Alkylation nucleic acids

The chloroethyl moiety of these nitrosoureas is capable of alkylating nucleic acids and proteins and producing single-strand breaks and interstrand cross-linkage... 

S. L. Price, F. Lo Celso, J. A. Treichel, J. M. Goodfellow, and Y. Umrania, /. Chem. Soc., Faraday Trans., 89, 3407 (1993). What Base Pairings Can Occur in DNA A Distributed Multipole Study of the Electrostatic Interactions Between Normal and Alkylated Nucleic Acid Bases. 

Oxidative attack on unsaturated aliphatic systems. Carbon-carbon double bonds are oxidized by cytochromes P450 to reactive epoxides. Thus, vinyl chloride yields epoxychlor-ethane, an alkylating metabolite which can for example alkylate nucleic acids (Fig. 31.10). 

Amine bases in nucleic acids can react with alkylating agents in typical Sjsj2 reactions. Look at the following electrostatic potential maps, and tell which is the better nucleophile, guanine or adenine. The reactive positions in each are indicated. 

Whatever the true details of the metabolic pathway shown in Scheme 1 might be, there are certain facts which are very secure. Among these are that the nitrosamines are oxidatively dealkylated, that electrophilic intermediates which alkylate proteins and nucleic acids are formed, and that one of the... 

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... 

Asai, A. Nagamura, S. Saito, H. Takahashi, I. Nakano, H. The reversible DNA-alkylating activity of duocarmycin and its analogue. Nucleic Acids Res. 1994, 22, 88-93. 

The mechanism of carcinogenesis by PAHs is believed to involve alkylation of an informational macromolecule in a critical, but at present unknown, manner. Such an interaction with a protein has been modelled by alkylation of a peptide this showed a conformational change occurred on alkylation. It has not yet been possible to study the structure of DNA alkylated by an activated carcinogen this is because DNA is a fiber and the structural order in it is not sufficient for a crystal structure determination. However the crystal structures of some alkylated portions of nucleic acids are described, particularly some nucleosides alkylated by chloromethyl derivatives of DMBA. In crystals of these alkylation products the PAH portion of the adduct shows a tendency to lie between the bases of other nucleoside... 

In a similar way the effect of alkylation of DNA by an activated PAH may be drastic, as the hydrophobic aromatic group of the alkylating agent tries to avoid the aqueous environment of the nucleic acid. 

Methods currently available for chemiluminescent detection of nucleic acids are not based on derivatization techniques that directly recognize one of the nucleic acid bases or nucleotides. For chemical derivatization-based chemiluminescent detection, the specific reactivity of alkyl glyoxals and arylglyoxals with adenine or guanine nucleotides has been investigated. 

The pH value in a solid tumor is typically 0.2-0.5 units lower than in normal tissues. Therefore it may be possible to design pH-depen-dent cell-selective antitumor agents. Some free radicals are known to damage biological targets and especially to cleave nucleic acids (233). Alkylcobalt(III) complexes such as 53 generate alkyl radicals via ho-... 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

Sundheimer DW, White R, Sipes IG, et al. 1981. Nucleic acid alkylation and production of DNA strand breaks by ethylene dibromide in isolated rat hepatocytes. Fed Proc Fed Am Soc Exp Biol 40 688. 

---