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Synlett 2003(9): 1323-1326
DOI: 10.1055/s-2003-40351
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Neomycin Analogs to Investigate Aminoglycoside-RNA Interactions

Peter H. Seeberger*a, Michael Baumanna,, Guangtao Zhanga,, Takuya Kanemitsua, Eric E. Swayzeb, Steven A. Hofstadlerb, Richard H. Griffeyb
a Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge MA 02139, USA
Fax: +1(617)2537929; e-Mail: seeberg@mit.edu;
b Ibis Therapeutics, 2292 Faraday Avenue, Carlsbad, CA 92008
Further Information

Publication History

Received 28 May 2003
Publication Date:
30 June 2003 (online)

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Abstract

A series of novel aminoglycoside oligosaccharide analogs containing a 2,5-dideoxystreptamine core scaffold was prepared to study aminoglycoside binding to the small subunit of 16S rRNA. A set of monosaccharide building blocks carrying amino groups in different positions and conformations around the pyranose ring was utilized in the assembly of oligosaccharides. These aminoglycoside analogs were analyzed for their RNA-binding capacity using a high throughput mass spectroscopy assay.

Key words

aminoglycosides - antibiotics - oligosaccharides - RNA-targeting

    References

  • 1a

    Present address: Aventis Pharma Deutschland GmbH, 65926 Frankfurt, Germany

  • 1b

    Present address: Provid Pharmaceuticals, Piscataway, NJ 08854, USA

  • 2 Pearson ND. Prescott CD. Chem. Biol.  1997,  4:  409 
    CrossrefGoogle Scholar
  • 3 Baumann M. Bischoff H. Schmidt D. Griesinger C. J. Med. Chem.  2001,  44:  2172 
    CrossrefGoogle Scholar
  • 4 Michael K. Tor Y. Chem.-Eur. J.  1998,  4:  2091 
    Google Scholar
  • 5 Stage TK. Hertel KJ. Uhlenbeck OC. RNA  1995,  1:  95 
    Google Scholar
  • 6 Sears P. Wong C.-H. Angew. Chem. Int. Ed.  1999,  38:  2300 
    Google Scholar
  • 7 Hendrix M. Priestley ES. Joyce GF. Wong C.-H. J. Am. Chem. Soc.  1997,  119:  3641 
    Google Scholar
  • 8 Tor Y. Hermann T. Westhof E. Chem. Biol.  1985,  5:  277 
    Google Scholar
  • 9 Carter AP. Clemons WM. Brodersen DE. Morgan-Warren RJ. Wimberly BT. Ramakrishnan V. Nature  2000,  407:  340 
    CrossrefGoogle Scholar
  • 10 Alper PB. Hendrix M. Sears P. Wong CH. J. Am. Chem. Soc.  1998,  120:  1965 
    CrossrefGoogle Scholar
  • 11 Kavadias G. Velkof S. Belleau B. Can. J. Chem.  1978,  56:  404 
    Google Scholar
  • 12a Vasella A. Witzig C. Chiara JL. Martin-Lomas M. Helv. Chim. Acta  1991,  74:  2073 
    CrossrefGoogle Scholar
  • 12b Lemieux R. Cushley S. Can. J. Chem.  1963,  43:  858 
    CrossrefGoogle Scholar
  • 12c Baeschlin DK. Chaperon AR. Green LG. Hahn MG. Ince SJ. Ley SV. Chem.-Eur. J.  2000,  6:  172 
    CrossrefGoogle Scholar
  • 12d Contour MO. Deaye J. Little M. Wong E. Carbohydr. Res.  1989,  193:  283 
    CrossrefGoogle Scholar
  • 14 Greenberg WA. Priestley ES. Sears PS. Alper PB. Rodenbohm C. Hendrix M. Hung S.-C. Wong C. J. Am. Chem. Soc.  1999,  121:  6527 
    CrossrefGoogle Scholar
  • 15 Garegg PJ. Adv. Carbohydr. Chem. Biochem.  1997,  52:  179 
    PubMedGoogle Scholar
  • 17 Deprotection. General procedure. Protected di- or trisaccharide (0.052 mmol) was dried 48 h at high vacuum, dissolved in MeOH (5 mL) and stirred at room temperature with Pd(OH2)/C (60 mg) while bubbling hydrogen through the mixture. After 5 h AcOH (2 mL, 50% aqueous) was added to the solution and the mixture was hydrogenated for an additional 2 h. The catalyst was filtered off and the solvent was removed under reduced pressure. The residue was dissolved in water (5 mL) and freeze dried to afford the deprotected aminoglycoside.
  • 18 Hofstadler SA. Griffey RH. Chem. Rev.  2001,  101:  377 
    CrossrefGoogle Scholar
13

7: Rf = 0.81 (hexanes-EtOAc, 1:1); 1H NMR (300 MHz, CDCl3): δ = 7.40-7.28 (m, 10 H), 5.25 (d, J = 3.0 Hz, 1 H), 4.83 (dd, J = 10.1, 10.1 Hz, 2 H), 4.79 (dd, J = 10.2, 10.2 Hz, 2 H), 4.51 (d, J = 9.4 Hz, 1 H), 4.44 (dd, J = 6.3, 10.2 Hz, 1 H), 4.27 (dd, J = 6.8, 10.4 Hz, 1 H), 3.91 (dd, J = 6.6, 6.6 Hz, 1 H), 3.69 (dd, J = 3.0, 9.3 Hz, 1 H), 3.58 (dd, J = 9.4, 9.4 Hz, 1 H), 3.07 (s, 3 H), 3.03 (s, 3 H), 2.75 (m, 2 H), 1.32 (t, J = 7.4 Hz, 3 H); 13C NMR (75 MHz, CD3Cl): δ = 137.7, 137.0, 128.8, 128.6, 128.5, 128.4, 128.2, 85.9, 80.5, 76.1, 76.0, 74.1, 73.6, 67.1, 39.4, 37.8, 25.5, 15.5; HRMS (FAB+) Calcd for m/z C24H32O9S3Na [(M + Na)+] 583.1106, found 583.1112. 9: Rf = 0.38 (hexanes-EtOAc, 1:1); 1H NMR (300 MHz, CDCl3): δ = 7.41 -7.30 (m, 10 H), 4.90 (dd, J = 11.1, 11.1 Hz, 2 H), 4.57 (dd, J = 11.1,11.1 Hz, 2 H), 4.32 (d, J = 9.5 Hz, 1 H), 3.74 (dd, J = 2.3, 4.5 Hz, 1 H), 3.78-3.65 (m, 2 H), 3.44 (dd, J = 4.7, 9.6 Hz, 1 H), 3.38 (dd, J = 6.7, 6.7 Hz, 1 H), 3.36 (m, 1 H), 2.82 (br s, 1 H), 2.75 (m, 2 H), 1.32 (t, J = 7.4 Hz, 3 H); 13C NMR (75 MHz, CD3Cl): δ = 138.2, 137.8, 128.8, 128.7, 128.4, 128.3, 128.1, 128.0, 84.7, 84.5, 78.0, 75.5, 73.9, 72.6, 70.7, 65.6, 24.9, 15.3; HRMS (FAB+) Calcd for m/z C22H27N3O4SNa [(M + Na)+] 452.1619, found 552.1624. 10: Rf = 0.53 (hexanes-Et2O, 1:2); 1H NMR (300 MHz, CDCl3): δ = 7.40-7.32 (m, 10 H), 4.72 (dd, J = 11.6, 11.6 Hz, 2 H), 4.57 (s, 2 H), 4.24 (d, J = 10.3 Hz, 1 H), 4.08 (d, J = 3.2 Hz, 1 H), 3.77-3.67 (m, 2 H), 3.54 (dd, J 1 = 7.1, 7.1 Hz, 1 H), 3.40 (dd, J = 3.1, 9.4 Hz, 1 H), 2.75 (m, 2 H), 1.31 (t, J = 7.2 Hz, 3 H); 13C NMR (75 MHz, CD3Cl): δ =138.0, 137.2, 128.8, 128.7, 128.5, 128.3, 128.1, 128.0, 84.2, 81.3, 77.2, 73.9, 72.1, 69.4, 65.8, 62.1, 24.6, 15.2; HRMS (FAB+) Calcd for m/z C22H27N3O4SNa [(M + Na)+] 452.1619, found 552.1634.

16

Glycosylation. General procedure. Thioethyl glycoside (0.1 mmol) and acceptor 2 (0.1 mmol) were coevaporated with toluene and dried under vacuum. Et2O (1.5 mL), CH2Cl2 (0.5 mL), toluene (0.2 mL), and 4 Å MS (40 mg) were added and the mixture was cooled to -40 °C. Addition of NIS (0.071 mmol) and AgOTf (0.020 mmol) followed. The mixture was stirred for 5 h at -40 °C, EtOAc (20 mL) was added and the filtrate was washed with Na2S2O3 (5% aqueous, 5 mL) and dried over MgSO4. After removal of the solvents, the residue was purified by silica gel column chromatography to afford the disaccharides as two diastereomers.