Triphenylphosphonium-desferrioxamine as a candidate mitochondrial iron chelator

Abstract

Cell-impermeant iron chelator desferrioxamine (DFO) can have access to organelles if appended to suitable vectors. Mitochondria are important targets for the treatment of iron overload-related neurodegenerative diseases. Triphenylphosphonium (TPP) is a delocalized lipophilic cation used to ferry molecules to mitochondria. Here we report the synthesis and characterization of the conjugate TPP–DFO as a mitochondrial iron chelator. TPP–DFO maintained both a high affinity for iron and the antioxidant activity when compared to parent DFO. TPP–DFO was less toxic than TPP alone to A2780 cells (IC50 = 135.60 ± 1.08 and 4.34 ± 1.06 μmol L−1, respectively) and its native fluorescence was used to assess its mitochondrial localization (Rr = +0.56). These results suggest that TPP–DFO could be an interesting alternative for the treatment of mitochondrial iron overload e.g. in Friedreich’s ataxia.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Abián J, Carrascal M, Gay M (2008) Introducción a la Espectrometría de masas para la caracterización de Péptidos y proteínas en Proteómica. Sepro 2:16–34

    Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  3. Alta RYP, Vitorino HA, Goswami D et al (2017) Mitochondria-penetrating peptides conjugated to desferrioxamine as chelators for mitochondrial labile iron. PLoS ONE 12:e0171729. doi:10.1371/journal.pone.0171729

    Article  PubMed  PubMed Central  Google Scholar 

  4. Baccan MM, Chiarelli-Neto O, Pereira RMS, Espósito BP (2012) Quercetin as a shuttle for labile iron. J Inorg Biochem 107:34–39. doi:10.1016/j.jinorgbio.2011.11.014

    CAS  Article  PubMed  Google Scholar 

  5. Cabantchik ZI (2014) Labile iron in cells and body fluids: physiology, pathology, and pharmacology. Front Pharmacol 5:1–11. doi:10.3389/fphar.2014.00045

    CAS  Article  Google Scholar 

  6. Domagal-Goldaman SD, Paul KW, Sparks DL, Kubicki JD (2009) Quantum chemical study of the Fe(III)-deferrioxamine B siderophore complex-Electronic structure, vibrational frecuencies, and equilibrium Fe-isotope fractionation. Geochim Cosmochim Acta 73:1–12

    Article  Google Scholar 

  7. Esposito BP et al (2003) Labile plasma iron in iron overload: redox activity and susceptibility to chelation. Blood 102:2670–2677. doi:10.1182/blood-2003-03-0807

    CAS  Article  PubMed  Google Scholar 

  8. Espósito BP, Epsztejn S, Breuer W, Cabantchik ZI (2002) A review of fluorescence methods for assessing labile iron in cells and biological fluids. Anal Biochem 304:1–18. doi:10.1006/abio.2002.5611

    Article  PubMed  Google Scholar 

  9. Filipovska A, Kelso GF, Brown SE et al (2005) Synthesis and characterization of a triphenylphosphonium-conjugated peroxidase mimetic: insights into the interaction of ebselen with mitochondria. J Biol Chem 280:24113–24126. doi:10.1074/jbc.M501148200

    CAS  Article  PubMed  Google Scholar 

  10. Fonseca SB, Pereira MP, Mourtada R et al (2011) Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells. Chem Biol 18:445–453. doi:10.1016/j.chembiol.2011.02.010

    CAS  Article  PubMed  Google Scholar 

  11. Goswami D, Machini MT, Silvestre DM et al (2014) Cell penetrating peptide (CPP)-conjugated desferrioxamine for enhanced neuroprotection: synthesis and in vitro evaluation. Bioconjugate Chem 25:2067–2080. doi:10.1021/bc5004197

    CAS  Article  Google Scholar 

  12. Goswami D, Vitorino HA, Alta RYP et al (2015) Deferasirox-TAT(47–57) peptide conjugate as a water soluble, bifunctional iron chelator with potential use in neuromedicine. Biometals 28:869–877. doi:10.1007/s10534-015-9873-5

    CAS  Article  PubMed  Google Scholar 

  13. Gottlieb HE, Kotlyar V, Nudelman A (1997) NMR chemical shifts of common laboratory solvents as trace impurities. J Org Chem 62:7512–7515

    CAS  Article  PubMed  Google Scholar 

  14. Horton KL, Kelley SO (2009) Engineered apoptosis-inducing peptides with enhanced mitochondrial localization and potency. J Med Chem 52:3293–3299. doi:10.1021/jm900178n

    CAS  Article  PubMed  Google Scholar 

  15. Horton KL, Stewart KM, Fonseca SB et al (2008) Mitochondria-penetrating peptides. Chem Biol 15:375–382. doi:10.1016/j.chembiol.2008.03.015

    CAS  Article  PubMed  Google Scholar 

  16. Kalinowski D, Richardson D (2005) The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol Rev 57:547–583. doi:10.1124/pr.57.4.2.547

    CAS  Article  PubMed  Google Scholar 

  17. Kelley SO, Stewart KM, Mourtada R (2011) Development of novel peptides for mitochondrial drug delivery: amino acids featuring delocalized lipophilic cations. Pharm Res 28:2808–2819. doi:10.1007/s11095-011-0530-6

    CAS  Article  PubMed  Google Scholar 

  18. Kelso GF, Porteous CM, Coulter CV et al (2001) Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem 276:4588–4596. doi:10.1074/jbc.M009093200

    CAS  Article  PubMed  Google Scholar 

  19. Kolevzon N, Kuflik U, Shmuel M et al (2011) Multiple triphenylphosphonium cations as a platform for the delivery of a pro-apoptotic peptide. Pharm Res 28:2780–2789. doi:10.1007/s11095-011-0494-6

    CAS  Article  PubMed  Google Scholar 

  20. Lei W, Xie J, Hou Y et al (2010) Mitochondria-targeting properties and photodynamic activities of porphyrin derivatives bearing cationic pendant. J Photochem Photobiol B 98:167–171. doi:10.1016/j.jphotobiol.2009.12.003

    CAS  Article  PubMed  Google Scholar 

  21. Liberman EA, Topaly VP, Tsofina LM et al (1969) Mechanism of coupling of oxidative phosphorylation and the membrane potential of mitochondria. Nature 222:1076–1078

    CAS  Article  PubMed  Google Scholar 

  22. Liu J, Obando D, Schipanski LG et al (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 53:1370–1382. doi:10.1021/jm9016703

    CAS  Article  PubMed  Google Scholar 

  23. Lou P-H, Hansen BS, Olsen PH et al (2007) Mitochondrial uncouplers with an extraordinary dynamic range. Biochem J 407:129–140. doi:10.1042/BJ20070606

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Ma Y, Abbate V, Hider RC (2014) Iron-sensitive fluorescent probes: monitoring intracellular iron pools. Metallomics 7:212–222. doi:10.1039/c4mt00214h

    Article  Google Scholar 

  25. Malouitre S, Dube H, Selwood D, Crompton M (2010) Mitochondrial targeting of cyclosporin A enables selective inhibition of cyclophilin-D and enhanced cytoprotection after glucose and oxygen deprivation. Biochem J 425:137–148. doi:10.1042/BJ20090332

    CAS  Article  Google Scholar 

  26. Mourtada R, Fonseca SB, Wisnovsky SP et al (2013) Re-directing an alkylating agent to mitochondria alters drug target and cell death mechanism. PLoS ONE 8:1–9. doi:10.1371/journal.pone.0060253

    Article  Google Scholar 

  27. Murphy MP, Smith RA (2000) Drug delivery to mitochondria: the key to mitochondrial medicine. Adv Drug Deliv Rev 41:235–250

    CAS  Article  PubMed  Google Scholar 

  28. Murphy MP, Smith RAJ (2007) Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol Toxicol 47:629–656. doi:10.1146/annurev.pharmtox.47.120505.105110

    CAS  Article  PubMed  Google Scholar 

  29. Nishikawa T, Edelstein D, Du XL et al (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404:787–790. doi:10.1038/35008121

    CAS  Article  PubMed  Google Scholar 

  30. Pathania D, Millard M, Neamati N (2009) Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism. Adv Drug Deliv Rev 61:1250–1275. doi:10.1016/j.addr.2009.05.010

    CAS  Article  PubMed  Google Scholar 

  31. Pitkanen S, Robinson BH (1996) Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase. J Clin Investig 98:345–351. doi:10.1172/JCI118798

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Puccio H, Simon D, Cossée M et al (2001) Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet 27:181–186. doi:10.1038/84818

    CAS  Article  PubMed  Google Scholar 

  33. Rin Jean S, Tulumello DV, Wisnovsky SP et al (2014) Molecular vehicles for mitochondrial chemical biology and drug delivery. ACS Chem Biol 9:323–333. doi:10.1021/cb400821p

    CAS  Article  PubMed  Google Scholar 

  34. Ross MF, Filipovska A, Smith RAJ et al (2004) Cell-penetrating peptides do not cross mitochondrial membranes even when conjugated to a lipophilic cation: evidence against direct passage through phospholipid bilayers. Biochem J 383:457–468. doi:10.1042/BJ20041095

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Ross MF, Kelso GF, Blaikie FH et al (2005) Lipophilic triphenylphosphonium cations as tools in mitochondrial bioenergetics and free radical biology. Biochemistry 70:222–230. doi:10.1007/s10541-005-0104-5

    CAS  PubMed  Google Scholar 

  36. Smith RAJ, Kelso GF, Blaikie FH et al (2003a) Using mitochondria-targeted molecules to study mitochondrial radical production and its consequences. Biochem Soc Trans 31:1295–1299. doi:10.1042/BST0311295

    CAS  Article  PubMed  Google Scholar 

  37. Smith RAJ, Porteous CM, Gane AM, Murphy MP (2003b) Delivery of bioactive molecules to mitochondria in vivo. Proc Natl Acad Sci USA 100:5407–5412. doi:10.1073/pnas.0931245100

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Smith RAJ, Hartley RC, Murphy MP (2011) Mitochondria-targeted small molecule therapeutics and probes. Antioxid Redox Signal 15:3021–3038. doi:10.1089/ars.2011.3969

    CAS  Article  PubMed  Google Scholar 

  39. Smith RAJ, Hartley RC, Cochemé HM, Murphy MP (2012) Mitochondrial pharmacology. Trends Pharmacol Sci 33:341–352. doi:10.1016/j.tips.2012.03.010

    CAS  Article  PubMed  Google Scholar 

  40. Suresh R, Kamalakkannan D, Ranganathan K et al (2013) Solvent-free synthesis, spectral correlations and antimicrobial activities of some aryl imines. Spectrochim Acta 101:239–248. doi:10.1016/j.saa.2012.09.039

    CAS  Article  Google Scholar 

  41. Vitorino HA, Mantovanelli L, Zanotto FP, Espósito BP (2015) Iron metallodrugs: stability, redox activity and toxicity against Artemia salina. PLoS ONE 10:e0121997. doi:10.1371/journal.pone.0121997

    Article  PubMed  PubMed Central  Google Scholar 

  42. Wade LG (2003) Aminoacids, peptides and proteins. Organic chemistry, 5th edn. Pearson Prentice Hall, Pearson, pp 1145–1151

    Google Scholar 

  43. Waters (1999) Background Ion List for ESI. Tech Note 1–4

  44. Wilson JJ, Lippard SJ (2012) In vitro anticancer activity of cis -diammineplatinum(II) complexes with β-diketonate leaving group ligands. J Med Chem 55:5326–5336. doi:10.1021/jm3002857

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Wisnovsky SP, Wilson JJ, Radford RJ et al (2013) Targeting mitochondrial DNA with a platinum-based anticancer agent. Chem Biol 20:1323–1328. doi:10.1016/j.chembiol.2013.08.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Wittig G, Schoch‐Grübler U (1978) Kombination von Carbonyl-Olefinierungsreaktion und gezielter Aldolkondensation. Eur J Org Chem 2:362–375

    Google Scholar 

  47. Yousif LF, Stewart KM, Kelley SO (2009) Targeting mitochondria with organelle-specific compounds: strategies and applications. ChemBioChem 10:1939–1950. doi:10.1002/cbic.200900185

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by CAPES, FAPESP and CNPq (Brazilian government agencies). The authors thank Dr. Cleber Wanderlei Liria for discussions and technical assistance.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Roxana Y. P. Alta.

Ethics declarations

Conflict of interest

The authors declare no conflict of interests.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 1826 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Alta, R.Y.P., Vitorino, H.A., Goswami, D. et al. Triphenylphosphonium-desferrioxamine as a candidate mitochondrial iron chelator. Biometals 30, 709–718 (2017). https://doi.org/10.1007/s10534-017-0039-5

Download citation

Keywords

  • Iron overload
  • Antioxidant
  • Mitochondria
  • Triphenylphosphonium