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Biophys. J. BioFAST: First Published April 1, 2005. doi:10.1529/biophysj.104.054650
© 2005 by the Biophysical Society.

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Olivier Delalande
Jaroslav Malina
Viktor Brabec
Jiri Kozelka
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NUCLEIC ACIDS

Chiral Differentiation of DNA Adducts Formed by Enantiomeric Analogues of Antitumor Cisplatin Is Sequence-Dependent

Olivier Delalande 1, Jaroslav Malina 1, Viktor Brabec 1* and Jiri Kozelka 2

1 Institute of Biophysics AS CR, Brno
2 Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques

* To whom correspondence should be addressed. E-mail: brabec{at}ibp.cz.

Submitted on October 17, 2004
Revised on January 14, 2005
Accepted on 29 March 2005


  Abstract
1,2-GG intrastrand cross-links formed in DNA by the enantiomeric complexes [PtCl2(R,R-DAB)] and [PtCl2(S,S-DAB)] (DAB = 2,3-diaminobutane) were studied by biophysical methods. Molecular modeling revealed that structure of the cross-links formed at the TGGT sequence was affected by repulsion between the 5'-directed methyl group of the DAB ligand and methyl group of the 5' thymine of the TGGT fragment. Molecular dynamics simulations of the solvated platinated duplexes and our recent structural data (Biophys. J., 2000, 78:2008-2021), indicated that the adduct of [PtCl2(R,R-DAB)] alleviated this repulsion by unwinding the TpG step, whereas the adduct of [PtCl2(S,S-DAB)] avoided the unfavorable methyl-methyl interaction by decreasing the kink angle. Electrophoretic retardation measurements on DNA duplexes containing 1,2-GG intrastrand cross-links of Pt(R,R-DAB 2+ or Pt(S,S-DAB)2+ at a CGGA site showed that in this sequence both enantiomers distorted the double helix to the identical extent similar to that found previously for the same sequence containing the cross-links of the parent antitumor cis-Pt(NH3)22+ (cisplatin). In addition, the adducts showed similar affinities toward the HMGB1 proteins. Hence, whereas the structural perturbation induced in DNA by 1,2-GG intrastrand cross-links of cisplatin does not depend largely on the bases flanking the cross-links, the perturbation related to GG-cross-linking by bulkier platinum diamine derivatives does.

Key Words: DNA conformation, HMG-domain proteins, chemical probes, enantiomeric cis-dichloro-2,3-diaminebutaneplatinum(II), molecular dynamics simulations, platinum anticancer drugs




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J. Malina, O. Novakova, M. Vojtiskova, G. Natile, and V. Brabec
Conformation of DNA GG Intrastrand Cross-Link of Antitumor Oxaliplatin and Its Enantiomeric Analog
Biophys. J., December 1, 2007; 93(11): 3950 - 3962.
[Abstract] [Full Text] [PDF]


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Copyright © 2005 by the Biophysical Society.