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Mixed-mode separation of antisense oligonucleotides using a single column with complementary anion-exchange and hydrophobic interaction chromatography approaches.
J Chromatogr A
January 2025
Genetics Guided Dementia Discovery (G2D2), Eisai, Inc. 35 Cambridge Park Drive, Suite 200, Cambridge, MA, 02140, USA.
The current study investigates the use of mixed-mode chromatography as a combination of anion-exchange (AEX) and hydrophobic interaction chromatography (HIC) for the analysis and purification of single-stranded antisense oligonucleotides with stereo-controlled phosphorothioate inter- nucleotide linkages. Initially a Scherzo-SS-C18 trimodal stationary phase with reversed-phase/AEX/ cation-exchange (CEX) functionalities is systematically evaluated to reveal the presence of U-shaped retention composed of two retention modes namely AEX and HIC, where the latter was also observed on related trimodal Scherzo SM and SW analogues. For the first time, retention and separation of deprotected oligonucleotides was described on a single mixed-mode column using a combination of AEX and HIC.
View Article and Find Full Text PDFStereocontrolled access to thioisosteres of nucleoside di- and triphosphates.
Nat Chem
February 2024
Department of Chemistry, Scripps Research, La Jolla, CA, USA.
Nucleoside diphosphates and triphosphates impact nearly every aspect of biochemistry; however, the use of such compounds as tools or medicinal leads for nucleotide-dependent enzymes and receptors is hampered by their rapid in vivo metabolism. Although a successful strategy to address the instability of the monophosphate moiety in oligonucleotide therapeutics has been accomplished by their isosteric replacement with phosphorothioates, no practical methods exist to rapidly and controllably access stereopure di- and triphosphate thioisosteres of both natural and unnatural nucleosides. Here we show how a modular, reagent-based platform can enable the stereocontrolled and scalable synthesis of a library of such molecules.
View Article and Find Full Text PDFStereo-Controlled Liquid Phase Synthesis of Phosphorothioate Oligonucleotides on a Soluble Support.
J Org Chem
July 2023
Department of Chemistry, University of Turku, 20500 Turku, Finland.
5'--(2-Methoxyisopropyl) (MIP)-protected 2'-deoxynucleosides as chiral P(V)-building blocks, based on the limonene-derived oxathiaphospholane sulfide, were synthesized and used for the assembly of di-, tri-, and tetranucleotide phosphorothioates on a tetrapodal pentaerythritol-derived soluble support. The synthesis cycle consisted of two reactions and two precipitations: (1) the coupling under basic conditions, followed by neutralization and precipitation and (2) an acid catalyzed 5'--deacetalization, followed by neutralization and precipitation. The simple P(V) chemistry together with the facile 5'--MIP deprotection proved efficient in the liquid phase oligonucleotide synthesis (LPOS).
View Article and Find Full Text PDFConvertible and Constrained Nucleotides: The 2'-Deoxyribose 5'-C-Functionalization Approach, a French Touch.
Molecules
September 2021
Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, UMR CNRS 5068, Université Paul Sabatier, 118 Route de Narbonne, CEDEX 9, 31062 Toulouse, France.
Many strategies have been developed to modulate the biological or biotechnical properties of oligonucleotides by introducing new chemical functionalities or by enhancing their affinity and specificity while restricting their conformational space. Among them, we review our approach consisting of modifications of the 5'-C-position of the nucleoside sugar. This allows the introduction of an additional chemical handle at any position on the nucleotide chain without disturbing the Watson-Crick base-pairing.
View Article and Find Full Text PDFCatalytic asymmetric and stereodivergent oligonucleotide synthesis.
Science
February 2021
Department of Chemistry, Yale University, New Haven, CT 06520, USA.
We report the catalytic stereocontrolled synthesis of dinucleotides. We have demonstrated, for the first time to our knowledge, that chiral phosphoric acid (CPA) catalysts control the formation of stereogenic phosphorous centers during phosphoramidite transfer. Unprecedented levels of diastereodivergence have also been demonstrated, enabling access to either phosphite diastereomer.
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