Stereocontrolled Synthesis of Dithymidine Phosphorothioates by Use of a Functionalized 5'- Protecting Group Bearing an Imidazole Residue

Wada, Takehiko; Kobayashi, Naotake; Mori, T.; Sekine, Mitsuo

doi:10.1080/07328319808005183

Cited by 12 publications

(7 citation statements)

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“…The Hayakawa's attempt at the stereoselective synthesis based on using of tetrazole attached to a bulky chiral auxiliary resulted in only partial success, since in the best case the diastereoselection leading to corresponding phosphites was at the level of 65% [68]. Several other modifications of phosphoramidite method have been published but non of them allowed synthesis of constructs longer than dimers [69][70][71][72][73][74]. Also important results from Agrawal's works [75,76] on the synthesis of nearly-stereopure PS-oligos should be mentioned as well as successful stereocontrolled synthesis of long-mers reported from Beaucage's [77] and Hayakawa's [78] laboratories.…”

Section: Phosphorothioatesmentioning

confidence: 99%

P-Chiral Oligonucleotides in Biological Recognition Processes

Guga

2007

CTMC

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Internucleotide phosphodiester linkages in non-modified oligonucleotides are quickly degraded by nucleolytic enzymes present in the cells and this feature practically eliminates natural DNA and RNA molecules from medical applications and from many structural and mechanistic studies. P-chiral oligonucleotide analogs, in which one of the non-bridging phosphate oxygen atoms is substituted with another heteroatom (e.g. S, Se) or a chemical group (e.g. CH3, BH3(-)), have significantly greater nuclease resistance and also offer important possibilities for detailed studies of interactions with other biomolecules at the molecular level. Notably, these substitutions do not disrupt hydrogen bonding between nucleobases and affect the overall geometry of the oligomers to only low or moderate extent, although important changes of hydration patterns and changes of interactions with metal ions are observed. Such the probes, including isotopomeric species labeled with a heavy oxygen isotope, possessing phosphorus atoms of selected absolute configurations, have been used for elucidation of the mode of action of many enzymes (nucleases, transferases, kinases), ribozymes and DNA-zymes, as well as for investigations on thermodynamic stability of nucleic acids complexes (duplexes, triplexes, i-motif) and for studies on a mechanism of conformational changes of B-Z type. They are also useful tools for analysis of interactions of the phosphoryl oxygen atoms in natural precursors with functional groups of proteins. The synthetic routes to stereodefined forms of selected types of P-chiral oligonucleotides are presented, as well as recently developed methods for their configurational analysis at micromolar concentration. Selected examples of application of diastereomerically pure P-chiral oligonucleotides for structural, biochemical and biological experiments are discussed.

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Section: Phosphorothioatesmentioning

confidence: 99%

P-Chiral Oligonucleotides in Biological Recognition Processes

Guga

2007

CTMC

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“…Therefore approaches that replace this group are an attractive pathway toward improving stereoselectivity synthesis. Such strategies have involved the use of 2-trityl-4,5-dicyanoimidazole derivatives (Schell, Laux, & Engels, 1999), other trityl groups having an imidazolyl group (Wada, Kobayashi, Mori, & Sekine, 1998), and the addition of a linker to the phosphorus atom (Seio, Kumura, Bologna, & Sekine, 2003).…”

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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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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“…Various attempts at stereocontrolled synthesis of PS‐oligos undertaken by other research establishments have been reported, among them efforts directed towards stereospecific synthesis of dinucleoside 3′,5′‐phosphorothioates (Jin et al, ; Jin and Just, ; Wada et al, ; Wang and Just, ; Lu and Just, ; Oka et al, ), Agrawal's work on the synthesis of nearly stereopure PS‐oligos (Iyer et al, ), and the successful stereocontrolled synthesis of long‐mers reported by Beaucage's laboratory (Wilk et al, ). These groups utilized the ingenious phosphoramidite methodology originally developed by Beaucage and Caruthers ().…”

Section: Commentarymentioning

confidence: 99%

Synthesis of Phosphorothioate Oligonucleotides with Stereodefined Phosphorothioate Linkages

Guga

Stec

2003

CP Nucleic Acid Chemistry

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A method for solid-phase synthesis of stereodefined PS-oligos via an oxathiaphospholane approach using pure P-diastereomers of nucleoside oxathiaphospholane monomers is described. The oxathiaphospholane monomers are synthesized by phosphitylation of 5'-O-DMTr-N-protected deoxyribonucleosides with 2-chloro-spiro-4,4-pentamethylene-1,3,2-oxathiaphospholane followed by sulfurization. The procedure is general and may be applied to other analogs, depending on the aldehyde (or mercaptoalcohol) used. Starting from an 18O-labeled mercaptoalcohol, the corresponding 18O-labeled phosphitylating reagent and nucleoside monomers can be obtained and used for synthesis of labeled stereodefined PS-oligos, which are useful for studying mechanisms of enzymatic reactions. Details are provided for chromatographic separation of the 5'-O-DMTr-N-protected-deoxyribonucleoside-3'-O-(2-thio-spiro-4,4-pentamethylene-1,3,2-oxathiaphospholane)s into their P-diastereomers, and for manual solid-phase synthesis of PS-oligos. Oxidation of 5'-O-DMTr-N-protected-deoxyribonucleoside-3'-O-(2-thio-spiro-4,4-pentamethylene-1,3,2-oxathiaphospholane)s with selenium dioxide yields their 2-oxo-analogs, which are suitable either for elongation of stereodefined PS-oligos with segments consisting of unmodified nucleotide units possessing phosphate internucleotide linkages, or for generating isotopomeric 18O-labeled PO-oligos of predetermined P-chirality.

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Stereocontrolled Synthesis of Dithymidine Phosphorothioates by Use of a Functionalized 5'- Protecting Group Bearing an Imidazole Residue

Cited by 12 publications

References 0 publications

P-Chiral Oligonucleotides in Biological Recognition Processes

P-Chiral Oligonucleotides in Biological Recognition Processes

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

Synthesis of Phosphorothioate Oligonucleotides with Stereodefined Phosphorothioate Linkages

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