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Synthesis 2010(16): 2708-2712  
DOI: 10.1055/s-0030-1258170
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Efficient Synthesis of N 4-Methyl- and N 4-Hydroxycytidine Phosphoramidites

Jun Lu, Nan-Sheng Li, Selene C. Koo, Joseph A. Piccirilli*
Department of Biochemistry and Molecular Biology and Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA
Fax: +1(773)7020271; e-Mail: jpicciri@uchicago.edu;
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Publication History

Received 22 February 2010
Publication Date:
12 July 2010 (online)

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Abstract

Nucleotide analogues empower chemical biologists to investigate the relationship between RNA structure and function on a level deeper than would be possible using only the four natural nucleotides. N 4-Methylcytidine and N 4-hydroxycytidine represent two cytidine analogues whose physicochemical properties enable biochemical tests for specific aspects of cytidine function within RNA. Here, we describe an efficient synthesis of N 4-methylcytidine and N 4-hydroxycytidine derivatives, and their corresponding phosphoramidites in 40.7% and 25.2% yield, respectively, starting from uridine. These phosphoramidites couple efficiently during solid-phase synthesis, although N 4-hydroxycytidine reverts partially to cytidine (5-10%) during oligonucleotide synthesis and deprotection.

Key words

N 4-methylcytidine - N 4-hydroxycytidine - nucleotides - phosphoramidites - oligonucleotides

    References

  • 1a Fazakerley GV. Kraszewski A. Teoule R. Guschlbauer W. Nucleic Acids Res.  1987,  15:  2191 
    Google Scholar
  • 1b Ono A. Ueda T. Nucleic Acids Res.  1987,  15:  219 
    Google Scholar
  • 1c Butkus V. Klimasauskas S. Petrauskiene L. Maneliene Z. Janulaitis A. Minchenkova LE. Schyolkina AK. Nucleic Acids Res.  1987,  15:  8467 
    Google Scholar
  • 2 Grasby JA. Singh M. Karn J. Gait MJ. Nucleosides Nucleotides  1995,  14:  1129 
    CrossrefGoogle Scholar
  • 3a Brown DM. Hewlins MJE. Schell P. J. Chem. Soc. C  1968,  1925 
    Google Scholar
  • 3b Dreyfus M. Bensaude O. Dodin G. Dubois JE. J. Am. Chem. Soc.  1976,  98:  6338 
    Google Scholar
  • 3c Les A. Adamowicz L. Rode W. Biochim. Biophys. Acta  1993,  1173:  39 
    Google Scholar
  • 3d Shugar D. Huber C. Birnbaum G. Biochim. Biophys. Acta  1976,  447:  274 
    Google Scholar
  • 3e Moriyama K. Okada T. Negishi K. In Recent Research Developments in Organic and Bioorganic Chemistry   Vol. 5:  Loakes D. Transworld Research Network; Kerala / India: 2002.  p.152-161  
    Google Scholar
  • 3f Suzuki T. Moriyama K. Otsuka C. Loakes D. Negishi K. Nucleic Acids Res.  2006,  34:  6438 
    Google Scholar
  • 3g Negishi K. Bessho T. Hayatsu H. Mutat. Res.  1994,  318:  227 
    Google Scholar
  • 3h Harris VH. Smith CL. Cummins WJ. Hamilton AL. Adams H. Dickman M. Hornby DP. Williams DM. J. Mol. Biol.  2003,  326:  1389 
    Google Scholar
  • 4a Saladino R. Crestini C. Bernini R. Frachey G. Mincione E. J. Chem. Soc., Perkin Trans. 1  1994,  3053 
    Google Scholar
  • 4b Saladino R. Mincione E. Crestini C. Mezzetti M. Tetrahedron  1996,  52:  6759 
    Google Scholar
  • 4c Yakovlev DY. Simukova NA. Budowsky EI. Chekhov VO. Savin FA. Morozov YV. J. Photochem.  1982,  20:  253 
    Google Scholar
  • 5 Mahto SK. Chow CS. Bioorg. Med. Chem.  2008,  16:  8795 
    CrossrefGoogle Scholar
  • 6 Miah A. Reese CB. Song Q. Nucleosides Nucleotides  1997,  16:  53 
    CrossrefGoogle Scholar
  • 7 Zhang J. Chang H.-M. Kane RR. Synlett  2001,  643 
    Google Scholar
  • 8a Wempen I. Miller N. Falco EA. Fox JJ. J. Med. Chem.  1968,  11:  144 
    Google Scholar
  • 8b Simukova NA. Yakovlev DY. Budowsky EI. Nucleic Acids Res.  1975,  2:  2269 
    Google Scholar
  • 9 Felczak K. Miazga A. Poznański J. Bretner M. Kulikowski T. Dzik JM. Goos B. Zieliński Z. Cieśla J. Rode W. J. Med. Chem.  2000,  43:  4647 
    CrossrefGoogle Scholar
  • 10 Kanai T. Ichino M. J. Med. Chem.  1974,  17:  1076 
    CrossrefGoogle Scholar
  • 11a Iion T. Yoshimura Y. Matsuda A. Tetrahedron  1994,  50:  10397 
    Google Scholar
  • 11b Li N.-S. Piccirilli JA. J. Org. Chem.  2007,  72:  1198 
    Google Scholar
  • 12 Saito Y. Nyilas A. Agrofoglio LA. Carbohydr. Res.  2001,  331:  83 
    CrossrefGoogle Scholar
  • 13 Furusawa K. Ueno K. Katsura T. Chem. Lett.  1990,  97 
    CrossrefGoogle Scholar
  • 14 Ding Y. Girardet JL. Hong Z. Lai VCH. An H. Koh YH. Shaw SZ. Zhong W. Bioorg. Med. Chem. Lett.  2005,  15:  709 
    CrossrefGoogle Scholar
  • 15 Trost BM. Caldwell CG. Tetrahedron Lett.  1981,  22:  4999 
    CrossrefGoogle Scholar
  • 16 Jones SS. Reese CB. J. Chem. Soc., Perkin Trans. 1  1979,  2762 
    CrossrefGoogle Scholar
  • 17 Sun S. Yoshida A. Piccirilli JA. RNA  1997,  3:  1352 
    Google Scholar
  • 18 Wincott F. DiRenzo A. Shaffer C. Grimm S. Tracz D. Workman C. Sweedler D. Gonzalez C. Scaringe S. Usman N. Nucleic Acids Res.  1995,  23:  2677 
    CrossrefGoogle Scholar
  • 19 Ochiai E. J. Org. Chem.  1953,  18:  534 
    CrossrefGoogle Scholar