Insight on spectral, thermal and biological behaviour of some Cu(II) complexes with saturated pentaazamacrocyclic ligands bearing amino acid residues


A novel series of Cu(II) complexes with formula M(HLn)(ClO4)2·mH2O [HLn: 13-membered pentaazamacrocyclic ligand resulted from condensation of N,N′-bis(2-aminoethyl)ethane-1,2-diamine, l-tyrosine (HL1)/l-tryptophan (HL2)/l-phenylalanine (HL3) and formaldehyde] were synthesized by one-pot method. Techniques such as ESI–MS, IR, UV–Vis and EPR spectroscopy provided data characterizing the complexes as mononuclear species. The course of thermal decomposition was followed using TG/DSC–MS analysis in air atmosphere. The TG curves showed a gradual decomposition in several stages that comprise dehydration, decomposition of perchlorate ions as well as fragmentation and oxidative degradation of the organic part. The intermediates formed after first stage of water elimination are stable on 40, 15 and 80 °C interval for complexes (1), (2) and (3), respectively. The compounds were tested on the eukaryotic unicellular organism Saccharomyces cerevisiae, showing variable actions in terms of toxicity, cellular uptake and capacity to alleviate growth defects associated with Cu, Zn-superoxide dismutase (SOD1) depletion.

This is a preview of subscription content, access via your institution.

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6


  1. 1.

    Bertini I, Grey HB, Stiefel EI, Valentine JS, editors. Biological inorganic chemistry. Structure and reactivity. Sausalito: University Science Books; 2007.

    Google Scholar 

  2. 2.

    Riley DP. Functional mimics of superoxide dismutase enzymes as therapeutic agents. Chem Rev. 1999;99:2573–87.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Henke SL. Superoxide dismutase mimics as future therapeutics. Expert Opin Ther Patents. 1999;9:169–80.

    CAS  Article  Google Scholar 

  4. 4.

    Salvemini D, Doyle TM, Cuzzocrea S. Superoxide, peroxynitrite and oxidative/nitrative stress in inflammation. Biochem Soc Trans. 2006;34:965–70.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Youssef P, Chami B, Lim J, Middleton T, Sutherland GT, Witting PK. Evidence supporting oxidative stress in a moderately affected area of the brain in Alzheimer’s disease. Sci Rep. 2018;8:11553.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Oberley LW, Buettner GR. Role of superoxide dismutase in cancer: a review. Cancer Res. 1979;39:1141–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Ma S, Fu A, Lim S, Chiew GGY, Luo KQ. MnSOD mediates shear stress-promoted tumor cell migration and adhesion. Free Rad Biol Med. 2018;129:46–58.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Hayyan M, Hashim MA, Al-Nashef IM. Superoxide ion: generation and chemical implications. Chem Rev. 2016;116:3029–85.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Deroche A, Morgenstern-Badarau I, Cesario M, Guilhem J, Keita B, Najdo L, Houee-Levin CA. Seven-coordinate manganese(II) complex formed with a single tripodal heptadentate ligand as a new superoxide scavenger. J Am Chem Soc. 1996;118:4567–73.

    CAS  Article  Google Scholar 

  10. 10.

    Facchin G, Torre MH, Kremer E, Piro OE, Castellano EE, Baran EJ. Structural and spectroscopic characterization of two new Cu(II)-dipeptide complexes. Z Naturforsch. 2000;55:1157–62.

    CAS  Article  Google Scholar 

  11. 11.

    Zhang J-J, Luo Q-H, Long D-L, Chen J-T, Li F-M, Liu AD. A superoxide dismutase mimic with high activity: crystal structure, solution equilibrium and pulse radiolysis. J Chem Soc Dalton Trans. 2000;12:1893–900.

    Article  Google Scholar 

  12. 12.

    Kerim S, Ahmet C, Saadettin G, Serdar K, Fatma K. Copper(II)-manganese(II) complexes of 3,3′-(1,3-propanediyldiimine)bis-(3-methyl-2-butanone)dioxime with superoxide dismutase-like activity. Trans Met Chem. 2001;26:625–9.

    Article  Google Scholar 

  13. 13.

    Vanco J, Svajlenová O, Ramanská E, Muselık J, Valentová J. Antiradical activity of different copper(II) Schiff base complexes and their effect on alloxan-induced diabetes. J Trace Elem Med Biol. 2004;18:155–61.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Zhou Y-H, Tao J, Sun D-L, Chen L-Q, Jia W-G, Cheng Y. Synthesis, structure and superoxide dismutase-like activity of copper(II) complexes based on N,N′-bis(2-quinolinylmethyl)amantadine. Polyhedron. 2015;85:849–56.

    CAS  Article  Google Scholar 

  15. 15.

    Puchoňová M, Švorec J, Švorc L, Pavlik J, Mazúr M, Dlhán L, Růžičková Z, Moncol’ J, Valigura D. Synthesis, spectral, magnetic properties, electrochemical evaluation and SOD mimetic activity of four mixed-ligand Cu(II) complexes. Inorg Chim Acta. 2017;455:298–306.

    Article  CAS  Google Scholar 

  16. 16.

    Shahid M, Anjuli, Tasneem S, Mantasha I, Naqi Ahamad M, Sama F, Fatma K, Siddiqi ZA. Spectral characterization, crystal structures and biological activities of iminodiacetate ternary complexes. J Mol Struct. 2017;1146:424–31.

    CAS  Article  Google Scholar 

  17. 17.

    Singh YP, Patel RN, Singh Y, Butcher RJ, Vishakarma PK, Bhubon Singh RK. Structure and antioxidant superoxide dismutase activity of copper(II) hydrazone complexes. Polyhedron. 2017;122:1–15.

    CAS  Article  Google Scholar 

  18. 18.

    Ceolin J, Siqueira JD, Martins FM, Piquini PC, Iglesias BA, Back DF, de Oliveira GM. Oxazolidine copper complexes: synthesis, characterization and superoxide dismutase activity of copper(II) complexes with oxazolidine ligands derived from hydroxyquinoline carboxaldehyde. Appl Organomet Chem. 2018;32:e4218.

    Article  CAS  Google Scholar 

  19. 19.

    Patel RN, Singh Y, Singh YP, Patel AK, Patel N, Singh R, Butcher RJ, Jasinski JP, Colacio E, Palacios MA. Varying structural motifs, unusual X-band electron paramagnetic spectra, DFT studies and superoxide dismutase enzymatic activity of copper(II) complexes with N′-[(E)-phenyl(pyridin-2-yl)methylidene]benzohydrazide. New J Chem. 2018;42:3112–36.

    CAS  Article  Google Scholar 

  20. 20.

    Tang Q, Wu J-Q, Li H-Y, Feng Y-F, Zhang Z, Liang Y-N. Dinuclear Cu(II) complexes based on p-xylylene-bridged bis(1,4,7-triazacyclononane) ligands: synthesis, characterization, DNA cleavage abilities and evaluation of superoxide dismutase- and catalase like activities. Appl Organomet Chem. 2018;32:e4297.

    Article  CAS  Google Scholar 

  21. 21.

    Parajon Costa BS, Totaro RM, Ferrer EG, Williams PA. Superoxide dismutase activity and electrochemical study of the binuclear [Cu(TSA)2py]2 complex. J Trace Elem Med Biol. 2002;16:183–6.

    PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Patel RN. Magnetic, EPR and SOD studies of some Cu(II)–Cu(II), Cu(II)–Ni(II) and Cu(II)–Zn(II) imidazolate bridged complexes. Spectrochim Acta A Mol Biomol Spectrosc. 2003;59:713–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Li D, Li S, Yang D, Yu J, Huang J, Li Y, Tang W. Syntheses, structures, and properties of imidazolate-bridged Cu(II)–Cu(II) and Cu(II)–Zn(II) dinuclear complexes of a single macrocyclic ligand with two hydroxyethyl pendats. Inorg Chem. 2003;42:6071–80.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Li Q-X, Luo Q-H, Li Y-Z, Shen M-C. A study on the mimics of Cu–Zn superoxide dismutase with high activity and stability: two copper(II) complexes of 1,4,7-triazacyclononane with benzimidazole groups. J Chem Soc Dalton Trans. 2004;15:2329–35.

    Article  CAS  Google Scholar 

  25. 25.

    Li Q-X, Wang X-F, Cai L, Li Q, Meng X-G, Xuan A-G, Huang S-Y, Ai J. Crystal structure, superoxide dismutase activity and electrochemical property of complex [Cu(dtne)]·(ClO4)2·CH3CH2OH. Inorg Chem Commun. 2009;12:145–7.

    CAS  Article  Google Scholar 

  26. 26.

    Yuan Q, Cai K, Qi Z-P, Bai Z-S, Su Z, Sun W-Y. Imidazolate-bridged dicopper(II) and copper(II)–zinc(II) complexes of macrocyclic ligand with methylimidazol pendants: model study of copper(II)–zinc(II) superoxide dismutase. J Inorg Biochem. 2009;103:1156–61.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Belda R, Blasco S, Begoña Verdejo HRJ, Doménech-Carbó A, Soriano C, Latorre J, Terencio C, García-España E. Homo- and heterobinuclear Cu2+ and Zn2+ complexes of abiotic cyclic hexaazapyridinocyclophanes as SOD mimics. Dalton Trans. 2013;42:11194–204.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Li Q-X, Chen X, Wang W-L, Meng X-G. A copper(II) complex of an asymmetrically N-functionalized derivative of 1,4,7-triazacyclononane: synthesis, crystal structure and SOD activity. J Coord Chem. 2017;70:1554–63.

    CAS  Article  Google Scholar 

  29. 29.

    Guijarro L, Inclán M, Pitarch-Jarque J, Doménech-Carbó A, Chicote JU, Trefler S, García-España E, García-España A, Verdejo B. Homo- and heterobinuclear Cu2+ and Zn2+ complexes of ditopic aza scorpiand ligands as superoxide dismutase mimics. Inorg Chem. 2017;56:13748–58.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Nebot-Guinot A, Liberato A, Angeles Máñez M, Paz Clares M, Doménech A, Pitarch-Jarque J, Martínez-Camarena A, Basallote MG, García-España E. Methylation as an effective way to generate SOD-activity in copper complexes of scorpiand-like azamacrocyclic receptors. Inorg Chim Acta. 2018;472:139–48.

    CAS  Article  Google Scholar 

  31. 31.

    Fleming AM, Muller JG, Ji I, Burrows CJ. Characterization of 2′-deoxyguanosine oxidation products observed in the Fenton-like system Cu(II)/H2O2/reductant in nucleoside and oligodeoxynucleotide contexts. Org Biomol Chem. 2011;9:3338–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Biver T, Secco F, Venturini M. Mechanistic aspects of the interaction of intercalating metal complexes with nucleic acids. Coord Chem Rev. 2008;252:1163–77.

    CAS  Article  Google Scholar 

  33. 33.

    Santini C, Pellei M, Gandin V, Porchia M, Tisato F, Marzano C. Advances in copper complexes as anticancer agents. Chem Rev. 2014;114:815–62.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    McGivern TJP, Afsharpour S, Marmion CJ. Copper complexes as artificial DNA metallonucleases: from Sigman’s reagent to next generation anti-cancer agent? Inorg Chim Acta. 2018;472:12–39.

    CAS  Article  Google Scholar 

  35. 35.

    Erxleben A. Interactions of copper complexes with nucleic acids. Coord Chem Rev. 2018;360:92–121.

    CAS  Article  Google Scholar 

  36. 36.

    El-Boraey HA, Emam SM, Tolan DA, El-Nahas AM. Structural studies and anticancer activity of a novel (N6O4) macrocyclic ligand and its Cu(II) complexes. Spectrochim Acta Part A. 2011;78A:360–70.

    CAS  Article  Google Scholar 

  37. 37.

    El-Boraey HA, El-Gammal OA. New 15-membered tetraaza (N4) macrocyclic ligand and its transition metal complexes: spectral, magnetic, thermal and anticancer activity. Spectrochim Acta Mol Biomol Spectrosc. 2015;138:553–62.

    CAS  Article  Google Scholar 

  38. 38.

    Montagner D, Gandin V, Marzano C, Erxleben A. DNA damage and induction of apoptosis in pancreatic cancer cells by a new dinuclear bis(triazacyclonane) copper complex. J Inorg Biochem. 2015;145:101–7.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Ribeiro TP, Fonseca FL, de Carvalho MD, Godinho RM, de Almeida FP, Saint’Pierre TD, Rey NA, Fernandes C, Horn A Jr, Pereira MD. Metal-based superoxide dismutase and catalase mimics reduce oxidative stress biomarkers and extend life span of Saccharomyces cerevisiae. Biochem J. 2017;47:301–15.

    Article  CAS  Google Scholar 

  40. 40.

    Ribeiro TP, Fernandes C, Melo KV, Ferreira SS, Lessa JA, Franco RW, Schenk G, Pereira MD, Horn A Jr. Iron, copper, and manganese complexes with in vitro superoxide dismutase and/or catalase activities that keep Saccharomyces cerevisiae cells alive under severe oxidative stress. Free Radic Biol Med. 2015;80:67–76.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Dumitru I, Ene CD, Ofiteru AM, Paraschivescu C, Madalan AM, Baciu I, Farcasanu IC. Identification of [CuCl(acac)(tmed)], a copper(II) complex with mixed ligands, as a modulator of Cu, Zn superoxide dismutase (Sod1p) activity in yeast. J Biol Inorg Chem. 2012;17:961–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Sherman F. Getting started with yeast. Methods Enzymol. 2002;350:3–41.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Amberg DC, Burke DJ, Strathern JN. Measuring yeast cell density by spectrophotometry. In: Burke D, Dawson D, Stearns T, editors. Methods in yeast genetics. A cold spring harbor laboratory course manual. New York: Cold Spring Harbor Laboratory Press; 2005.

    Google Scholar 

  44. 44.

    Kwolek-Mirek M, Zadrag-Tecza R. Comparison of methods used for assessing the viability and vitality of yeast cells. FEMS Yeast Res. 2014;14:1068–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Marczenko Z, Balcerzak M. Copper. In: Kloczko E, editor. Separation, preconcentration and spectrophotometry in inorganic analysis. Amsterdam: Elsevier Science; 2000.

    Google Scholar 

  46. 46.

    Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1974;72:248–54.

    Article  Google Scholar 

  47. 47.

    Geary WJ. The use of conductivity measurements in organic solvents for the characterisation of coordination compounds. Coord Chem Rev. 1971;7:81–122.

    CAS  Article  Google Scholar 

  48. 48.

    Hathaway BJ. Oxyanions. In: Wilkinson G, Gillard RD, McCleverty JA, editors. Comprehensive coordination chemistry. New York: Pergamon Press; 1987.

    Google Scholar 

  49. 49.

    Nakamoto K. Infrared and Raman spectra of inorganic and coordination compounds. Part B. Applications in coordination, organometallic, and bioinorganic chemistry. 6th ed. Hoboken: Wiley; 2009.

    Google Scholar 

  50. 50.

    Solomon EI, Lever ABP. Inorganic electronic structure and spectroscopy, vol. II. Applications and case studies. Hoboken: Wiley; 2006.

    Google Scholar 

  51. 51.

    Weil JA, Bolton JR, Wertz E. Electron paramagnetic resonance—elementary theory and practical application. Hoboken: Wiley; 1993.

    Google Scholar 

  52. 52.

    Donoso JP, Magen GJ, Lima IF, Nascimento OR, Benavente E, Moreno M, Gonzales G. EPR study of Cu(II) ethylenediamine complex ion intercalated in bentonite. J Phys Chem C. 2013;117:24042–55.

    CAS  Article  Google Scholar 

  53. 53.

    Badea M, Calu L, Čelan Korošin N, David IG, Chifiriuc MC, Bleotu C, Ionita G, Silvestro L, Maurer M, Olar R. Thermal behaviour of some biological active perchlorate complexes with a triazolopyrimidine derivative. J Therm Anal Calorim. 2018;134:665–77.

    CAS  Article  Google Scholar 

  54. 54.

    Calu L, Badea M, Čelan Korošin N, Chifiriuc MC, Bleotu C, Stanică N, Silvestro L, Maurer M, Olar R. Spectral, thermal and biological characterization of complexes with a Schiff base bearing triazole moiety as potential antimicrobial species. J Therm Anal Calorim. 2018;134:1839–50.

    CAS  Article  Google Scholar 

  55. 55.

    Crapo JD, Oury T, Rabouille C, Slot JW, Chang LY. Copper, zinc superoxide dismutase is primarily a cytosolic protein in human cells. Proc Natl Acad Sci USA. 1992;89:10405–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Weisiger RA, Fridovich I. Mitochondrial superoxide dismutase. Site of synthesis and intramitochondrial localization. J Biol Chem. 1973;248:4793–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    Gralla EB, Kosman DJ. Molecular genetics of superoxide dismutases in yeasts and related fungi. Adv Genet. 1992;30:251–319.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Culotta VC. Superoxide dismutase, oxidative stress, and cell metabolism. Curr Top Cell Regul. 2000;36:117–32.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

Download references


Slovenian authors would like to thank the Slovenian Research Agency—Slovenia (ARRS) for foundation by Programme P1-0134.

Author information



Corresponding author

Correspondence to Rodica Olar.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pătraşcu, E., Badea, M., Čelan Korošin, N. et al. Insight on spectral, thermal and biological behaviour of some Cu(II) complexes with saturated pentaazamacrocyclic ligands bearing amino acid residues. J Therm Anal Calorim 143, 173–184 (2021).

Download citation


  • Formaldehyde
  • Amino acid
  • Pentaazamacrocyclic ligand
  • SOD1
  • Thermal stability
  • Yeast