Stereocontrolled Solid-Phase Synthesis of Phosphate/Phosphorothioate (PO/PS) Chimeric Oligodeoxyribonucleotides on an Automated Synthesizer Using an Oxazaphospholidine-Phosphoramidite Method.
Identifieur interne : 001015 ( Main/Exploration ); précédent : 001014; suivant : 001016Stereocontrolled Solid-Phase Synthesis of Phosphate/Phosphorothioate (PO/PS) Chimeric Oligodeoxyribonucleotides on an Automated Synthesizer Using an Oxazaphospholidine-Phosphoramidite Method.
Auteurs : Yohei Nukaga [Japon] ; Natsuhisa Oka [Japon] ; Takeshi Wada [Japon]Source :
- The Journal of organic chemistry [ 1520-6904 ] ; 2016.
Abstract
Stereocontrolled solid-phase synthesis of phosphate/phosphorothioate chimeric oligodeoxyribonucleotides (PO/PS-ODNs) was achieved by integrating the conventional phosphoramidite method into a previously developed oxazaphospholidine method for the stereocontrolled synthesis of P-chiral oligonucleotides. P-Stereodefined PO/PS-ODNs with mixed sequences (up to 12-mers) were obtained in good yields and high stereoselectivities by reacting different combinations of monomers (conventional phosphoramidites/diastereopure nucleoside 3'-O-oxazaphospholidines), activators (ETT/CMPT), capping reagents (Pac2O/CF3COIm), and oxidizing/sulfurizing reagents (TBHP/POS) on an automated synthesizer. A thermal denaturation study examined the resultant diastereopure PO/PS-ODN 12-mers with three consecutive (Rp)- or (Sp)-PS-linkages at the internal or terminal regions of the molecules. We found that (Rp)-PO/PS-ODNs can only moderately destabilize duplexes with complementary oligoribonucleotides (ORNs) compared with their unmodified ODN counterparts (ΔTm = -0.4 °C per modification). In contrast, (Sp)-PO/PS-ODNs have larger destabilizing effects (ΔTm = -1.2 to -0.8 °C per modification). Although smaller destabilizing effects were observed when the (Sp)-PS-linkages were incorporated into the terminal regions of the molecule, there was a weaker correlation between the location of an incorporated (Rp)-PS-linkage and its destabilizing effect.
DOI: 10.1021/acs.joc.5b02793
PubMed: 26939010
Affiliations:
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278-8510</wicri:noRegion></affiliation></author><author><name sortKey="Oka, Natsuhisa" sort="Oka, Natsuhisa" uniqKey="Oka N" first="Natsuhisa" last="Oka">Natsuhisa Oka</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University , 1-1 Yanagido, Gifu 501-1193, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University , 1-1 Yanagido, Gifu 501-1193</wicri:regionArea><wicri:noRegion>Gifu 501-1193</wicri:noRegion></affiliation></author><author><name sortKey="Wada, Takeshi" sort="Wada, Takeshi" uniqKey="Wada T" first="Takeshi" last="Wada">Takeshi Wada</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science , 2641 Yamazaki, Noda, Chiba 278-8510, Japan.</nlm:affiliation><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science , 2641 Yamazaki, Noda, Chiba 278-8510</wicri:regionArea><wicri:noRegion>Chiba 278-8510</wicri:noRegion></affiliation></author></analytic><series><title level="j">The Journal of organic chemistry</title><idno type="eISSN">1520-6904</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Stereocontrolled solid-phase synthesis of phosphate/phosphorothioate chimeric oligodeoxyribonucleotides (PO/PS-ODNs) was achieved by integrating the conventional phosphoramidite method into a previously developed oxazaphospholidine method for the stereocontrolled synthesis of P-chiral oligonucleotides. P-Stereodefined PO/PS-ODNs with mixed sequences (up to 12-mers) were obtained in good yields and high stereoselectivities by reacting different combinations of monomers (conventional phosphoramidites/diastereopure nucleoside 3'-O-oxazaphospholidines), activators (ETT/CMPT), capping reagents (Pac2O/CF3COIm), and oxidizing/sulfurizing reagents (TBHP/POS) on an automated synthesizer. A thermal denaturation study examined the resultant diastereopure PO/PS-ODN 12-mers with three consecutive (Rp)- or (Sp)-PS-linkages at the internal or terminal regions of the molecules. We found that (Rp)-PO/PS-ODNs can only moderately destabilize duplexes with complementary oligoribonucleotides (ORNs) compared with their unmodified ODN counterparts (ΔTm = -0.4 °C per modification). In contrast, (Sp)-PO/PS-ODNs have larger destabilizing effects (ΔTm = -1.2 to -0.8 °C per modification). Although smaller destabilizing effects were observed when the (Sp)-PS-linkages were incorporated into the terminal regions of the molecule, there was a weaker correlation between the location of an incorporated (Rp)-PS-linkage and its destabilizing effect. </div></front></TEI><affiliations><list><country><li>Japon</li></country></list><tree><country name="Japon"><noRegion><name sortKey="Nukaga, Yohei" sort="Nukaga, Yohei" uniqKey="Nukaga Y" first="Yohei" last="Nukaga">Yohei Nukaga</name></noRegion><name sortKey="Oka, Natsuhisa" sort="Oka, Natsuhisa" uniqKey="Oka N" first="Natsuhisa" last="Oka">Natsuhisa Oka</name><name sortKey="Wada, Takeshi" sort="Wada, Takeshi" uniqKey="Wada T" first="Takeshi" last="Wada">Takeshi Wada</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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