DNA DOUBLE HELIX PROMOTES A LINKAGE ISOMERIZATION REACTION IN TRANS-DIAMMINEDICHLOROPLATINUM(II)-MODIFIED DNA

In the reaction between trans-diamminedichloroplatinum(II) and a singl e-stranded pyrimidine-rich oligodeoxyribonucleotide (22-mer) containin g the central sequence TGAGT, the 1,3-trans-{Pt(NH3)(2)[d(GAG)]} cross link is formed. The 1,3-intrastrand cross-tink is inert within the sin gle-stranded oligonucleotide. In contrast, it rearranges to an interst rand cross-link when the platinated oligonucleotide is paired with its complementary deoxyribo- or ribonucleotide strand. The half-life of t he 1,3-intrastrand cross-link, approximate to 6 h at 37 degrees C, is independent of the nature and concentration of the salt (NaCl or NaClO 4). It is not dramatically affected when the intervening adenine resid ue between the chelated guanine residues is replaced by a cytosine or a thymine residue or when the T A base pair adjacent to the 5' or 3' s ide of the adduct is replaced by a C-G base pair. On the other hand, a mismatch on the 3' or 5' side of the adduct prevents the rearrangemen t. We propose that the linkage isomerization reaction results from a d irect nucleophile attack of the cytosine residue complementary to the platinated 5' guanine residue on the platinum residue. Among others, t he potential use of the DNA-RNA-promoted reaction is discussed in the context of the antisense strategy to irreversibly cross-link the antis ense oligonucleotides to their targets.