Effect of the hydroxamate group in the antitumoral activity and toxicity toward normal cells of new copper(II) complexes

Abstract

The synthesis, physico–chemical characterization and cytotoxicity of four copper(II) coordination complexes, i.e. [Cu(HBPA)Cl2] (1), [Cu(BHA)2] (2), [Cu(HBPA)(BHA)Cl] CH3OH (3) and [Cu(HBPA)2]Cl2·4H2O (4), are reported. HBPA is the tridentate ligand N-(2-hydroxybenzyl)-N-(2-pyridylmethyl)amine and HBHA is the benzohydroxamic acid. The reaction between the HBHA and CuCl2.2H2O has resulted in the new complex (2) and the reaction between complex (1) and HBHA has resulted in the new complex (3). X-ray diffraction studies for complex (3) indicated the effective coordination of HBHA as BHA. Their cytotoxicity was evaluated against three human tumoral cell lines (Colo-205, NCI-H460 and U937) and PBMC (peripheral blood mononuclear cells), using the MTT cytotoxic assay. The results toward PBMC reveal that the new copper(II) complex (2) presents lower toxicity toward normal cells. Furthermore, complex (2) presents IC50 values lower than cisplatin toward NCI-H460 and the best selectivity index obtained towards NCI-H460 (SI = 2.2) and U937 cell lines (SI = 2.0), as a result of the presence of two molecules of HBHA in its structure. Complex (3) presents IC50 values lower than cisplatin toward NCI-H460, Colo-205 and comparable to cisplatin toward U937. The evaluation of the cell death type promoted by complexes (2) and (4) was investigated toward NCI-H460 revealing better results than the standard drug cisplatin, according to the Annexin V and propidium iodide (PI) labeling experiment. Based on the studies here performed, HBHA seems to be related to lower toxicity toward PBMC and HBPA is improving directly the cytotoxity.

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
Fig. 7

References

  1. Addison AW, Rao TN, Reedijk J et al (1984) Synthesis, structure, and spectroscopic properties of copper(II) compounds containing nitrogen-sulphur donor ligands; the crystal and molecular structure of aqua[1,7-bis(N-methylbenzimidazol-2′;-yl)-2,6-dithiaheptane]copper(II) perchlorate. J Chem Soc Dalt Trans https://doi.org/10.1039/DT9840001349

    Article  Google Scholar 

  2. Azeredo NFB, Bull ES, Resende JALC et al (2015) Crystal structure and behavior in solution of [Cu(HBPA)2]Cl2·4H2O [HBPA = (2-hydroxybenzyl-2-pyridylmethyl)amine]. J Chem Crystallogr. https://doi.org/10.1007/s10870-015-0617-8

    Article  Google Scholar 

  3. Ballestreri E, Simon D, de Souza AP et al (2018) Resistance mechanism to cisplatin in NCIH-460 non-small cell lung cancer cell line: investigating apoptosis, autophagy, and cytogenetic damage. Cancer Drug Resist. https://doi.org/10.20517/cdr.2017.02

    Article  Google Scholar 

  4. Borges LJH, Bull ÉS, Fernandes C et al (2016) In vitro and in vivo studies of the antineoplastic activity of copper (II) compounds against human leukemia THP-1 and murine melanoma B16–F10 cell lines. Eur J Med Chem. https://doi.org/10.1016/j.ejmech.2016.07.018

    Article  PubMed  Google Scholar 

  5. Brabec V, Griffith DM, Kisova A et al (2012) Valuable insight into the anticancer activity of the platinum-histone deacetylase inhibitor conjugate, cis-[Pt(NH3)2malSAHA -2H)]. Mol Pharm. https://doi.org/10.1021/mp300038f

    Article  PubMed  Google Scholar 

  6. BRUKER, APEX2 (2012) Bruker AXS Inc., Madison, WI, USA.

  7. Codd R, Braich N, Liu J et al (2009) Zn(II)-dependent histone deacetylase inhibitors: Suberoylanilide hydroxamic acid and trichostatin A. Int J Biochem Cell Biol 41(736):739

    Google Scholar 

  8. Cooper AL, Greenberg VL, Lancaster PS et al (2007) In vitro and in vivo histone deacetylase inhibitor therapy with suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer. Gynecol Oncol. https://doi.org/10.1016/j.ygyno.2006.09.011

    Article  PubMed  Google Scholar 

  9. Costa RO, Ferreira SS, Pereira CA et al (2018) A new mixed-valence Mn(II)Mn(III) compound with catalase and superoxide dismutase activities. Front Chem. https://doi.org/10.3389/fchem.2018.00491

    Article  PubMed  PubMed Central  Google Scholar 

  10. Faggi E, Gavara R, Bolte M et al (2015) Copper(ii) complexes of macrocyclic and open-chain pseudopeptidic ligands: synthesis, characterization and interaction with dicarboxylates. Dalt Trans. https://doi.org/10.1039/c5dt01496d

    Article  Google Scholar 

  11. Fernandes C, Horn A, Vieira-da-Motta O et al (2010) Synthesis, characterization and antibacterial activity of FeIII CoII, CuII and ZnII complexes probed by transmission electron microscopy. J Inorg Biochem. https://doi.org/10.1016/j.jinorgbio.2010.07.011

    Article  PubMed  Google Scholar 

  12. Fernandes C, Horn A, Vieira-Da-Motta O et al (2014) Synthesis, characterization, antibacterial and antitumoral activities of mononuclear zinc complexes containing tridentate amine based ligands with N3 or N2O donor groups. Inorganica Chim Acta. https://doi.org/10.1016/j.ica.2014.02.040

    Article  Google Scholar 

  13. Fernandes C, Horn A, Lopes BF et al (2015) Induction of apoptosis in leukemia cell lines by new copper(II) complexes containing naphthyl groups via interaction with death receptors. J Inorg Biochem. https://doi.org/10.1016/j.jinorgbio.2015.09.014

    Article  PubMed  Google Scholar 

  14. Geary WJ (1971) The use of conductivity measurements in organic solvents for the characterisation of coordination compounds. Coord Chem Rev. https://doi.org/10.1016/S0010-8545(00)80009-0

    Article  Google Scholar 

  15. Griffith DM, Duff B, Suponitsky KY et al (2011a) Novel trans-platinum complexes of the histone deacetylase inhibitor valproic acid; synthesis, in vitro cytotoxicity and mutagenicity. J Inorg Biochem. https://doi.org/10.1016/j.jinorgbio.2011.03.001

    Article  PubMed  Google Scholar 

  16. Griffith DM, Szocs B, Keogh T et al (2011b) Suberoylanilide hydroxamic acid, a potent histone deacetylase inhibitor; its X-ray crystal structure and solid state and solution studies of its Zn(II) Ni(II), Cu(II) and Fe(III) complexes. J Inorg Biochem. https://doi.org/10.1016/j.jinorgbio.2011.03.003

    Article  PubMed  Google Scholar 

  17. Gupta SP, Sharma A (2013) The chemistry of hydroxamic acids. In: Hydroxamic acids: a unique family of chemicals with multiple biological activities

  18. Halaburková A, Jendželovský R, Kovaľ J et al (2017) Histone deacetylase inhibitors potentiate photodynamic therapy in colon cancer cells marked by chromatin-mediated epigenetic regulation of CDKN1A. Clin Epigenetics. https://doi.org/10.1186/s13148-017-0359-x

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hathaway BJ, Billing DE (1970) The electronic properties and stereochemistry of mono-nuclear complexes of the copper(II) ion. Coord Chem Rev. https://doi.org/10.1016/S0010-8545(00)80135-6

    Article  Google Scholar 

  20. Kalfaolu E, Karabulut B (2011) Theoretical investigation of EPR and molecular orbital coefficient parameters for [Cu(hsm)2(sac)2] complex. Chem Phys Lett. https://doi.org/10.1016/j.cplett.2011.02.038

    Article  Google Scholar 

  21. Kenny RG, Marmion CJ (2019) Toward multi-targeted platinum and ruthenium drugs—a new paradigm in cancer drug treatment regimens? Chem Rev 119.2:1058–1137

    Article  Google Scholar 

  22. Kenny RG, Ude Z, Docherty JR, Marmion CJ (2020) Vorinostat and Belinostat, hydroxamate-based anti-cancer agents, are nitric oxide donors. J Inorg Biochem. https://doi.org/10.1016/j.jinorgbio.2019.110981

    Article  PubMed  Google Scholar 

  23. Kim MS, Blake M, Baek JH et al (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63(7291):7300

    Google Scholar 

  24. Kivelson D, Neman R (1961) ESR studies on the bonding in copper complexes. J Chem Phys doi. https://doi.org/10.1063/11731880

    Article  Google Scholar 

  25. Kovacic P, Edwards CL (2011) Hydroxamic acids (therapeutics and mechanism): Chemistry, acyl nitroso, nitroxyl, reactive oxygen species, and cell signaling. J Recept Signal Transduct 31(10):19

    Google Scholar 

  26. Končić MZ, Barbarić M, Perković I, Zorc B (2011) Antiradical, chelating and antioxidant activities of hydroxamic acids and hydroxyureas. Molecules. https://doi.org/10.3390/molecules16086232

    Article  PubMed  PubMed Central  Google Scholar 

  27. Luu TH, Morgan RJ, Leong L et al (2008) A phase II trial of vorinostat (suberoylanilide hydroxamic acid) in metastatic breast cancer: a California cancer consortium study. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-08-0122

    Article  PubMed  PubMed Central  Google Scholar 

  28. Maciel LLF, de Freitas WR, Bull ES et al (2020) In vitro and in vivo anti-proliferative activity and ultrastructure investigations of a copper(II) complex toward human lung cancer cell NCI-H460. J Inorg Biochem. https://doi.org/10.1016/j.jinorgbio.2020.111166

    Article  PubMed  Google Scholar 

  29. Manal M, Chandrasekar MJN, Gomathi Priya J, Nanjan MJ (2016) Inhibitors of histone deacetylase as antitumor agents: a critical review. Bioorg Chem 67(18):42

    Google Scholar 

  30. Marks PA (2007) Discovery and development of SAHA as an anticancer agent. Oncogene 26(1351):1356

    Google Scholar 

  31. Marmion CJ, Parker JP, Nolan KB (2013) Hydroxamic acids: an important class of metalloenzyme inhibitors. In: Comprehensive inorganic chemistry II (second edition): from elements to applications

  32. Maurice AM (1980) Acquisition of anisotropic information by computational analysis of isotropic EPR spectra. (PhD thesis). University of Illinois, Urbana.

  33. Morcelli SR, Bull ÉS, Terra WS et al (2016) Synthesis, characterization and antitumoral activity of new cobalt(II)complexes: effect of the ligand isomerism on the biological activity of the complexes. J Inorg Biochem. https://doi.org/10.1016/j.jinorgbio.2016.05.003

    Article  PubMed  Google Scholar 

  34. Moreira RO, Morcelli SR, Kanashiro MM et al (2019) Modulating the antitumoral activity by the design of new platinum(II) compounds: synthesis, characterization, DFT, ultrastructure and mechanistic studies. J Inorg Biochem. https://doi.org/10.1016/j.jinorgbio.2018.12.016

    Article  PubMed  Google Scholar 

  35. Muller PY, Milton MN (2012) The determination and interpretation of the therapeutic index in drug development. Nat Rev Drug Discov 11.10(751):761

    Google Scholar 

  36. Neves A, de Brito MA, Vencato I et al (1993) Synthesis, crystal structure and properties of a new binuclear iron(III) complex as a model for the purple acid phosphatases. Inorganica Chim Acta. https://doi.org/10.1016/S0020-1693(00)87516-7

    Article  Google Scholar 

  37. Park S, Park JA, Kim YE et al (2015) Suberoylanilide hydroxamic acid induces ROS-mediated cleavage of HSP90 in leukemia cells. Cell Stress Chaperones. https://doi.org/10.1007/s12192-014-0533-4

    Article  PubMed  PubMed Central  Google Scholar 

  38. Parker JP, Nimir H, Griffith DM et al (2013) A novel platinum complex of the histone deacetylase inhibitor belinostat: Rational design, development and in vitro cytotoxicity. J Inorg Biochem. https://doi.org/10.1016/j.jinorgbio.2013.03.011

    Article  PubMed  Google Scholar 

  39. Rieger AM, Nelson KL, Konowalchuk JD, Barreda DR (2011) Modified annexin V/propidium iodide apoptosis assay for accurate assessment of cell death. J Vis Exp. https://doi.org/10.3791/2597

    Article  PubMed  PubMed Central  Google Scholar 

  40. Rodrigues DA, Ferreira-Silva GA, Ferreira ACS et al (2016) Design, synthesis, and pharmacological evaluation of novel n-acylhydrazone derivatives as potent histone deacetylase 6/8 dual inhibitors. J Med Chem. https://doi.org/10.1021/acs.jmedchem.5b01525

    Article  PubMed  Google Scholar 

  41. Saban N, Bujak M (2009) Hydroxyurea and hydroxamic acid derivatives as antitumor drugs. Cancer Chemother Pharmacol 64:213

    CAS  Article  Google Scholar 

  42. Sheldrick GM (2008) A short history of SHELX. Acta Crystallogr Sect A Found Crystallogr 64:112

    CAS  Article  Google Scholar 

  43. Silva GC, Parrilha GL, Carvalho NMF et al (2008) A bio-inspired Fe(III) complex and its use in the cyclohexane oxidation. Catal Today. https://doi.org/10.1016/j.cattod.2007.12.036

    Article  Google Scholar 

  44. Sirichanchuen B, Pengsuparp T, Chanvorachote P (2012) Long-term Cisplatin exposure impairs autophagy and causes cisplatin resistance in human lung cancer cells. Mol Cell Biochem. https://doi.org/10.1007/s11010-011-1199-1

    Article  PubMed  Google Scholar 

  45. Ungerstedt J, Du Y, Zhang H et al (2012) In vivo redox state of Human thioredoxin and redox shift by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Free Radic Biol Med. https://doi.org/10.1016/j.freeradbiomed.2012.09.019

    Article  PubMed  Google Scholar 

  46. Wang XX, Wan RZ, Liu ZP (2018) Recent advances in the discovery of potent and selective HDAC6 inhibitors. Eur J Med Chem 143:1406–1418

    CAS  Article  Google Scholar 

  47. Wlodkowic D, Telford W, Skommer J, Darzynkiewicz Z (2011) Apoptosis and beyond: cytometry in studies of programmed cell death a review on hydroxamic acids: widespectrum chemotherapeutic agents. Int J Biol Biomed Eng. https://doi.org/10.46300/91011.2020.14.12

    Article  Google Scholar 

Download references

Acknowledgements

The authors are grateful to financial support received from CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and FAPERJ (Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro), and Capes (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) for the scholarship.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Christiane Fernandes.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 487 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Azeredo, N.F.B., Borges, F.V., Mathias, M.S. et al. Effect of the hydroxamate group in the antitumoral activity and toxicity toward normal cells of new copper(II) complexes. Biometals (2021). https://doi.org/10.1007/s10534-020-00275-9

Download citation

Keywords

  • Copper(II) complex
  • Antitumor activity
  • Benzo hydroxamic acid (HBHA)
  • PBMC
  • Apoptosis