Electron paramagnetic resonance and Mössbauer studies of metal chelation by adriamycin

Jay L. Zweier, Abraham Levy

Research output: Contribution to journalArticle

Abstract

EPR and Mössbauer studies demonstrate that iron chelation by adriamycin is complex, with several different chelation structures. At physiological pH in aqueous solution, three different EPR spectra are observed: a spectrum at g = 4.2 of Fe3+ in a rhombic crystal field (type 1); a spectrum at g = 2.01 with symmetric Gaussian lineshape linewidth 225 G (1 G = 10−4 T), suggestive of Fe3+ bound in an octahedral crystal field (type 2); and a broad spectrum centered at g = 2.0 suggestive of ferromagnetically coupled Fe3+ (type 3). The type 1 and 2 spectra are observed at adriamycin/Fe3+ ratios >4, the type 3 spectrum is observed at ratios <4 and at ratios <2 an increasing amount of Fe3+ gives rise to EPR silent iron(III) hydroxide polymers. At 4 K the type 1 and 2 complexes exhibit a broad doublet Mössbauer signal with an isomer shift δ = 0.56 (1) mm s−1 and quadrupole splitting δEQ = 0.74 (1) mm s−1. The type 3 complex gives rise to a sextet signal with isomer shift ΔEq = 0.47 (1) mm s−1 and hyperfine splitting HF = 476 (1) kG with exhibits superparamagnetic relaxation behavior with a blocking temperature of 23 K, consistent with a microcrystal size of 25 Å. Cu2+ binds to adriamycin at adriamycin/Cu2+ ratios >4:1 giving rise to an EPR spectrum with axial symmetry g = 2.26, g = 2.066, A = 188 G, while 2:1 complexes exhibit a single Gaussian line at g = 2.09 indicative of exchange‐coupled Cu2+. The exchange‐coupled Cu2+ and ferromagnetically coupled Fe3+ complexes can be explained by the formation of stacked 2:1 adriamycin‐metal polymers. On titration of adriamycin with Fe3+‐nitrilotriacetate a different spectrum is observed at g = 4.3 and its intensity plateaus at an adriamycin/iron ratio of 2. The iron adriamycin complexes cycle to reduce molecular oxygen and this cycle has been hypothesized to be a mechanism mediating the therapeutic and toxic effects of the drug. Both EPR and Mössbauer experiments demonstrate that the type 1 and 2 chelates reduce their Fe3+ to Fe2+ while the type 3 chelate does not. Therefore, the stoichiometry and method of complex preparation can profoundly effect the properties of these complexes.

Original languageEnglish (US)
Pages (from-to)S114-S122
JournalMagnetic Resonance in Chemistry
Volume33
Issue number13
DOIs
StatePublished - 1995

Keywords

  • adriamycin
  • coordination structure
  • electron paramagnetic resonance
  • free radical
  • iron
  • metal chelation

ASJC Scopus subject areas

  • Chemistry(all)
  • Materials Science(all)

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