Skip to main content

Advertisement

SpringerLink
Log in

Reactions of copper macrocycles with antioxidants and HOCl: potential for biological redox sensing

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

A series of simple copper N2S2 macrocycles were examined for their potential as biological redox sensors, following previous characterization of their redox potentials and crystal structures. The divalent species were reduced by glutathione or ascorbate at a biologically relevant pH in aqueous buffer. A less efficient reduction was also achieved by vitamin E in DMSO. Oxidation of the corresponding univalent copper species by sodium hypochlorite resulted in only partial (~65 %) recovery of the divalent form. This was concluded to be due to competition between metal oxidation and ligand oxidation, which is believed to contribute to macrocycle demetallation. Electrospray mass spectrometry confirmed that ligand oxidation had occurred. Moreover, the macrocyclic complexes could be demetallated by incubation with EDTA and bovine serum albumin, demonstrating that they would be inappropriate for use in biological systems. The susceptibility to oxidation and demetallation was hypothesized to be due to oxidation of the secondary amines. Consequently these were modified to incorporate additional oxygen donor atoms. This modification led to greater resistance to demetallation and ligand oxidation, providing a better platform for further development of copper macrocycles as redox sensors for use in biological systems.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

cis-H4NenSen :

5,6,13,14-Bisbenzo-8,11-diaza-1,4-dithia-cyclotetradecane

cis-H4NprSen :

5,6,14,15-Bisbenzo-8,12-diaza-1,4-dithia-cyclopentadecane

cis-H4NenSpr :

6,7,14,15-Bisbenzo-9,12-diaza-1,5-dithia-cyclopentadecane

cis-H4NprSpr :

6,7,15,16-Bisbenzo-9,13-diaza-1,5-dithia-cyclohexadecane

trans-H4(N-en-S)2 :

6,7,13,14-Bisbenzo-4,11-diaza-1,8-dithiacyclotetradecane

cis-H2Nen(CH2CH2OH)2Spr :

6,7,14,15-Bisbenzo-9,12,-diaza-1,5-dithiacyclopentadecine-9,12-diethanol

References

  • Aslund F, Berndt KD, Holmgren A (1997) Redox potentials of glutaredoxins and other thiol-disulfide oxidoreductases of the thioredoxin superfamily determined by direct protein-protein redox equilibria. J Biol Chem 272:30780–30786

    Google Scholar 

  • Augustyniak A, Bartosz G, Cipak A, Duburs G, Horáková L, Luczaj W, Majekova M, Odysseos AD, Rackova L, Skrzydlewska E, Stefek M, Strosová M, Tirzitis G, Venskutonis PR, Viskupicova J, Vraka PS, Zarković N (2010) Natural and synthetic antioxidants: an updated overview. Free Radic Res 44:1216–1262

    Article  PubMed  CAS  Google Scholar 

  • Bal W, Christodoulou J, Sadler PJ, Tucker A (1998) Multi-metal binding site of serum albumin. J Inorg Biochem 70:33–39

    Article  PubMed  CAS  Google Scholar 

  • Barbaro B, Bianchini C, Capannesi G, Di Luca L, Laschi F, Petroni D, Salvadori PA, Vacca A, Vizza F (2000) Synthesis and characterization of the tetraazamacrocycle 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (H2Me2DOTA) and of its neutral copper(II) complex [Cu(Me2DOTA)]. A new 64Cu-labeled macrocyclic complex for positron emission tomography imaging. J Chem Soc Dalton Trans 2393–2401

  • Barnard PJ, Bayly SR, Holland JP, Dilworth JR, Waghorn PA (2008) In vitro assays for assessing the potential for copper complexes to function as radiopharmaceutical agents. Q J Nucl Med Mol Imaging 52:235–244

    PubMed  CAS  Google Scholar 

  • Basset J, Denney RC, Jeffrey GH, Mendham J (1986) Vogels textbook of quantitative inorganic analysis, 4th edn. Longman Scientific & Technical, London

    Google Scholar 

  • Bentfield R, Ehlers N, Mattes R (1995) Synthesis and characterization of copper(II) complexes of a 14-membered cis-N2S2 dibenzo macrocycle and of its bis-acetato and bis(methylpyridyl) derivatives. Chem Ber 128:1199–1205

    Article  Google Scholar 

  • Borsook H, Keighley G (1933) Oxidation-reduction potential of ascorbic acid (vitamin C). Proc Natl Acad Sci USA 19:875–878

    Google Scholar 

  • Cavallini D, De Marco C, Dupre S, Rotilio G (1969) The copper catalyzed oxidation of cysteine to cystine. Arch Biochem Biophys 130:354–361

    Article  PubMed  CAS  Google Scholar 

  • Ehlers N, Funkemeiser D, Mattes R (1994) Synthesis and structure of cobalt(III) complexes of 14-membered cis- and trans-N2S2 dibenzo macrocycles with two pendant acetato groups. Z Anorg Allg Chem 620:796–800

    Article  CAS  Google Scholar 

  • Fernandes AS, Gaspar J, Cabral MF, Caneiras C, Guedes R, Rueff J, Castro M, Costa J, Oliveira NG (2007) Macrocyclic copper(II) complexes: superoxide scavenging activity, structural studies and cytotoxicity evaluation. J Inorg Biochem 101:849–858

    Google Scholar 

  • Gokel GW (2004) Dean’s handbook of organic chemistry, 2nd edn. McGraw Hill, New York

    Google Scholar 

  • Halliwell B, Gutteridge JM (1998) Free radicals in biology and medicine, 3rd edn. Oxford University Press, Oxford

    Google Scholar 

  • Jameson RF, Blackburn NJ (1982) The copper-catalysed oxidation of ascorbic acid by dioxygen. Part 4. The effect of chloride ions on the kinetics and mechanism. J Chem Soc Dalton Trans 9–12

  • Lau SJ, Sarkar B (1971) Ternary coordination complex between human serum albumin, Cu(II), and l-histidine. J Biol Chem 246:5938–5943

    PubMed  CAS  Google Scholar 

  • Martin JWL, Organ GJ, Wainwright KP, Weerasuria KDV, Willis AC, Wild SB (1987) Copper(I) complexes of 14- and 16-membered chelating macrocycles with trans-disposed pairs of imine-N and thioether-S donors: crystal and molecular structures of [Cu(C18H18N2S2)]CF3SO3 and [Cu(C20H22N2S2)]CF3SO3. Inorg Chem 26:2963–2968

    Article  CAS  Google Scholar 

  • Masuoka J, Saltman P (1994) Zinc(II) and copper(II) binding to serum albumin. A comparative study of dog, bovine, and human albumin. J Biol Chem 269:25557–25561

    PubMed  CAS  Google Scholar 

  • McArdle HJ, Gross SM, Danks DM, Wedd AG (1990) Role of albumin’s copper binding site in copper uptake by mouse hepatocytes. Am J Physiol Gastrointest Liver Physiol 258:G988–G991

    CAS  Google Scholar 

  • Rorabacher DB (2004) Electron transfer by copper centers. Chem Rev 104:651–698

    Article  PubMed  CAS  Google Scholar 

  • Taylor MK, Stevenson DE, Berlouis LEA, Kennedy AR, Reglinski J (2006a) Modelling the impact of geometric parameters on the redox potential of blue copper proteins. J Inorg Biochem 100:250–259

    Article  PubMed  CAS  Google Scholar 

  • Taylor MK, Berlouis LEA, Kennedy AR, Reglinski J (2006b) The effect of donor groups and geometry on the redox potential of copper Schiff base complexes. Inorg Chim Acta 359:2455–2464

    Article  CAS  Google Scholar 

  • Taylor MK, Trotter KD, Reglinski J, Berlouis LEA, Kennedy AR, Spickett CM, Sowden RJ (2008) Copper N2S2 Schiff base macrocycles: the effect of structure on redox potential. Inorg Chim Acta 361:2851–2862

    Article  CAS  Google Scholar 

  • Trotter KD, Reglinski J, Robertson K, Forgie JC, Parkinson JA, Kennedy AR, Armstrong DR, Sowden RJ, Spickett CM (2009) Structural studies of trans-N2S2 copper macrocycles. Inorg Chim Acta 362:4065–4072

    Article  CAS  Google Scholar 

  • Trotter KD, Taylor MK, Forgie JC, Reglinski J, Berlouis LEA, Kennedy AR, Spickett CM, Sowden RJ (2010) The structural and electrochemical consequences of hydrogenating Copper N2S2 Schiff base macrocycles. Inorg Chim Acta 363:1529–1538

    Article  CAS  Google Scholar 

  • Winyard PG, Spickett CM, Griffiths HR (2011) Analysis of radicals and radical reaction products in cell signalling and biomolecular damage: the long hard road to gold-standard measures. Biochem Soc Trans 39:1217–1220

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

KDT would like to thank Strathclyde University and WestChem for financial assistance. JR, CMS and RJS gratefully acknowledge the support of the BBSRC (BBS/B/01553) and would also like to thank Prof. Peter J Halling for helpful discussion.

Author information

Author notes

  1. Corinne M. Spickett

    Present address: School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK

Authors and Affiliations

  1. Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde University, 27 Taylor Street, Glasgow, G4 0NR, UK

    Rebecca J. Sowden & Corinne M. Spickett

  2. Department of Pure and Applied Chemistry, Strathclyde University, 295 Cathedral Street, Glasgow, G1 1XL, UK

    Katherine D. Trotter, Lynsey Dunbar, Gemma Craig, Omer Erdemli & John Reglinski

Authors
  1. Rebecca J. Sowden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katherine D. Trotter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lynsey Dunbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gemma Craig
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Omer Erdemli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Corinne M. Spickett
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John Reglinski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Corinne M. Spickett.

Additional information

Corinne M. Spickett and John Reglinski contributed equally to the research programme and manuscript preparation.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPT 206 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sowden, R.J., Trotter, K.D., Dunbar, L. et al. Reactions of copper macrocycles with antioxidants and HOCl: potential for biological redox sensing. Biometals 26, 85–96 (2013). https://doi.org/10.1007/s10534-012-9596-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-012-9596-9

Keywords

Search

Navigation