Synthesis and Pairing Properties of Oligodeoxynucleotides Containing Bicyclo-RNA and Bicyclo-ANA Modifications

The synthesis of the ribo­(bc-rT)- and arabino­(bc-araT)-version of bicyclothymidine (bc-dT) has been achieved. A conformational analysis by X-ray and/or 1H NMR spectroscopy on the corresponding 3′,5′-benzyl-protected nucleosides featured a rigid C(2′)-endo conformation for the furanose ring, irrespective of the configuration of the OH group at C(2′). The conformation of the carbocyclic ring in these nucleosides was found to be less defined and thus more flexible. Both nucleosides were converted into the corresponding phosphoramidites and incorporated into oligodeoxynucleotides by standard DNA chemistry. Tm-data of duplexes with cDNA and RNA revealed that a bc-rT unit strongly destabilized duplexes with cDNA and RNA by 6–8 °C/mod, while bc-araT was almost Tm neutral. A rationale based on a previous structure of a bc-DNA mini duplex suggests that the strong destabilization caused by a bc-rT unit arises from unfavorable steric interactions of the equatorial 2′-OH group with the sugar residue of the 3′-neighboring nucleotide unit.