H2qtp1)(OTf)](OTf), 2) and 1830124 (H2qtp1). Copies of the data can be obtained free of charge from www.ccdc.cam.ac.uk/structures/. All other data supporting the findings of this study are available within the Article and its Supplementary Information, and/or from the corresponding authors upon reasonable request

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Acknowledgements

The authors thank C. Kreitzer and R. Boothe for technical assistance. T. Hutchinson collected the 19F NMR and IR data for 2. E. Hardy assisted with solution of the crystal structure of H2qtp1. The authors thank Auburn University, the Auburn University Research Initiative in Cancer, and the National Science Foundation (NSF-CHE-1662875) for financial support. NSF EPSCoR/AU-CMB summer fellowships provided additional support to M.Y. and M.B.W.

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Author notes

  1. These authors contributed equally: Meghan B. Ward, Andreas Scheitler.

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, Auburn University, Auburn, AL, USA

    Meghan B. Ward, Meng Yu, John D. Gorden & Christian R. Goldsmith

  2. Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg, Erlangen, Germany

    Andreas Scheitler, Laura Senft, Annika S. Zillmann & Ivana Ivanović-Burmazović

  3. Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA

    Dean D. Schwartz

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Contributions

M.B.W. prepared and characterized the complex and analysed its catalytic activity using lucigenin and DPPH assays and spectroscopy. M.Y. first prepared the complex and carried out the preliminary characterization. A.S. performed and interpreted the stopped-flow kinetics, interpreted the data obtained by ultra-high resolution cold-spray ionization mass spectrometry (UHR-CSI-MS) and contributed to the formulation of the proposed mechanism. L.S. performed UHR-CSI-MS measurements. A.S.Z. conducted the cytochrome c assay. J.D.G. collected and analysed crystallographic data. D.D.S. assisted with the DPPH and lucigenin assays. I.I.-B. directed the work of A.S., L.S. and A.S.Z., interpreted the data, formulated the proposed mechanism, and wrote part of the manuscript. C.R.G. directed the work of M.B.W. and M.Y., interpreted the data, and was the chief author of the manuscript.

Corresponding authors

Correspondence to Ivana Ivanović-Burmazović or Christian R. Goldsmith.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

Experimental section, Supplementary Figures 1–20, SupplementaryTable 1

Crystallographic data

CIF for ligand H2qtp1; CCDC reference: 1830124

Crystallographic data

Structure-factor file for ligand H2qtp1; CCDC reference: 1830124

Crystallographic data

CIF for compound 2; CCDC reference: 1830123

Crystallographic data

CIF for compound 3; CCDC reference: 1830122

Crystallographic data

Structure-factor file for compound 3; CCDC reference: 1830122

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Ward, M.B., Scheitler, A., Yu, M. et al. Superoxide dismutase activity enabled by a redox-active ligand rather than metal. Nature Chem 10, 1207–1212 (2018). https://doi.org/10.1038/s41557-018-0137-1

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