Skip to main content
SpringerLink
Log in

Novel diaroylhydrazine ligands as iron chelators: coordination chemistry and biological activity

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

Abstract

The search for orally effective drugs for the treatment of iron overload disorders is an important goal in improving the health of patients suffering diseases such as β-thalassemia major. Herein, we report the syntheses and characterization of some new members of a series of N-aroyl-N′-picolinoyl hydrazine chelators (the H2IPH analogs). Both 1:1 and 1:2 FeIII:L complexes were isolated and the crystal structures of Fe(HPPH)Cl2, Fe(4BBPH)Cl2, Fe(HAPH)(APH) and Fe(H3BBPH)(3BBPH) were determined (H2PPH=N,N′-bis-picolinoyl hydrazine; H2APH=N-4-aminobenzoyl-N′-picolinoyl hydrazine, H23BBPH=N-3-bromobenzoyl-N′-picolinoylhydrazine and H24BBPH=N-(4-bromobenzoyl)-N′-(picolinoyl)hydrazine). In each case, a tridentate N,N,O coordination mode of each chelator with Fe was observed. The FeIII complexes of these ligands have been synthesized and their structural, spectroscopic and electrochemical characterization are reported. Five of these new chelators, namely H2BPH (N-(benzoyl)-N′-(picolinoyl)hydrazine), H2TPH (N-(2-thienyl)-N′-(picolinoyl)-hydrazine), H2PPH, H23BBPH and H24BBPH, showed high efficacy at mobilizing 59Fe from cells and inhibiting 59Fe uptake from the serum Fe transport protein, transferrin (Tf). Indeed, their activity was much greater than that found for the chelator in current clinical use, desferrioxamine (DFO), and similar to that observed for the orally active chelator, pyridoxal isonicotinoyl hydrazone (H2PIH). The ability of the chelators to inhibit 59Fe uptake could not be accounted for by direct chelation of 59Fe from 59Fe–Tf. The most effective chelators also showed low antiproliferative activity which was similar to or less than that observed with DFO, which is important in terms of their potential use as agents to treat Fe-overload disease.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

DFO:

Desferrioxamine

Tf:

Transferrin

HPCIH:

2-Pyridylcarbaldehyde isonicotinoyl hydrazone

H2IPH:

N-isonicotinoyl-N′-picolinoyl hydrazine

H2BPH:

N-benzoyl-N′-picolinoyl hydrazine

H2APH:

N-4-aminobenzoyl-N′-picolinoyl hydrazine

H23BBPH:

N-3-bromobenzoyl-N′-picolinoyl hydrazine

H2PPH:

N,N′-bis-picolinoyl hydrazine

H2TPH:

N-2-thienyl-N′-picolinoyl hydrazine

H2IIH:

N,N′ bis-isonicotinoyl hydrazine

H2PIH:

Pyridoxal isonicotinoyl hydrazone

FA:

Friedreich’s ataxia

References

  1. Lovejoy DB, Richardson DR (2003) Curr Med Chem 10:1035–1049

    Article  PubMed  CAS  Google Scholar 

  2. Tam TF, Leung-Toung R, Li WR, Wang YS, Karimian K, Spino M (2003) Curr Med Chem 10:983–995

    Article  PubMed  CAS  Google Scholar 

  3. Buss JL, Torti FM, Tort SV (2003) Curr Med Chem 10:1021–1034

    Article  PubMed  CAS  Google Scholar 

  4. Richardson DR (2003) Exp Opin Investigat Drugs 12:235–245

    CAS  Google Scholar 

  5. Richardson DR (2004) Ann N Y Acad Sci 1012:326–341

    Article  PubMed  CAS  Google Scholar 

  6. Richardson DR, Ponka P (1998) Am J Hematol 58:299–305

    Article  PubMed  CAS  Google Scholar 

  7. Wong C, Richardson DR (2003) Int J Biochem Cell Biol 35:1144–1149

    Article  PubMed  CAS  Google Scholar 

  8. Kontoghiorghes GJ, Pattichis K, Neocleous K, Kolnagou A (2004) Curr Med Chem 11:2161–2183

    PubMed  CAS  Google Scholar 

  9. Hider RC, Liu ZD (2003) Curr Med Chem 10:1051–1064

    Article  PubMed  CAS  Google Scholar 

  10. Nick H, Acklin P, Lattman R, Buehlmayer P, Hauffle A, Schupp J, Alberti D (2003) Curr Med Chem 10:1065–1076

    Article  PubMed  CAS  Google Scholar 

  11. Nisbet-Brown E, Olivieri NF, Giardina PJ, Grady RW, Neufeld EJ, Sechaud R, Krebs-Brown AJ, Anderson JR, Alberti D, Sizer KC, Nathan DG (2003) Lancet 361:1597–1602

    Article  PubMed  CAS  Google Scholar 

  12. Becker E, Richardson DR (1999) J Lab Clin Med 134:510–521

    Article  PubMed  CAS  Google Scholar 

  13. Armstrong CM, Bernhardt PV, Chin P, Richardson DR (2003) Eur J Inorg Chem 1145–1156

  14. Wong CSM, Kwok JC, Richardson DR (2004) Biochim Biophys Acta 1739:70–80

    PubMed  CAS  Google Scholar 

  15. Bernhardt PV, Chin P, Richardson DR (2001) J Biol Inorg Chem 6:801–809

    Article  PubMed  CAS  Google Scholar 

  16. Zhao H, Burke TR Jr (1997) Tetrahedron 53:4219–4230

    Article  CAS  Google Scholar 

  17. Gans P, Sabatini A, Vacca A (1985) J Chem Soc Dalton Trans 1195–1200

  18. Farrugia LJ (1999) J Appl Cryst 32:837–838

    Article  Google Scholar 

  19. Sheldrick GM (1997 Release 97-2) SHELXL-97—a program for crystal structure refinement

  20. Farrugia LJ (1997) J Appl Cryst 30:565

    Article  CAS  Google Scholar 

  21. Richardson DR, Baker E (1990) Biochim Biophys Acta 1053:1–12

    Article  PubMed  CAS  Google Scholar 

  22. Richardson D, Baker E (1992) J Biol Chem 267:13972–13979

    PubMed  CAS  Google Scholar 

  23. Richardson DR, Tran EH, Ponka P (1995) Blood 86:4295–4306

    PubMed  CAS  Google Scholar 

  24. Richardson DR, Milnes K (1997) Blood 89:3025–3038

    PubMed  CAS  Google Scholar 

  25. Darnell G, Richardson DR (1999) Blood 94:781–792

    PubMed  CAS  Google Scholar 

  26. Becker EM, Lovejoy DB, Watts RN, Richardson DR (2003) Br J Pharmacol 138:819–830

    Article  PubMed  CAS  Google Scholar 

  27. Chaston TB, Richardson DR (2003) J Biol Inorg Chem 8:427–438

    PubMed  CAS  Google Scholar 

  28. Yuan J, Lovejoy DB, Richardson DR (2004) Blood 104:1450–1458

    Article  PubMed  CAS  Google Scholar 

  29. Baker E, Richardson D, Gross S, Ponka P (1992) Hepatology 15:492–501

    Article  PubMed  CAS  Google Scholar 

  30. Florence AT, Attwood D (1988) Physiochemical principles of pharmacy, 2nd edn. Macmillan, London

    Google Scholar 

  31. Richardson DR, Vitolo LMW, Hefter GT, May PM, Clare BW, Webb J, Wilairat P (1990) Inorg Chim Acta 170:165–170

    Article  CAS  Google Scholar 

  32. Shao SC, Zhu DR, Song Y, You XZ, Raj SSS, Fun HK (1999) Acta Crystallogr Sect C Cryst Struct Commun 55:1841–1843

    Article  Google Scholar 

  33. Bernhardt PV, Chin P, Richardson DR (2004) Dalton Trans 3342–3346

  34. Dogan A, Schwederski B, Schleid T, Lissner F, Fiedler J, Kaim W (2004) Inorg Chem Commun 7:220–223

    Article  CAS  Google Scholar 

  35. Knoedler A, Fiedler J, Kaim W (2004) Polyhedron 23:701–707

    Article  CAS  Google Scholar 

  36. Richardson DR, Bernhardt PV (1999) J Biol Inorg Chem 4:266–273

    Article  PubMed  CAS  Google Scholar 

  37. Avramovici-Grisaru S, Sarel S, Cohen S, Bauminger RE (1985) Isr J Chem 25:288–292

    CAS  Google Scholar 

  38. Bernhardt PV, Caldwell LM, Chaston TB, Chin P, Richardson DR (2003) J Biol Inorg Chem 8:866–880

    Article  PubMed  CAS  Google Scholar 

  39. Addison AW, Rao TN, Reedijk J, Vanrijn J, Verschoor GC (1984) J Chem Soc Dalton Trans 1349–1356

  40. Murphy TB, Johnson DK, Rose NJ, Aruffo A, Schomaker V (1982) Inorg Chim Acta 66:L67–L68

    Article  CAS  Google Scholar 

  41. Chaston TB, Lovejoy DB, Watts RN, Richardson DR (2003) Clin Cancer Res 9:402–414

    PubMed  CAS  Google Scholar 

  42. Chaston TB, Richardson DR (2003) Am J Hematol 73:200–210

    Article  PubMed  CAS  Google Scholar 

  43. Chandra SK, Chakravorty A (1992) Inorg Chem 31:760–765

    Article  CAS  Google Scholar 

  44. Collins TJ, Kostka KL, Uffelman ES, Weinberger TL (1991) Inorg Chem 30:4204–4210

    Article  CAS  Google Scholar 

  45. Spasojevic I, Armstrong SK, Brickman TJ, Crumbliss AL (1999) Inorg Chem 38: 449–454

    Article  PubMed  CAS  Google Scholar 

  46. Ponka P, Richardson DR, Edward JT, Chubb FL (1994) Can J Physiol Pharmacol 72:659–666

    PubMed  CAS  Google Scholar 

  47. Edward JT, Ponka P, Richardson DR (1995) Biometals 8:209–217

    Article  CAS  Google Scholar 

  48. Edward JT (1998) Biometals 11:203–205

    Article  CAS  Google Scholar 

  49. Rai BL, Dekhordi LS, Khodr H, Jin Y, Liu ZD, Hider RC (1998) J Med Chem 41:3347–3359

    Article  PubMed  CAS  Google Scholar 

  50. Thomas F, Baret P, Imbert D, Pierre JL, Serratrice G (1999) Bioorg Med Chem Lett 9:3035–3040

    Article  PubMed  CAS  Google Scholar 

  51. Edward JT, Chubb FL, Sangster J (1997) Can J Physiol Pharmacol 75:1362–1368

    Article  PubMed  CAS  Google Scholar 

  52. Meyer KH, Hemmi H (1935) Biochem Z 39:277

    Google Scholar 

  53. Davson H, Danielli JF (1952) The permeability of natural membranes, 2nd edn. Cambridge University Press, Cambridge

    Google Scholar 

  54. Hansch C (1967) Ann Rep Med Chem 1966:347–359

    Article  Google Scholar 

  55. Hansch C (1968) Ann Rep Med Chem 1967:348–357

    Google Scholar 

  56. Penniston JT, Beckett L, Bentley DL, Hansch C (1969) Mol Pharmacol 5:333–341

    PubMed  CAS  Google Scholar 

  57. Hansch C (1969) Acc Chem Res 2:232–239

    Article  CAS  Google Scholar 

  58. Hansch C, Lien EJ (1971) J Med Chem 14:653–670

    Article  PubMed  CAS  Google Scholar 

  59. Zanninelli G, Glickstein H, Breuer W, Milgram P, Brissot P, Hider RC, Konijn AM, Libman J, Shanzer A, Cabantchik ZI (1997) Mol Pharmacol 51:842–852

    PubMed  CAS  Google Scholar 

  60. Lowther N, Tomlinson B, Fox R, Faller B, Sergejew T, Donnelly H (1998) J Pharm Sci 87:1041–1045

    Article  PubMed  CAS  Google Scholar 

  61. Lowther N, Fox P, Faller B, Nick H, Jin Y, Sergejew T, Hirschberg Y, Oberle R, Donnelly H (1999) Pharm Res 16:434–440

    Article  PubMed  CAS  Google Scholar 

  62. Rai BL, Liu ZD, Liu DY, Lu SL, Hider RC (1999) Eur J Med Chem 34:475–485

    Article  CAS  Google Scholar 

  63. Ihnat PM, Vennerstrom JL, Robinson DH (2000) J Pharm Sci 89:1525–1536

    Article  PubMed  CAS  Google Scholar 

  64. Faller B, Spanka C, Sergejew T, Tschinke V (2000) J Med Chem 43:1467–1475

    Article  PubMed  CAS  Google Scholar 

  65. Henry C, Rakba N, Imbert D, Thomas F, Baret P, Serratrice G, Gaude D, Pierre JL, Ward RJ, Crichton RR, Lescoat G (2001) Biochem Pharmacol 62:1355–1362

    Article  PubMed  CAS  Google Scholar 

  66. Buss JL, Arduini E, Ponka P (2002) Biochem Pharmacol 64:1689–1701

    Article  PubMed  CAS  Google Scholar 

  67. Lidgate D, Brandl M, Holper M, Abubakari A, Wu XY (2002) Drug Dev Ind Pharm 28:1275–1283

    Article  PubMed  CAS  Google Scholar 

  68. Imbert D, Baret P, Gaude D, Gautier-Luneau I, Gellon G, Thomas F, Serratrice G, Pierre JL (2002) Chem-Eur J 8:1091–1100

    Article  CAS  Google Scholar 

  69. Buss JL, Hermes-Lima M, Ponka P (2002) Adv Exp Med Biol 509:205–229

    PubMed  CAS  Google Scholar 

  70. Richardson DR, Ponka P (1998) J Lab Clin Med 131:306–315

    Article  PubMed  CAS  Google Scholar 

  71. Richardson D, Bernhardt PV, Becker EM (2001) PCT Int Appl 50 pp

Download references

Acknowledgements

We gratefully acknowledge support from the Australian Research Council (DP0450001) to P.V.B and D.R.R. and the National Health and Medical Research Council of Australia for Project and Fellowship Support to D.R.R. D.R.R. also thanks the National Ataxia Foundation USA and Muscular Dystrophy Association USA for grant support. Children’s Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children’s Hospital. Dr. David Lovejoy and Ms. Danuta Kalinowski are thanked for their helpful comments on this manuscript.

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Queensland, Brisbane, 4072, QLD, Australia

    Paul V. Bernhardt, Piao Chin & Philip C. Sharpe

  2. Children’s Cancer Institute Australia for Medical Research, PO Box 81, High Street, Randwick, Sydney, 2031, NSW, Australia

    Jing-Yan C. Wang & Des R. Richardson

Authors
  1. Paul V. Bernhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Piao Chin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip C. Sharpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing-Yan C. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Des R. Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Paul V. Bernhardt or Des R. Richardson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bernhardt, P.V., Chin, P., Sharpe, P.C. et al. Novel diaroylhydrazine ligands as iron chelators: coordination chemistry and biological activity. J Biol Inorg Chem 10, 761–777 (2005). https://doi.org/10.1007/s00775-005-0018-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00775-005-0018-0

Keywords

Search

Navigation