This paper describes for the first time the synthesis of α-oligonucleotides containing the four usual bases. Two unnatural hexadeoxyribonucleotidesi α-[d(CPAPTPGPCPG)] and α-[d(CPGPCPHPTPG)], consisting only of a-anomeric nucleotide units, were obtained by an improved phosphotriester method, in solution. Starting material was the four base-protected α-deoxyribo-nucleosides 3-d. Pyrimidine a-deoxynucleosides 3a and 3b were prepared by self-anomerization reactions followed by selective deprotection of sugar hydroxyles, while the two purine α-deoxynucleosides 3c and 3d were prepared by glycosylation reactions. In the case of guanine α-nucleoside derivative a supplementary base-protecting group: N, N-diphenylcarbamoyl was introduced on O⁶-position in order to avoid side-reactions during oligonucleotide assembling. The hexadeorynucleotide α-[d(CPAPTPGPCPG)] was tested as substrate of selected endo- and exonucleases. In conditions where the natural corresponding β-hexamer was completely degradated by nuclease s1 and calf spleen phosphodiesterase, the α-oligonucleotide remained almost intact.

α and ß-anomeric d(G₂T₁₂G₂) oligodeoxyribonucleotides were compared for their hybridization to rA₁₂ : the observed melting temperatures are 27°C for ß-oligodeoxyribonucleotide/RNA hybrid and 53°C for α-oligodeoxyribonucleotide/RNA. α-oligonucleotides with the four bases, complementary to natural mRNAs, were synthesized for the first time, labeled at their 5′-end with [³²P] and used as probes in Northern blot experiments. In spite of these higher affinities for their target RNA's, they were unable to block translation of natural or synthetic mRNA's in rabbit reticulocyte lysate. We have studied the RNase H activity on model rA₁₂:α- or ß-d(G₂T₁₂G₂) hybrids or on mRNA:α- or ß-oligonucleotides hybrids. Specific hybridization protects RNA strech when using α-oligonucleotides but not ß-oligonucleotides. Thus, our results show the inability of RNase H to degrade RNA in α-oligodeoxyribonucleotides:RNA duplexes.