| Abstract
| - Reaction of the anthracycline, antitumor drugs adriamycin anddaunomycin with the self-complementary DNA oligonucleotide GCGCGCGC, (GC)4, in thepresence of the reducing agentdithiothreitol, the oxidizing agent hydrogen peroxide, or thealkylating agent formaldehydegives a similar mixture of DNA−drug adducts. Negative ionelectrospray mass spectra indicatethat adduct formation involves coupling of the DNA to the anthracyclinevia a methylene groupand that the major adduct is duplex DNA containing two molecules ofanthracycline, eachbound to a separate strand of the DNA via a methylene group.The source of the methylenegroup is formaldehyde. A molecular structure with eachanthracycline intercalated at a 5‘-CpG-3‘ site and covalently bound from its 3‘-amino group to a 2-aminogroup of a 2‘-deoxyguanosine nucleotide is proposed based upon spectral data and arelevant crystal structure.The reaction of (GC)4 with the anthracyclines andformaldehyde forms an equilibrium mixturewith DNA−drug adducts which is shifted toward free DNA by dilution.The results suggest apathway to the inhibition of transcription by reductively activatedadriamycin and daunomycin.Reductive activation in the presence of oxygen yields hydrogenperoxide; hydrogen peroxideoxidizes constituents in the reaction mixture to formaldehyde; andformaldehyde couples thedrug to DNA. In this regard, hydrogen peroxide reacts withadriamycin via Baeyer−Villigerreactions at the 13-position to yield 2, 3, andformaldehyde. Formaldehyde also results fromhydrogen peroxide oxidation of Tris[tris(hydroxymethyl)aminomethane] present intranscriptionbuffer and spermine, a polyamine commonly associated with DNA invivo, presumably via theFenton reaction.
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