Synthesis and biophysical evaluation of 2',4'-constrained 2'O-methoxyethyl and 2',4'-constrained 2'O-ethyl nucleic acid analogues

The Journal of Organic Chemistry
Punit P SethEric E Swayze

Abstract

We have recently shown that combining the structural elements of 2'O-methoxyethyl (MOE) and locked nucleic acid (LNA) nucleosides yielded a series of nucleoside modifications (cMOE, 2',4'-constrained MOE; cEt, 2',4'-constrained ethyl) that display improved potency over MOE and an improved therapeutic index relative to that of LNA antisense oligonucleotides. In this report we present details regarding the synthesis of the cMOE and cEt nucleoside phosphoramidites and the biophysical evaluation of oligonucleotides containing these nucleoside modifications. The synthesis of the cMOE and cEt nucleoside phosphoramidites was efficiently accomplished starting from inexpensive commercially available diacetone allofuranose. The synthesis features the use of a seldom used 2-naphthylmethyl protecting group that provides crystalline intermediates during the synthesis and can be cleanly deprotected under mild conditions. The synthesis was greatly facilitated by the crystallinity of a key mono-TBDPS-protected diol intermediate. In the case of the cEt nucleosides, the introduction of the methyl group in either configuration was accomplished in a stereoselective manner. Ring closure of the 2'-hydroxyl group onto a secondary mesylate leaving gro...Continue Reading

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Citations

Oct 5, 2010·Journal of the American Chemical Society·Punit P SethEric E Swayze
May 23, 2012·Chemical Communications : Chem Comm·Pradeep S PallanMartin Egli
Mar 31, 2011·Future Medicinal Chemistry·Tsuyoshi YamamotoSatoshi Obika
Jan 15, 2015·Molecular Therapy. Nucleic Acids·Tomoko NishinaTakanori Yokota
Apr 17, 2012·Nature Chemical Biology·Frank RigoC Frank Bennett
Sep 17, 2011·Chemistry & Biodiversity·Thazha P Prakash
Feb 26, 2013·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Alberto Dávalos, Carlos Fernández-Hernando
Sep 18, 2013·Artificial DNA, PNA & XNA·Masayasu Kuwahara, Satoshi Obika
Dec 5, 2013·Artificial DNA, PNA & XNA·Venubabu KotikamVaijayanti A Kumar
Jul 15, 2016·RNA Biology·Philipp ReautschnigThorsten Stafforst
Jul 20, 2016·Journal of Medicinal Chemistry·W Brad Wan, Punit P Seth
Aug 5, 2015·Organic & Biomolecular Chemistry·Hubert HřebabeckýRadim Nencka
Dec 15, 2017·Nucleic Acids Research·Xiulong Shen, David R Corey
Jul 27, 2017·Chemistry : a European Journal·Mirjam MenziJonathan Hall
Jan 15, 2016·Organic & Biomolecular Chemistry·Robert D GiacomettiStephen Hanessian
Aug 31, 2018·Organic & Biomolecular Chemistry·Naohiro HorieSatoshi Obika
Aug 11, 2015·Nature Communications·Kazutaka NishinaTakanori Yokota
Jun 6, 2019·Nucleic Acids Research·Xue-Hai LiangStanley T Crooke
Nov 30, 2012·Chembiochem : a European Journal of Chemical Biology·Punit P SethMartin Egli
Jun 20, 2017·Current Protocols in Nucleic Acid Chemistry·Oleksandr PlashkevychJyoti Chattopadhyaya

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