INSTABILITY OF THE MONOFUNCTIONAL ADDUCTS IN CIS-[PT(NH3)(2)(N7-N-METHYL-2-DIAZAPYRENIUM)CL](2+)-MODIFIED DNA - RATES OF CROSS-LINKING REACTIONS IN CIS-PLATINUM-MODIFIED DNA

Single- and double-stranded oligonucleotides containing a single monofunctional cis-[Pt(NH3)(2)(dG)(N7-N-methyl-2-diazapyrenium)](3+) adducts have been studied at two NaCl concentrations. In 50 mM and 1 M NaCl, the adducts within the single-stranded oligonucleotides are stable. In contrast, they are unstable within the corresponding double-stranded oligonucleotides. In 50 mM NaCl, the bonds between platinum and guanine or N-methyl-2,7-diazapyrenium residues are cleaved and subsequently, intra- or interstrand cross-links are formed as in the reaction between DNA and cis-DDP. In 1 M NaCl, the main reaction is the replacement of N-methyl-2,7-diazapyrenium residues by chloride which generates double-stranded oligonucleotides containing a single monofunctional cis-[Pt(NH3)(2)(dG)Cl](+) adduct. The rates of closure of these monofunctional adducts to bifunctional cross-links have been studied in 60 mM NaClO4. Within d(TG.CT/AGCA), d(CG.CT/AGCG) and d(AG.CT/AGCT) (the symbol . indicates the location of the adducts in the central sequences of oligonucleotides), the half-lifes (t(1/2)) of the cis-[Pt(NH3)(2)(dG)Cl](+) adducts are respectively 12, 6 and 2.8 hr and ther cross-linking reactions occur between guanine residues on the opposite strands. Within d(AG.TC/GACT), d(CG.AT/ATCG) and d(TGTG./CACA) or d(TG.TG/CACA) t(1/2) are respectively 1.6, 8 and larger than 20 hr and the intrastrand cross-links are formed at the d(AG), d(GA) and d(GTG) sites, respectively. The conclusion is that the rates of conversion of cis-platinum - DNA monofunctional adducts to minor bifunctional cross-links are dependent on base sequence. The potential use of the instability of cis-[Pt(NH3)(2)(dG)(N7-N-methyl-2-diazapyrenium)](3+) adducts is discussed in the context of the antisense strategy.