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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Mosley, R. L. et al. Neuroinflammation, oxidative stress, and the pathogenesis of Parkinson’s disease. Clin. Neurosci. Res. 6, 261–281 (2006).

  2. 2.

    Fearon, I. M. & Faux, S. P. Oxidative stress and cardiovascular disease: novel tools give (free) radical insight. J. Mol. Cell. Cardiol. 47, 372–3381 (2009).

  3. 3.

    Roberts, C. K. & Sindhu, K. K. Oxidative stress and metabolic syndrome. Life. Sci. 84, 705–712 (2009).

  4. 4.

    Eskici, G. & Axelsen, P. H. Copper and oxidative stress in the pathogenesis of Alzheimer’s disease. Biochemistry 51, 6289–6311 (2012).

  5. 5.

    AbdulSalam, S. F., Thowfeik, F. S. & Merino, E. J. Excessive reactive oxygen species and exotic DNA lesions as an exploitable liability. Biochemistry 55, 5341–5352 (2016).

  6. 6.

    Ali, D. K., Oriowo, M., Tovmasyan, A., Batinic-Haberle, I. & Benov, L. Late administration of Mn porphyrin-based SOD mimic enhances diabetic complications. Redox Biol. 1, 457–466 (2013).

  7. 7.

    Tovmasyan, A. et al. Rational design of superoxide dismutase (SOD) mimics: the evaluation of the therapeutic potential of new cationic Mn porphyrins with linear and cyclic substituents. Inorg. Chem. 53, 11467–11483 (2014).

  8. 8.

    Riley, D. P. et al. Synthesis, characterization, and stability of manganese(ii) C-substituted 1,4,7,10,13-pentaazacyclopentadecane complexes exhibiting superoxide dismutase activity. Inorg. Chem. 35, 5213–5231 (1996).

  9. 9.

    Zhang, D. et al. Iron(iii) complexes as superoxide dismutase mimics: synthesis, characterization, crystal structure, and superoxide dismutase (SOD) activity of iron(iii) complexes containing pentaaza macrocyclic ligands. Inorg. Chem. 37, 956–963 (1998).

  10. 10.

    Lieb, D. et al. Dinuclear seven-coordinate Mn(ii) complexes: effect of manganese(ii)-hydroxo species on water exchange and superoxide dismutase activity. Inorg. Chem. 52, 222–236 (2013).

  11. 11.

    Friedel, F. C., Lieb, D. & Ivanović-Burmazović, I. Comparative studies on manganese-based SOD mimetics, including the phosphate effect, by using global spectral analysis. J. Inorg. Biochem. 109, 26–32 (2012).

  12. 12.

    Aitken, J. B. et al. Intracellular targeting and pharmacological activity of the superoxide dismutase mimics MnTE-2-PyP5+ and MnTnHex-2-PyP5+ regulated by their porphyrin ring substituents. Inorg. Chem. 52, 4121–4123 (2013).

  13. 13.

    Iranzo, O. Manganese complexes displaying superoxide dismutase activity: a balance between different factors. Bioorg. Chem. 39, 73–87 (2011).

  14. 14.

    Stallings, W. C., Pattridge, K. A., Strong, R. K. & Ludwig, M. L. Manganese and iron superoxide dismutases are structural homologs. J. Biol. Chem. 259, 10695–10699 (1984).

  15. 15.

    Zhang, C. X. & Lippard, S. J. New metal complexes as potential therapeutics. Curr. Opin. Chem. Biol. 7, 481–489 (2003).

  16. 16.

    Chen, P. et al. Manganese homeostasis in the nervous system. J. Neurochem. 134, 601–610 (2015).

  17. 17.

    Martell, A. E. Critical Stability Constants (Plenum Press, New York, 1974).

  18. 18.

    Wada, A., Jitsukawa, K. & Masuda, H. Superoxide disproportionation driven by zinc complexes with various steric and electrostatic properties. Angew. Chem. Int. Ed. 52, 12293–12297 (2013).

  19. 19.

    Yu, M. et al. A mononuclear manganese(ii) complex demonstrates a strategy to simultaneously image and treat oxidative stress. J. Am. Chem. Soc. 136, 12836–12839 (2014).

  20. 20.

    Chan, T.-L. & Mak, T. C. W. X-ray crystallographic study of guest-molecule orientations in the β-hydroquinone clathrates of acetonitrile and methyl isocyanide. J. Chem. Soc. Perkin Trans. 2, 777–781 (1983).

  21. 21.

    Gale, E. M., Mukherjee, S., Liu, C., Loving, G. S. & Caravan, P. Structure–redox–relaxivity relationships for redox responsive manganese-based magnetic resonance imaging probes. Inorg. Chem. 53, 10748–10761 (2014).

  22. 22.

    Sahoo, S. C., Dubey, M., Alam, M. A. & Ray, M. Effect of metal coordination and intra-molecular H-bond on the acidity of phenolic proton in a set of structurally characterized octahedral Ni(ii) complexes of l-histidine derivative. Inorg. Chim. Acta 363, 3055–3060 (2010).

  23. 23.

    Yu, M. et al. Adding a second quinol to a redox-responsive MRI contrast agent improves its relaxivity response to H2O2. Inorg. Chem. 56, 2812–2826 (2017).

  24. 24.

    Batinic-Haberle, I. et al. Diverse functions of cationic Mn(iii) N-substituted pyridylporphyrins, recognized as SOD mimics. Free Rad. Biol. Med. 51, 1035–1053 (2011).

  25. 25.

    McCord, J. M. & Fridovich, I. Superoxide dismutase: an enzymic function for erythrocuprein (hemocuprein). J. Biol. Chem. 244, 6049–6055 (1969).

  26. 26.

    Taubert, D. et al. Reaction rate constants of superoxide scavenging by plant antioxidants. Free Rad. Biol. Med. 35, 1599–1607 (2003).

  27. 27.

    Kedare, S. B. & Singh, R. P. Genesis and development of DPPH method of antioxidant assay. J. Food Sci. Technol. 48, 412–422 (2011).

  28. 28.

    Blois, M. S. Antioxidant determinations by use of a stable free radical. Nature 181, 1199–1200 (1958).

  29. 29.

    Milaeva, E. R. et al. Metal complexes with functionalised 2,2′-dipicolylamine ligand containing an antioxidant 2,6-di-tert-butylphenol moiety: synthesis and biological studies. Dalton Trans. 42, 6817–6828 (2013).

  30. 30.

    Fridovich, I. Superoxide anion radical (O2 •−), superoxide dismutases, and related matters. J. Biol. Chem. 272, 18515–18517 (1997).

  31. 31.

    Liochev, S. I. Superoxide dismutase mimics, other mimics, antioxidants, prooxidants, and related matters. Chem. Res. Toxicol. 26, 1312–1319 (2013).

  32. 32.

    Riley, D. P., Rivers, W. J. & Weiss, R. H. Stopped-flow kinetic analysis for monitoring superoxide decay in aqueous systems. Anal. Biochem. 196, 344–349 (1991).

  33. 33.

    Liochev, S. I. & Fridovich, I. Lucigenin (bis-N-methylacridinium) as a mediator of superoxide anion production. Arch. Biochem. Biophys. 337, 115–120 (1997).

  34. 34.

    Dees, A. et al. Water exchange on seven-coordinate Mn(ii) complexes with macrocyclic pentadentate ligands: insight in the mechanism of Mn(ii) SOD mimetics. Inorg. Chem. 46, 2459–2470 (2007).

  35. 35.

    Ivanović-Burmazović, I. & Filipović, M. R. Reactivity of manganese superoxide dismutase mimics toward superoxide and nitric oxide: selectivity versus cross-reactivity. Adv. Inorg. Chem. 64, 53–95 (2012).

  36. 36.

    Ivanović-Burmazović, I. Catalytic dismutation vs. reversible binding of superoxide. Adv. Inorg. Chem. 60, 59–100 (2008).

  37. 37.

    Riley, D. P. & Schall, O. F. Structure–activity studies and the design of synthetic superoxide dismutase (SOD) mimetics as therapeutics. Adv. Inorg. Chem. 59, 233–263 (2006).

  38. 38.

    Kenkel, I. et al. 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. J. Am. Chem. Soc. 139, 1472–1484 (2017).

  39. 39.

    Bergwitz, C. & Jüppner, H. Phosphate sensing. Adv. Chronic Kidney Dis. 18, 132–144 (2011).

  40. 40.

    Bevington, A. et al. A study of intracellular orthophosphate concentration in human muscle and erythrocytes by 31P nuclear magnetic resonance spectroscopy and selective chemical assay. Clin. Sci. 71, 729–735 (1986).

  41. 41.

    He, Z., Colbran, S. B. & Craig, D. C. Could redox‐switched binding of a redox‐active ligand to a copper(ii) centre drive a conformational proton pump gate? A synthetic model study. Chem. Eur. J. 9, 116–129 (2003).

  42. 42.

    Weekley, C. M. et al. Cellular fates of manganese(ii) pentaazamacrocyclic superoxide dismutase (SOD) mimetics: fluorescently labeled MnSOD mimetics, X-ray absorption spectroscopy, and X-ray fluorescence microscopy studies. Inorg. Chem. 56, 6076–6093 (2017).

  43. 43.

    Casanova, D., Alemany, P., Bofill, J. M. & Alvarez, S. Shape and symmetry of heptacoordinate transition-metal complexes: structural trends. Chem. Eur. J. 9, 1281–1295 (2003).

  44. 44.

    Duerr, K. et al. Studies on an iron(iii)-peroxo porphyrin. Iron(iii)-peroxo or iron(ii)-superoxo? Dalton Trans. 39, 2049–2056 (2010).

  45. 45.

    Ohtsu, H. & Fukuzumi, S. Coordination of semiquinone and superoxide radical anions to the zinc ion in SOD model complexes that act as the key step in disproportionation of the radical anions. Chem. Eur. J. 7, 4947–4953 (2001).

  46. 46.

    Ohtsu, H. & Fukuzumi, S. The essential role of a ZnII ion in the disproportionation of semiquinone radical anion by an imidazolate-bridged CuII–ZnII model of superoxide dismutase. Angew. Chem. Int. Ed. 39, 4537–4539 (2000).

Download references


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.

Author information

Author notes

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


  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


  1. Search for Meghan B. Ward in:

  2. Search for Andreas Scheitler in:

  3. Search for Meng Yu in:

  4. Search for Laura Senft in:

  5. Search for Annika S. Zillmann in:

  6. Search for John D. Gorden in:

  7. Search for Dean D. Schwartz in:

  8. Search for Ivana Ivanović-Burmazović in:

  9. Search for Christian R. Goldsmith in:


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.

Competing interests

The authors declare no competing interests.

Corresponding authors

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

Supplementary information

  1. Supplementary Information

    Experimental section, Supplementary Figures 1–20, SupplementaryTable 1

  2. Crystallographic data

    CIF for ligand H2qtp1; CCDC reference: 1830124

  3. Crystallographic data

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

  4. Crystallographic data

    CIF for compound 2; CCDC reference: 1830123

  5. Crystallographic data

    CIF for compound 3; CCDC reference: 1830122

  6. Crystallographic data

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

About this article

Publication history




Issue Date



Further reading