Determinants of Selectivity in Alkylation of Nucleosides and DNA by Secondary Diazonium Ions: Evidence for, and Consequences of, a Preassociation Mechanism
- 28 October 2004
- journal article
- Published by American Chemical Society (ACS) in Chemical Research in Toxicology
- Vol. 17 (11), 1531-1539
- https://doi.org/10.1021/tx0498004
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 6-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.Keywords
This publication has 19 references indexed in Scilit:
- Structure, Energetics, and Dynamics of the Nucleic Acid Base Pairs: NonempiricalAb InitioCalculationsChemical Reviews, 1999
- Mechanisms of Benzyl Group Transfer in the Decay of (E)-Arylmethanediazoates and Aryldiazomethanes in Aqueous SolutionsJournal of the American Chemical Society, 1995
- Nitrosamines and RelatedN-Nitroso CompoundsACS Symposium Series, 1994
- Why do O6-alkylguanine and O4-alkylthymine miscode? The relationship between the structure of DNA containing O6-alkylguanine and O4-alkylthymine and the mutagenic properties of these basesMutation Research, 1990
- Synthesis of 2'-deoxytubercidin, 2'-deoxyadenosine, and related 2'-deoxynucleosides via a novel direct stereospecific sodium salt glycosylation procedureJournal of the American Chemical Society, 1984
- N-Nitrosamines: Environmental occurrence, in vivo formation and metabolismJournal of Toxicology: Clinical Toxicology, 1982
- N-NitrosaminesPublished by American Chemical Society (ACS) ,1979
- General acid-base catalysis of complex reactions in waterChemical Reviews, 1972
- Requirements for general acid-base catalysis of complex reactionsJournal of the American Chemical Society, 1972
- Synthesis of Potential Anticancer Agents. XXV. Preparation of 6-Alkoxy-2-aminopurines2The Journal of Organic Chemistry, 1960