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  • Title: Determinants of selectivity in alkylation of nucleosides and DNA by secondary diazonium ions: evidence for, and consequences of, a preassociation mechanism.
    Author: Blans P, Fishbein JC.
    Journal: Chem Res Toxicol; 2004 Nov; 17(11):1531-9. PubMed ID: 15540951.
    Abstract:
    Reactions have been carried out in which 1,3-diisopropyltriazene or N-isopropyl-N-(1-hydroxyethyl)nitrosamine has been decomposed in neutral, buffered aqueous media in the presence of (15N2)2'-deoxyguanosine and (15N6)2'-deoxyadenosine. The products of covalent attachment of the isopropyl cation, derived from the isopropyl diazonium ion, to the heteroatoms of the purines have been separated and quantified by HPLC/electrospray mass spectrometry by employing isotopically distinct synthetic standards. The results indicate that the two different precursors of the isopropyl cation result in the formation of different yields of products in the reactions at all of the heteroatoms of both purines, outside experimental error, except possibly in the case of the N3 position of dAdo. For the different alkylating agents, the ratios of yields at any two sites vary as well. This leads to the conclusion that isopropylation occurs by a preassociation mechanism in which the isopropyl cation intermediate reacts in the solvation shell in which it is generated from its precursors. The reaction of N-isopropyl-N-(1-hydroxyethyl)nitrosamine results in alkylation of 2'-deoxyguanosine in preference to 2-deoxyadenosine, by a factor of 3-4. In this reaction, the yields for reaction at N1, N3, N6, and N7 of adenine vary over less than a factor of 2, whereas the yields for N2, N3, O6, and N7 of guanine vary over less than a factor of 4. The N1 atom of guanine is disfavored over the major product, the O6 adduct, by a factor of <8. The reaction of 1,3-diisopropyltriazene shows a similar preference for alkylation of 2-deoxyguanosine, with a similar range of product distribution in the reactions at adenine heteroatoms and a somewhat larger range of distribution at guanine heteroatoms. In particular, the yield of 1-isopropylguanosine is 50-fold lower than that of O6-isopropylguanosine. The comparable yields of products of reaction at the "hard" and "soft" sites of the purines lead to the conclusion that nucleophilicity is unimportant in site selectivity of alkylation by the isopropyl cation. The noteworthy selectivities, above, are rationalized by: differences in the association constants of the precursors of the cations with the two nucleosides; steric, statistical, and electrostatic effects that favor reaction of the O6 atom of guanine; and larger steric and/or desolvation requirements for association of the 1,3-diisopropyltriazenium cation with the N1 atom of guanine. The reaction of N-isopropyl-N-(1-hydroxyethyl)nitrosamine with double-stranded DNA has been similarly analyzed. The product distribution is remarkably similar in profile to that observed for the nucleosides in solution. In particular, exocyclic amino groups are competitive with the more traditional sites of diazonium ion-mediated alkylation. A comparison to earlier literature data on alkylation by methyl- and ethyl-diazonium ions illustrates some fundamental differences between the reaction of the diazonium ions and the isopropyl cation derived from the isopropyl diazonium ion.
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