The First Stereocontrolled Solid-Phase Synthesis of Di-, Tri-, and Tetra[adenosine (2‘,5‘) phosphorothioate]s

Yang, Xianbin; Sierzchala, Agnieszka; Misiura, Konrad; Niewiarowski, Wojciech; Sochacki, Marek; Stec, Wojciech J.; Wieczorek, Michał W.

doi:10.1021/jo980522l

Cited by 19 publications

(13 citation statements)

References 34 publications

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“…Under these conditions the Sp diasteromers were the faster eluting conformers with the corresponding Rp diasteromers eluting next. The diasteromers can also be separated and isolated using RP‐HPLC and then identified and characterized using 31 P NMR, LC–MS and TLC (Sierzchala, Okruszek, & Stec, ; Stec et al, , ; Suska et al, ; Yang et al, ).…”

Section: Chirality Of Ps Oligonucleotidesmentioning

confidence: 99%

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Chromatographic approaches for the characterization and quality control of therapeutic oligonucleotide impurities

Zahar

Magdy

El-Kosasy

et al. 2017

Biomedical Chromatography

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Phosphorothioate (PS) oligonucleotides are a rapidly rising class of drugs with significant therapeutic applications. However, owing to their complex structure and multistep synthesis and purification processes, generation of low-level impurities and degradation products are common. Therefore, they require significant investment in quality control and impurity identification. This requires the development of advanced methods for analysis, characterization and quantitation. In addition, the presence of the PS linkage leads to the formation of chiral centers which can affect their biological properties and therapeutic efficiency. In this review, the different types of oligonucleotide impurities and degradation products, with an emphasis on their origin, mechanism of formation and methods to reduce, prevent or even eliminate their production, will be extensively discussed. This review will focus mainly on the application of chromatographic techniques to determine these impurities but will also discuss other approaches such as mass spectrometry, capillary electrophoresis and nuclear magnetic resonance spectroscopy. Finally, the chirality and formation of diastereomer mixtures of PS oligonucleotides will be covered as well as approaches used for their characterization and the application for the development of stereochemically-controlled PS oligonucleotides.

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Section: Chirality Of Ps Oligonucleotidesmentioning

confidence: 99%

“…The diasteromers can also be separated and isolated using RP-HPLC and then identified and characterized using 31 P NMR, LC-MS and TLC (Sierzchala, Okruszek, & Stec, 1996;Stec et al, 1995Stec et al, , 1998Suska et al, 1993;Yang et al, 1998).…”

Section: Chirality Of Ps Oligonucleotidesmentioning

confidence: 99%

Chromatographic approaches for the characterization and quality control of therapeutic oligonucleotide impurities

Zahar

Magdy

El-Kosasy

et al. 2017

Biomedical Chromatography

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“…Thioaptamers with incorrect phosphoromonothioate configurations may bind with lower affinity to the target and decrease the overall binding affinity [83][84]. While stereocontrolled synthesis of P-chiral phosphoromonothioate [126][127][128][129][130][131] represents one possible solution to this problem, another lies in the synthesis of phosphorodithioate aptamers which are achiral at phosphorus [87][88][89]. As discussed above, phosphorodithioate aptamers can be isolated based on a bead-based strategy [110].…”

Section: B Dithioate Aptamersmentioning

confidence: 99%

Progress in Thioaptamer Development

Yang¹,

Gorenstein²

2004

CDT

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Thioaptamers are thiophosphate ester modified nucleic acids that are isolated via in vitro or bead-based thioaptamer selection against a target molecule such as a protein. Thioaptamers offer advantages over traditional aptamers in their enhanced affinity and specificity and higher stability, largely due to the properties of the sulfur backbone-modifications. An in vitro thioaptamer selection procedure that simultaneously selects for sequence and optimized hybrid phosphoromonothioate or phosphate backbone substitutions is outlined. A novel bead-based thioaptamer selection protocol that can produce mixed phosphorodithioate, phosphoromonothioate or phosphate hybrid backbones is also described. Several examples of thioaptamers targeting specific protein are provided. Such thioaptamers are shown to modulate protein activity in vivo.

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“…Thiophosphorylation of nucleosides (Horn and Urdea, ; Uhlmann and Engels, ) requires protection of reactive groups at the sugar and/or nucleobase moiety. Additionally, synthesis of phosphorothioates and phosphorodithioates have been reported in solution by the reaction of nucleophiles with 1,3,2‐oxathiaphospholane or dithiaphospholane (Okruszec et al, , , ; Yang et al, ; Baraniak et al, ; Olesiak et al, ; Misiura and Stec, ; Zmudzka et al, ; Misiura et al, ).…”

Section: Commentarymentioning

confidence: 99%

Solid‐Supported Reagents for Synthesis of Nucleoside Monothiophosphates, Dithiodiphosphates, and Trithiotriphosphates

Ahmadibeni

Parang

2009

CP Nucleic Acid Chemistry

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This unit describes procedures for the selective synthesis of nucleoside monothiophosphates, dithiodiphosphates, and trithiotriphosphates from solid-supported phosphitylating reagents. Rigid and sterically hindered polymer-bound 1,3,2-oxathiaphospholane is reacted selectively with the 5'-hydroxyl group of nucleosides in the presence of 1H-tetrazole. Sulfurization in the presence of Beaucage's reagent (3H-1,2-benzodithiole-3-one 1,1-dioxide) followed by ring-opening with 3-hydroxypropionitrile and basic cleavage in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) through the elimination of polymer-bound ethylene episulfide afford nucleoside monothiophosphates. Furthermore, reaction of polymer-bound diphosphitylating and triphosphitylating reagents, prepared from polymer-bound benzyl alcohol, with unprotected nucleosides, sulfurization with Beaucage's reagent, and acidic cleavage using trifluoroacetic acid cocktail produce nucleoside dithiodiphosphates and trithiotriphosphates in moderate yields.

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The First Stereocontrolled Solid-Phase Synthesis of Di-, Tri-, and Tetra[adenosine (2‘,5‘) phosphorothioate]s

Cited by 19 publications

References 34 publications

Chromatographic approaches for the characterization and quality control of therapeutic oligonucleotide impurities

Chromatographic approaches for the characterization and quality control of therapeutic oligonucleotide impurities

Progress in Thioaptamer Development

Solid‐Supported Reagents for Synthesis of Nucleoside Monothiophosphates, Dithiodiphosphates, and Trithiotriphosphates

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