Bioorganic & Medicinal Chemistry 2004-06-01

Hexofuranosyl thymidines inserted into oligodeoxynucleotides via their two exocyclic hydroxy groups. Oligo synthesis and RNase H activity.

Vyacheslav V Filichev, Birte Vester, Erik B Pedersen

Index: Bioorg. Med. Chem. 12 , 2843-2851, (2004)

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Abstract

Hexofuranosyl nucleosides are considered as conformationally restricted acyclic nucleosides using a furanose ring to link the diol backbone to the nucleobase. The phosphoramidite of 1-(2,3-dideoxy-beta-D-erythro-hexofuranosyl)thymine was synthesized from thymidine with formation of a new stereocentre at C-5' and the nucleoside was used in oligodeoxynucleotide (ODN) synthesis. Binding of mixed sequence ODNs towards complementary DNA and RNA showed decreased affinity compared to the wild-type oligos. Insertion in the middle of poly alphaT sequence led to stabilization of ODN/dA(14) duplexes at low ionic strength, but a decrease was observed in medium and high salt buffers compared to d(alphaT)(14)/dA(14). Both beta and alpha hexofuranosyl thymidines allowed cleavage of complementary mixed-sequence RNA by RNase H to the 3'-site of the modification in ODNs whereas a limited inhibition was detected from the 5'-site.