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Prof. Opatz: Synthesis of 1,3-Diglycosylindoles and their use as Glycomimetics for Selectin Inhibition
Prof. Dr. Till Opatz's group conducts research in the following fields: α-aminonitriles as building blocks, synthesis and research of natural products, glycosylated templates as potential saccharide mimetics. We thank Prof. Opatz for providing this article.
Diglycosylindoles as Trisaccharide Mimetics Research Article
Synthesis of 1,3-Diglycosylindoles and their use as Glycomimetics for Selectin Inhibition
Jens Langhanki, Christine Wiebe, Claudine Schlemmer, Dorota Ferenc, Danuta Kowalczyk, Stefanie Wedepohl, Patrick Ziegelmüller, Jens Dernedde, Stefan Weck, Silvia Fusté de la Sotilla, and Till Opatz*
Prof. Dr. Till Opatz
Institute of Organic Chemistry, University of Mainz,
Duesbergweg 10–14, D-55128
Mainz, Germany
Chem. Asian J. 2014, 9, 2119-2125; Synthesis 2012, 44, 1385-1397; Chem. Comm. 2011, 47, 9212-9214.
Introduction
Glycomimetics are compounds of various structural classes that are able to imitate the function of biologically active oligosaccharides. Herein, a facile synthesis of 1,3‑diglycosylindoles as functional trisaccharide mimetics in which central indole ring mimics an internal hexose unit is reported. These compounds can be readily obtained by C-glycosylation of 1-glycosylidoles which are available from aldohexoses and indoline in only two steps.[2]
Synthesis of 1,3-diglycosylindoles:
Monosaccharides 1 – 4 were reacted with indoline to the N-glycosides and then peracetylated and dehydrogenated with DDQ to the protected N-glycosylindoles 13 – 16 or vice versa.[2] Both routes gave comparable yields.[3] The second carbohydrate moiety was introduced by way of glycosyl trichloroacetimidates 17 and 18 which were prepared from partially protected saccharides according to literature procedures.[4]
1,3-Diglycosylindoles 19 – 27 were obtained by C-glycosylation of the reactive 3-position in substrates 13 – 16 with glycosyl donors 17 or 18 in combination with boron trifluoride diethyl etherate as the promotor.
Preparation of a Selectin Inhibitor
1-(2,3,4,5-Tetra-O-acetyl-β-d-galactopyranosyl)-3-(2,3,4,6-tetra-O-acetyl-α-d-mannopyranosyl)-indole (19) was deprotected by Zemplén deacetylation and subsequently subjected to an enzymatic sialylation reaction using nitrophenyl sialoside donor 29.[5]
The reaction yielded glycomimetic 30 in 13% yield (24% based on recovered starting material).[6]
The binding of tetrasaccharide mimetic 30, which should be able to imitate the sialyl LewisX tetrasaccharide 31, to various human selectins was investigated in a competitive inhibition assay. Here, potential inhibitors compete with the binding of L-, P-, or E-selectin to the synthetic sulfo-tyrosine/sLex biligand under flow conditions.[7]
Mimetic 30 was compared to the natural ligand 31 in this assay. Binding of L- and P-selectin was not inhibited by the sialyl Lewisx within the tested concentration range. Indole-based mimetic 30 could however inhibit all three selectins with IC50 values from 0.7 mm (P-selectin) to 7.4 mm (E-selectin), and is also an effective glycomimetic for L-selectin inhibition.
Conclusion
1,3-Diglycosylindoles can be readily synthesized. One representative imitating a trisaccharide portion of the sialyl LewisX cell adhesion molecule was enzymatically sialylated to yield a potent mimetic of its natural counterpart.
Acknowledgments
This work was supported by the German Federal Ministry for Education and Research (T.O., grant no. 0315139) and the Deutsche Forschungsgemeinschaft (J. D., SFB 765).
References:
- 1)C. Wiebe, C. Schlemmer, S. Weck, T. Opatz, Chem. Commun. 2011, 47, 9212-9214.
- 2)S. Mel'nik, A. A. Bakhmedova, L. D. Garaeva, O. V. Goriunova, T. D. Miniker, I. L. Plikhtiak, L. V. Ektova, I. V. Iartseva, Bioorganicheskaia khimiia 1996, 22, 458-467.
- 3)C. Wiebe, S. Fusté de la Sotilla, T. Opatz, Synthesis 2012, 44, 1385-1397.
- 4)a) R. R. Schmidt, B. Wegmann, K.-H. Jung, Liebigs Ann. Chem. 1991, 1991, 121-124; b) M. Mori, Y. Ito, T. Ogawa, Carbohydr. Res. 1990, 195, 199-224.
- 5)a) B. Neubacher, D. Schmidt, P. Ziegelmüller, J. Thiem, Org. Biomol. Chem. 2005, 3, 1551-1556; b) A. Schroven, S. Meinke, P. Ziegelmüller, J. Thiem, Chem. Eur. J. 2007, 13, 9012-9021; c) M. L. Cremona, O. Campetella, D. O. Sánchez, A. C. C. Frasch, Glycobiology 1999, 9, 581-587.
- 6)C. Schlemmer, C. Wiebe, D. Ferenc, D. Kowalczyk, S. Wedepohl, P. Ziegelmüller, J. Dernedde, T. Opatz, Chem. - Asian J. 2014, 9, 2119-2125.
- 7)S. Enders, G. Bernhard, A. Zakrzewicz, R. Tauber, Biochimica et Biophysica Acta (BBA) - General Subjects 2007, 1770, 1441-1449.