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

• Published in: RSC advances Vol. 1; no. 68; pp. 4191 - 41914
• Main Authors: Zhou, Yujun, Kajino, Ryohei, Ishii, Seiichiro, Yamagishi, Kenji, Ueno, Yoshihito
• Format: Journal Article
• Published: 17.11.2020
• DOI: 10.1039/d0ra08468a

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. We designed and synthesized two novel thymidine analogs: ( S )-5′- C -aminopropyl-thymidine and ( S )-5′- C -aminopropyl-2′-β-fluoro-thymidine.