Alkylation of nucleic acids

One goal of our current investigation is to show that genetically important cellular constituents can initiate the release of an alkylating agent from the N-nitrosamide. This might explain how highly reactive diazohydroxide metabolites effect the alkylation of nucleic acids within the cell nucleus. Preliminary evidence ( ) summarised in Table II shows that the decomposition of... 

Swann, PF. Magee, P.N. (1968) Nitrosamine-induced carcinogenesis. The alkylation of nucleic acids of the rat by A-methyl-A -nitrosourea, dimethylnitrosamine, dimethyl sulphate and methyl methanesulphonate. Biochem. J., 110, 39-47... 

Table 7.6 Some examples of the classes and compounds of anti-cancer agents that act by alkylation of nucleic acids. It is emphasized that this table only lists some of the classes of alkylating compound that are active against cancers...

Recently, several nucleophilic reagents have been used to establish the mode of action of the metabolites of polycyclic aromatic hydrocarbons (PAH). Among them, several phosphodiesters have been examined to clarify the possibility of reaction of PAH epoxides with the phosphate groups(P-alkylation) of nucleic acids (22). In this context we have studied the reaction of 3,4-epoxyprecocene II with dibenzyl phosphate under a variety of conditions. In all cases, instead of the formation of phenol or phosphotriesters observed with PAH epoxides, we obtained predominantly dimer XI. This compound was also the main component of the mixtures obtained by reaction of the above precocene epoxide with other acid catalysts, along with dimers XII and XII. Dimer XII was formed almost exclusively by thermal treatment. The structure and configuration for compound XII has been established by spectral and X-ray diffraction analyses (23). 

The mechanisms of toxicity are not yet understood however, it is likely that, in general, the toxic effects of ethylene oxide are due to its ability to react with cellular molecules, altering function. The carcinogenicity of ethylene oxide noted in experimental animals is probably due to its direct alkylation of nucleic acids. 

Trialkyl phosphates are useful for the A-alkylation of nucleic acid bases, and some regioselectivity is to be observed tris(2,2,2-trifluoroethyl) phosphate has been used for the trifluoroethylation of primary aromatic amines. ... 

Pegg AE, Perry W. 1981. Alkylation of nucleic acids and metabolism of small doses of dimethylnitrosamine in the rat. Cancer Res 41 3128-3132. 

Hawks A, Magee PN. 1974. The alkylation of nucleic acids of rat and mouse in vivo by the carcinogen... 

A special subgroup of alkylating agents are the nitrosoureas (Table 4-4). A feature of these agents is their considerable lipophilicity when compared with the other alkylating compounds. Lomustine and semustine do not even ionize at physiological pH. This permits them to cross more readily the blood-brain barrier and to pass into the cerebrospinal fluid. Furthermore, the nitrosoureas have a dual mechanism of action alkylation of nucleic acids and carbamoylation of various proteins via the 8-NH2 group of lysine residues. 

TBAF is very useful for alkylation of nucleic acid derivatives. Methylation or benzylation of uracil gives almost quantitative yields of alkylated product when using alkyl bromides, diaUcyl sulfates (eq 17), trialkyl phosphates, or alkyl chlorides with TBAF. Alkylation of the thiol anions generated from deprotection by 1,2-dibromoethane produces interesting tetrachalcogenofulvalenes. Under phase-transfer conditions, selective mono- and dialkylations of malononitrile have been achieved by using neat TBAF with Potassium Carbonate or Potassium tert-Butoxide and controlling the amount of alkyl bromides or iodides used (eqs 18 and 19). ... 

By virtue of the propargyl substituent of 369, efficient and predictable site-specific alkylation of nucleic acids with the possibility of bioconjugation via Huisgen [2-I-3] cycloaddition can occur. Thus, DNA lesion of 372 could afford triazole 374 following reaction with alkyl azides 373 (Scheme 77). 

P. D. Lawley and P. Brookes, Further studies on the alkylation of nucleic acids and their constiuent nucleotides, Biochem.]., 1963, 89,127-138. 

Alkylation of nucleic acid components and nucleic acids has been of considerable interest in recent years. SERS spectroscopy on Ag electrode is a useful technique for the identification of methyl derivatives of nucleic acids. The methylation of guanine leads to a specific change in the SERS spectrum. 

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