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Potential bio-protective effect of copper compounds: mimicking SOD and peroxidases enzymes and inhibiting acid phosphatase as a target for anti-osteoporotic chemotherapeutics

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Abstract

Copper complexes with transformed methimazole ligand have been synthesized and characterized by elemental analysis, conductivity measurements, thermogravimetric analysis, EPR, FTIR and UV–Vis spectroscopies. Results support their stoichiometries and geometrical structures: [Cu(C4H5N2S)2Cl2]·2H2O(1), [Cu(C8H10N4S)SO4H2O](2) and [Cu(C8H10N4S)SO4](3). ((C4H5N2)2S: bis(l-methylimidazol-2-yl)sulfide; (C4H5N2S)2 = Bis[bis(l-methylimidazol-2-yl)disulfide]) Concurrently, the structurally distinct soluble species corresponding to complexes (1) and (2) were subsequently used in an in vitro investigation of their potential biological properties. In view of their possible pharmaceutical activity, the complexes were in vitro evaluated as phosphatase acid inhibitors. Their radical bio-protective effects were also studied measuring the effect against DPPH• and O2•− radicals. Additional catalytic properties as peroxidase mimics were evaluated using Michaelis–Menten kinetic model by means of phenol red and pyrogallol assays. The complexes exhibited catalytic bromination activity and the ability to oxidize pyrogallol substrate indicating that they can be considered as functional models. The relationships between the structures and the in vitro biological activities have also been considered. Serum protein albumin has attracted the greatest interest as drug carrier and the affinity of biological/pharmaceutical compound is relevant to the development of new medicine. In that sense, interaction studies by fluorescence and EPR spectroscopies were performed showing the binding capacity of the complexes.

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Abbreviations

[Cu(C4H5N2S)2Cl2]·2H2O:

Complex(1)

[Cu(C8H10N4S)SO4H2O]:

Complex(2)

[Cu(C8H10N4S)SO4]:

Complex(3)

ABTS:

2,2′-Azinobis(3-ethyl-benzothiazoline-6-sulfonic acid) diammonium salt

AcP:

Acid phosphatase

BSA:

Bovine serum albumin

DMF:

Dimethylformamide

DMSO:

Dimethyl sulfoxide

FCS:

Fetal calf serum

HEPES:

Buffered saline, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium

NADH:

Reduced nicotinamide adenine dinucleotide

NBT:

Nitroblue tetrazolium

NTA:

Nitrilotriacetic acid

PMS:

Phenazine methosulfate

p-NPP:

Paranitrophenyl phosphate

Tris–HCl:

Tris(hydroxymethyl)aminomethane hydrochloride

References

  1. Holzwarth MS, Plietker B (2013) Biorelevant metals in sustainable metal catalysis—a survey. ChemCatChem 5:1650–1679

    Article  CAS  Google Scholar 

  2. Ngo AH, Bose S, Do LH (2018) Intracellular chemistry: integrating molecular inorganic catalysts with living systems. Chem Eur J 24:1–12

    Article  CAS  Google Scholar 

  3. Renuka MK, Gayathri V (2018) Synthesis of secondary amides by direct amidation using polymer supported copper(II) complex. Polyhedron 148:195–202

    Article  CAS  Google Scholar 

  4. Li F, Hu D, Yuan Y, Luo B, Song Y, Xiao S, Chen G, Fang Y, Lu F (2018) Zeolite Y encapsulated Cu (II) and Zn (II)-imidazole-salen catalysts for benzyl alcohol oxidation. MolCatalysis 452:75–82

    CAS  Google Scholar 

  5. Silva AR, Mourão T, Rocha J (2013) Oxidation of cyclohexane by transition-metal complexes with biomimetic ligands. Catal Today 203:81–86

    Article  CAS  Google Scholar 

  6. Castro KADF, Figueira F, Mendes RF, Cavaleiro JAS, da Graça M, Neves PMS, Simões MMQ, Almeida Paz FA, Tomé JPC, Nakagaki S (2017) Copper–porphyrin–metal–organic frameworks as oxidative heterogeneous catalysts. ChemCatChem 9:2939–2945

    Article  CAS  Google Scholar 

  7. Wischang D, Brucher O, Hartung J (2011) Bromoperoxidases and functional enzyme mimics as catalysts for oxidative bromination—a sustainable synthetic approach. Coord Chem Rev 255:2204–2217

    Article  CAS  Google Scholar 

  8. Meng X-G, Guo Y, Hu C-W, Zeng X-C (2004) Mimic models of peroxidase- kinetic studies of the catalytic oxidation of hydroquinone by H2O2. J Inorg Biochem 98:2107–2113

    Article  CAS  PubMed  Google Scholar 

  9. Wang C, Gao J, Cao Y, Tan H (2018) Colorimetric logic gate for alkaline phosphatase based on copper(II)-based metal-organic frameworks with peroxidase-like activity. Anal Chim Acta 1004:74–81

    Article  CAS  PubMed  Google Scholar 

  10. Chang Y, Zhang Z, Hao J, Yang W, Tang J (2016) A simple label free colorimetric method for glyphosate detectionbased on the inhibition of peroxidase-like activity of Cu(II). Sens Actuator B 228:410–415

    Article  CAS  Google Scholar 

  11. Yan Z, Niu Q, Mou M, Wu Y, Liu X, Liao S (2017) A novel colorimetric method based on copper nanoclusters with intrinsic peroxidase-like for detecting xanthine in serum samples. J Nanopart Res 19:235

    Article  CAS  Google Scholar 

  12. Wang S, Deng W, Yang L, Tan Y, Xie Q, Yao S (2017) Copper-based metal—organic framework nanoparticles with peroxidase-like activity for sensitive colorimetric detection of Staphylococcus aureus. ACS Appl Mater Interfaces 9:24440–24445

    Article  CAS  PubMed  Google Scholar 

  13. Henke SL (1999) Superoxide dismutase mimics as future therapeutics. Expert Opin Ther Pat 9:169–180

    Article  CAS  Google Scholar 

  14. Louie AY, Meade TJ (1999) Metal complexes as enzyme inhibitors Chem. Rev 99:2711–2734

    CAS  Google Scholar 

  15. Schenk G, Miti N, Hanson GR, Comba P (2013) Purple acid phosphatase: a journey into the function and mechanism of a colorful enzyme. Coord Chem Rev 257:473–482

    Article  CAS  Google Scholar 

  16. McGeary RP, Schenk G, Guddat LW (2014) The applications of binuclear metallohydrolases in medicine: recent advances in the design and development of novel drug leads for purple acid phosphatases, metallo-b-lactamases and arginases. Eur J Med Chem 76:132–144

    Article  CAS  PubMed  Google Scholar 

  17. Stoll S, Schweiger A (2006) EasySpin, a comprehensive software package for spectral simulation and analysis in EPR. J Magn Reson 178:42–55

    Article  CAS  PubMed  Google Scholar 

  18. Lobana TS, Sultana R, Hundal G, Butcher RJ (2010) Metal mediated C–S rupture of heterocyclic thioamides in situ generation of 2,2′-thio-di-2-imidazoline, 1,1′-dimethyl-2,2′-di-imidazolylsulfide, SO4 2– and their variable coordination to CuII. Dalton Trans 39:7870–7872

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Blum U, Schwedt G (1998) Inhibition behavior of acid phosphatase and adenosine deaminase phosphodiesterase I as trace metal analysis tools and speciation. Anal Chim Acta 360:101–108

    Article  CAS  Google Scholar 

  21. Martini N, Parente JE, Toledo ME, Escudero GE, Laino CH, Martínez Medina JJ, Echeverría GA, Piro OE, Lezama L, Williams PAM, Ferrer EG (2017) Evidence of promising biological-pharmacological activities of the sertraline-based copper complex: (SerH2)2[CuCl4]. J Inorg Biochem 174:76–89

    Article  CAS  PubMed  Google Scholar 

  22. Feng XD, Zhang R, Wang XY, Zhang XX,. Wang JX, Xing YH, Sun LX (2015) Mimicing bromoperoxidase for copper complexes: synthesis, structures and properties of Cu(II)–triazine pyrazolyl complex. Polyhedron 90:69–76

    Article  CAS  Google Scholar 

  23. Shahlaei M, Rahimi B, Nowroozi A, Ashrafi-Kooshk MR (2015) Exploring binding properties of sertraline with human serum albumin: combination of spectroscopic and molecular modeling studies. Chem-Biol Interact 242:235–246

    Article  CAS  PubMed  Google Scholar 

  24. Urquiza NM, Manca SG, Moyano MA, Arrieta Dellmans R, Lezama L, Rojo T, Naso LG, Williams PAM, Ferrer EG (2010) Copper(II) complexes of methimazole, an anti Grave’s disease drug. Synthesis, characterization and its potential biological behavior as alkaline phosphatase inhibitor. Biometals 23:255–264

    Article  CAS  PubMed  Google Scholar 

  25. Raper ES (1996) Complexes of heterocyclic thionates. Part 1. Complexes of monodentate and chelating ligands. Coord Chem Rev 153:199–255

    Article  CAS  Google Scholar 

  26. Raper ES (1997) Complexes of heterocyclic thionates, Part 2: complexes of bridging ligands. Coord Chem Rev 165:475–567

    Article  CAS  Google Scholar 

  27. Johnson TB, Edens CO (1942) Complex formations between Iodine and µ-mercapto-dihydroglyoxalines. J Am Chem Soc 64:2706–2708

    Article  CAS  Google Scholar 

  28. Allum KG, Creiohton JA, S.Green JH, Minkoff GJ, Prence LJS (1968) The British vibrational spectra of some dialkyl and diaryl disulphides and of di-n-butyl diselenide. Spectrochim Acta 24A:927–941

    Article  Google Scholar 

  29. Kadooka MM, Warner LG, Seff K (1976) The novel crystal and molecular structure of Bis[bis(2-pyridyl) disulfide]copper(I) perchlorate. J Am Chem Soc 98:24:7569–7568

    Article  Google Scholar 

  30. Bell NA, Clegg W, Coles SJ, Constable CP, Harrington RW, Hursthouse MB, Light ME, Raper ES, Sammon C, Walker MR (2004) Complexes of heterocyclic thiones and group 12 metals: Part VI. Preparation and characterisation of complexes of cadmium(II) halides with 1-methylimidazoline-2(3H)-thione, 1,3-thiazolidine-2-thione and 1,3-benzothiazoline-2-thione.Crystal structures of polymeric(1,3-thiazolidine-2-thione)cadmium(II) chloride, bis(1,3-thiazolidine-2-thione)cadmium(II) iodide and monomericbis(1-methylimidazoline-2(3H)-thione)cadmium(II) bromide. Inorg Chim Acta 357:2091–2099

    Article  CAS  Google Scholar 

  31. Jolley J, Cross WI, Pritchard RG, McAuliffe CA, Nolan KB (2000) Synthesis and characterization of mercaptoimidazole, mercaptopyrimidine complexes of platinun(II) and platinun(III).The crystal and molecular structures of tetra(2-ercaptobenzimidazole)- and tetra(2-mercaptoimidazole)platinun(II)choride. Inorg Chim Acta 315:36–43

    Article  Google Scholar 

  32. Nakamoto K (2009) Infrared and Raman Spectra of inorganic and coordination compounds. Part A: theory and applications in inorganic chemistry, 6th edn. Wiley, Hoboken

    Google Scholar 

  33. Creighton JR, Gardiner DJ, Gorvin AC, Guttridge C, Jackson ARW, Raper ES, Sherwood PMA (1985) Copper(I) halide complexes of imidazole thiones: crystal structure of dimeric monochloro bis(1-methylimidazoline-2-thione) Copper(I). Inorg Chim Acta 103:195–205

    Article  CAS  Google Scholar 

  34. Baldwin DA, Boeyens JCA, Copperthwaite RG, Loubser JHN, Markwell AJ (1984) Crystal and molecular structure of diaquobis (1,1′-dimethyl-2,2′-diimidazolylsulfide)copper(II)methylsulfate, (C5H10N4S)2Cu(II)(OH2)2(CH3OSO3)2. J Crystallogr Spectrosc Res 14:157–167

    Article  CAS  Google Scholar 

  35. Dudley R, Hathaway BJ (1970) Single-crystal electronic and electron spin resonance spectra of dichlorobis-(2-methylpyridine)copper(II). J Chem Soc (A). https://doi.org/10.1039/J19700002799

    Article  Google Scholar 

  36. McDonald RG, Hitchman MA (1990) Electronic spectra and bonding parameters of three planar complexes trans-CuCl2N2 Where N Is a heterocyclic amine. Inorg Chem 29:3074–3080

    Article  CAS  Google Scholar 

  37. Repich HH, Orysyk SI, Orysyk VV, Zborovskii YL, Melnyk AK, Trachevskyi VV, Pekhnyo VI, Vovk MV (2017) Influence of synthesis conditions on complexation of Cu (II) with O,N,O tridentate hydrazone ligand. X-ray diffraction and spectroscopic investigations. J Mol Struct 1146:222–232

    Article  CAS  Google Scholar 

  38. Urquiza NM, Islas MS, Ariza ST, Jori N, Martínez Medina JJ, Lavecchia MJ, López Tévez LL, Lezama L, Rojo T, Williams PAM, Ferrer EG (2015) Anti-thyroid and antifungal activities, BSA interaction and acid phosphatase inhibition of methimazole copper(II) complexes. Chem Biol Interact 229:64–72

    Article  CAS  PubMed  Google Scholar 

  39. Alimoradi N, Ashrafi-Kooshk MR, Shahlaei M, Maghsoudi S, Adibi H, McGeary RP, Khodarahmi R (2017) Diethylalkylsulfonamido(4-methoxyphenyl)methylphosphonate/phosphonic acid derivatives act as acid phosphatase inhibitors:synthesis accompanied by experimental and molecular modeling assessments. J Enzyme Inhib Med Chem 32:20–28

    Article  CAS  PubMed  Google Scholar 

  40. Valizadeh M, Schenk G, Nash K, Oddie GW, Guddat LW, Hume DA, Jersey J, Burke Jr TR, Hamilton S (2004) Phosphotyrosyl peptides and analogues as substrates and inhibitors of purple acid phosphatases. Arch Biochem Biophys 424:154–162

    Article  CAS  PubMed  Google Scholar 

  41. Schenk G, Mitić N, Hanson GR, Comba P (2013) Purple acid phosphatase: a journey into the function and mechanism of a colorful enzyme. Coord Chem Rev 257:473–482

    Article  CAS  Google Scholar 

  42. McGeary RP, Schenk G, Guddat LW (2014) The applications of binuclear metallohydrolases in medicine: recent advances in the design and development of novel drug leads for purple acid phosphatases, metallo-β-lactamases and arginases. Eur J Med Chem 76:132–144

    Article  CAS  PubMed  Google Scholar 

  43. Feder D, Hussein WM, Clayton DJ, Kan M-W, Schenk G, McGeary RP, Guddat LW (2012) Identification of purple acid phosphatase inhibitors by fragment-based screening: promising new leads for osteoporosis. Chem Biol Drug Des 80:665–674

    Article  CAS  PubMed  Google Scholar 

  44. McLauchlan CC, Hooker JD, Jones MA, Dymon Z, Backhus EA, Greiner BA, Dorner NA, Youkhana MA, Manus LM (2010) Inhibition of acid, alkaline, and tyrosine (PTP1B) phosphatases by novel vanadium complexes. J Inorg Biochem 104:274–281

    Article  CAS  PubMed  Google Scholar 

  45. Sheng Y, Abreu IA, Cabelli DE, Maroney MJ, Miller A-F, Teixeira M, Valentine JS (2014) Superoxide dismutases and superoxide reductases. Chem Rev 114:3854–3918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jitsukawa K, Harata M, Arii H, Sakurai H, Masuda H (2001) SOD activities of the copper complexes with tripodal polypyridylamine ligands having a hydrogen bonding site. Inorg Chim Acta 324:108–116

    Article  CAS  Google Scholar 

  47. Patel RN, Singh N, Gundla VLN (2006) Synthesis, structure and properties of ternary copper(II) complexes of ONO donor Schiff base, imidazole, 2,20-bipyridine and 1,10-phenanthroline. Polyhedron 25:3312–3318

    Article  CAS  Google Scholar 

  48. Bendary E, Francis RR, Ali HMG, Sarwat MI, El Hady S (2013) Antioxidant and structure–activity relationships (SARs) of some phenolic and anilines compounds. AOAS 58:173–181

    Google Scholar 

  49. Jing P, Zhao S-J, Jian W-J, Qian B-J, Dong Y, Pang J (2012) Quantitative studies on structure-DPPH• scavenging activity relationships of food phenolic acids. Molecules 17:12910–12924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ordoudi SA, Tsimidou MZ, Vafiadis AP, Bakalbassis EG (2006) Structure-DPPH• scavenging activity relationships: parallel study of catechol and guaiacol acid derivatives. J Agric Food Chem 54:5763–5768

    Article  CAS  PubMed  Google Scholar 

  51. Chai D-F, Ma Z, Yan H, Qiu YF, Liu H, Guo H-D, Gao G-G (2015) Synergistic effect of sandwich polyoxometalates and copper–imidazole complexes for enhancing the peroxidase-like activity. RSC Adv 5:78771–78779

    Article  CAS  Google Scholar 

  52. Leblanc C, Vilter H, Fournier J-B, Delage L, Potin P, Rebuffet E, Michel G, Solari PL, Feiters MC, Czjzek M (2015) Vanadium haloperoxidases: from the discovery 30 years ago to X-ray crystallographic and V K-edge absorption spectroscopic studies. Coord Chem Rev 301–302:134–146

    Article  CAS  Google Scholar 

  53. Lo SM-F, Chui SS-Y, Shek L-Y, Lin Z, Zhang XX, Wen G-H, Williams ID (2000) Polymer with Copper-I-Copper-II dimer units: [Cu4{1,4-C6H4(COO)2}3(4,4¢-bipy)2]n. J Am Chem Soc 122:6293–6294

    Article  CAS  Google Scholar 

  54. Xiong Y, Qin Y, Su L, Ye F (2018) Bioinspired synthesis of Cu2+-modified covalent triazine framework: a new highly efficient and promising peroxidase mimic. Chem Eur J 24:1–12

    Article  CAS  Google Scholar 

  55. Maurya MR, Chaudhary N, Avecilla F, Correia I (2015) Mimicking peroxidase activity by a polymer-supported oxidovanadium(IV) Schiff base complex derived from salicylaldehyde and 1,3-diamino-2-hydroxypropane. J Inorg Biochem 147:181–192

    Article  CAS  PubMed  Google Scholar 

  56. Li R, Zhou Y, Zou L, Li S, Wang J, Shu C, Wang C, Ge J, Ling L (2017) In situ growth of gold nanoparticles on hydrogen-bond supramolecular structures with high peroxidase-like activity at neutral pH and their application to one-pot blood glucose. Sens Actuators B 245:656–664

    Article  CAS  Google Scholar 

  57. Maurya MR, Uprety B, Avecilla F (2016) Dioxidomolybdenum(VI) complexes of tripodal tetradentate ligands for catalytic oxygen atom transfer between benzoin and dimethyl sulfoxide and for oxidation of pyrogallol. Eur J Inorg Chem 2016:4802–4803

  58. Ording-Wenker ECM, Siegler MA, Lutz M, Bouwman E (2015) Catalytic catechol oxidation by copper complexes: development of a structure–activity relationship. Dalton Trans 44:12196–12209

    Article  CAS  PubMed  Google Scholar 

  59. Kratz F, Elsadek BT (2012) Clinical impact of serum proteins on drug delivery. J Controll Release 161:429–445

    Article  CAS  Google Scholar 

  60. Ross PD, Subramanian S (1981) Thermodynamics of protein association reactions: forces contributing to stability. Biochemistry 20:3096–3102

    Article  CAS  PubMed  Google Scholar 

  61. Silveira VC, Abbott MP, Cavicchioli M, Gonçalves MB, Petrilli HM, de Rezende L, Amaral AT, Fonseca DEP, Caramoric GF, da Costa Ferreira AM (2013) Peculiar reactivity of a di-imine copper(II) complex regarding its binding to albumin protein. Dalton Trans 42:6386–6396

    Article  CAS  PubMed  Google Scholar 

  62. Sawada T, Fukumaru K, Sakurai H (1996) Coordination-dependent ESR spectra of Copper(II) complexes with a CuN4 type coordination mode: relationship between ESR parameters and stability constants or redox potentials of the complexes. Chem Pharm Bull 44:1009–1016

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by CONICET (PIP 0611, PIP 0550), ANPCyT (PICT16-1814, PICT14-1742, PICT17-2186), UNLP (X777), UNL (CAI+D 2016-50420150100070LI) of Argentina. LGN and EGF are Research Fellows of CONICET. JEP and PAMW are Research Fellows of CICPBA, Argentina.

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  1. CEQUINOR, CONICET-CICPBA-UNLP, Faculty of Exact Sciences, National University of La Plata, Bv. 120 No 1465, 1900, La Plata, Argentina

    Nancy Martini, Juliana E. Parente, Franco D´Alessandro, Patricia A. M. Williams & Evelina G. Ferrer

  2. Physics Department, Faculty of Biochemistry and Biological Sciences, National University of the Litoral, Ciudad Universitaria-Paraje El Pozo, 3000, Santa Fe, Argentina

    Marilin Rey & Alberto Rizzi

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  1. Nancy Martini
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Martini, N., Parente, J.E., D´Alessandro, F. et al. Potential bio-protective effect of copper compounds: mimicking SOD and peroxidases enzymes and inhibiting acid phosphatase as a target for anti-osteoporotic chemotherapeutics. Mol Biol Rep 46, 867–885 (2019). https://doi.org/10.1007/s11033-018-4542-8

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