ISSN:
0749-1581
Keywords:
electron paramagnetic resonance
;
adriamycin
;
metal chelation
;
coordination structure
;
iron
;
free radical
;
Chemistry
;
Analytical Chemistry and Spectroscopy
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
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.
Additional Material:
11 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/mrc.1260331318
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