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Originally published as Biophys J. BioFAST on April 1, 2005.
doi:10.1529/biophysj.104.054650
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Biophysical Journal 88:4159-4169 (2005)
© 2005 The Biophysical Society

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

Olivier Delalande * {dagger}, Jaroslav Malina *, Viktor Brabec * and Jirí Kozelka {dagger}

* Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic; and {dagger} Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université René Descartes, Paris, France

Correspondence: Address reprint requests to Viktor Brabec, Tel.: 420-541-517-148; Fax: 420-541-240-499; E-mail: brabec{at}ibp.cz; or to Jirí Kozelka, Tel.: 331-42-86-20-86; Fax: 331-42-86-83-87; E-mail: jiri.kozelka{at}univ-paris5.fr.

1,2-GG intrastrand cross-links formed in DNA by the enantiomeric complexes [PtCl2(R,R-2,3-diaminobutane (DAB))] and [PtCl2(S,S-DAB)] 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 the methyl group of the 5'-thymine of the TGGT fragment. Molecular dynamics simulations of the solvated platinated duplexes and our recent structural data 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 (cisplatin). In addition, the adducts showed similar affinities toward the high-mobility-group box 1 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.




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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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