Skip to main content
SpringerLink
Log in

The stereochemistry of amide side chains containing carboxyl groups influences water exchange rates in EuDOTA-tetraamide complexes

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

Abstract

Many Eu(III) complexes formed with DOTA-tetraamide ligands (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) have sufficiently slow water exchange kinetics to meet the slow-to-intermediate condition required to serve as chemical exchange saturation transfer (CEST) contrast agents for MRI. This class of MRI contrast agents offers an attractive platform for creating biological sensors because water exchange is exquisitely sensitive to subtle ligand stereochemistry and electronic effects. Introduction of carboxyl groups or carboxyl ethyl ester groups on the amide substituents has been shown to slow water exchange in these complexes, but less is known about the orientation or position of these side-chain groups relative to the inner-sphere Eu(III)-bound water molecule. In this study, a series of Eu(III) complexes having one or more carboxyl groups or carboxyl esters at the δ-position of the pendant amide side chains were prepared. Initial attempts to prepare optically pure EuDOTA-[(S)-Asp]4 resulted in a chemically pure ligand consisting of a mixture of stereochemical isomers. This was traced to racemization of (S)-aspartate diethyl ester during the synthetic procedure. Nevertheless, NMR studies of the Eu(III) complexes of this mixture revealed that each isomer had a different water exchange rate, differing by a factor of 2 or more. A second controlled synthesis and CEST study of EuDOTA-[(S)-Asp]4 and cis-EuDOTA-[(S)-Asp]2[(R)-Asp]2 confirmed that the water exchange rates in these diastereomeric complexes are controlled by the axial versus equatorial orientation of the carboxyl groups on the amide side chains. These observations provide new insights toward the development of even more slowly water exchanging systems which will be necessary for practical in vivo applications.

Graphical abstract

The axial versus equatorial arrangement of carboxyl groups in δ-substituted EuDOTA-tetraamide complexes plays a key role in determining water exchange rates

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

Similar content being viewed by others

Abbreviations

Arm-2:

(S)-3-(2-Bromoacetylamino)propionic acid ethyl ester

Arm-4:

(S)-2-(2-Bromoacetylamino)succinic acid diethyl ester

CEST:

Chemical exchange saturation transfer

DOTA:

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

ESI–MS+:

Positive electrospray ionization mass spectrometry

MRI:

Magnetic resonance imaging

PARACEST:

Paramagnetic chemical exchange saturation transfer

SAP:

Square antiprism

TSAP:

Twisted square antiprism

References

  1. Sherry AD, Wu Y (2013) Curr Opin Chem Biol 17:167–174

    Article  CAS  PubMed  Google Scholar 

  2. Zhang S, Winter P, Wu K, Sherry AD (2001) J Am Chem Soc 123:1517–1518

    Article  CAS  PubMed  Google Scholar 

  3. Woods M, Woessner DE, Sherry AD (2006) Chem Soc Rev 35:500–511

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Zhang S, Merritt M, Woessner DE, Lenkinski RE, Sherry AD (2003) Acc Chem Res 36:783–790

    Article  CAS  PubMed  Google Scholar 

  5. Aime S, Barge A, Delli Castelli D, Fedeli F, Mortillaro A, Nielsen FU, Terreno E (2002) Magn Reson Med 47:639–648

    Article  CAS  PubMed  Google Scholar 

  6. Woods M, Zhang S, Ebron VH, Sherry AD (2003) Chem Eur J 9:4634–4640

    Article  CAS  PubMed  Google Scholar 

  7. Delli Castelli D, Terreno E, Aime S (2011) Angew Chem Int Ed 50:1798–1800

    Article  CAS  Google Scholar 

  8. Liu G, Li Y, Sheth VR, Pagel MD (2012) Mol Imaging 11:47–57

    PubMed  Google Scholar 

  9. Sheth VR, Liu G, Li Y, Pagel MD (2012) Contrast Media Mol Imaging 7:26–34

    Article  CAS  PubMed  Google Scholar 

  10. Zhang S, Malloy CR, Sherry AD (2005) J Am Chem Soc 127:17572–17573

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Ratnakar SJ, Viswanathan S, Kovacs Z, Jindal AK, Green KN, Sherry AD (2012) J Am Chem Soc 134:5798–5800

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Ratnakar SJ, Woods M, Lubag AJ, Kovacs Z, Sherry AD (2008) J Am Chem Soc 130:6–7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Hingorani DV, Randtke EA, Pagel MD (2013) J Am Chem Soc 135:6396–6398

    Article  CAS  PubMed  Google Scholar 

  14. Liu G, Liang Y, Bar-Shir A, Chan KWY, Galpoththawela CS, Bernard SM, Tse T, Yadav NN, Walczak P, McMahon MT, Bulte JWM, van Zijl PCM, Gilad AA (2011) J Am Chem Soc 133:16326–16329

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Yoo B, Pagel MD (2006) J Am Chem Soc 128:14032–14033

    Article  CAS  PubMed  Google Scholar 

  16. Zhang S, Trokowski R, Sherry AD (2003) J Am Chem Soc 125:15288–15289

    Article  CAS  PubMed  Google Scholar 

  17. Trokowski R, Zhang S, Sherry AD (2004) Bioconjug Chem 15:1431–1440

    Article  CAS  PubMed  Google Scholar 

  18. Ren J, Trokowski R, Zhang S, Malloy CR, Sherry AD (2008) Magn Reson Med 60:1047–1055

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Gilad AA, McMahon MT, Walczak P, Winnard PT, Raman V, van Laarhoven HWM, Skoglund CM, Bulte JWM, van Zijl PCM (2007) Nat Biotechnol 25:217–219

    Article  CAS  PubMed  Google Scholar 

  20. Aime S, Barge A, Botta M, De Sousa AS, Parker D (1998) Angew Chem Int Ed 37:2673–2675

    Article  CAS  Google Scholar 

  21. Aime S, Barge A, Bruce JI, Botta M, Howard JAK, Moloney JM, Parker D, de Sousa AS, Woods M (1999) J Am Chem Soc 121:5762–5771

    Article  CAS  Google Scholar 

  22. Woods M, Kovacs Z, Zhang S, Sherry AD (2003) Angew Chem Int Ed 42:5889–5892

    Article  CAS  Google Scholar 

  23. Zhang S, Wu K, Sherry AD (2002) J Am Chem Soc 124:4226–4227

    Article  CAS  PubMed  Google Scholar 

  24. Terreno E, Boniforte P, Botta M, Fedeli F, Milone L, Mortillaro A, Aime S (2003) Eur J Inorg Chem 2003:3530–3533

    Article  Google Scholar 

  25. Mani T, Tircso G, Togao O, Zhao P, Soesbe TC, Takahashi M, Sherry AD (2009) Contrast Media Mol Imaging 4:183–191

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Ward KM, Aletras AH, Balaban RS (2000) J Magn Reson 143:79–87

    Article  CAS  PubMed  Google Scholar 

  27. Woessner DE, Zhang S, Merritt M, Sherry AD (2005) Magn Reson Med 53:790–799

    Article  CAS  PubMed  Google Scholar 

  28. Dixon WT, Ren J, Lubag AJ, Ratnakar J, Vinogradov E, Hancu I, Lenkinski RE, Sherry AD (2010) Magn Reson Med 63:625–632

    Article  CAS  PubMed  Google Scholar 

  29. Dutta PL, Foye WO (1990) J Pharm Sci 79:447–452

    Article  CAS  PubMed  Google Scholar 

  30. Barge A, Cravotto G, Gianolio E, Fedeli F (2006) Contrast Media Mol Imaging 1:184–188

    Article  PubMed  Google Scholar 

  31. Woods M, Aime S, Botta M, Howard JAK, Moloney JM, Navet M, Parker D, Port M, Rousseaux O (2000) J Am Chem Soc 122:9781–9792

    Article  CAS  Google Scholar 

  32. Levy SG, Jacques V, Zhou KL, Kalogeropoulos S, Schumacher K, Amedio JC, Scherer JE, Witowski SR, Lombardy R, Koppetsch K (2009) Org Process Res Dev 13:535–542

    Article  CAS  Google Scholar 

  33. Kovacs Z, Sherry AD (1995) J Chem Soc Chem Commun 185–186

  34. Bleaney B (1972) J Magn Reson 8:91–100

    CAS  Google Scholar 

  35. Piguet C, Geraldès CFGC (2003) In: Gschneidner J, Bunzli J-CG, Pecharsky VK (eds) Handbook on the physics and chemistry of rare earths, vol 43. Elsevier, Amsterdam, pp 353–463

    Google Scholar 

  36. Sherry AD, Geraldes CFGC (1989) In: Bunzli J-CG, Choppin GR (eds) Lanthanide probes in life, chemical, and earth sciences. Elsevier, Amsterdam

    Google Scholar 

  37. Green KN, Viswanathan S, Rojas-Quijano FA, Kovacs Z, Sherry AD (2011) Inorg Chem 50:1648–1655

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Mani T, Tircso G, Zhao P, Sherry AD, Woods M (2009) Inorg Chem 48:10338–10345

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported in part by grants to A.D.S. from the National Institutes of Health (CA-115531, EB-015908, and EB-04582) and the Robert A. Welch Foundation (AT-584). G. T. is grateful to the Hungarian Scientific Research Fund (OTKA K-84291), the TÁMOP-4.2.2.A-11/1/KONV-2012-0043 project (implemented through the New Hungary Development Plan, cofinanced by the European Social Fund and the European Regional Development Fund), and the Hungarian Academy of Science (János Bolyai Research Scholarship) for financial support.

Author information

Author notes

  1. Tomoyasu Mani

    Present address: Department of Biochemistry and Biophysics, University of Pennsylvania, 1015 Stellar-Chance Bldg, 422 Curie Blvd, Philadelphia, PA, 19104, USA

  2. Gyula Tircso

    Present address: Department of Inorganic and Analytical Chemistry, University of Debrecen, Egyetem tér 1, P.O. Box 21, Debrecen, 4010, Hungary

Authors and Affiliations

  1. Department of Chemistry, University of Texas at Dallas, 800 W. Campbell Road, Richardson, TX, 75080, USA

    Tomoyasu Mani, Ana Christina L. Opina, Piyu Zhao, Osasere M. Evbuomwan, Nate Milburn, Gyula Tircso, Cemile Kumas & A. Dean Sherry

  2. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75235, USA

    A. Dean Sherry

Authors
  1. Tomoyasu Mani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ana Christina L. Opina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Piyu Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Osasere M. Evbuomwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nate Milburn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gyula Tircso
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cemile Kumas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A. Dean Sherry
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Dean Sherry.

Additional information

Responsible Editor: Valerie C. Pierre.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mani, T., Opina, A.C.L., Zhao, P. et al. The stereochemistry of amide side chains containing carboxyl groups influences water exchange rates in EuDOTA-tetraamide complexes. J Biol Inorg Chem 19, 161–171 (2014). https://doi.org/10.1007/s00775-013-1031-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-013-1031-3

Keywords

Search

Navigation