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. 1985 Dec;64:19–35. doi: 10.1289/ehp.856419

ESR of copper and iron complexes with antitumor and cytotoxic properties.

W E Antholine, B Kalyanaraman, D H Petering
PMCID: PMC1568621  PMID: 2420582

Abstract

The relatively few iron and copper metal complexes which have been examined in cells and tissues for their redox properties, radical generation properties, and antitumor activity are discussed for studies which utilized electron spin resonance spectroscopy (ESR). A common property of a number of metal complexes, which include bleomycin, adriamycin, and thiosemicarbazones described in this review, is that they are readily reduced by thiol compounds and oxidized by oxygen or reduced species of oxygen to produce radicals. Structural features of these reactions are identified by ESR spectroscopy in model systems and often in cells. Furthermore, ESR spectroscopy has been most useful to probe the environment of the complexes in cells and to measure the rate of reduction of their oxidized forms. As a result of these studies, it is anticipated that more attention will be given to the exploration of redox-active metal complexes as drugs.

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Selected References

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  1. Antholine W. E., Hyde J. S., Sealy R. C., Petering D. H. Structure of cupric bleomycin. Nitrogen and proton couplings from EPR and electron nuclear double resonance spectroscopy. J Biol Chem. 1984 Apr 10;259(7):4437–4440. [PubMed] [Google Scholar]
  2. Antholine W. E., Petering D. H. Reaction of FeBlm with DNA: Fe(II)Blm-NO. Biochem Biophys Res Commun. 1979 Nov 28;91(2):528–533. doi: 10.1016/0006-291x(79)91554-7. [DOI] [PubMed] [Google Scholar]
  3. Antholine W. E., Petering D. H., Saryan L. A., Brown C. E. Interactions among iron(II) bleomycin, Lewis bases, and DNA. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7517–7520. doi: 10.1073/pnas.78.12.7517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Antholine W. E., Riedy G., Hyde J. S., Basosi R., Petering D. H. ESR parameters for cupric bleomycin in the mobilized state. J Biomol Struct Dyn. 1984 Oct;2(2):469–480. doi: 10.1080/07391102.1984.10507580. [DOI] [PubMed] [Google Scholar]
  5. Antholine W. E., Solaiman D., Saryan L. A., Petering D. H. Studies on the chemical reactivity of copper bleomycin. J Inorg Biochem. 1982 Oct;17(2):75–94. doi: 10.1016/s0162-0134(00)80077-x. [DOI] [PubMed] [Google Scholar]
  6. Antholine W., Taketa F. Binding of 2-formylpyridine monothiosemicarbazonato copper II to cat and normal human hemoglobins. J Inorg Biochem. 1982 Apr;16(2):145–154. doi: 10.1016/s0162-0134(00)80222-6. [DOI] [PubMed] [Google Scholar]
  7. Bartkowiak A., Grzelinska E., Bartosz G., Zabłocka J., Leyko W. The crypto-OH radical in the damage of DNA by bleomycin-Fe2+? Int J Biochem. 1982;14(12):1051–1053. doi: 10.1016/0020-711x(82)90160-4. [DOI] [PubMed] [Google Scholar]
  8. Burger R. M., Adler A. D., Horwitz S. B., Mims W. B., Peisach J. Demonstration of nitrogen coordination in metal--bleomycin complexes by electron spin--echo envelope spectroscopy. Biochemistry. 1981 Mar 17;20(6):1701–1704. doi: 10.1021/bi00509a045. [DOI] [PubMed] [Google Scholar]
  9. Burger R. M., Horwitz S. B., Peisach J., Wittenberg J. B. Oxygenated iron bleomycin. A short-lived intermediate in the reaction of ferrous bleomycin with O2. J Biol Chem. 1979 Dec 25;254(24):12999–12302. [PubMed] [Google Scholar]
  10. Burger R. M., Peisach J., Blumberg W. E., Horwitz S. B. Iron-bleomycin interactions with oxygen and oxygen analogues. Effects on spectra and drug activity. J Biol Chem. 1979 Nov 10;254(21):10906–10912. [PubMed] [Google Scholar]
  11. Burger R. M., Peisach J., Horwitz S. B. Activated bleomycin. A transient complex of drug, iron, and oxygen that degrades DNA. J Biol Chem. 1981 Nov 25;256(22):11636–11644. [PubMed] [Google Scholar]
  12. Burger R. M., Peisach J., Horwitz S. B. Stoichiometry of DNA strand scission and aldehyde formation by bleomycin. J Biol Chem. 1982 Aug 10;257(15):8612–8614. [PubMed] [Google Scholar]
  13. D'Aurora V., Stern A. M., Sigman D. S. 1,10-Phenanthroline-cuprous ion complex, a potent inhibitor of DNA and RNA polymerases. Biochem Biophys Res Commun. 1978 Feb 28;80(4):1025–1032. doi: 10.1016/0006-291x(78)91348-7. [DOI] [PubMed] [Google Scholar]
  14. D'Aurora V., Stern A. M., Sigman D. S. Inhibition of E. coli DNA polymerase I by 1,10-phenanthroline. Biochem Biophys Res Commun. 1977 Sep 9;78(1):170–176. doi: 10.1016/0006-291x(77)91236-0. [DOI] [PubMed] [Google Scholar]
  15. Dabrowiak J. C., Greenaway F. T., Longo W. E., Van Husen M., Crooke S. T. A spectroscopic investigation of the metal binding site of bleomycin A2. The Cu(II) and Zn(II) derivatives. Biochim Biophys Acta. 1978 Feb 16;517(2):517–526. doi: 10.1016/0005-2787(78)90218-6. [DOI] [PubMed] [Google Scholar]
  16. DeConti R. C., Toftness B. R., Agrawal K. C., Tomchick R., Mead J. A., Bertino J. R., Sartorelli A. C., Creasey W. A. Clinical and pharmacological studies with 5-hydroxy-2-formylpyridine thiosemicarbazone. Cancer Res. 1972 Jul;32(7):1455–1462. [PubMed] [Google Scholar]
  17. Downey K. M., Que B. G., So A. G. Degradation of DNA by 1,-10-phenanthroline. Biochem Biophys Res Commun. 1980 Mar 13;93(1):264–270. doi: 10.1016/s0006-291x(80)80275-0. [DOI] [PubMed] [Google Scholar]
  18. Eliot H., Gianni L., Myers C. Oxidative destruction of DNA by the adriamycin-iron complex. Biochemistry. 1984 Feb 28;23(5):928–936. doi: 10.1021/bi00300a021. [DOI] [PubMed] [Google Scholar]
  19. Falchuk K. H., Krishan A. 1,10-Phenanthroline inhibition of lymphoblast cell cycle. Cancer Res. 1977 Jul;37(7 Pt 1):2050–2056. [PubMed] [Google Scholar]
  20. Freedman J. H., Horwitz S. B., Peisach J. Reduction of copper(II)-bleomycin: a model for in vivo drug activity. Biochemistry. 1982 Apr 27;21(9):2203–2210. doi: 10.1021/bi00538a032. [DOI] [PubMed] [Google Scholar]
  21. Gosálvez M., Blanco M. F., Vivero C., Vallés F. Quelamycin, a new derivative of adriamycin with several possible therapeutic advantages. Eur J Cancer. 1978 Nov;14(11):1185–1190. doi: 10.1016/0014-2964(78)90224-4. [DOI] [PubMed] [Google Scholar]
  22. Hyde J. S., Froncisz W. The role of microwave frequency in EPR spectroscopy of copper complexes. Annu Rev Biophys Bioeng. 1982;11:391–417. doi: 10.1146/annurev.bb.11.060182.002135. [DOI] [PubMed] [Google Scholar]
  23. Iitaka Y., Nakamura H., Nakatani T., Muraoka Y., Fujii A., Takita T., Umezawa H. Chemistry of bleomycin. XX. The X-ray structure determination of P-3A Cu(II)-complex a biosynthetic intermediate of bleomycin. J Antibiot (Tokyo) 1978 Oct;31(10):1070–1072. doi: 10.7164/antibiotics.31.1070. [DOI] [PubMed] [Google Scholar]
  24. Kalyanaraman B., Sealy R. C., Sinha B. K. An electron spin resonance study of the reduction of peroxides by anthracycline semiquinones. Biochim Biophys Acta. 1984 Jun 29;799(3):270–275. doi: 10.1016/0304-4165(84)90270-8. [DOI] [PubMed] [Google Scholar]
  25. Lin P. S., Kwock L., Goodchild N. T. Copper chelator enhancement of bleomycin cytotoxicity. Cancer. 1980 Dec 1;46(11):2360–2364. doi: 10.1002/1097-0142(19801201)46:11<2360::aid-cncr2820461108>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  26. Marshall L. E., Graham D. R., Reich K. A., Sigman D. S. Cleavage of deoxyribonucleic acid by the 1,10-phenanthroline-cuprous complex. Hydrogen peroxide requirement and primary and secondary structure specificity. Biochemistry. 1981 Jan 20;20(2):244–250. doi: 10.1021/bi00505a003. [DOI] [PubMed] [Google Scholar]
  27. Minkel D. T., Dolhun P. J., Calhoun B. L., Saryan L. A., Petering D. H. Zinc deficiency and growth of Ehrlich ascites tumor. Cancer Res. 1979 Jul;39(7 Pt 1):2451–2456. [PubMed] [Google Scholar]
  28. Minkel D. T., Petering D. H. Initial reaction of 3-ethyoxy-2-oxobutyraldehyde bis(thiosemicarbazonato) copper(II) with Ehrlich ascites tumor cells. Cancer Res. 1978 Jan;38(1):117–123. [PubMed] [Google Scholar]
  29. Minkel D. T., Saryan L. A., Petering D. H. Structure-function correlations in the reaction of bis(thiosemicarbazonato) copper(II) complexes with Ehrlich ascites tumor cells. Cancer Res. 1978 Jan;38(1):124–129. [PubMed] [Google Scholar]
  30. Myers C. E., Gianni L., Simone C. B., Klecker R., Greene R. Oxidative destruction of erythrocyte ghost membranes catalyzed by the doxorubicin-iron complex. Biochemistry. 1982 Apr 13;21(8):1707–1712. doi: 10.1021/bi00537a001. [DOI] [PubMed] [Google Scholar]
  31. Peisach J., Blumberg W. E. Structural implications derived from the analysis of electron paramagnetic resonance spectra of natural and artificial copper proteins. Arch Biochem Biophys. 1974 Dec;165(2):691–708. doi: 10.1016/0003-9861(74)90298-7. [DOI] [PubMed] [Google Scholar]
  32. Peisach J., Stern J. O., Blumberg W. E. Optical and magnetic probes of the structure of cytochrome P-450's. Drug Metab Dispos. 1973 Jan-Feb;1(1):45–61. [PubMed] [Google Scholar]
  33. Sartorelli A. C., Agrawal K. C., Moore E. C. Mechanism of inhibition of ribonucleoside diphosphate reductase by a-(N)-heterocyclic aldehyde thiosemicarbazones. Biochem Pharmacol. 1971 Nov;20(11):3119–3123. doi: 10.1016/0006-2952(71)90116-x. [DOI] [PubMed] [Google Scholar]
  34. Saryan L. A., Ankel E., Krishnamurti C., Petering D. H., Elford H. Comparative cytotoxic and biochemical effects of ligands and metal complexes of alpha-N-heterocyclic carboxaldehyde thiosemicarbazones. J Med Chem. 1979 Oct;22(10):1218–1221. doi: 10.1021/jm00196a013. [DOI] [PubMed] [Google Scholar]
  35. Saryan L. A., Mailer K., Krishnamurti C., Antholine W., Petering D. H. Interaction of 2-formylpyridine thiosemicarbazonato copper (II) with Ehrlich ascites tumor cells. Biochem Pharmacol. 1981 Jun 15;30(12):1595–1604. doi: 10.1016/0006-2952(81)90386-5. [DOI] [PubMed] [Google Scholar]
  36. Sausville E. A., Peisach J., Horwitz S. B. Effect of chelating agents and metal ions on the degradation of DNA by bleomycin. Biochemistry. 1978 Jul 11;17(14):2740–2746. doi: 10.1021/bi00607a007. [DOI] [PubMed] [Google Scholar]
  37. Sausville E. A., Stein R. W., Peisach J., Horwitz S. B. Properties and products of the degradation of DNA by bleomycin and iron(II). Biochemistry. 1978 Jul 11;17(14):2746–2754. doi: 10.1021/bi00607a008. [DOI] [PubMed] [Google Scholar]
  38. Shields H., McGlumphy C., Hamrick P. J., Jr The conformation and orientation of copper (II)-bleomycin intercalated with DNA. Biochim Biophys Acta. 1982 Apr 26;697(1):113–120. doi: 10.1016/0167-4781(82)90051-3. [DOI] [PubMed] [Google Scholar]
  39. Solaiman D., Rao E. A., Petering D. H., Sealy R. C., Antholine W. E. Chemical, biochemical, and cellular properties of copper and iron bleomycins. Int J Radiat Oncol Biol Phys. 1979 Sep;5(9):1519–1521. doi: 10.1016/0360-3016(79)90762-4. [DOI] [PubMed] [Google Scholar]
  40. Sugioka K., Nakano H., Nakano M., Tero-Kubota S., Ikegami Y. Generation of hydroxyl radicals during the enzymatic reductions of the Fe3+-ADP-phosphate-adriamycin and Fe3+-ADP-EDTA systems. Less involvement of hydroxyl radical and a great importance of proposed perferryl ion complexes in lipid peroxidation. Biochim Biophys Acta. 1983 Oct 11;753(3):411–421. doi: 10.1016/0005-2760(83)90065-6. [DOI] [PubMed] [Google Scholar]
  41. Sugioka K., Nakano M. Mechanism of phospholipid peroxidation induced by ferric ion-ADP-adriamycin-co-ordination complex. Biochim Biophys Acta. 1982 Nov 12;713(2):333–343. [PubMed] [Google Scholar]
  42. Sugiura Y. Comparison of metal complexes between depyruvamide bleomycin and bleomycin: an important effect of axial donor on metal coordination and oxygen activation. Biochem Biophys Res Commun. 1979 Jun 13;88(3):913–918. doi: 10.1016/0006-291x(79)91495-5. [DOI] [PubMed] [Google Scholar]
  43. Sugiura Y., Ishizu K., Miyoshi K. Studies of metallobleomycins by electronic spectroscopy, electron spin resonance spectroscopy, and potentiometric titration. J Antibiot (Tokyo) 1979 May;32(5):453–461. doi: 10.7164/antibiotics.32.453. [DOI] [PubMed] [Google Scholar]
  44. Sugiura Y., Ishizu K., Miyoshi K. Studies of metallobleomycins by electronic spectroscopy, electron spin resonance spectroscopy, and potentiometric titration. J Antibiot (Tokyo) 1979 May;32(5):453–461. doi: 10.7164/antibiotics.32.453. [DOI] [PubMed] [Google Scholar]
  45. Sugiura Y., Kikuchi T. Formation of superoxide and hydroxy radicals in iron(II)-bleomycin-oxygen system: electron spin resonance detection by spin trapping. J Antibiot (Tokyo) 1978 Dec;31(12):1310–1312. doi: 10.7164/antibiotics.31.1310. [DOI] [PubMed] [Google Scholar]
  46. Sugiura Y. Metal coordination core of bleomycin : comparison of metal complexes between bleomycin and its biosynthetic intermediate. Biochem Biophys Res Commun. 1979 Mar 30;87(2):643–648. doi: 10.1016/0006-291x(79)91842-4. [DOI] [PubMed] [Google Scholar]
  47. Sugiura Y., Muraoka Y., Fujii A., Takita T., Umezawa H. Chemistry of bleomycin. XXIV. Deadmido bleomycin from viewpoint of metal coordination and oxygen activation. J Antibiot (Tokyo) 1979 Jul;32(7):756–758. doi: 10.7164/antibiotics.32.756. [DOI] [PubMed] [Google Scholar]
  48. Sugiura Y. Poduction of free radicals from phenol and tocopherol by bleomycin-iron(II) complex. Biochem Biophys Res Commun. 1979 Mar 30;87(2):649–653. doi: 10.1016/0006-291x(79)91843-6. [DOI] [PubMed] [Google Scholar]
  49. Sugiura Y., Suzuki T., Kawabe H., Tanaka H., Watanabe K. Spectroscopic studies on bleomycin-iron complexes with carbon monoxide, nitric oxide, isocyanide, azide, and cyanide and comparison with iron-porphyrin complexes. Biochim Biophys Acta. 1982 May 5;716(1):38–44. doi: 10.1016/0304-4165(82)90200-8. [DOI] [PubMed] [Google Scholar]
  50. Sugiura Y., Suzuki T., Muraoka Y., Umezawa Y., Takita T., Umezawa H. Deglyco-bleomycin-iron complexes: implications for iron-binding site and role of the sugar portion in bleomycin antibiotics. J Antibiot (Tokyo) 1981 Sep;34(9):1232–1236. doi: 10.7164/antibiotics.34.1232. [DOI] [PubMed] [Google Scholar]
  51. Takeshita M., Grollman A. P., Ohtsubo E., Ohtsubo H. Interaction of bleomycin with DNA. Proc Natl Acad Sci U S A. 1978 Dec;75(12):5983–5987. doi: 10.1073/pnas.75.12.5983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Winkelmann D. A., Bermke Y., Petering D. H. Comparative properties of the antineoplastic agent, 3-ethoxy-2-oxobutyraldehyde bis(thiosemicarbazonato) copper(II) and related chelates: linear free energy correlations. Bioinorg Chem. 1974 Apr;3(3):261–277. doi: 10.1016/s0006-3061(00)80074-5. [DOI] [PubMed] [Google Scholar]
  53. Zweier J. L. Reduction of O2 by iron-adriamycin. J Biol Chem. 1984 May 25;259(10):6056–6058. [PubMed] [Google Scholar]

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