Download PDF
Synlett 2008(14): 2175-2177  
DOI: 10.1055/s-2008-1078249
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Mucin Glycans from the Protozoon Parasite Trypanosoma cruzi

Renate M. van Wella, Beatrice Y. M. Colleta, Robert A. Field*a,b
a School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK
b Department of Biological Chemistry, John Innes Centre, Colney Lane, Norwich NR4 7UH, UK
Fax: +44(1603)450018; e-Mail: rob.field@bbsrc.ac.uk;
Further Information

Publication History

Received 2 June 2008
Publication Date:
05 August 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

A short, blockwise, 2+2-glycosylation approach to the synthesis of a tetrasaccharide component of Trypanosoma cruzi mucin is reported. Despite the use of a 1,2-linked disaccharide donor, high yield (79%) and good stereocontrol (>10:1, β:α) were achieved in the key glycosylation step. Preliminary studies indicate that this branched tetrasaccharide can serve as a substrate for enzymatic sialylation by the parasite cell surface trans-sialidase.

Key words

oligosaccharide - synthesis - parasite - mucin - trans-sialidase - drug target

    References and Notes

  • 2 Spiro RG. Glycobiology  2002,  12:  43R 
    CrossrefGoogle Scholar
  • 3 Buscaglia CA. Campo VA. Frasch ACC. DiNoia JM. Nature Rev. Microbiol.  2006,  4:  229 
    Google Scholar
  • 4a Schenkman S. Jiang M.-S. Hart GW. Nussenzweig V. Cell  1991,  65:  1117 
    Google Scholar
  • 4b Cross GAM. Takle GB. Annu. Rev. Microbiol.  1993,  47:  385 ; and citations thereof
    Google Scholar
  • 5 Ferguson MAJ. Brimacombe JS. Cottaz S. Field RA. Guther LS. Homans SW. McConville MJ. Mehlert A. Milne KG. Ralton JE. Roy YA. Schneider P. Zitzmann N. Parasitology  1994,  108:  S45 
    CrossrefGoogle Scholar
  • For instance, see:
  • 6a Damager I. Buchini S. Amaya MF. Buschiazzo A. Alzari P. Frasch AC. Watts A. Withers SG. Biochemistry  2008,  47:  3507 
    Google Scholar
  • 6b Blume A. Neubacher B. Thiem J. Peters T. Carbohydr. Res.  2007,  342:  1904 
    Google Scholar
  • 6c Amaya MF. Watts AG. Damager I. Wehenkel A. Nguyen T. Buschiazzo A. Paris G. Frasch AC. Withers SG. Alzari PM. Structure  2004,  12:  775 
    Google Scholar
  • 6d Haselhorst T. Wilson JC. Liakatos A. Kiefel MJ. Dyason JC. von Itzstein M. Glycobiology  2004,  14:  895 
    Google Scholar
  • 6e Watts AG. Damager I. Amaya ML. Buschiazzo A. Alzari P. Frasch AC. Withers SG. J. Am. Chem. Soc.  2003,  125:  7532 
    Google Scholar
  • For representative examples, see:
  • 7a Agusti R. Giorgi ME. de Lederkremer RM. Carbohydr. Res.  2007,  342:  2465 
    Google Scholar
  • 7b Kroeger L. Scudlo A. Thiem J. Adv. Synth. Catal.  2006,  348:  1217 
    Google Scholar
  • 7c Neubacher B. Schmidt D. Ziegelmuller P. Thiem J. Org. Biomol. Chem.  2005,  3:  1551 
    Google Scholar
  • 7d Turnbull WB. Harrison JA. Kartha KPR. Schenkman S. Field RA. Tetrahedron  2002,  58:  3207 
    Google Scholar
  • 7e Singh S. Scigelova M. Hallberg ML. Howarth OW. Schenkman S. Crout DHG. Chem. Commun.  2000,  1013 
    Google Scholar
  • 7f Probert MA. Milton MJ. Harris R. Schenkman S. Brown JM. Homans SW. Field RA. Tetrahedron Lett.  1997,  38:  5861 
    Google Scholar
  • 8 Harrison JA. Kartha KPR. Turnbull WB. Scheuerl SL. Naismith JH. Schenkman S. Field RA. Bioorg. Med. Chem. Lett.  2001,  11:  141 
    Google Scholar
  • 9a Harris R. Kiddle GR. Field RA. Milton MJ. Ernst B. Magnani JL. Homans SW. J. Am. Chem. Soc.  1999,  121:  2546 
    Google Scholar
  • 9b Milton MJ. Harris R. Probert MA. Field RA. Homans SW. Glycobiology  1998,  8:  147 
    Google Scholar
  • 10 Islam T. von Itzstein M. Adv. Chem. Biochem.  2008,  61:  292 
    Google Scholar
  • 11 Neres J. Bryce RA. Douglas KT. Drug Discov. Today  2008,  13:  110 
    CrossrefGoogle Scholar
  • For instance, see:
  • 12a Agusti R. Giorgi ME. Mendoza VM. Gallo-Rodriguez C. de Lederkremer RM. Bioorg. Med. Chem.  2007,  15:  2611 
    Google Scholar
  • 12b Mendoza VM. Agusti R. Gallo-Rodriguez C. de Lederkremer RM. Carbohydr. Res.  2006,  341:  1488 
    Google Scholar
  • 12c Agusti R. Mendoza VM. Gallo-Rodriguez C. de Lederkremer RM. Tetrahedron: Asymmetry  2005,  16:  541 ; and references cited therein
    Google Scholar
  • 13 Campo VL. Carvalho I. Allman S. Davis BG. Field RA. Org. Biomol. Chem.  2007,  5:  2645 
    Google Scholar
  • 14 Previato JO. Jones C. Xavier MT. Wait R. Travassos LR. Parodi A. Mendonca-Previato L. J. Biol. Chem.  1995,  270:  7241 
    Google Scholar
  • 15 Bongat AFG. Demchenko AV. Carbohydr. Res.  2007,  342:  374 
    CrossrefGoogle Scholar
  • 17 Byramova NE. Ovchinnikov MV. Backinowsky LV. Kochetkov NK. Carbohydr. Res.  1983,  124:  C8 
    CrossrefGoogle Scholar
  • 18a Doboszewski B. Zamojski A. Carbohydr. Res.  1984,  132:  29 
    Google Scholar
  • 18b Nepogodiev SA. Backinowsky LV. Grzeszczyk B. Zamojski A. Carbohydr. Res.  1994,  254:  43 
    Google Scholar
  • 19 Schmidt RR. Kinzy W. Adv. Carbohydr. Chem. Biochem.  1994,  50:  21 
    PubMedGoogle Scholar
  • 20 Fujiwara T. Arai K. Carbohydr. Res.  1980,  87:  11 
    CrossrefGoogle Scholar
  • 21a Schmidt RR. Behrendt M. Toepfer A. Synlett  1990,  694 
    Google Scholar
  • 21b Braccini I. Derouet C. Esnault J. Herve du Penhoat C. Mallet J.-M. Michon V. Sinay P. Carbohydr. Res.  1993,  246:  23 
    Google Scholar
  • 24 Winans KA. King DS. Rao VR. Bertozzi CR. Biochemistry  1999,  38:  11700 
    CrossrefPubMedGoogle Scholar
1

http://www.who.int/topics/chagas_disease/en/.

Scheme 3 Action of recombinant T. cruzi trans-sialidase on synthetic mucin tetrasaccharide 1. [7d]

16

The studies reported herein have been conducted in parallel with efforts that replace the reducing terminal N-acetyl-glucosamine unit with mannose, which offers more straightforward entry to an α-linked amino acid-glycan linkage.

22

In the parallel series with a mannose at the reducing terminus, the corresponding coupling gave complete
β-stereocontrol albeit in lower yield (54%).

23

Selected Analytical Data
Imidate 3: [α]D ²0 +41.0 (c 1, CHCl3). ¹H NMR (400MHz, CDCl3): δ = 8.65 (s, 1 H, NH), 6.51 (d, 1 H, H1, J 1,2 = 3.6 Hz), 4.66 (d,1 H, H1′, J 1 ′ ,2 ′ = 7.8 Hz). ¹³C NMR (100 MHz, CDCl3): δ = 160.7 (C=NH), 101.3 (C1′), 94.9 (C1). HRMS: m/z calcd for C28O18NCl3H36 [M + NH4]: 797.1336; found: 797.1339.
Tetrasaccharide 5: [α]D ²0 -4.0 (c 1 in CHCl3). ¹H NMR (600 MHz, CDCl3): δ = 4.78 (d, 1 H, H1c, J 1,2 = 8.0 Hz), 4.70 (d, 1 H, H1a, J 1,2 = 10.0 Hz), 4.60 (d, 1 H, H1b, J 1,2 = 7.7 Hz), 4.55 (d, 1 H, H1d, J 1,2 = 7.9 Hz). ¹³C NMR (100 MHz, CDCl3): δ = 101.7 (C1b), 100.9 (C1c), 100.3 (C1d), 85.5 (C1a). MS (ES): m/z = 1372.5 [M + Na]+.
Tetrasaccharide 1: [α]D ²0 +15.0 (c 1 in H2O). ¹H NMR, (400 MHz, D2O): δ = 4.87 (d, 1 H, H1a, J 1,2 = 10.4 Hz), 4.37 (d, 1 H, H1b, J 1,2 = 6.8 Hz), 4.34 (d, 1 H, H1c, J 1,2 = 8.0 Hz), 4.31 (d, 1 H, H1d, J 1,2 = 7.9 Hz). ¹³C NMR (75 MHz, D2O): δ = 175.1 (C=ONHAc), 104.2 (C1c), 103.8 (C1d), 102.2 (C1b), 85.9 (C1a). HRMS: m/z calcd for C32H49N3O20S [M + Na]+: 822.2461; found: 822.2487.