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

  • Elena Pătraşcu
  • Mihaela Badea
  • Nataša Čelan Korošin
  • Romana Cerc Korošec
  • Lavinia L. Ruţă
  • Ileana C. Farcaşanu
  • Maria Nicoleta Grecu
  • Gérald Guillaumet
  • Rodica OlarEmail author


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.


Formaldehyde Amino acid Pentaazamacrocyclic ligand SOD1 Thermal stability Yeast 



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


  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.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Henke SL. Superoxide dismutase mimics as future therapeutics. Expert Opin Ther Patents. 1999;9:169–80.CrossRefGoogle Scholar
  4. 4.
    Salvemini D, Doyle TM, Cuzzocrea S. Superoxide, peroxynitrite and oxidative/nitrative stress in inflammation. Biochem Soc Trans. 2006;34:965–70.PubMedCrossRefGoogle 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.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Oberley LW, Buettner GR. Role of superoxide dismutase in cancer: a review. Cancer Res. 1979;39:1141–9.PubMedGoogle 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.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Hayyan M, Hashim MA, Al-Nashef IM. Superoxide ion: generation and chemical implications. Chem Rev. 2016;116:3029–85.PubMedCrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.CrossRefGoogle 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.PubMedPubMedCentralCrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.CrossRefGoogle Scholar
  35. 35.
    Erxleben A. Interactions of copper complexes with nucleic acids. Coord Chem Rev. 2018;360:92–121.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.CrossRefGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.PubMedCrossRefGoogle Scholar
  42. 42.
    Sherman F. Getting started with yeast. Methods Enzymol. 2002;350:3–41.PubMedCrossRefPubMedCentralGoogle 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.PubMedGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle Scholar
  56. 56.
    Weisiger RA, Fridovich I. Mitochondrial superoxide dismutase. Site of synthesis and intramitochondrial localization. J Biol Chem. 1973;248:4793–6.PubMedGoogle Scholar
  57. 57.
    Gralla EB, Kosman DJ. Molecular genetics of superoxide dismutases in yeasts and related fungi. Adv Genet. 1992;30:251–319.PubMedCrossRefGoogle Scholar
  58. 58.
    Culotta VC. Superoxide dismutase, oxidative stress, and cell metabolism. Curr Top Cell Regul. 2000;36:117–32.PubMedCrossRefGoogle Scholar

Copyright information

© Akadémiai Kiadó, Budapest, Hungary 2020

Authors and Affiliations

  • Elena Pătraşcu
    • 1
  • Mihaela Badea
    • 1
  • Nataša Čelan Korošin
    • 2
  • Romana Cerc Korošec
    • 2
  • Lavinia L. Ruţă
    • 3
  • Ileana C. Farcaşanu
    • 3
  • Maria Nicoleta Grecu
    • 4
  • Gérald Guillaumet
    • 5
  • Rodica Olar
    • 1
    Email author
  1. 1.Department of Inorganic Chemistry, Faculty of ChemistryUniversity of BucharestBucharestRomania
  2. 2.Faculty of Chemistry and Chemical TechnologyUniversity of LjubljanaLjubljanaSlovenia
  3. 3.Department of Organic Chemistry, Biochemistry and Catalysis, Faculty of ChemistryUniversity of BucharestBucharestRomania
  4. 4.National Institute of Materials PhysicsMăgureleRomania
  5. 5.Institut de Chimie Organique et Analytique (ICOA), Université d’Orléans, UMR-CNRS 7311Orléans Cedex 2France

Personalised recommendations