Methyl-substituted nucleobases

The effect of the aqueous medium on the reactivity and on the stability of the resulting adducts has been investigated to assess which adduct arises from the kinetically favorable path or from an equilibrating process. The calculations indicate that the most nucleophilic site of the methyl-substituted nucleobases in the gas phase is the guanine oxygen atom, followed by the adenine N1, while other centers exhibit a substantially lower nucleophilicity (see activation Gibbs energies in Table 2.2). 

The mechanisms by which the nucleobases return to the groimd state are subtly connected to the molecular structure of these bases. For instance, simple tautomerization of adenine into 2-aminopurine results in an increase of excited-state lifetime from 1.1 to 30 ps (Canuel et al. 2005). Methyl-substitution of cytosine or cytidine at Cs position increases the lifetime in water solution by a factor of seven (Malone et al. 2003). Fluoro-substitution at the same site or acetyl-substitution at N4 have even larger effects, increasing the lifetime from Ips to, respectively, 88 and 280 ps (Malone et al. 2003). Double methyl substitution in positions Ni and N3 of thymine increases its lifetime in gas phase from 5 ps (Canuel et al. 2005) to about 150 ps (He et al. 2003). Similar effects were also reported for single and double methyl substitutions in macil (He et al. 2003). 

Substitution of the aromatic C(5)H in uracil by a methyl group (to give thymine) decreases the acidity of N(3)H by 0.5 log units (cf. Table I). Replacement of protons of endocyclic N atoms and of exocyclic amino groups by alkyl groups in general has a relatively minor effect on the pkl, values of nucleobases. For example, the pvalues of N1 protonated 9-methyladenine (9-MeA), 6,9-dimethyladenine (6,9-DiMeA), and 6,6,9-trimethyladenine (6,6,9-TriMeA) are... 

A series of novel acyclic nucleoside phosphonates (819) with various nucleobases in the oo-position and variously substituted in the p-position of alkylphosphonate chain, have been prepared by Hockowa et al. Several derivatives exhibited antiviral activity against HIV and vaccinia virus, HSV-1, HSV-2, VZV and CMV, although the parent unsubstituted derivatives were anti vitally inactive. Adenine as a nucleobase and the p-methyl group attached to the alkylphosphonate chain proved to be a prerequisite to afford pronounced antiviral activity. " ... 

---