Identification of a Tricyclic PIII Chiral Auxiliary for Solid‐Supported Synthesis of Stereopure Phosphorothioate‐Containing Oligonucleotides. (6th February 2020)

• Record Type: Journal Article
• Authors: Sakamuri, Sukumar; Liu, Dingguo; Eltepu, Laxman; Liu, Bin; Reboton, Lisa Jo; Preston, Ryan; Bradshaw, Curt W.
• Is Part Of: Chembiochem. Volume 21:Number 9(2020)
• Page Start: 1298
• Page End: 1303
• Publication Date: 2020-02-06
• Subjects: chiral auxiliaries -- oligonucleotides -- solid-supported synthesis -- phosphorothioates -- synthesis design; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201900631
• Languages: English
• ISSNs: 1439-4227

Abstract

Abstract: 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 2 n 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 P III chiral auxiliary and its application in solid‐supported synthesis of stereopure PS‐containing oligonucleotides is reported. Abstract : Supporting role : A P III 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.