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RNA Bioisosteres: Chemistry and Properties of 4′-thioRNA and 4′-selenoRNA

  • Noriaki Minakawa
  • Noriko Saito-Tarashima
  • Akira Matsuda
Chapter

Abstract

The design and synthesis of nucleic acid-based therapeutics is one of the most promising approaches to drug development and disease therapy. In order to develop agents with improved nuclease resistance and hybridization ability, a large number of chemically modified oligonucleotides (ONs), especially RNA analogs, have been designed and prepared. However, this has led to ONs with overly complex structures, resulting in a lack of biocompatibility with natural RNA. With this in mind, 4′-thioRNA, which has a sulfur atom in place of the furanose ring oxygen, was proposed as a natural RNA bioisostere. The building blocks for 4′-thioRNA, i.e., 4′-thioribonucleosides, were prepared stereoselectively via the Pummerer reaction between a silylated nucleobase and the corresponding sulfoxide, which was obtained from a 4-thiosugar. The resulting 4′-thioRNA exhibited sufficient hybridization ability and nuclease resistance, as well as biocompatibility with natural RNA, and was used effectively as a chemically modified siRNA and for isolation of 4′-thioRNA aptamers. Current progress in the development of a new RNA bioisostere 4′-selenoRNA, which contains a selenium atom, is also described.

Keywords

RNA bioisostere RNA analog 4′-thioRNA 4′-selenoRNA RNA interference SiRNA RNA aptamer 

Notes

Acknowledgement

We thank all of our colleagues, especially Mr. T. Naka, Dr. S. Hoshika, Dr. M. Takahashi and Ms. Y. Kato (Hokkaido University), and Mr. H. Taniike, Mr. K. Hayashi and Mr. K. Ishii (Tokushima University), who contributed to the studies described here. This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS).

References

  1. 1.
    Bellon L, Barascut JL, Maury G et al (1993) 4-Thio-oligo-β-D-ribonucleotides: synthesis of β -4′-thio-oligouridylates, nuclease resistance, base pairing properties, and interaction with HIV-1 reverse transcriptase. Nucleic Acids Res 21:1587–1593Google Scholar
  2. 2.
    Bobek M, Bloch A, Parthasarathy R et al (1975) Synthesis and biological activity of 5-fluoro-4′-thiouridine and some related nucleosides. J Med Chem 18:784–787Google Scholar
  3. 3.
    Bock LC, Griffin LC, Latham JA et al (1992) Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature 355:564–566Google Scholar
  4. 4.
    Cummins LL, Owens SR, Risen LM et al (1995) Characterization of fully 2′-modified oligoribonucleotide hetero- and homoduplex hybridization and nuclease sensitivity. Nucleic Acids Res 23:2019–2024Google Scholar
  5. 5.
    Elbashir SM, Harborth J, Lendeckel W et al (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498Google Scholar
  6. 6.
    Esau CC (2008) Inhibition of microRNA with antisense oligonucleotides. Methods 44:55–60Google Scholar
  7. 7.
    Hoshika S, Minakawa N, Kamiya H et al (2005) RNA interference induced by siRNAs modified with 4′-thioribonucleosides in cultured mammalian cells. FEBS Lett 579:3115–3118Google Scholar
  8. 8.
    Hoshika S, Minakawa N, Matsuda A (2004) Synthesis and physical and physiological properties of 4′-thioRNA: application to post-modification of RNA aptamer toward NF-κB. Nucleic Acids Res 32:3815–3825Google Scholar
  9. 9.
    Hoshika S, Minakawa N, Shionoya A et al (2007) Study of modification pattern–RNAi activity relationships by using siRNAs modified with 4′-thioribonucleosides. ChemBiochem 8:2133–2138Google Scholar
  10. 10.
    Imanishi T, Obika S (2002) BNAs: novel nucleic acid analogs with a bridged sugar moiety. Chem Commun 0:1653–1659Google Scholar
  11. 11.
    Inagaki Y, Minakawa N, Matsuda A (2007) Synthesis of 4′-selenoribo nucleosides. Nucleic Acids Symp Ser 51:139–140Google Scholar
  12. 12.
    Inagaki Y, Minakawa N, Matsuda A (2008) Synthesis and properties of oligonucleotides containing 4′-selenoribonucleosides. Nucleic Acids Symp Ser 52:329–330Google Scholar
  13. 13.
    Ishii K, Saito-Tarashima N, Ota M et al (2016) Practical synthesis of 4′-selenopurine nucleosides by combining chlorinated purines and ‘armed’ 4-selenosugar. Tetrahedron 72:6589–6594Google Scholar
  14. 14.
    Jayakanthan K, Johnston BD, Pinto BM (2008) Stereoselective synthesis of 4′-selenonucleosides using the Pummerer glycosylation reaction. Carbohydr Res 343:1790–1800Google Scholar
  15. 15.
    Jayasena SD (1999) Aptamers: an emerging class of molecules that rival antibodies in diagnostics. Clin Chem 45:1628–1650Google Scholar
  16. 16.
    Jeong LS, Tosh DK, Kim HO et al (2008) First synthesis of 4′-selenonucleosides showing unusual Southern conformation. Org Lett 10:209–212Google Scholar
  17. 17.
    Kato Y, Minakawa N, Komatsu Y et al (2005) New NTP analogs: the synthesis of 4′-thioUTP and 4′-thioCTP and their utility for SELEX. Nucleic Acids Res 33:2942–2951Google Scholar
  18. 18.
    Kawasaki AM, Casper MD, Freier SM et al (1993) Uniformly modified 2′-deoxy-2′-fluoro-phosphorothioate oligonucleotides as nuclease-resistant antisense compounds with high affinity and specificity for RNA targets. J Med Chem 36:831–841Google Scholar
  19. 19.
    Kubik MF, Stephens AW, Schneider D et al (1994) High-affinity RNA ligands to human α-thrombin. Nucleic Acids Res 22:2619–2626Google Scholar
  20. 20.
    Kurreck J (2003) Antisense technologies. Improvement through novel chemical modifications. Eur J Biochem 270:1628–1644Google Scholar
  21. 21.
    Lesnik EA, Guinosso CJ, Kawasaki AM et al (1993) Oligodeoxynucleotides containing 2′-O-modified adenosine: synthesis and effects on stability of DNA:RNA duplexes. Biochemistry 32:7832–7838Google Scholar
  22. 22.
    Leydier C, Bellon L, Barascut J-L et al (1995) 4′-thio-RNA: synthesis of mixed base 4′-thiooligoribonucleotides, nuclease resistance, and base pairing properties with complementary single and double strand. Antisense Res Develop 5:167–174Google Scholar
  23. 23.
    Manoharan M (2004) RNA interference and chemically modified small interfering RNAs. Curr Opin Chem Biol 8:570–579Google Scholar
  24. 24.
    Manoharan M, Akinc A, Pandey RK, Antisense Research and Development (2011) Unique gene-silencing and structural properties of 2′-fluoro-modified siRNAs. Angew Chem Int Ed 50:2284–2288Google Scholar
  25. 25.
    Minakawa N, Sanji M, Kato Y et al (2008) Investigations toward the selection of fully-modified 4′-thioRNA aptamers: optimization of in vitro transcription steps in the presence of 4′-thioNTPs. Bioorg Med Chem 16:9450–9456Google Scholar
  26. 26.
    Naka T, Minakawa N, Abe H et al (2000) The stereoselective synthesis of 4′-β-thioribonucleosides via the Pummerer reaction. J Am Chem Soc 122:7233–7243Google Scholar
  27. 27.
    Naka T, Nishizono N, Minakawa N et al (1999) Nucleosides and nucleotides. 189. Investigation of the stereoselective coupling of thymine with meso-thiolane-3,4-diol-1-oxide derivatives via the pummerer reaction. Tetrahedron Lett 40:6297–6300Google Scholar
  28. 28.
    Ng EW, Shima DT, Calias P et al (2006) Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov 5:123–132Google Scholar
  29. 29.
    Obika S, Rahman SMA, Fujisaka A et al (2010) Bridged nucleic acids: development, synthesis and properties. Heterocycles 81:1347–1392Google Scholar
  30. 30.
    Ono T, Scalf M, Smith LM (1997) 2′-Fluoro modified nucleic acids: polymerase-directed synthesis, properties and stability to analysis by matrix-assisted laser desorption/ionization mass spectrometry. Nucleic Acids Res 25:4581–4588Google Scholar
  31. 31.
    Osborne SE, Ellington AD (1997) Nucleic acid selection and the challenge of combinatorial chemistry. Chem Rev 97:349–370Google Scholar
  32. 32.
    Pagratis NC, Bell C, Chang Y-F et al (1997) Potent 2′-amino-, and 2′-fluoro-2′- deoxyribonucleotide RNA inhibitors of keratinocyte growth factor. Nat Biotech 15:68–73Google Scholar
  33. 33.
    Prakash TP (2011) An overview of sugar-modified oligonucleotides for antisense therapeutics. Chem Biodivers 8:1616–1641Google Scholar
  34. 34.
    Reist EJ, Gueffroy DE, Goodman L (1964) Synthesis of 4-thio- D- and -L-ribofuranose and the corresponding adenine nucleosides. J Am Chem Soc 86:5658–5663Google Scholar
  35. 35.
    Saito Y, Hashimoto Y, Arai M et al (2014) Chemistry, properties, and in vitro and in vivo applications of 2′-O-methoxyethyl-4′-thioRNA, a novel hybrid type of chemically modified RNA. ChemBiochem 15:2535–2540Google Scholar
  36. 36.
    Takahashi M, Minakawa N, Matsuda A (2009) Synthesis and characterization of 2′-modified-4′-thioRNA: a comprehensive comparison of nuclease stability. Nucleic Acids Res 37:1353–1362Google Scholar
  37. 37.
    Takahashi M, Nagai C, Hatakeyama H et al (2012) Intracellular stability of 2′-OMe-4′-thioribonucleoside modified siRNA leads to long-term RNAi effect. Nucleic Acids Res 40:5787–5793Google Scholar
  38. 38.
    Takahashi M, Yamada N, Hatakeyama H et al (2013) In vitro optimization of 2′-OMe-4′-thioribonucleoside-modified anti-microRNA oligonucleotides and its targeting delivery to mouse liver using a liposomal nanoparticle. Nucleic Acids Res 41:10659–10667Google Scholar
  39. 39.
    Taniike H, Inagaki Y, Matsuda A et al (2011) Practical synthesis of 4′-selenopyrimidine nucleosides using hypervalent iodine. Tetrahedron 67:7977–7982Google Scholar
  40. 40.
    Tarashima N, Hayashi K, Terasaki M et al (2014) First synthesis of fully modified 4′-selenoRNA and 2′-OMe-4′-selenoRNA based on the mechanistic considerations of an unexpected strand break. Org Lett 16:4710–4713Google Scholar
  41. 41.
    Thomas GS, Cromwell WC, Ali S et al (2013) Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol 62:2178–2184Google Scholar
  42. 42.
    Wahlestedt C, Salmi P, Good L et al (2000) Potent and nontoxic antisense oligonucleotides containing locked nucleic acids. Proc Natl Acad Sci U S A 97:5633–5638Google Scholar
  43. 43.
    Wan WB, Seth PP (2016) The medicinal chemistry of therapeutic oligonucleotides. J Med Chem 59:9645–9667Google Scholar
  44. 44.
    Watts JK, Johnston BD, Jayakanthan K et al (2008) Synthesis and biophysical characterization of oligonucleotides containing a 4′-selenonucleotide. J Am Chem Soc 130:8578–8579Google Scholar
  45. 45.
    Wengel J, Petersen M, Nielsen KE et al (2001) LNA (locked nucleic acid) and the diastereoisomeric α-L-LNA: conformational tuning and high-affinity recognition of DNA/RNA targets. Nucleosides Nucleotides Nucleic Acids 20:389–396Google Scholar
  46. 46.
    Yu J, Kim JH, Lee HW et al (2013) New RNA purine building blocks, 4′-selenopurine nucleosides: first synthesis and unusual mixture of sugar puckerings. Chem Eur J 19:5528–5532Google Scholar
  47. 47.
    Zimmermann TS, Lee AC, Akinc A et al (2006) RNAi-mediated gene silencing in non-human primates. Nature 441:111–114Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Noriaki Minakawa
    • 1
  • Noriko Saito-Tarashima
    • 1
  • Akira Matsuda
    • 2
  1. 1.Graduate School of Pharmaceutical ScienceTokushima UniversityTokushimaJapan
  2. 2.Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical SciencesHokkaido UniversitySapporoJapan

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