Oligonucleotides containing novel 4 '-C- or 3 '-C-(aminoalkyl)-branched thymidines

The synthesis of four novel 3'-C-branched and 4'-C-branched nucleosides and their transformation into the corresponding 3'-O-phosphoramidite building blocks for automated oligonucleotide synthesis is reported. The 4'-C-branch ed key intermediate 11 was synthesized by a convergent strategy and convert ed to its 2'-O-methyl and 2'-deoxy-2'-fluoro derivatives, leading to the pr eparation of novel oligonucleotide analogues containing 4'-C-(aminomethyl)- 2'-O-methyl monomer X and 4'-C-(aminomethyl)-2'-deoxy-2'-fluoro monomer Y ( Schemes 2 and 3). In general, increased binding affinity towards complement ary single-stranded DNA and RNA was obtained with these analogues compared to the unmodified references (Table 1). The presence of monomer X or monome r Y in a 2'-O-methyl-RNA oligonucleotide had a negative effect on the bindi ng affinity of the 2'-O-methyl-RNA oligonucleotide towards DNA and RNA. Sta rting from the 3'-C-allyl derivative 28, 3'-C-(3-aminopropyl)-protected nuc leosides and 3'-O-phosphoramidite derivatives were synthesized, leading to novel oligonucleotide analogues containing 3'-C-(3-aminopropyl)thymidine mo nomer Z or the corresponding 3'-C-(3-aminopropyl)-2'-O,5-dimethyluridine mo nomer W (Schemes 4 and 5). Incorporation of the 2'-deoxy monomer Z induced no significant changes in the binding affinity towards DNA but decreased bi nding affinity towards RNA, while the 2'-O-methyl monomer Z induced decreas ed binding affinity towards DNA as well as RNA complements (Table 2).