DNA Interstrand Cross-Links of an Antitumor Trinuclear Platinum(II) Complex: Thermodynamic Analysis and Chemical Probing

Authors

  • Dr. Jaroslav Malina,

    1. Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Kralovopolska 135, CZ-61265 Brno (Czech Republic), Fax: (+420) 541240499
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  • Prof. Dr. Nicholas P. Farrell,

    1. Department of Chemistry, Virginia Commonwealth University, Richmond, Virginia 23284-2006 (USA)
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  • Prof. Dr. Viktor Brabec

    Corresponding author
    1. Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Kralovopolska 135, CZ-61265 Brno (Czech Republic), Fax: (+420) 541240499
    • Institute of Biophysics, Academy of Sciences of the Czech Republic v.v.i., Kralovopolska 135, CZ-61265 Brno (Czech Republic), Fax: (+420) 541240499

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Abstract

The trinuclear platinum compound [{trans-PtCl(NH3)2}2(μ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)]4+ (BBR3464) belongs to the polynuclear class of platinum-based anticancer agents. These agents form in DNA long-range (Pt,Pt) interstrand cross-links, whose role in the antitumor effects of BBR3464 predominates. Our results show for the first time that the interstrand cross-links formed by BBR3464 between two guanine bases in opposite strands separated by two base pairs (1,4-interstrand cross-links) exist as two distinct conformers, which are not interconvertible, not only if these cross-links are formed in the 5′-5′, but also in the less-usual 3′-3’ direction. Analysis of the conformers by differential scanning calorimetry, chemical probes of DNA conformation, and minor groove binder Hoechst 33258 demonstrate that each of the four conformers affects DNA in a distinctly different way and adopts a different conformation. The results also support the thesis that the molecule of antitumor BBR3464 when forming DNA interstrand cross-links may adopt different global structures, including different configurations of the linker chain of BBR3464 in the minor groove of DNA. Our findings suggest that the multiple DNA interstrand cross-links available to BBR3464 may all contribute substantially to its cytotoxicity.

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