Synthesis and hybridization studies of oligonucleotides containing 1-(2-deoxy-2- -C-hydroxymethyl- -D-ribofuranosyl)thymine (2'- -hm-dT)

Abstract

We report the first investigation of oligoribonucleotides containing a few 1-(2-deoxy-2-α-C-hydroxymethyl-β-d-ribofuranosyl)thymine units (or 2′-hm-dT, abbreviated in this work as ‘H’). Both the 2′-CH2O-phosphoramidite and 3′-O-phosphoramidite derivatives of H were synthesized and incorporated into both 2′,5′-RNA and RNA chains. The hybridization properties of the modified oligonucleotides have been studied via thermal denaturation and circular dichroism studies. While 3′,5′-linked H was shown previously to significantly destabilize DNA:RNA hybrids and DNA:DNA duplexes (modification in the DNA strand; ΔTm ∼ −3°C/insert), we find that 2′,5′-linked H have a smaller effect on 2′,5′-RNA:RNA and RNA:RNA duplexes (ΔTm = −0.3°C and −1.2°C, respectively). The incorporation of 3′,5′-linked H into 2′,5′-RNA:RNA and RNA:RNA duplexes was found to be more destabilizing (−0.7°C and −3.6°C, respectively). Significantly, however, the 2′,5′-linked H units confer marked stability to RNA hairpins when they are incorporated into a 2′,5′-linked tetraloop structure (ΔTm = +1.5°C/insert). These results are rationalized in terms of the compact and extended conformations of nucleotides.

2′‐Deoxy‐2′‐α‐C‐(hydroxymethyl)adenosine as Potential anti‐HCV Agent

“…Indeed, a limited number of successful selective substitutions at C-2Ј are reported [7,8,[10][11][12][13][14][15] and only few publications report the synthesis of 2Ј-deoxy-2Ј-α-C-(hydroxymethyl)pyrimidine nucleosides. [10][11][12][13][14][15] This can be explained by the inherent lower reactivity at C-2Ј. It has been reported that the electronegative anomeric carbon C-1Ј effectively prevents ionization of a 2Ј-leaving group to produce a cationic S N 1 intermediate for 2Ј modification.…”

“…A variety of procedures for preparing synthetic branched-chain sugar nucleosides have been described. However, the number of 2Ј-deoxy-2Ј-α-C-branched ribonucleosides reported are limited, [10][11][12][13][14][15] and their biological activities have not yet been investigated in a systematic manner, perhaps because of a lack of the availability of efficient synthetic methods leading to 2Ј-deoxy-2Ј-α-C-branched ribonucleosides.…”

“…Only few publications report the synthesis of 2Ј-deoxy-2Ј-α-C-hydroxymethylpyrimidine nucleosides. [10][11][12][13][14][15] As far as we know, the synthesis of 2Ј-deoxy-2Ј-α-C-(hydroxymethyl)purine nucleosides has not been reported yet. Two schemes are used to synthesize such pyrimidine nucleosides.…”

“…Two schemes are used to synthesize such pyrimidine nucleosides. First, the preparation of 2Ј-deoxy-2Ј-α-C-(hydroxymethyl)thymidine, [10] uridine, [11] or cytidine, [12] from the d-ribose sugar was described using a synthetic strategy as previously reported by Schmidt et al [13] The second way to synthesize these modified nucleosides involves a radical reaction starting from the corresponding nucleoside. Two radical methods were investigated.…”

Structure-Editing of Nucleic Acids for Selective Targeting of RNA

“…This point was considered by Peng and Damha, when they introduced an extra C-atom in 2'-hydroxymethyl-2',5'-RNA oligomers, in order to lengthen the backbone and reduce the interstrand P-P repulsion, still keeping compact geometry. This modification unfortunately destabilized the complex with RNA [52].…”