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Phenylnitreniumion (PhNH+) may bind to nucleophiles through nitrogen aswell as through C2 or C4 carbons. However, only adducts of the formertype have been hitherto reported after its reaction with purine nucleosides.In this study, reactions of N-acetoxyaniline (PhNHOAc),a precursor to PhNH+, with 2′-deoxyadenosine (dA),2′-deoxyguanosine (dG), and with DNA in vitroat physiological conditions are described. The reaction of PhNHOAcwith dA followed by a hydrolytic deribosylation afforded 8-phenylaminoadenine(C8-PhNHA) together with a smaller amount of N6-(4-aminophenyl)adenine (N6-4APA). A similar reactionwith dG afforded 8-phenylaminoguanine (C8-PhNHG) together with tracesof 7-(4-aminophenyl)guanine (N7-4APG). The same adducts were foundalso in the DNA treated with PhNHOAc, and all of them were identifiedby comparison of their HPLC retention times and MS2spectrawith a set of synthesized authentic adenine adducts at C2, C8, N7, and N6positions and guanineadducts at C8, N7, and N2positions. The newly identified minor adduct, N7-4APG, representsthe first proof of arylnitrenium adduction at the N7 position of dG, which is the prominent site of attack by most C-electrophiles. [ABSTRACT FROM AUTHOR]

The reactivity of new biologically active thymine derivatives substituted with 2-(arylsulfonamidino)ethyl group at N1 and N3 position was investigated in the gas phase using CID experiments (ESI-MS/MS) and by density functional theory (DFT) calculations. Both derivatives show similar chemistry in the negative mode with a retro-Michael addition (Path A) being the most abundant reaction channel, which correlate well with the fluoride induced retro-Michael addition observed in solution. The difference in the fragmentation of N-3 substituted thymine 5 and N-1 substituted thymine 1 in the positive mode relates to the preferred cleavage of the sulfonyl group ( m/z 155, Path B) in N-3 isomer and the formation of the acryl sulfonamidine 3 ( m/z 309) via Path A in N-1 isomer. Mechanistic studies of the cleavage reaction conducted by DFT calculations give the trend of the calculated activation energies that agree well with the experimental observations. A mechanism of the retro-Michael reaction was interpreted as a McLafferty type of fragmentation, which includes H proton shift to one of the neighboring oxygen atoms in a 1,5-fashion inducing N1(N3)-C bond scission. This mechanism was found to be kinetically favorable over other tested mechanisms. Significant difference in the observed fragmentation pattern of N-1 and N-3 isomers proves the ESI-MS/MS technique as an excellent method for tracking the fate of similar sulfonamidine drugs. Also, the observed N-1 and/or N-3 thymine alkylation with in situ formed reactive acryl sulfonamidine 3 as a Michael acceptor may open interesting possibilities for the preparation of other N-3 substituted pyrimidines. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]