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Stability and iron coordination in DNA adducts of Anthracycline based anti-cancer drugs

Journal article
Authors A. Eizaguirre
M. Yanez
Leif A Eriksson
Published in Physical Chemistry Chemical Physics
Volume 14
Issue 36
Pages 12505-12514
ISSN 1463-9076
Publication year 2012
Published at Department of Chemistry and Molecular Biology
Pages 12505-12514
Language en
Links dx.doi.org/10.1039/c2cp40931c
Keywords hydroxyl radical formation, antitumor drugs, self-reduction, tumor-cells, cross-links, force-field, adriamycin, doxorubicin, complex, cardiotoxicity
Subject categories Physical Chemistry, Chemical Sciences, Theoretical Chemistry, Biophysical chemistry

Abstract

There is evidence that the interaction of the alpha-ketol group of the Doxorubicin and Epirubicin anti-cancer drugs with Fe(III) generates hydroxyl radicals under aerobic conditions, causing cardiotoxicity in patients. Considering that the formation of DNA adducts is one of the main targets of Anthracycline drugs, we have in the present study characterized several [Anthracycline-DNA]Fe(III) complexes with respect to their stability and Fe(III) coordination, by means of MD simulations. Iron is found to coordinate well to the drugs containing an alpha-ketol group, this being the only group of the drug that binds to the metal. The complexes containing an alpha-ketol group, [Doxorubicin-DNA]Fe(III) and [Epirubicin-DNA]Fe(III), thus show greater stability than those not containing it, i.e., [Daunorubicin-DNA]Fe(III), [Idarubicin-DNA]Fe(III) and [5-Imino-Daunorubicin]Fe(III). Metal attachment to the alpha-ketol group is furthermore facilitated by the phosphate groups of DNA. The coordination to iron in the [Doxorubicin-DNA]Fe(III) system is smaller than that found for the [Epirubicin-DNA]Fe(III) system, and the corresponding number of coordinating waters in the former is larger than in the latter. This may in turn result in higher hydroxyl radical production, thus explaining the increased cardiotoxicity noted for Doxorubicin.

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