Advertisement

JBIC Journal of Biological Inorganic Chemistry

, Volume 8, Issue 8, pp 866–880 | Cite as

Cytotoxic iron chelators: characterization of the structure, solution chemistry and redox activity of ligands and iron complexes of the di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues

  • Paul V. Bernhardt
  • Lorraine M. Caldwell
  • Timothy B. Chaston
  • Piao Chin
  • Des R. Richardson
Original Article

Abstract

Di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) and a range of its analogues comprise a series of monobasic acids that are capable of binding iron (Fe) as tridentate (N,N,O) ligands. Recently, we have shown that these chelators are highly cytotoxic, but show selective activity against cancer cells. Particularly interesting was the fact that cytotoxicity of the HPKIH analogues is maintained even after complexation with Fe. To understand the potent anti-tumor activity of these compounds, we have fully characterized their chemical properties. This included examination of the solution chemistry and X-ray crystal structures of both the ligands and Fe complexes from this class and the ability of these complexes to mediate redox reactions. Potentiometric titrations demonstrated that all chelators are present predominantly in their charge-neutral form at physiological pH (7.4), allowing access across biological membranes. Keto–enol tautomerism of the ligands was identified, with the tautomers exhibiting distinctly different protonation constants. Interestingly, the chelators form low-spin (diamagnetic) divalent Fe complexes in solution. The chelators form distorted octahedral complexes with FeII, with two tridentate ligands arranged in a meridional fashion. Electrochemistry of the Fe complexes in both aqueous and non-aqueous solutions revealed that the complexes are oxidized to their ferric form at relatively high potentials, but this oxidation is coupled to a rapid reaction with water to form a hydrated (carbinolamine) derivative, leading to irreversible electrochemistry. The Fe complexes of the HPKIH analogues caused marked DNA degradation in the presence of hydrogen peroxide. This observation confirms that Fe complexes from the HPKIH series mediate Fenton chemistry and do not repel DNA. Collectively, studies on the solution chemistry and structure of these HPKIH analogues indicate that they can bind cellular Fe and enhance its redox activity, resulting in oxidative damage to vital biomolecules.

Keywords

Crystal structure Electrochemistry Hydrazone Iron chelator Protonation constant 

Abbreviations

DFO

desferrioxamine

HPKIH

di-2-pyridyl ketone isonicotinoyl hydrazone

HNIH

2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone

HPCIH

2-pyridinecarbaldehyde isonicotinoyl hydrazone

HPIH

pyridoxal isonicotinoyl hydrazone

L

linear DNA

OC

open circular DNA

SC

supercoiled DNA

Notes

Acknowledgements

The Children’s Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children’s Hospital. This project was supported by a fellowship and projects grant from the National Health and Medical Research Council of Australia (D.R.R.) and an Australian Research Council Large Grant (D.R.R.). T.B.C. thanks the Friedreich’s Ataxia Foundation of New South Wales and Victoria for a PhD Scholarship. P.V.B. acknowledges financial support from the University of Queensland.

Supplementary material

supp.pdf (28 kb)
Supplementary material (PDF 26 KB)

References

  1. 1.
    Lovejoy DB, Richardson DR (2003) Curr Med Chem 10:1035–1049PubMedGoogle Scholar
  2. 2.
    Liu ZD, Hider RC (2002) Coord Chem Rev 232:151–171CrossRefGoogle Scholar
  3. 3.
    Faa G, Crisponi G (1999) Coord Chem Rev 184:291–310CrossRefGoogle Scholar
  4. 4.
    Williams RE, Zweier JL, Flaherty JJ (1991) Circulation 83:1006–1114PubMedGoogle Scholar
  5. 5.
    Visseren FLJ, Verkerk MSA, van der Bruggen T, Marx JJM, van Asbeck BS, Diepersloot RJA (2002) Eur J Clin Invest 32:84–90CrossRefGoogle Scholar
  6. 6.
    Hider RC, Liu Z (1997) J Pharm Pharmacol 49:59–64Google Scholar
  7. 7.
    Kemp JD, Smith KM, Kanner LJ, Gomez F, Thorson JA, Naumann PW (1990) Blood 76:991–995PubMedGoogle Scholar
  8. 8.
    Richardson DR (1998) Leukemia Lymphoma 31:47–60PubMedGoogle Scholar
  9. 9.
    Richardson DR, Tran EH, Ponka P (1995) Blood 86:4295–4306PubMedGoogle Scholar
  10. 10.
    Richardson DR, Milnes K (1997) Blood 89:3025–3038PubMedGoogle Scholar
  11. 11.
    Richardson DR, Ponka P (1998) J Lab Clin Med 131:306–315PubMedGoogle Scholar
  12. 12.
    Richardson DR (2002) Crit Rev Oncol Hematol 42:267–281CrossRefPubMedGoogle Scholar
  13. 13.
    Boger DL, Cai H (1999) Angew Chem Int Ed 38:448–476CrossRefGoogle Scholar
  14. 14.
    Richardson DR, Bernhardt PV (1999) J Biol Inorg Chem 4:266–273CrossRefPubMedGoogle Scholar
  15. 15.
    Becker EM, Lovejoy DB, Greer JM, Watts RN, Richardson DR (2003) Br J Pharmacol 138:819–830CrossRefPubMedGoogle Scholar
  16. 16.
    Richardson D, Mouralian C, Ponka P, Becker E (2001) Biochim Biophys Acta 1536:133–140CrossRefPubMedGoogle Scholar
  17. 17.
    Armstrong CM, Bernhardt PV, Chin P, Richardson DR (2003) Eur J Inorg Chem 1145–1146Google Scholar
  18. 18.
    Chaston TB, Richardson DR (2003) J Biol Inorg Chem 8:427–438PubMedGoogle Scholar
  19. 19.
    Bakir M, Brown O (2002) J Mol Struct 609:129–136CrossRefGoogle Scholar
  20. 20.
    Dean RT, Nicholson P (1994) Free Radical Res 20:83–101Google Scholar
  21. 21.
    Gutteridge JM (1990) Free Radical Res Commun 9:119–125Google Scholar
  22. 22.
    Hermes-Lima M, Nagy E, Ponka P, Schulman HM (1998) Free Radical Biol Med 25:875–880CrossRefGoogle Scholar
  23. 23.
    Gans P, Sabatani A, Vacca A (1985) J Chem Soc Dalton Trans 1195–1200Google Scholar
  24. 24.
    Martinelli RA, Hanson GR, Thompson JS, Holmquist B, Pilbrow JR, Auld DS, Vallee BL (1989) Biochemistry 28:2251–2258PubMedGoogle Scholar
  25. 25.
    Farrugia LJ (1999) J Appl Crystallogr 32:837CrossRefGoogle Scholar
  26. 26.
    Sheldrick GM (1997) SHELX97: programs for crystal structure analysis, release 97-2. University of Göttingen, GermanyGoogle Scholar
  27. 27.
    Farrugia LJ (1997) J Appl Crystallogr 30:565CrossRefGoogle Scholar
  28. 28.
    Tossidis IA (1983) Chim Chron 12:181–197Google Scholar
  29. 29.
    Garcia-Vargas M, Belizon M, Hernandez-Artiga MP, Martinez C, Perez-Bustamante JA (1986) Appl Spectrosc 40:1058–1062Google Scholar
  30. 30.
    Al-Nuri MA, Abu-Eid M, Zatar NA, Khalaf S, Hannoun M, Khamis M (1992) Anal Chim Acta 259:175–179Google Scholar
  31. 31.
    Nakanishi T, Otomo M (1986) Microchem J 33:172–178Google Scholar
  32. 32.
    Zatar NA, Al-Nuri MA, Abu-Eid M, Hannoun M, Abu-Zuhri AZ, Khalaf S, Khamis M (1991) Spectrosc Lett 24:1145–1152Google Scholar
  33. 33.
    Abu-Eid M, Zatar NA, Al-Nuri MA, Khamis M, Khalaf S (1992) Spectrosc Lett 25:585–592Google Scholar
  34. 34.
    Manuel-Vez MP, Garcia-Vargas M (1993) An Quim 89:218–222Google Scholar
  35. 35.
    Abu Zuhri AZ, El-Shahawi MS, Kamal MM, Al-Nuri M, Hannoun M (1994) Anal Lett 27:1907–1919Google Scholar
  36. 36.
    Rossi MV, Suarez-Iha MEV, Hoffmann MR (1995) Spectrosc Lett 28:1153–1166Google Scholar
  37. 37.
    Terra LHSA, Encarnacion M, Suarez-Iha V (1997) Spectrosc Lett 30:625–639Google Scholar
  38. 38.
    Da Cunha Areias MC, Avila-Terra LHS, Gaubeur I, Suarez-Iha MEV (2001) Spectrosc Lett 34:289–300CrossRefGoogle Scholar
  39. 39.
    Pinto JJ, Moreno C, Garcia-Vargas M (2002) Anal Bioanal Chem 373:844–848CrossRefPubMedGoogle Scholar
  40. 40.
    Hearn MJ (2002) PCT Int Appl 0243668Google Scholar
  41. 41.
    Bacchi A, Carcelli M, Costa M, Pelagatti P, Pelizzi C, Pelizzi G (1996) J Chem Soc Dalton Trans 4239–4244Google Scholar
  42. 42.
    Ianelli S, Mazza P, Orcesi M, Pelizzi C, Pelizzi G, Zani F (1995) J Inorg Biochem 60:89–108CrossRefPubMedGoogle Scholar
  43. 43.
    Ishak CF, Pflaum RT, Baenziger NC (1984) Acta Crystalloge Sect C 40:2047–2049CrossRefGoogle Scholar
  44. 44.
    Carcelli M, Pelizzi C, Pelizzi G, Mazza P, Zani F (1995) J Organomet Chem 488:55–61CrossRefGoogle Scholar
  45. 45.
    Bakir M, Green O (2002) Acta Crystallogr Sect C 58:o263–o265CrossRefGoogle Scholar
  46. 46.
    Richardson DR, Wis Vitolo LM, Hefter GT, May PM, Clare BW, Webb J, Wilairat P (1990) Inorg Chim Acta 170:165–170CrossRefGoogle Scholar
  47. 47.
    Dogan A, Köseoglu F, Kiliç E (2001) Anal Biochem 296:237–239CrossRefGoogle Scholar
  48. 48.
    Bernhardt PV, Chin P, Richardson DR (2001) J Biol Inorg Chem 6:801–809CrossRefPubMedGoogle Scholar
  49. 49.
    West DX, Swearingen JK, Valdes-Martinez J, Hernandez-Ortega S, El-Sawaf AK, van Meurs F, Castineiras A, Garcia I, Bermejo E (1999) Polyhedron 18:2919–2929CrossRefGoogle Scholar
  50. 50.
    Holland JM, Mc Allister JA, Lu Z, Kilner CA, Thronton-Pett M, Halcrow MA (2001) Chem Commun 577Google Scholar
  51. 51.
    Pilbrow JR (1990) Transition ion electron paramagnetic resonance. Oxford University Press, New YorkGoogle Scholar
  52. 52.
    Garcia-Tojal J, Pizarro JL, Lezama L, Arriortua MI, Rojo T (1998) Inorg Chim Acta 278:150–158CrossRefGoogle Scholar
  53. 53.
    Rudolf M, Feldberg SW (1996) DigiSim 2.1. West Lafayette, Ind., USAGoogle Scholar
  54. 54.
    Burger RM, Alder AD, Horwitz SB, Mims WB, Peisach J (1981) Biochemistry 20:1701–1704PubMedGoogle Scholar
  55. 55.
    Muller I, Niethammer D, Bruchelt G (1998) Int J Mol Med 1:491–494PubMedGoogle Scholar
  56. 56.
    Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NYGoogle Scholar
  57. 57.
    Mello Filho AC, Meneghini R (1984) Biochim Biophys Acta 781:56–63PubMedGoogle Scholar
  58. 58.
    Eliot H, Gianni L, Myers C (1984) Biochemistry 23:928–936PubMedGoogle Scholar
  59. 59.
    Aruoma OI, Halliwell B, Dizdaroglu M (1989) J Biol Chem 264:13024–13028PubMedGoogle Scholar
  60. 60.
    Lloyd DR, Phillips DH (1999) Mutat Res 424:23–36CrossRefPubMedGoogle Scholar
  61. 61.
    Gutteridge JM, Quinlan GJ, Evans TW (2001) Free Radical Res 34:439–443Google Scholar
  62. 62.
    Dhungana S, White PS, Crumbliss AL (2001) J Biol Inorg Chem 6:810–818PubMedGoogle Scholar

Copyright information

© SBIC 2003

Authors and Affiliations

  1. 1.Department of ChemistryUniversity of QueenslandBrisbaneAustralia
  2. 2.Children’s Cancer Institute Australia for Medical ResearchSydneyAustralia

Personalised recommendations