Regioselective 3-O-Substitution of Unprotected Thiodigalactosides: Direct Route to Galectin Inhibitors
Language English Country Germany Media print-electronic
Document type Journal Article
Grant support
LTC18038
Ministerstvo Školství, Mládeže a Tělovýchovy
LTC19038
Ministerstvo Školství, Mládeže a Tělovýchovy
LM2018133
Ministerstvo Školství, Mládeže a Tělovýchovy
LM2018140
Ministerstvo Školství, Mládeže a Tělovýchovy
LM2015047
Ministerstvo Školství, Mládeže a Tělovýchovy
- Keywords
- carbohydrates, glycomimetics, glycosides, inhibitors, molecular modeling,
- MeSH
- Galactose MeSH
- Galectin 1 chemistry metabolism MeSH
- Galectin 3 chemistry metabolism MeSH
- Galectins chemistry metabolism MeSH
- Blood Proteins MeSH
- Humans MeSH
- Models, Molecular MeSH
- Carbohydrates chemistry MeSH
- Thiogalactosides chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Galactose MeSH
- Galectin 1 MeSH
- Galectin 3 MeSH
- Galectins MeSH
- Blood Proteins MeSH
- LGALS3 protein, human MeSH Browser
- Carbohydrates MeSH
- thiodigalactoside MeSH Browser
- Thiogalactosides MeSH
The synthesis of tailored bioactive carbohydrates usually comprises challenging (de)protection steps, which lowers synthetic yields and increases time demands. We present here a regioselective single-step introduction of benzylic substituents at 3-hydroxy groups of β-d-galactopyranosyl-(1→1)-thio-β-d-galactopyranoside (TDG) employing dibutyltin oxide in good yields. These glycomimetics act as inhibitors of galectins-human lectins, which are biomedically attractive targets for therapeutic inhibition in, for example, cancerogenesis. The affinity of the prepared glycomimetics to galectin-1 and galectin-3 was studied in enzyme-linked immunosorbent (ELISA)-type assays and their potential to inhibit galectin binding on the cell surface was shown. We used our original in vivo biotinylated galectin constructs for easy detection by flow cytometry. The results of the biological experiments were compared with data from molecular modeling with both galectins. The present work reveals a facile and elegant synthetic route for the preparation of TDG-derived glycomimetics that exhibit differing selectivity and affinity to galectins depending on the choice of 3-O-substitution.
See more in PubMed
P. Bojarová, V. Křen, Biomater. Sci. 2016, 4, 1142-1160.
D. Laaf, P. Bojarová, L. Elling, V. Křen, Trends Biotechnol. 2019, 37, 402-415.
K. Wdowiak, T. Francuz, E. Gallego-Colon, N. Ruiz-Agamez, M. Kubeczko, I. Grochoła, J. Wojnar, Int. J. Mol. Sci. 2018, 19, 210.
V. Sundblad, L. G. Morosi, J. R. Geffner, G. A. Rabinovich, Immunol. 2017, 199, 3721-3730.
N. Suthahar, W. C. Meijers, H. H. W. Silljé, J. E. Ho, F.-T. Liu, R. A. de Boer, Theranostics 2018, 8, 593-609.
J. Hirabayashi, T. Hashidate, Y. Arata, N. Nishi, T. Nakamura, M. Hirashima, T. Urashima, T. Oka, M. Futai, W. E. G. Muller, F. Yagi, K. Kasai, Biochim. Biophys. Acta Gen. Subj. 2002, 1572, 232-254.
L. Bumba, D. Laaf, V. Spiwok, L. Elling, V. Křen, P. Bojarová, Int. J. Mol. Sci. 2018, 19, 372.
D. Laaf, P. Bojarová, H. Pelantová, V. Křen, L. Elling, Bioconjugate Chem. 2017, 28, 2832-2840;
D. Laaf, H. Steffens, H. Pelantová, P. Bojarová, V. Křen, L. Elling, Adv. Synth. Catal. 2017, 359, 4015-4024.
A. David, Isr. J. Chem. 2010, 50, 204-219.
P. Sörme, P. Arnoux, B. Kahl-Knutsson, H. Leffler, J. M. Rini, U. J. Nilsson, J. Am. Chem. Soc. 2005, 127, 1737-1743;
T. Delaine, I. Cumpstey, L. Ingrassia, M. Le Mercier, P. Okechukwu, H. Leffler, R. Kiss, U. J. Nilsson, J. Med. Chem. 2008, 51, 8109-8114;
U. Nilsson, WO2009/139719, 2009.
T. Delaine, P. Collins, A. MacKinnon, G. Sharma, J. Stegmayr, V. K. Rajput, S. Mandal, I. Cumstey, A. Larumbe, B. A. Salameh, B. Kahl-Knutsson, H. van Hattum, M. van Scherpenzeel, R. J. Pieters, T. Sethi, H. Schambye, S. Oredsson, H. Leffler, H. Blanchard, U. J. Nilsson, ChemBioChem 2016, 17, 1759-1770.
I. Cumpstey, A. Sundin, H. Leffler, U. J. Nilsson, Angew. Chem. Int. Ed. 2005, 44, 5110-5112;
Angew. Chem. 2005, 117, 5240-5242.
B. A. Salameh, I. Cumpstey, A. Sundin, H. Leffler, U. J. Nilsson, Bioorg. Med. Chem. 2010, 18, 5367-5378.
V. K. Rajput, A. MacKinnon, S. Mandal, P. Collins, H. Blanchard, H. Leffler, T. Sethi, H. Schambye, B. Mukhopadhyay, U. J. Nilsson, J. Med. Chem. 2016, 59, 8141.
T. J. Hsieh, H. Y. Lin, Z. Tu, T. C. Lin, S. C. Wu, Y. Y. Tseng, F. T. Liu, S. T. Hsu, C. H. Lin, Sci. Rep. 2016, 6, 29457.
S. Mandal, U. J. Nilsson, Org. Biomol. Chem. 2014, 12, 4816-4819.
D. Giguère, R. Patnam, M. Bellefleur, C. St-Pierre, S. Sato, R. Roy, Chem. Commun. 2006, 2379-2381.
S. David, A. Thieffry, A. Veyrières, J. Chem. Soc. Perkin. Trans.1 1981, 1796-1801;
G. Yang, F. Kong, S. Zhou, Carbohydr. Res. 1991, 211, 179-182.
M. Giordano, A. Iadonisi, Tetrahedron Lett. 2013, 54, 1550-1552;
M. Giordano, A. Iadonisi, J. Org. Chem. 2014, 79, 213-222.
L. Ballell, J. A. F. Joosten, F. A. el Maate, R. M. J. Liskamp, R. J. Pieters, Tetrahedron Lett. 2004, 45, 6685-6687.
V. K. Zishiri, R. Hunter, P. J. Smith, D. Taylor, R. Summers, K. Kirk, R. E. Martin, T. J. Egan, Eur. J. Med. Chem. 2011, 46, 1729-1742.
G. N. Wang, S. André, H.-J. Gabius, P. V. Murphy, Org. Biomol. Chem. 2012, 10, 6893-6907.
K. Peterson, R. Kumar, O. Stenstrom, P. Verma, P. R. Verma, M. Hakansson, B. Kahl-Knutsson, F. Zetterberg, H. Leffler, M. Akke, D. T. Logan, U. J. Nilsson, J. Med. Chem. 2018, 61, 1164-1175.
K. A. Stannard, P. M. Collins, K. Ito, E. M. Sullivan, S. A. Scott, E. Gabutero, I. D. Grice, P. Low, U. J. Nilsson, H. Leffler, H. Blanchard, S. J. Ralph, Cancer Lett. 2010, 299, 95-110.
C. Møller, M. S. Plesset, Phys. Rev. 1934, 46, 618-622.
M. R. Tavares, M. Bláhová, L. Sedláková, L. Elling, H. Pelantová, R. Konefał, T. Etrych, V. Křen, P. Bojarová, P. Chytil, Biomacromolecules 2020, 21, 641-652.
R. A. Friesner, R. B. Murphy, M. P. Repasky, L. L. Frye, J. R. Greenwood, T. A. Halgren, P. C. Sanschagrin, D. T. Mainz, J. Med. Chem. 2006, 49, 6177-6196.
M. J. Abraham, T. Murtola, R. Schulz, S. Páll, J. C. Smith, B. Hess, E. Lindahl, SoftwareX 2015, 1-2, 19-25.
A. Šali, T. L. Blundell, J. Mol. Biol. 1993, 234, 779-815.
K. Lindorff-Larsen, S. Piana, K. Palmo, P. Maragakis, J. L. Klepeis, R. O. Dror, D. E. Shaw, Proteins Struct. Funct. Bioinf. 2010, 78, 1950-1958.
K. N. Kirschner, A. B. Yongye, S. M. Tschampel, J. González-Outeiriño, C. R. Daniels, B. L. Foley, R. J. Woods, J. Comput. Chem. 2008, 29, 622-655.
J. Wang, R. M. Wolf, J. W. Caldwell, P. A. Kollman, D. A. Case, J. Comput. Chem. 2004, 25, 1157-1174.
A. Jakalian, D. B. Jack, C. I. Bayly, J. Comput. Chem. 2002, 23, 1623-1641.
S. F. Boys, F. Bernardi, Mol. Phys. 1970, 19, 553-566.
Gaussian 09, Revision A.02, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, D. J. Fox, Gaussian, Inc., Wallingford CT, 2016.
