Synthesis of (2-Deoxy-α- and -β-d-erythro-pentofuranosyl)(thymin-1-yl)alkanes and Their Incorporation into Oligodeoxyribonucleotides. Effect of Nucleobase−Sugar Linker Flexibility on the Formation of DNA−DNA and DNA−RNA Hybrids

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Abstract

On the basis of modeling studies, the (2-deoxy-α- and β-d-erythro-pentofuranosyl) (thymin-1-yl) alkanes 1a,b and 2a,b were selected as potential conformational probes for altDNA oligonucleotides. A straightforward approach to the synthesis of 1a,b and 2a,b from commercial 2-deoxy-d-ribose (3) and 1-O-methyl-2-deoxy-3,5-di-O-p-toluoyl-d-erythro-pentofuranose (13), respectively, was developed. These nucleoside analogues were converted to the phosphoramidite derivatives 27a,b−30a,b and incorporated into oligonucleotide 31 at predetermined sites and defined internucleotidic motifs. The insertion of 1a,b according to either a (3‘ → 5‘)- or a (3‘ → 3‘)-internucleotidic polarity produced oligonucleotides exhibiting a slightly higher affinity for their complementary unmodified DNA sequence than for the corresponding RNA sequence (Table 3). Conversely, the incorporation of 2a into 31 according to a (3‘ → 3‘)-orientation generated, for the first time, an altDNA oligonucleotide displaying a greater affinity for its complementary unmodified RNA sequence (ΔTm = 6 °C) than for the corresponding DNA sequence (ΔTm = 10 °C). This hybrid was, however, thermodynamically less stable than the duplex having unmodified α-2‘-deoxythymidine similarly incorporated into 31 (ΔΔTm = 3 °C).

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