Nucleic acid bases alkylation

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. 

These compounds contain alkyl groups that form strong, covalent bonds with the nucleic acid bases of DNA, especially guanine. This interferes with DNA transcription and replication, inhibiting mitosis (Figure 16.1). They have a broad spectrum of antitumour activity and are used in the treatment of lymphoma, breast and ovarian carcinoma, melanoma and multiple myeloma. 

The study of the nucleic acid bases is interesting because they possess many possible sites of protonation or electrophilic attack. Isopotential maps have been constructed for adenine, cytosine, and thymine.244 They may be used to study theoretically the proton affinities of the different atoms in these molecules. It is well known that protonation of cytosine, its nucleotide or nucleoside, occurs at N-394,245-247 (cf. Section II) alkylation also occurs at N-3.103-248-249 Nevertheless protonation of the oxygen of cytosine in DNA has been reported.250 The basic pA of cytosine is higher than that of adenine. The isopotential map in the molecular plane of cytosine (Tig. 8) shows that the potential well is deeper for N-3 than for 0 and the minimum for N-3 in cytosine is deeper than for any nitrogen in adenine. These maps, and their confrontation with the experimental facts have been discussed228-244... 

There are many other alkylating agents which often display widely varying reactivity and specificity toward particular nucleic acid bases and particular nucleotide sequences. 

To rationalize the remarkable regioselectivity and stereoselectivity of these alkylation reactions, Potier and co-workers (777,775) proposed that a stacking interaction occurs between quinone imine 256 and the nucleic acid base prior to covalent bond formation. Moreover, the appropriate intermolecular NOE is observed to support this contention. The fact that these ribonucleotide adducts form so easily may suggest that ellipticine quinone imines could alkylate at the 3 end of transfer RNA or at similar sites on other RNA molecules to inhibit protein synthesis. Thus, RNA would seem to be a reasonable target for elliptinium and related ellipticines (775). 

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. 

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. ... 

In step 2, a DNA nucleophile conducts an intermolecular nucleophilic attack, which breaks the aziridine ring and alkylates DNA. Although guanine is the preferred nucleic acid base involved in the alkylation reaction, adenine also is known to react. Of critical importance is the fact that the lone pair of electrons on the mustard nitrogen is regenerated when the aziridine ring cleaves. 

In contrast to the DNA alkylating agents discussed earlier in this chapter, one nucleic acid-based chemotherapeutic agent, azacitidine, blocks abnormal cellular proliferation by dealkylating (specifically... 

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