An RNA modification with remarkable resistance to RNase A

Alice Ghidini,Anna Winqvist,Charlotte Ander,Roger Strömberg

doi:10.1039/c3cc44621b

Abstract

A 3'-deoxy-3'-C-methylenephosphonate modified diribonucleotide is highly resistant to degradation by spleen phosphodiesterase and not cleaved at all by snake venom phosphodiesterase. The most remarkable finding is that, despite the fact that both the vicinal 2-hydroxy nucleophile and the 5'-oxyanion leaving group are intact, the 3'-methylenephosponate RNA modification is also highly resistant towards the action of RNase A.

Highlights

A 30-deoxy-30-C-methylenephosphonate modified diribonucleotide is highly resistant to degradation by spleen phosphodiesterase and not cleaved at all by snake venom phosphodiesterase
An interesting modification that was introduced in diribonucleotides in 197012 was internucleoside 30-deoxy-30-C-methylenephosphonate linkage (Fig. 1)
We have since developed synthetic methods for key steps towards ribonucleoside 30-deoxy-30-Cmethylenephosphinates, i.e., a 30-carbon extension at the nucleoside level,[16] synthesis of methylenephosphinate building blocks[17] and oxidation of methylenephosphinate linkages[18] as well as evaluation of condensing agents for formation of the methylenephosphinate internucleoside linkage.[19]

Summary

Introduction

A 30-deoxy-30-C-methylenephosphonate modified diribonucleotide is highly resistant to degradation by spleen phosphodiesterase and not cleaved at all by snake venom phosphodiesterase. Modified di- and oligonucleotides have been used as potential enzyme inhibitors and in investigations of enzymatic mechanisms for a number of decades, and the use has increased with the number of analogues available.[11] An interesting modification that was introduced in diribonucleotides in 197012 was internucleoside 30-deoxy-30-C-methylenephosphonate linkage (Fig. 1).

Results

Conclusion