Synthesis and evaluation of (S)-5′-C-aminopropyl and (S)-5′-C-aminopropyl-2′-arabinofluoro modified DNA oligomers for novel RNase H-dependent antisense oligonucleotides

Abstract

We designed and synthesized two novel thymidine analogs: (S)-5′-C-aminopropyl-thymidine and (S)-5′-C-aminopropyl-2′-β-fluoro-thymidine. Then, DNA oligomers containing these analogs were synthesized, and their functional properties were evaluated. Compared with the naturally occurring thymidine, it was revealed that (S)-5′-C-aminopropyl-2′-arabinofluoro-thymidine was sufficiently thermally stable, while (S)-5′-C-aminopropyl-thymidine featured thermal destabilization. The difference in thermal stability resulted from a moderate change in the secondary structure of the DNA/RNA duplexes and a molecular fluctuation in monomers derived from the (S)-5′-C-aminopropyl side chain, as well as from a variation in sugar puckering derived from the 2′-arabinofluoro modification. Meanwhile, the incorporation of these analogs significantly enhanced the nuclease resistance of the DNA oligomers. Moreover, the (S)-5′-C-aminopropyl-2′-arabinofluoro-modified DNA/RNA duplexes showed a superior ability to activate RNase H-mediated cleavage of the RNA strand compared to the (S)-5′-C-aminopropyl-modified DNA/RNA duplexes.