LINKAGE ISOMERIZATION REACTION OF INTRASTRAND CROSS-LINKS IN TRANS-DIAMMINEDICHLOROPLATINUM(II)-MODIFIED SINGLE-STRANDED OLIGONUCLEOTIDES

The stability of trans-{Pt(NH3)(2)[d(CGAG)-N7-G, N7-G]} adducts, resulting from cross-links between two guanine residues at d(CGAG) sites within single-stranded oligonucleotides by trans-diamminedichloroplatinum(II), has been studied under various conditions of temperature, salt and pH. The trans-{Pt(NH3)(2)[d(C GAG)-N7-G,N7-G]} cross-links rearrange into trans-{Pt(NH3)(2)[d(CGAG)-N3-C,N7-G]} cross-links. The rate of rearrangement is independent of pH, in the range 5-9, and of the nature and concentration of the salt (NaCl or NaClO4) in the range 10-400 mM. The reaction rate depends upon temperature, the t(1/2) values for the disappearence of the (G,G) intrastrand crosslink ranging from 120 h at 30 degrees C to 70 min at 80 degrees C. The linkage isomerization reaction occurs in oligonucleotides as short as the platinated tetramer d(CGAG). Replacement of the intervening residue A by T has no major effect on the reaction. The C residue adjacent to the adduct on the 5' side plays a key-role in the reaction; its replacement by a G, A or T residue prevents the reaction occuring. No rearrangement was observed with the C residue adjacent to the adduct on the 3' side. It is proposed that the linkage isomerization reaction results from a direct attack of the base residue on the platinum(II) square complex.