Skip to main content

Advertisement

SpringerLink
Log in

Influence of the metal center and linker on the intracellular distribution and biological activity of organometal–peptide conjugates

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

Abstract

Organometallic complexes conjugated to cell-penetrating peptides (CPPs) are promising systems for diagnostic imaging and therapeutic applications in human medicine. Recently, we reported on the synthesis of cymantrene(CpMn(CO)3)–CPP conjugates with biological activity on different cancer cell lines. However, the precise mechanism of cytotoxicity remained elusive in these studies. To investigate the role of the metal center and the linker between the CpM(CO)3 moiety and the peptide, a number of derivatives with manganese replaced by rhenium and the keto linker originally used substituted by a methylene group were prepared and fully characterized by 1H NMR spectroscopy, infrared spectroscopy, electrospray ionization mass spectrometry, and elemental analysis as well as X-ray structure determination. The organometal–peptide conjugates as well as carboxyfluorescein-labeled derivatives thereof were prepared by solid-phase peptide synthesis, purified by high-performance liquid chromatography, and analyzed by mass spectrometry. Fluorescence microscopy studies of MCF-7 human breast cancer cells revealed an efficient cellular uptake and pronounced nuclear localization of the bioconjugates with the methylene linker compared with systems with the keto group. In addition, the latter also showed a higher cytotoxicity. In contrast, the variation of the metal center from manganese to rhenium had a negligible effect. The structure–activity relationships determined in the present work will aid in the further tuning of the biological activity of organometal–peptide conjugates.

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

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

ATR:

Attenuated total reflection

CF:

5(6)-Carboxyfluorescein

CPP:

Cell-penetrating peptide

Cym2:

Cyclopentadien-1-yl-(3-carboxylato-1-oxopropyl) manganese tricarbonyl

Cym2*:

Cyclopentadien-1-yl-(3-carboxylatopropyl) manganese tricarbonyl

Cyr2:

Cyclopentadien-1-yl-(3-carboxylato-1-oxopropyl) rhenium tricarbonyl

Cyr2*:

Cyclopentadien-1-yl-(3-carboxylatopropyl) rhenium tricarbonyl

DCM:

Dichloromethane

DIEA:

N,N-Diisopropylethylamine

DMF:

N,N-Dimethylformamide

ESI:

Electrospray ionization

Fmoc:

Fluorenylmethyloxycarbonyl

HATU:

2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

HPLC:

High-performance liquid chromatography

IR:

Infrared

LDH:

Lactate dehydrogenase

MALDI:

Matrix-assisted laser desorption ionization

MS:

Mass spectrometry

RP:

Reversed phase

TFA:

Trifluoroacetic acid

ToF:

Time of flight

References

  1. Hartinger CG, Dyson PJ (2009) Chem Soc Rev 38:391–401

    Article  PubMed  CAS  Google Scholar 

  2. Melchart M, Sadler PJ (2006) In: Jaouen G (ed) Bioorganometallics. Wiley-VCH, Weinheim, pp 39–64

  3. Strohfeldt K, Tacke M (2008) Chem Soc Rev 37:1174–1187

    Article  PubMed  CAS  Google Scholar 

  4. Todd RC, Lippard SJ (2009) Metallomics 1:280–291

    Article  PubMed  CAS  Google Scholar 

  5. Brooks H, Lebleu B, Vives E (2005) Adv Drug Deliv Rev 57:559–577

    Article  PubMed  CAS  Google Scholar 

  6. Fischer R, Fotin-Mleczek M, Hufnagel H, Brock R (2005) ChemBioChem 6:2126–2142

    Article  PubMed  CAS  Google Scholar 

  7. Turner JJ, Ivanova GD, Verbeure B, Williams D, Arzumanov AA, Abes S, Lebleu B, Gait MJ (2005) Nucleic Acids Res 33:6837–6849

    Article  PubMed  CAS  Google Scholar 

  8. Delehanty JB, Medintz IL, Pons T, Brunel FM, Dawson PE, Mattoussi H (2006) Bioconjug Chem 17:920–927

    Article  PubMed  CAS  Google Scholar 

  9. Lebleu B, Moulton HM, Abes R, Ivanova GD, Abes S, Stein DA, Iversen PL, Arzumanov AA, Gait MJ (2008) Adv Drug Deliv Rev 60:517–529

    Article  PubMed  CAS  Google Scholar 

  10. Schwarze SR, Ho A, Vocero-Akbani A, Dowdy SF (1999) Science 285:1569–1572

    Article  PubMed  CAS  Google Scholar 

  11. Langel Ü (2006) Handbook of cell-penetrating peptides. CRC Press, Boca Raton

    Book  Google Scholar 

  12. Joliot A, Prochiantz A (2004) Nat Cell Biol 6:189–196

    Article  PubMed  CAS  Google Scholar 

  13. Mäe M, Langel Ü (2006) Curr Opin Pharmacol 6:509–514

    Article  PubMed  Google Scholar 

  14. Stewart KM, Horton KL, Kelley SO (2008) Org Biomol Chem 6:2242–2255

    Article  PubMed  CAS  Google Scholar 

  15. Neundorf I, Hoyer J, Splith K, Rennert R, Peindy N’Dongo HW, Schatzschneider U (2008) Chem Commun 5604–5606

  16. Splith K, Neundorf I, Hu W, Peindy N’Dongo HW, Vasylyeva V, Merz K, Schatzschneider U (2010) Dalton Trans 39:2536–2545

    Article  PubMed  CAS  Google Scholar 

  17. Splith K, Hu W, Schatzschneider U, Gust R, Ott I, Onambele LA, Prokop A, Neundorf I (2010) Bioconjug Chem 21:1288–1296

    Article  PubMed  CAS  Google Scholar 

  18. Neundorf I, Rennert R, Hoyer J, Schramm F, Loebner K, Kitanovic I, Woelfl S (2009) Pharmaceuticals 2:49–65

    Article  CAS  Google Scholar 

  19. Fulmer GR, Miller AJM, Sherden NH, Gottlieb HE, Nudelman A, Stoltz BM, Bercaw JE, Goldberg KI (2010) Organometallics 29:2176–2179

    Article  CAS  Google Scholar 

  20. Peindy N’Dongo HW, Neundorf I, Merz K, Schatzschneider U (2008) J Inorg Biochem 102:2114–2119

    Article  PubMed  Google Scholar 

  21. Fischer R, Mader O, Jung G, Brock R (2003) Bioconjug Chem 14:653–660

    Article  PubMed  Google Scholar 

  22. Sheldrick GM (1996) SADABS. University of Göttingen

  23. Sheldrick GM (1997) SHELXL-97. University of Göttingen

  24. Peindy N’Dongo HW, Ott I, Gust R, Schatzschneider U (2009) J Organomet Chem 694:823–827

    Article  Google Scholar 

  25. Rosita D, DeWit MA, Luyt LG (2009) J Med Chem 52:2196–2203

    Article  PubMed  CAS  Google Scholar 

  26. Bhattacharyya S (1998) J Org Chem 63:7101–7102

    Article  PubMed  CAS  Google Scholar 

  27. Peindy N’Dongo HW, Liu Y, Schmutz P, Spingler B, Alberto R (2009) J Organomet Chem 694:981–987

    Article  Google Scholar 

  28. Fitzpatrick PJ, Le Page Y, Butler IS (1981) Acta Crystallogr Sect B 37:1052–1058

    Article  Google Scholar 

  29. Schaffer P, Gleave JA, Lemon JA, Reid LC, Pacey LK, Farncombe TH, Boreham DR, Zubieta J, Babich JW, Doering LC, Valliant JF (2008) Nucl Med Biol 35:159–169

    Article  PubMed  CAS  Google Scholar 

  30. Policar C, Waern JB, Plamont MA, Clede S, Mayet C, Prazeres R, Ortega JM, Vessieres A, Dazzi A (2011) Angew Chem Int Ed 50:860–864

    Article  CAS  Google Scholar 

  31. Uehara T, Koike M, Nakata H, Miyamoto S, Motoishi S, Hashimoto K, Oku N, Nakayama M, Arano Y (2003) Nucl Med Biol 30:327–334

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft within FOR 630 “Biological function of organometallic compounds.” I.N. and U.S. thank Annette Beck-Sickinger (Universität Leipzig) and Nils Metzler-Nolte (Ruhr-Universität Bochum) for generous access to all facilities of the respective institutes.

Author information

Authors and Affiliations

  1. Institut für Anorganische Chemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany

    Wanning Hu & Ulrich Schatzschneider

  2. Institut für Biochemie, Universität Leipzig, Brüderstr. 34, 04103, Leipzig, Germany

    Katrin Splith & Ines Neundorf

  3. Institut für Biochemie, Universität zu Köln, Zülpicher Str. 47, 50674, Cologne, Germany

    Katrin Splith & Ines Neundorf

  4. Lehrstuhl für Anorganische Chemie I—Bioanorganische Chemie, Ruhr-Universität Bochum, Universitätsstr. 150, 44801, Bochum, Germany

    Klaus Merz

Authors
  1. Wanning Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katrin Splith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ines Neundorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Klaus Merz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ulrich Schatzschneider
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ulrich Schatzschneider.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hu, W., Splith, K., Neundorf, I. et al. Influence of the metal center and linker on the intracellular distribution and biological activity of organometal–peptide conjugates. J Biol Inorg Chem 17, 175–185 (2012). https://doi.org/10.1007/s00775-011-0840-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-011-0840-5

Keywords

Search

Navigation