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JBIC Journal of Biological Inorganic Chemistry

, Volume 20, Issue 7, pp 1205–1217 | Cite as

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

  • Rodrigo Bernardi Miguel
  • Philippe Alexandre Divina Petersen
  • Fernando A. Gonzales-Zubiate
  • Carla Columbano Oliveira
  • Naresh Kumar
  • Rafael Rodrigues do Nascimento
  • Helena Maria PetrilliEmail author
  • Ana Maria da Costa FerreiraEmail author
Original Paper

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

Keywords

Oxindolimine-metal complexes Cytotoxicity mechanism Kinase inhibitors Molecular dynamics Molecular docking 

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

Notes

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.

Supplementary material

775_2015_1300_MOESM1_ESM.pdf (1 mb)
Supplementary material 1 (PDF 1026 kb)

References

  1. 1.
    Harper JW, Adams PD (2001) Chem Rev 101:2511–2526CrossRefPubMedGoogle Scholar
  2. 2.
    Cohen P, Alessi DR (2013) ACS Chem Biol 8:96–104PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Hodgson DR, Schröder M (2011) Chem Soc Rev 40:1211–1223CrossRefPubMedGoogle Scholar
  4. 4.
    Liu J, Hu Y, Waller DL (2012) Nat Prod Rep 29:392–403CrossRefPubMedGoogle Scholar
  5. 5.
    Sanchez C, Mendez C, Salas JA (2006) Nat Prod Rep 23:1007–1045CrossRefPubMedGoogle Scholar
  6. 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 44:4339–4358CrossRefPubMedGoogle Scholar
  7. 7.
    Tell V, Mahmoud KA, Wichapong K, Schächtele C, Totzke F, Sippla W, Hilgerot A (2012) Med Chem Commun 3:1413–1418CrossRefGoogle Scholar
  8. 8.
    Lockman JW, Reeder MD, Robinson R, Ormonde PA, Cimbora DM, Williams BL, Willardsen JA (2011) Bioorg Med Chem Lett 21:1724–1727CrossRefPubMedGoogle Scholar
  9. 9.
    Knapp S, Sundström M (2014) Curr Opin Pharmacol 17:58–63CrossRefPubMedGoogle Scholar
  10. 10.
    Mullard A (2014) Nat Rev Drug Discov 13:85–89CrossRefPubMedGoogle Scholar
  11. 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 17:6257–6263CrossRefPubMedGoogle Scholar
  12. 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 26:9517–9532PubMedCentralCrossRefPubMedGoogle Scholar
  13. 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 55:7193–7207CrossRefPubMedGoogle Scholar
  14. 14.
    Pasha FA, Neaz MM (2013) J Mol Model 19:879–891CrossRefPubMedGoogle Scholar
  15. 15.
    Filomeni G, Cerchiaro G, Da Costa Ferreira AM, De Martino A, Pedersen JZ, Rotilio G, Ciriolo MR (2007) J Biol Chem 282:12010–12021Google Scholar
  16. 16.
    Zhang J, Yang PL, Gray NS (2009) Nat Rev Cancer 9:28–39CrossRefPubMedGoogle Scholar
  17. 17.
    Deborah JM, Cornelia RB, David CB, Ping U, Terence HJJ, Sung HK, Audie GR (2003) Biochem Biophys Res Commun 310:1026–1031CrossRefGoogle Scholar
  18. 18.
    Prakash CR, Theivendren P, Raja S (2012) Pharmacol Pharm 3:62–71CrossRefGoogle Scholar
  19. 19.
    Cerchiaro G, Aquilano K, Filomeni G, Rotilio G, Ciriolo MR, Da Costa Ferreira AM (2005) J Inorg Biochem 99:1433–1440CrossRefPubMedGoogle Scholar
  20. 20.
    Cerchiaro G, Saboya PL, Da Costa Ferreira AM, Tomazela DM, Eberlin MN (2004) Transit Met Chem 29:495–504Google Scholar
  21. 21.
    Da Silveira VC, Luz JS, Oliveira CC, Graziani I, Ciriolo MR, Da Costa Ferreira AM (2008) J Inorg Biochem 102:1090–1103CrossRefPubMedGoogle Scholar
  22. 22.
    Filomeni G, Piccirillo S, Graziani I, Cardaci S, Da Costa Ferreira AM, Rotilio G, Ciriolo MR (2009) Carcinogenesis 30:1115–1124PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Cerchiaro G, Micke GA, Tavares MFM, Da Costa Ferreira AM (2004) J Mol Catalysis A Chem 221:29–39CrossRefGoogle Scholar
  24. 24.
    Katkar P, Coletta A, Castelli S, Sabino GL, Couto RAA, Da Costa Ferreira AM, Desideri A (2014) Metallomics 6:117–125CrossRefPubMedGoogle Scholar
  25. 25.
    McGrath CF, Pattabiraman N, Kellogg GE, Lemcke T, Kunick C, Sausville EA, Zaharevitz DW, Gussio R (2005) J Biomol Struct Dyn 22:493–502CrossRefPubMedGoogle Scholar
  26. 26.
    Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massagué J, Pavletich NP (1995) Nature 376:313–320CrossRefPubMedGoogle Scholar
  27. 27.
    Trott O, Olson AJ (2010) J Comput Chem 31:455–461PubMedCentralPubMedGoogle Scholar
  28. 28.
    Oostenbrink C, Villa A, Mark AE, van Gunsteren WF (2004) J Comput Chem 25:1656–1676CrossRefPubMedGoogle Scholar
  29. 29.
    Berendsen HJC, Postma JPM, van Gunsteren WF, Hermans J (1981) In: Pullman B (ed) Intermolecular Forces. Reidel, Dordrecht, pp 331–342CrossRefGoogle Scholar
  30. 30.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE et al (2009) Gaussian 09, Revision B.01. Gaussian, Inc., WallingfordGoogle Scholar
  31. 31.
    Becke A (1993) J Chem Phys 98:5648–5652CrossRefGoogle Scholar
  32. 32.
    Becke A (1996) J Chem Phys 104:1040–1046CrossRefGoogle Scholar
  33. 33.
    Ditchfield R (1971) J Chem Phys 54:724–728CrossRefGoogle Scholar
  34. 34.
    Breneman CM, Wiberg KB (1990) J Comput Chem 11:361–373CrossRefGoogle Scholar
  35. 35.
    Malde AK, Zuo L, Breeze M, Stroet M, Poger D, Nair PC, Oostenbrink C, Mark AE (2011) J Chem Theory Comput 7:4026–4037CrossRefGoogle Scholar
  36. 36.
    Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) J Chem Phys 103:8577–8593CrossRefGoogle Scholar
  37. 37.
    Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR (1984) J Chem Phys 81:3684–3690CrossRefGoogle Scholar
  38. 38.
    Parrinello M (1981) J Appl Phys 52:7182–7190CrossRefGoogle Scholar
  39. 39.
    Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) J Chem Theory Comput 4:435–447CrossRefGoogle Scholar
  40. 40.
    Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC (2005) J Comput Chem 26:1701–1718Google Scholar
  41. 41.
    Daura X, Gademann K, Jaun B, Seebach D, van Gunsteren WF, Mark AE (1999) Angew Chemie Int Ed 38:236–240CrossRefGoogle Scholar
  42. 42.
    Da Silveira VC, Caramori GF, Abbott MP, Gonçalves MB, Petrilli HM, Da Costa Ferreira AM (2009) J Inorg Biochem 103:1331–1341CrossRefPubMedGoogle Scholar
  43. 43.
    Lau SJ, Sarkar BJ (1971) Biol Chem 246:5938–5943Google Scholar
  44. 44.
    Valko M, Morris H, Mazur M, Telser J, McInnes EJL, Mabbs FE (1999) J Phys Chem B 103:5591–5597CrossRefGoogle Scholar
  45. 45.
    Rózga M, Sokolowska M, Protas AM, Bal W (2007) J Biol Inorg Chem 12:913–918CrossRefPubMedGoogle Scholar
  46. 46.
    Masuoka J, Saltman P (1994) J Biol Chem 269:25557–25561PubMedGoogle Scholar
  47. 47.
    Bal W, Christodoulou J, Sadler PJ, Tucker A (1998) J Inorg Biochem 70:33–39CrossRefPubMedGoogle Scholar
  48. 48.
    Sakaguchi U, Addison AW (1979) J Chem Soc Dalton Trans 600–608Google Scholar
  49. 49.
    He L, Liao SY, Tan CP, Ye RR, Xu YW, Zhao M, Ji LN, Mao ZW (2013) Chem Eur J 19:12152–12160Google Scholar

Copyright information

© SBIC 2015

Authors and Affiliations

  • Rodrigo Bernardi Miguel
    • 1
  • Philippe Alexandre Divina Petersen
    • 2
  • Fernando A. Gonzales-Zubiate
    • 3
  • Carla Columbano Oliveira
    • 3
  • Naresh Kumar
    • 1
  • Rafael Rodrigues do Nascimento
    • 2
  • Helena Maria Petrilli
    • 2
    Email author
  • Ana Maria da Costa Ferreira
    • 1
    Email author
  1. 1.Departamento de Química FundamentalInstituto de Química, Universidade de São PauloSão PauloBrazil
  2. 2.Departamento de Física dos Materiais e MecânicaInstituto de Física, Universidade de São PauloSão PauloBrazil
  3. 3.Departamento de BioquímicaInstituto de Química, Universidade de São PauloSão PauloBrazil

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