Solid-phase stereoselective synthesis of oligonucleoside phosphorothioates: The nucleoside bicyclic oxazaphospholidines as novel synthons

Iyer, Radhakrishnan P.; Guo, Mao‐Jun; Yu, Dong; Agrawal, Sudhir

doi:10.1016/s0040-4039(98)00380-3

Cited by 55 publications

(25 citation statements)

References 11 publications

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“…1). It is only recently that methods of stereocontrolled chemical synthesis have been published, which, however, are by no means routine (Stec et al, 1998;Iyer et al, 1998). Enzy¬ matic incorporation of phosphorothioates by DNA or RNA polymerases, which exclusively accept the Sp-dNTPaS or SpNTPaS as substrates, respectively, always results in formation of the Rp configuration of the internucleotidic linkage (Eck¬ stein, 1985).…”

Section: Studies On Deoxycytidinementioning

confidence: 99%

Phosphorothioate Oligodeoxynucleotides: What Is Their Origin and What Is Unique About Them?

Eckstein

2000

Antisense and Nucleic Acid Drug Development

357

219

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The development of nucleoside phosphorothioates is described in its historical context. Examples of the interaction of phosphorothioate groups, present either in oligodeoxynucleotides or in DNA, with nucleases are presented. The structural features responsible for the resistance of the phosphorothioates toward degradation by nucleases are discussed, as are the possible reasons for the high-affinity interaction of phosphorothioate oligodeoxynucleotides with certain proteins.

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Section: Studies On Deoxycytidinementioning

confidence: 99%

Phosphorothioate Oligodeoxynucleotides: What Is Their Origin and What Is Unique About Them?

Eckstein

2000

Antisense and Nucleic Acid Drug Development

357

219

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“…These diastereomers do possess heterogeneous retention behavior leading to significant peak broadening (Agrawal, Tang, & Brown, ; Gilar et al, ; Metelev & Agrawal, ; Thayer, McCormick, & Avdalovic, ). To date, chromatographic methods have achieved limited success for the separation and characterization of PS therapeutic oligonucleotides except for short oligonucleotides with only two to six bases (Cummins, Winniman, & Gaus, ; Gaus, Owens, Winniman, Cooper, & Cummins, ; Iyer, Guo, Yu, & Agrawal, ; Kanehara, Mizuguchi, & Makino, ; Mayr, Holzl, Eder, Buchmeiser, & Huber, ; Murakami, Tamura, Wada, & Makino, ; Patil, Mane, & Salunkhe, ; Slim & Gait, ; Stec, Zon, & Uznanski, ; Tamura, Miyoshi, Yokota, Makino, & Murakami, ; Wilk & Stec, ). NMR and other methods based on optical rotation have also not demonstrated the ability to reliably resolve these mixtures (Furrer et al, ; Griffiths, Potter, & Eperon, ; Potter, Connolly, & Eckstein, ; Yu et al, ).…”

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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“…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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Solid-phase stereoselective synthesis of oligonucleoside phosphorothioates: The nucleoside bicyclic oxazaphospholidines as novel synthons

Cited by 55 publications

References 11 publications

Phosphorothioate Oligodeoxynucleotides: What Is Their Origin and What Is Unique About Them?

Phosphorothioate Oligodeoxynucleotides: What Is Their Origin and What Is Unique About Them?

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

P-Chiral Oligonucleotides in Biological Recognition Processes

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