Full Paper

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

  1. Dr. Jaroslav Malina1,
  2. Prof. Dr. Nicholas P. Farrell2,
  3. Prof. Dr. Viktor Brabec1,*

Article first published online: 29 MAR 2011

DOI: 10.1002/asia.201000935

Issue

Chemistry – An Asian Journal

Chemistry – An Asian Journal

Volume 6, Issue 6, pages 1566–1574, June 6, 2011

Additional Information

How to Cite

Malina, J., Farrell, N. P. and Brabec, V. (2011), DNA Interstrand Cross-Links of an Antitumor Trinuclear Platinum(II) Complex: Thermodynamic Analysis and Chemical Probing. Chemistry – An Asian Journal, 6: 1566–1574. doi: 10.1002/asia.201000935

Author Information

  1. 1

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

  2. 2

    Department of Chemistry, Virginia Commonwealth University, Richmond, Virginia 23284-2006 (USA)

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

Publication History

  1. Issue published online: 27 MAY 2011
  2. Article first published online: 29 MAR 2011
  3. Manuscript Received: 27 DEC 2010

Funded by

  • Ministry of Education. Grant Numbers: LC06030, ME10066, OC08003
  • Academy of Sciences of the CR. Grant Numbers: IAA400040803, M200040901
  • Czech Science Foundation. Grant Numbers: P301/10/0598, P205/11/0856

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Keywords:

  • calorimetry;
  • dna damage;
  • interstrand cross-link;
  • platinum drugs;
  • thermodynamics

Graphical Abstract

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Cross-Linked DNA: The unique properties of long-range DNA interstrand cross-links, which are formed by the antitumor trinuclear platinum complex, are described.

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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