Modification of nucleic acids by reactive derivatives of oligonucleotides carrying a 5'-terminal 4-[methyl-(2-chloroethyl)amino]benzylamine group attached through linkers of various sizes. Conformational dynamics of the reactive group in the complementary complexes

N. V. Bulychev, Yu. N. Vorobjev, A. A. Gall, A. A. Koshkin, G. V. Shishkin

Institute of Bioorganic Chemistry, Siberian Division, Academy of Sciences of the USSR, Novosibirsk

Abstract: By optimizing the length of a linker bearing 5'-terminal alkylating 4-[methyl-(2-chloroethyl)amino]benzylphosphoramide residue, a reactive oligodeoxyribonucleotide derivative has been constructed with an optimal ability to alkylate nucleic bases in a double-stranded region of the complementary complex between a target NA and the addressed oligonucleotide. Such oligonucleotide could be useful for modifying the target NA if the nucleophilic sites of its single-stranded 3'-terminal region are protected due to a specific tertiary structure. A molecular mechanical modelling suggested that the insertion of two additional methylene groups into the standard linker provides an optimal increase in the efficiency of the modification of the base sites exposed into the major groove of the complementary complex. Synthesis of an oligonucleotide derivative with the modified linker and experiments on the target alkylation showed a 23 fold increase of the modifying ability as compared with the reagent having the standard linker. The conformational dynamics of the reactive group is discussed.

Russian Journal of Bioorganic Chemistry 1991, 17 (6):795-805

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