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

• 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.

Ämnesord

NATURVETENSKAP  -- Kemi -- Teoretisk kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences -- Theoretical Chemistry (hsv//eng)

NATURVETENSKAP  -- Kemi -- Fysikalisk kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences -- Physical Chemistry (hsv//eng)

NATURVETENSKAP  -- Kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences (hsv//eng)

Nyckelord

hydroxyl radical formation

antitumor drugs

self-reduction

tumor-cells

cross-links

force-field

adriamycin

doxorubicin

complex

cardiotoxicity

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