Synthesis of 8,1′-ethano-2′-deoxyinosine-containing oligonucleotides, and their antiparallel Watson–Crick and parallel Hoogsteen duplex-forming abilities

Abstract

Recently, we developed oligonucleotides (ONs) containing syn-constrained 8,1′-ethano-2′-deoxyadenosine. In this study, we further explored the synthesis of 8,1′-ethano-2′-deoxyguanosine (ethano-dG) and 8,1′-ethano-2′-deoxyinosine (ethano-dI). Although ethano-dG could not be synthesized, ethano-dI, in which the inosine (^ethI) base was fixed in syn conformation, was successfully synthesized and incorporated into ONs. Subsequently, duplex-forming ability of ethano-dI-containing ONs was evaluated using ultraviolet (UV) melting experiments. Antiparallel Watson–Crick duplex containing the ^ethI:guanine base pair showed higher thermal stability than those containing other ^ethI:X base pairs (X = adenine, cytosine, or thymine) due to the formation of two Hoogsteen-type hydrogen bonds between ^ethI and guanine base at the Watson–Crick side. Although parallel Hoogsteen duplex formation generally requires acidic conditions, ethano-dI-containing ONs formed a parallel Hoogsteen duplex with the complementary DNA under neutral conditions, indicating that ^ethI stably recognized the cytosine base via two Watson–Crick-type hydrogen bonds. Overall, our findings suggest ethano-dI as a useful material to elucidate the biological functions of syn-oriented purine nucleosides in DNA.