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Nucleic Acids Research, 1993, Vol. 21, No. 25 5846-5851
© 1993

MOLECULAR BIOLOGY

Instability of the monofunctional adducts in cis-[Pt(NH3)2(N7-N-methyl-2-diazapyrenium)CI]2+;-modified DNA: rates of cross-linking reactions in cis-platinummodified DNA

Dominique Payet, Freédeéric Gaucheron, Miroslav Sip and Marc Leng

Centre de Biophysique Moleéculaire, CNRS, 1A avenue de la Recherche Scientifique 45071 Orleéans cedex 2, France

Received September 28, 1993. Revised November 5, 1993. Accepted November 5, 1993.

Single- and double-stranded oligonucleotides containing a single monofunctional cis-[Pt(NH3)2(dG)(N7-N-methyl-2-diazapyrenium)]3+ adduct have been studied at two NaCI concentrations. In 50 mM and 1 M NaCI, the adducts within the single-stranded oligonucleotides are stable. In contrast, they are unstable within the corresponding double-stranded oligonucleotides. In 50 mM NaCI, 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 NaCI, 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)CI]+ adduct. The rates of closure of these monofunctional adducts to bifunctional cross-links have been studied in 60 mM NaCIO4. Within d(TG CT/AGCA), d(CG CT/AGCG) and d(AGCT/AGCT) (the symbol' indicates the location of the adducts in the central sequences of oligonucleotides), the half-lifes (t1/2) of the cis-[Pt(NH3)2(dG)CI]+ adducts are respectively 12, 6 and 2.8 hr and the crosslinking reactions occur between guanine residues on the opposite strands. Within d(AG TC/GACT), d(CG AT/ATCG) and d(TGTG 7CACA) or d(TG TG/CACA) t1/2, 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 crosslinks 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.


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