Identification of a Tricyclic PIII Chiral Auxiliary for Solid‐Supported Synthesis of Stereopure Phosphorothioate‐Containing Oligonucleotides

Since the recognition of oligonucleotides as a therapeutic modality, significant work has been devoted to improving therapeutic properties, including nuclease stability. Phosphorothioate (PS) modifications of phosphodiesters are one of the most explored chemical modification and integral to currentl...

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Published inChembiochem : a European journal of chemical biology Vol. 21; no. 9; pp. 1298 - 1303
Main Authors Sakamuri, Sukumar, Liu, Dingguo, Eltepu, Laxman, Liu, Bin, Reboton, Lisa Jo, Preston, Ryan, Bradshaw, Curt W.
Format Journal Article
LanguageEnglish
Published Weinheim Wiley Subscription Services, Inc 04.05.2020
Subjects
Antisense oligonucleotides
Chemical modification
chiral auxiliaries
Identification methods
Nuclease
Oligonucleotides
Phosphodiesters
Phosphorothioate
phosphorothioates
siRNA
solid-supported synthesis
Stability
Sulfur
Synthesis
synthesis design
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Summary:Since the recognition of oligonucleotides as a therapeutic modality, significant work has been devoted to improving therapeutic properties, including nuclease stability. Phosphorothioate (PS) modifications of phosphodiesters are one of the most explored chemical modification and integral to currently approved oligonucleotide therapeutics, including antisense oligonucleotides (ASOs) and short interfering RNAs (siRNAs). Insertion of sulfur into the phosphate bridge in an n‐mer leads to 2n isomeric mixtures of PSs, with different nuclease stability and protein‐binding properties. Efforts to create stereopure PS‐containing oligonucleotides has spurred interest in identifying new synthetic methods. Herein, work on a novel and practical tricyclic PIII chiral auxiliary and its application in solid‐supported synthesis of stereopure PS‐containing oligonucleotides is reported. Supporting role: A PIII chiral auxiliary for use in the solid‐supported synthesis of stereopure phosphorothioate‐containing oligonucleotides is reported. The dihydroindole (DHI)‐based auxiliary provides excellent diastereoselectivity; is easier to synthesize; and is compatible with standard solid‐supported oligonucleotide synthesis reagents, conditions, equipment, and phosphoramidite chemistry.
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ISSN:1439-4227
1439-7633
DOI:10.1002/cbic.201900631