Oligonucleotides Containing Novel 4′-C- or 3′-C-(Aminoalkyl)-Branched Thymidines

Abstract

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-branched key intermediate 11 was synthesized by a convergent strategy and converted to its 2′-O-methyl and 2′-deoxy-2′-fluoro derivatives, leading to the preparation 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 complementary single-stranded DNA and RNA was obtained with these analogues compared to the unmodified references (Table 1). The presence of monomer X or monomer Y in a 2′-O-methyl-RNA oligonucleotide had a negative effect on the binding affinity of the 2′-O-methyl-RNA oligonucleotide towards DNA and RNA. Starting from the 3′-C-allyl derivative 28, 3′-C-(3-aminopropyl)-protected nucleosides and 3′-O-phosphoramidite derivatives were synthesized, leading to novel oligonucleotide analogues containing 3′-C-(3-aminopropyl)thymidine monomer Z or the corresponding 3′-C-(3-aminopropyl)-2′-O,5-dimethyluridine monomer W (Schemes 4 and 5). Incorporation of the 2′-deoxy monomer Z induced no significant changes in the binding affinity towards DNA but decreased binding affinity towards RNA, while the 2′-O-methyl monomer Z induced decreased binding affinity towards DNA as well as RNA complements (Table 2).