Skip to main content

Desferrioxamine-caffeine (DFCAF) as a cell permeant moderator of the oxidative stress caused by iron overload

Abstract

Desferrioxamine (DFO) is a potent iron chelator used in the treatment of iron overload (IO) disorders. However, due to its low cell permeability and fast clearance, DFO administration is usually prolonged and of limited use for the treatment of IO in tissues such as the brain. Caffeine is a safe, rapidly absorbable molecule that can be linked to other compounds to improve their cell permeability. In this work, we successfully prepared and described DFO-caffeine, a conjugate with iron scavenging ability, antioxidant properties and enhanced permeation in the HeLa cell model.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Afify AE-MMR, Shalaby EA, El-Beltagi HS (2011) Antioxidant activity of aqueous extracts of different caffeine products. J Med Plants Res 5(20):5071–5078

    CAS  Google Scholar 

  2. Andrews NC (2000) Iron homeostasis: insights from genetics and animal models. Nat Rev Genet 1(3):208–217

    CAS  PubMed  Article  Google Scholar 

  3. Arendash GW, Schleif W, Rezai-Zadeh K, Jackson EK, Zacharia LC, Cracchiolo JR, Shippy D, Tan J (2006) Caffeine protects Alzheimer’s mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience 142(4):941–952

    CAS  PubMed  Article  Google Scholar 

  4. Baccan MM, Chiarelli-Neto O, Pereira RMS, Esposito BP (2012) Quercetin as a shuttle for labile iron. J Inorg Biochem 107(1):34–39

    CAS  PubMed  Article  Google Scholar 

  5. Borgias B, Hugi AD, Raymond KN (1989) Isomerization and solution structures of desferrioxamine-B complexes of Al3+ and Ga3+. Inorg Chem 28(18):3538–3545

    CAS  Article  Google Scholar 

  6. Breuer W, Epsztejn S, Cabantchik ZI (1995) Iron acquired from transferrin by K562 cells is delivered into a cytoplasmic pool of chelatable iron(II). J Biol Chem 270(41):24209–24215

    CAS  PubMed  Article  Google Scholar 

  7. Dhungana S, White PS, Crumbliss AL (2001) Crystal structure of ferrioxamine B: a comparative analysis and implications for molecular recognition. J Biol Inorg Chem 6(8):810–818

    CAS  PubMed  Article  Google Scholar 

  8. Dinc E, Onur F (1998) Application of a new spectrophotometric method for the analysis of a ternary mixture containing metamizol, paracetamol and caffeine in tablets. Anal Chim Acta 359(1–2):93–106

    CAS  Article  Google Scholar 

  9. Epsztejn S, Kakhlon O, Glickstein H, Breuer W, Cabantchik ZI (1997) Fluorescence analysis of the labile iron pool of mammalian cells. Anal Biochem 248(1):31–40

    CAS  PubMed  Article  Google Scholar 

  10. Eskelinen MH, Ngandu T, Tuomilehto J, Soininen H, Kivipelto M (2009) Midlife coffee and tea drinking and the risk of late-life dementia: a population-based CAIDE Study. J Alzheimers Dis 16(1):85–91

    CAS  PubMed  Google Scholar 

  11. Esposito BP, Breuer W, Sirankapracha P, Pootrakul P, Hershko C, Cabantchik ZI (2003) Labile plasma iron in iron overload: redox activity and susceptibility to chelation. Blood 102(7):2670–2677

    CAS  PubMed  Article  Google Scholar 

  12. Forizs E, Debreczeni A, Patrut A, Kun A-Z, Cozar IB, David L, Silaghi-Dumitrescu I (2010) Synthesis, structure and DFT calculations on complexes of palladium(II) with theophylline. Rev Roum Chim 55(10):697–704

    CAS  Google Scholar 

  13. Glickstein H, El Ben R, Link G, Breuer W, Konijn AM, Hershko C, Nick H, Cabantchik ZI (2006) Action of chelators in iron-loaded cardiac cells: accessibility to intracellular labile iron and functional consequences. Blood 108(9):3195–3203

    CAS  PubMed  Article  Google Scholar 

  14. Ibrahim M, Koglin E (2004) Vibrational spectroscopic study of acetate group. Acta Chim Slov 51(3):453–460

    CAS  Google Scholar 

  15. Job P (1928) Studies on the formation of complex minerals in solution and on their stability. Ann Chim France 9:113–203

    CAS  Google Scholar 

  16. Kedare SB, Singh RP (2011) Genesis and development of DPPH method of antioxidant assay. J Food Sci Tech Mys 48(4):412–422

    CAS  Article  Google Scholar 

  17. Kolayli S, Ocak M, Kucuk M, Abbasoglu R (2004) Does caffeine bind to metal ions? Food Chem 84(3):383–388

    CAS  Article  Google Scholar 

  18. Kumar GSS, Seethalakshmi PG, Bhuvanesh N, Kumaresan S (2013) Studies on the syntheses, structural characterization, antimicrobial-, and DPPH radical scavenging activity of the cocrystals caffeine:cinnamic acid and caffeine:eosin dihydrate. J Mol Struct 1050:88–96

    Article  Google Scholar 

  19. Kwiatkowski JL (2011) Real-world use of iron chelators. Hematol Am Soc Hematol Educ Progr 451–458

  20. Lee C (2000) Antioxidant ability of caffeine and its metabolites based on the study of oxygen radical absorbing capacity and inhibition of LDL peroxidation. Clin Chim Acta 295(1–2):141–154

    CAS  PubMed  Article  Google Scholar 

  21. Liu J, Obando D, Schipanski LG, Groebler LK, Witting PK, Kalinowski DS, Richardson DR, Codd R (2010) Conjugates of desferrioxamine B (DFOB) with derivatives of adamantane or with orally available chelators as potential agents for treating iron overload. J Med Chem 53(3):1370–1382

    CAS  PubMed  Article  Google Scholar 

  22. Lloyd JB, Cable H, Riceevans C (1991) Evidence that desferrioxamine cannot enter cells by passive diffusion. Biochem Pharmacol 41(9):1361–1363

    CAS  PubMed  Article  Google Scholar 

  23. Maia L, de Mendonca A (2002) Does caffeine intake protect from Alzheimer’s disease? Eur J Neurol 9(4):377–382

    CAS  PubMed  Article  Google Scholar 

  24. Nunez MT, Urrutia P, Mena N, Aguirre P, Tapia V, Salazar J (2012) Iron toxicity in neurodegeneration. Biometals 25(4):761–776

    CAS  PubMed  Article  Google Scholar 

  25. Ponka P (2004) Hereditary causes of disturbed iron homeostasis in the central nervous system: redox-active metals in neurological disorders. Ann N Y Acad Sci 1012:267–281

    CAS  PubMed  Article  Google Scholar 

  26. Rosso A, Mossey J, Lippa CF (2008) Caffeine: neuroprotective functions in cognition and Alzheimer’s disease. Am J Alzheimers Dis 23(5):417–422

    Article  Google Scholar 

  27. Salas JM, Quiros M, Romero MA, Sanchez MP, Salas MA, Vilaplana R (1995) Metal-complexes of theophylline-7-acetic acid—crystal-structure of a nickel(II) compound containing noncoordinated theophylline-7-acetate ion. Polyhedron 14(5):611–616

    CAS  Article  Google Scholar 

  28. Sawynok J, Yaksh TL (1993) Caffeine as an analgesic adjuvant: a review of pharmacology and mechanisms of action. Pharmacol Rev 45(1):43–85

    CAS  PubMed  Google Scholar 

  29. Schleh FA, Chiarelli-Neto O, Fontes MN, Najjar R, Esposito BP (2014) Phytate decreases oxidative damage caused by labile forms of iron in solution, blood plasma and in HeLa cells. J Braz Chem Soc 25(6):1036–1040

    CAS  Google Scholar 

  30. Shi X, Dalal NS, Jain AC (1991) Antioxidant behavior of caffeine-efficient scavenging of hydroxyl radicals. Food Chem Toxicol 29(1):1–6

    CAS  PubMed  Article  Google Scholar 

  31. Siebner-Freibach H, Yariv S, Lapides Y, Hadar Y, Chen YN (2005) Thermo-FTIR spectroscopic study of the siderophore ferrioxamine B: spectral analysis and stereochemical implications of iron chelation, pH, and temperature. J Agric Food Chem 53(9):3434–3443

    CAS  PubMed  Article  Google Scholar 

  32. Sohn YS, Breuer W, Munnich A, Cabantchik ZI (2008) Redistribution of accumulated cell iron: a modality of chelation with therapeutic implications. Blood 111(3):1690–1699

    CAS  PubMed  Article  Google Scholar 

  33. Zanninelli G, Glickstein H, Breuer W, Milgram P, Brissot P, Hider RC, Konijn AM, Libman J, Shanzer A, Cabantchik ZI (1997) Chelation and mobilization of cellular iron by different classes of chelators. Mol Pharmacol 51(5):842–852

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by funds from FAPESP and CNPq (Brazilian agencies). ECPA received a MSc grant from CNPq and DG received a postdoctoral fellowship grant from FAPESP. The authors are grateful to Dr. C. W. Liria for technical assistance in RP-HPLC and LC–MS analysis.

Conflict of interest

The authors declare no conflict of interests.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Breno Pannia Espósito.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Alta, E.C.P., Goswami, D., Machini, M.T. et al. Desferrioxamine-caffeine (DFCAF) as a cell permeant moderator of the oxidative stress caused by iron overload. Biometals 27, 1351–1360 (2014). https://doi.org/10.1007/s10534-014-9795-7

Download citation

Keywords

  • Iron
  • Desferrioxamine
  • Caffeine
  • HeLa