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

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• 作者：Olivier Delal ; e ; Jaroslav Malina ; Viktor Brabec ; Jiř ; í ; Kozelka
• 刊名：Biophysical Journal
• 出版年：2005
• 出版时间：June 2005
• 年：2005
• 卷：88
• 期：6
• 页码：4159-4169
• 全文大小：376 K

文摘

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.