Chiral differentiation of DNA adducts formed by enantiomeric analogues of antitumor cisplatin is sequence-dependent.
1,2-GG intrastrand cross-links formed in DNA by the enantiomeric complexes [PtCl(2)(R,R-2,3-diaminobutane (DAB))] and [PtCl(2)(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 [PtCl(2)(R,R-DAB)] alleviated this repulsion by unwinding the TpG step, whereas the adduct of [PtCl(2)(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(NH(3))(2)(2+) (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.
Delalande
Olivier
O
Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno.
Malina
Jaroslav
J
Brabec
Viktor
V
Kozelka
Jirí
J
D001483:Base Sequence; D055592:Biophysical Phenomena; D001703:Biophysics; D002945:Cisplatin / Q000031:analogs & derivatives / Q000737:chemistry*; D003432:Cross-Linking Reagents; D018736:DNA Adducts / Q000737:chemistry* / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D024243:HMGB1 Protein / Q000737:chemistry; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D013237:Stereoisomerism; D013816:Thermodynamics
D003432:Cross-Linking Reagents; D018736:DNA Adducts; D024243:HMGB1 Protein; D008024:Ligands; C057270:cisplatin-DNA adduct; D002945:Cisplatin