Synthesis and Biophysical Characterization of RNAs Containing 2'-Fluorinated Northern Methanocarbacyclic Nucleotides

Masaaki Akabane-Nakata; Pawan Kumar; Rajat S Das; Namrata D Erande; Shigeo Matsuda; Martin Egli; Muthiah Manoharan

doi:10.1021/acs.orglett.8b04153

Synthesis and Biophysical Characterization of RNAs Containing 2'-Fluorinated Northern Methanocarbacyclic Nucleotides

Org Lett. 2019 Apr 5;21(7):1963-1967. doi: 10.1021/acs.orglett.8b04153. Epub 2019 Mar 20.

Authors

Masaaki Akabane-Nakata¹, Pawan Kumar¹, Rajat S Das¹, Namrata D Erande¹, Shigeo Matsuda¹, Martin Egli², Muthiah Manoharan¹

Affiliations

¹ Alnylam Pharmaceuticals , 300 Third Street , Cambridge , Massachusetts 02142 , United States.
² Department of Biochemistry, School of Medicine , Vanderbilt University , Nashville , Tennessee 37232 , United States.

PMID: 30892051
DOI: 10.1021/acs.orglett.8b04153

Abstract

2'-Fluorinated Northern methanocarbacyclic (2'-F-NMC) nucleosides and phosphoramidites, based on a bicyclo[3.1.0]hexane scaffold bearing all four natural nucleobases (U, C, A, and G), were synthesized to enable exploration of this novel nucleotide modification related to the clinically validated 2'-deoxy-2'-fluororibonucleotides (2'-F-RNA). Biophysical properties of the 2'-F-NMC-containing oligonucleotides were evaluated. A duplex of 2'-F-NMC-modified oligonucleotide with RNA exhibited thermal stability similar to that of the parent RNA duplex, 2'-F-NMC-modified oligonucleotides had higher stability against 5'- and 3'-exonucleolytic degradation than the corresponding oligonucleotides modified with 2'-F-RNA, and 2'-F-NMC-modified oligonucleotides exhibited higher lipophilicity than the corresponding RNA oligonucleotides as well as those modified with 2'-F-RNA.

Publication types

Research Support, Non-U.S. Gov't