Abstract
Methodology is reviewed for the preparation of oligodeoxynucleotides bearing site-specific adducts of mutagens. Examples are presented of the use of the three general synthetic approaches: (1) direct adduction of oligonucleotides, (2) introduction of adducted nucleosides during oligonucleotide assembly, and (3) post-oligomerization methods in which an oligonucleotide is assembled containing an electrophilic equivalent of the target nucleoside, followed by formation of the adduct by condensation with a nucleophilic equivalent of the mutagen. The merits and limitations of the three methods are discussed.
Highlights
Direct AdductionThe simplest way to prepare adducted oligodeoxynucleotides is direct reaction with an activated mutagen
Methodology is reviewed for the preparation of oligodeoxynucleotides bearing site-specific adducts of mutagens
Even under the best of circumstances, a further limitation is that the oligonucleotide can contain no more than one, two or at most three target nucleosides
Summary
The simplest way to prepare adducted oligodeoxynucleotides is direct reaction with an activated mutagen. Excellent results have been obtained in preparation of adducted oligonucleotides in cases where only one guanine is present in a chain but the presence of multiple guanines creates separation problems since all can potentially react with the epoxide (Scheme 1). It should be mentioned in passing that the adduct of aflatoxin epoxide is unstable to acid, base and heat These limitations on reaction conditions make direct adduction the method of choice for assembly of adducted oligonucleotides. Excellent results have been obtained with the dihydrodiol epoxides of benzo[a]pyrene when the reactions are carried out on single stranded oligodeoxynucleotides which give high selectivity for the trans adduct at the N2 position of guanine (Scheme 2).[7] Direct adduction has been used to prepare oligonucleotides containing adducts of a diol epoxide of benzo[c]phenanthrene which shows preference for reaction at N6 of deoxyadenosine.[8].
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