Synthesis and Incorporation into α-DNA of a Novel Conformationally Constrained α-Nucleoside Analogue

Abstract

The synthesis and incorporation into α-DNA of a novel conformationally constrained α-nucleoside analogue is described. The carbohydrate part of this analogue was prepared in 4 steps from the known bicyclic precursor 1 via a stereospecific, intramolecular, Et₃B-mediated radical addition to a keto function as the key step. The thus obtained intermediate 4 was transformed stereoselectively into the corresponding α-nucleoside analogues 7 and 8 containing the bases adenine and thymine, and were further elaborated into the phosphoramidite building blocks 11 and 12. Both building blocks were incorporated into α-oligodeoxynucleotides and their pairing behavior to parallel complementary DNA was studied by UV-melting experiments. Single substitutions of α-deoxyribnucleoside units by the new analogues in the center of duplexes were found to be thermally destabilizing by only -0.8 to -3.1 °C.

Key words

radical reactions - DNA - nucleosides - antisense agents - bioorganic chemistry

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