Nucleic Acids in Chemistry and Biology

8.5.2 Reactions with Nitrogen Electrophiles

The standard reaction of nitrousacid (as NO) in the deaminationof primary amines converts deoxyadeno-
sineinto deoxyinosine, deoxycytidine into deoxyuridine and deoxyguanosine into deoxyxanthosine.^17 In each
case, the reaction leads to a base with the oppositebase-pairing characteristic. The transitions dAdT→
dIdC and dCdG→dUdA are characteristic of the mutagenic action of nitrous acid (Figure 8.7).
Aromatic nitrogen cations are the second important class of nitrogen electrophiles. These species are
derived either from aromatic nitro-compounds by metabolic reduction or from aromatic amines by meta-
bolic oxidation. In both cases, an intermediate hydroxylamine species interacts with purine residues in
DNA or RNA either at C-8 or N-7 (Section 8.6.1).

8.5.3 Reactions with Carbon Electrophiles

A very large number of reagents form bonds from carbon to nucleic acids. The simplest are species like
formaldehyde and dimethyl sulfate. Among the most complex are carcinogens such as benzo[a]pyrene,
which requires transformation by three consecutive metabolic processes before it can become bound to
purine bases in DNA or RNA. Not surprisingly, there is a wide range in selectivity for the sites of attack
of these reactive species, some of which have been rationalized in terms of Pearson’s HSAB theory
(HSAB: hard and soft acids and bases). Frontier orbital analysis can provide a more rigorous picture of the
problem, but requires a deeper insight into theoretical chemistry. Other relevant factors may relate to the
degree of steric access of the electrophile to exposed bases or to intercalation of reagents prior to bonding
to nucleotide residues.

8.5.3.1 Formaldehyde. Covalent interactions of formaldehydewith RNA and its constituent nucle-

osides take place in a specific reaction of the amino bases. Formaldehyde first adds to the N^6 -amino group
of adenylate residues to give a 6-(hydroxymethylamino)purineand with guanylate residues to give a
2-(hydroxymethylamino)-6-hydroxypurine. These labile intermediates can react slowly with a second
amino group to give cross-linked products. These have a stable methylene bridge joining the amino groups
of two bases. All three possible species, pAdo-CH 2 -pAdo, pAdo-CH 2 -pGuo and pGuo-CH 2 -pGuo, have been
isolated from RNA that has been treated with formaldehyde and then hydrolysed with alkali (Figure 8.8).
The detailed mechanism of formaldehyde mutagenicity is not yet clear.^18

300 Chapter 8

N

N

N

N

N

PdR

H CH 2 OH

dAMP

+

HCHO

N

N

N

N

N

PdR

H

N N

N

N

N

dRP

H

CH 2

Figure 8.8 Formaldehyde mutagenesis of adenine residues

N

N

dR

O

NH 2

N

NH

dR

O

O

N

N

NH 2

HNO 2 N

N

dR

N

NH

O

N

N

dR

HNO 2

Figure 8.7 Pro-mutagenic deamination of dC→dU and of dA→dI by nitrous acid

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