Deglycosylation of alkylated nucleosides: a molecular orbital study

The glycoside bond in alkylated nucleosides is known to be more stable for $0^6$ -alkylguanosines and $0^4$ - alkylthymines, and less stable for $N^3$ - and $N^7$ -alkylpurine and $O^2$ - alkylpyrimidine nucleosides. These marked differences have been demonstrated through in vitro acidic hydrolysis and in vivo glycosylase repair. This study examines the relative facility of the deglycosylation reaction for various nucleosides through the use of theoretical indices derived from the semiempirical AM1 SCF-MO methodology, which furnish inferences much in consonance with experiment

Mutagenic significance of proton acidities in methylated guanine and thymine bases and deoxynucleosides: A theoretical study

Proton changes have been advanced as being the key molecular basis for the mutagenecity of alkylated DNA bases and nucleosides, leading to questions as to which protons are involved and whether the protic changes are tautomeric shifts or abstractions. This semiempirical molecular orbital study seeks to clarify the issue by examining the various possibilities open for these protic changes in a number of methylated guanines and thymines and their deoxynucleosides. Proton shifts leading to tautomer formation are not predicted as being thermodynamically favourable in most cases. The most feasible proton abstractions are predicted to involve the Watson-Crick protons in all cases, which corroborates Watson-Crick proton loss as providing the key molecular basis for the induction of point mutations. The calculated proton acidities correlate well with experimental data. The gas-phase deprotonation enthalpies for a number of alkylated nucleosides are found to correlate linearly with the solvent-phase pK(a) values. The theoretically calculated enthalpies in a simulated aqueous solvent phase of the deprotonation reactions of various nucleic acid bases are also found to have good linear correlations with experimental pK(a) values. The consensus of these calculations is that O-6-alkyldeoxyguanosines, and O-2- and O-4-alkyldeoxythymidines would be mutagenic while N-7-alkyldeoxyguanosines would not be mutagenic (as experiment indicates). The untested N-3-methyldeoxyguanosine is predicted to be mutagenic. (C) 1997 Elsevier Science B.V