Skip to main content
SpringerLink
Log in

Inhibition of cyclin-dependent kinase CDK1 by oxindolimine ligands and corresponding copper and zinc complexes

  • Original Paper
  • Published:
JBIC Journal of Biological Inorganic Chemistry Aims and scope Submit manuscript

Abstract

Oxindolimine-copper(II) and zinc(II) complexes that previously have shown to induce apoptosis, with DNA and mitochondria as main targets, exhibit here significant inhibition of kinase CDK1/cyclin B protein. Copper species are more active than the corresponding zinc, and the free ligand shows to be less active, indicating a major influence of coordination in the process, and a further modulation by the coordinated ligand. Molecular docking and classical molecular dynamics provide a better understanding of the effectiveness and kinase inhibition mechanism by these compounds, showing that the metal complex provides a stronger interaction than the free ligand with the ATP-binding site. The metal ion introduces charge in the oxindole species, giving it a more rigid conformation that then becomes more effective in its interactions with the protein active site. Analogous experiments resulted in no significant effect regarding phosphatase inhibition. These results can explain the cytotoxicity of these metal complexes towards different tumor cells, in addition to its capability of binding to DNA, and decreasing membrane potential of mitochondria.

Graphical Abstract

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

CDK:

Cyclin-dependent kinase

DFT:

Density functional theory

PDB:

Protein data bank

PERK:

Endoplasmic reticulum kinase

PKR:

Protein kinase R

SAR:

Structure activity relationship

References

  1. Harper JW, Adams PD (2001) Chem Rev 101:2511–2526

    Article  CAS  PubMed  Google Scholar 

  2. Cohen P, Alessi DR (2013) ACS Chem Biol 8:96–104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Hodgson DR, Schröder M (2011) Chem Soc Rev 40:1211–1223

    Article  CAS  PubMed  Google Scholar 

  4. Liu J, Hu Y, Waller DL (2012) Nat Prod Rep 29:392–403

    Article  CAS  PubMed  Google Scholar 

  5. Sanchez C, Mendez C, Salas JA (2006) Nat Prod Rep 23:1007–1045

    Article  CAS  PubMed  Google Scholar 

  6. Bramson HN, Corona J, Davis ST, Dickerson SH, Edelstein M, Frye SV, Gampe RT Jr, Harris PA, Hassell A, Holmes WD, Hunter RN, Lackey KE, Lovejoy B, Luzzio MJ, Montana V, Rocque WJ, Rusnak D, Shewchuk L, Veal JM, Walker DH, Kuyper LF (2001) J Med Chem 44:4339–4358

    Article  CAS  PubMed  Google Scholar 

  7. Tell V, Mahmoud KA, Wichapong K, Schächtele C, Totzke F, Sippla W, Hilgerot A (2012) Med Chem Commun 3:1413–1418

    Article  CAS  Google Scholar 

  8. Lockman JW, Reeder MD, Robinson R, Ormonde PA, Cimbora DM, Williams BL, Willardsen JA (2011) Bioorg Med Chem Lett 21:1724–1727

    Article  CAS  PubMed  Google Scholar 

  9. Knapp S, Sundström M (2014) Curr Opin Pharmacol 17:58–63

    Article  CAS  PubMed  Google Scholar 

  10. Mullard A (2014) Nat Rev Drug Discov 13:85–89

    Article  PubMed  Google Scholar 

  11. Beauchard A, Laborie H, Rouillard H, Lozach O, Ferandin Y, Le Guével R, Guguen-Guillouzo C, Meijer L, Besson T, Thiéry V (2009) Bioorg Med Chem 17:6257–6263

    Article  CAS  PubMed  Google Scholar 

  12. Blais JD, Addison CL, Edge R, Falls T, Zhao H, Wary K, Koumenis C, Harding HP, Ron D, Holcik M, Bell JC (2006) Mol Cell Biol 26:9517–9532

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WHH, Heerding DA, Minthorn E, Mencken T, Atkins C, Liu Q, Rabindran S, Kumar R, Hong X, Goetz A, Stanley T, Taylor JD, Sigethy SD, Tomberlin GH, Hassell AM, Kahler KM, Shewchuk LM, Gampe RT (2012) J Med Chem 55:7193–7207

    Article  CAS  PubMed  Google Scholar 

  14. Pasha FA, Neaz MM (2013) J Mol Model 19:879–891

    Article  CAS  PubMed  Google Scholar 

  15. Filomeni G, Cerchiaro G, Da Costa Ferreira AM, De Martino A, Pedersen JZ, Rotilio G, Ciriolo MR (2007) J Biol Chem 282:12010–12021

  16. Zhang J, Yang PL, Gray NS (2009) Nat Rev Cancer 9:28–39

    Article  PubMed  Google Scholar 

  17. Deborah JM, Cornelia RB, David CB, Ping U, Terence HJJ, Sung HK, Audie GR (2003) Biochem Biophys Res Commun 310:1026–1031

    Article  Google Scholar 

  18. Prakash CR, Theivendren P, Raja S (2012) Pharmacol Pharm 3:62–71

    Article  CAS  Google Scholar 

  19. Cerchiaro G, Aquilano K, Filomeni G, Rotilio G, Ciriolo MR, Da Costa Ferreira AM (2005) J Inorg Biochem 99:1433–1440

    Article  CAS  PubMed  Google Scholar 

  20. Cerchiaro G, Saboya PL, Da Costa Ferreira AM, Tomazela DM, Eberlin MN (2004) Transit Met Chem 29:495–504

  21. Da Silveira VC, Luz JS, Oliveira CC, Graziani I, Ciriolo MR, Da Costa Ferreira AM (2008) J Inorg Biochem 102:1090–1103

    Article  PubMed  Google Scholar 

  22. Filomeni G, Piccirillo S, Graziani I, Cardaci S, Da Costa Ferreira AM, Rotilio G, Ciriolo MR (2009) Carcinogenesis 30:1115–1124

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Cerchiaro G, Micke GA, Tavares MFM, Da Costa Ferreira AM (2004) J Mol Catalysis A Chem 221:29–39

    Article  CAS  Google Scholar 

  24. Katkar P, Coletta A, Castelli S, Sabino GL, Couto RAA, Da Costa Ferreira AM, Desideri A (2014) Metallomics 6:117–125

    Article  CAS  PubMed  Google Scholar 

  25. McGrath CF, Pattabiraman N, Kellogg GE, Lemcke T, Kunick C, Sausville EA, Zaharevitz DW, Gussio R (2005) J Biomol Struct Dyn 22:493–502

    Article  CAS  PubMed  Google Scholar 

  26. Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massagué J, Pavletich NP (1995) Nature 376:313–320

    Article  CAS  PubMed  Google Scholar 

  27. Trott O, Olson AJ (2010) J Comput Chem 31:455–461

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Oostenbrink C, Villa A, Mark AE, van Gunsteren WF (2004) J Comput Chem 25:1656–1676

    Article  CAS  PubMed  Google Scholar 

  29. Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J (1981) In: Pullman B (ed) Intermolecular Forces. Reidel, Dordrecht, pp 331–342

    Chapter  Google Scholar 

  30. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE et al (2009) Gaussian 09, Revision B.01. Gaussian, Inc., Wallingford

  31. Becke A (1993) J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  32. Becke A (1996) J Chem Phys 104:1040–1046

    Article  CAS  Google Scholar 

  33. Ditchfield R (1971) J Chem Phys 54:724–728

    Article  CAS  Google Scholar 

  34. Breneman CM, Wiberg KB (1990) J Comput Chem 11:361–373

    Article  CAS  Google Scholar 

  35. Malde AK, Zuo L, Breeze M, Stroet M, Poger D, Nair PC, Oostenbrink C, Mark AE (2011) J Chem Theory Comput 7:4026–4037

    Article  CAS  Google Scholar 

  36. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) J Chem Phys 103:8577–8593

    Article  CAS  Google Scholar 

  37. Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR (1984) J Chem Phys 81:3684–3690

    Article  CAS  Google Scholar 

  38. Parrinello M (1981) J Appl Phys 52:7182–7190

    Article  CAS  Google Scholar 

  39. Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) J Chem Theory Comput 4:435–447

    Article  CAS  Google Scholar 

  40. Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC (2005) J Comput Chem 26:1701–1718

  41. Daura X, Gademann K, Jaun B, Seebach D, van Gunsteren WF, Mark AE (1999) Angew Chemie Int Ed 38:236–240

    Article  CAS  Google Scholar 

  42. Da Silveira VC, Caramori GF, Abbott MP, Gonçalves MB, Petrilli HM, Da Costa Ferreira AM (2009) J Inorg Biochem 103:1331–1341

    Article  PubMed  Google Scholar 

  43. Lau SJ, Sarkar BJ (1971) Biol Chem 246:5938–5943

  44. Valko M, Morris H, Mazur M, Telser J, McInnes EJL, Mabbs FE (1999) J Phys Chem B 103:5591–5597

    Article  CAS  Google Scholar 

  45. Rózga M, Sokolowska M, Protas AM, Bal W (2007) J Biol Inorg Chem 12:913–918

    Article  PubMed  Google Scholar 

  46. Masuoka J, Saltman P (1994) J Biol Chem 269:25557–25561

    CAS  PubMed  Google Scholar 

  47. Bal W, Christodoulou J, Sadler PJ, Tucker A (1998) J Inorg Biochem 70:33–39

    Article  CAS  PubMed  Google Scholar 

  48. Sakaguchi U, Addison AW (1979) J Chem Soc Dalton Trans 600–608

  49. He L, Liao SY, Tan CP, Ye RR, Xu YW, Zhao M, Ji LN, Mao ZW (2013) Chem Eur J 19:12152–12160

Download references

Acknowledgments

This work was supported by Grants from the Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, Grants 2010/51842-3, 2011/50318-1, and 2013/07937-8), Conselho Nacional de Desenvolvimento Científico Tecnológico (CNPq, Grant 573530/2008-4), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Pro-Reitoria de Pesquisa da Universidade de São Paulo (PRPUSP, Grant 2011.1.9352.1.8). The authors are also grateful to the networks INCT INEO, INCT Redoxoma (FAPESP/CNPq/CAPES), NAP Redoxoma (PRPUSP), CEPID Redoxoma (FAPESP) and BioMol/CAPES (Computational Biology Project). We thank Marcos B. Gonçalves for discussions.

Author information

Author notes

    Authors and Affiliations

    1. Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, SP, 05508-000, Brazil

      Rodrigo Bernardi Miguel, Naresh Kumar & Ana Maria da Costa Ferreira

    2. Departamento de Física dos Materiais e Mecânica, Instituto de Física, Universidade de São Paulo, Rua do Matão, Travessa R 187, São Paulo, 05508-090, SP, Brazil

      Philippe Alexandre Divina Petersen, Rafael Rodrigues do Nascimento & Helena Maria Petrilli

    3. Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, 05508-000, SP, Brazil

      Fernando A. Gonzales-Zubiate & Carla Columbano Oliveira

    Authors
    1. Rodrigo Bernardi Miguel
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Philippe Alexandre Divina Petersen
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Fernando A. Gonzales-Zubiate
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Carla Columbano Oliveira
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Naresh Kumar
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Rafael Rodrigues do Nascimento
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Helena Maria Petrilli
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Ana Maria da Costa Ferreira
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Helena Maria Petrilli or Ana Maria da Costa Ferreira.

    Additional information

    R. B. Miguel and P. A. D. Petersen contribute equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (PDF 1026 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Miguel, R.B., Petersen, P.A.D., Gonzales-Zubiate, F.A. et al. Inhibition of cyclin-dependent kinase CDK1 by oxindolimine ligands and corresponding copper and zinc complexes. J Biol Inorg Chem 20, 1205–1217 (2015). https://doi.org/10.1007/s00775-015-1300-4

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00775-015-1300-4

    Keywords

    Search

    Navigation