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 language | English (US) |
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Pages (from-to) | S114-S122 |
Journal | Magnetic Resonance in Chemistry |
Volume | 33 |
Issue number | 13 |
DOIs | |
State | Published - 1995 |
Keywords
- adriamycin
- coordination structure
- electron paramagnetic resonance
- free radical
- iron
- metal chelation
ASJC Scopus subject areas
- General Chemistry
- General Materials Science