Structurally simple 1-thio-β-D-glucopyranosides were synthesized and tested as potential inhibitors toward several fungal glycosidases from Aspergillus oryzae and Penicillium canescens. Significant selective inhibition was observed for α- and β-glucosidases, while a weak to moderate activation for α- and β-galactosidases. 1. Introduction Thioglycosides are the hydrolysis- and metabolism-resistant synthetic S-analogs of natural O-glycosides. They attracted recently a rapidly increasing attention as competitive inhibitors of glycosidases and other enzymes involved in a variety of biochemical processes [1, 2] related in particular to metabolic disorders and diseases, such as diabetes [1, 3], to inflammations [2, 4] and viral or bacterial infections [5–17], including tuberculosis [9, 10], and to cancer [2, 18–20]. However, surprisingly little is known about the inhibition of glucosidases by 1-thio-β-D-glucosides so far [21–24] (see the discussion). In a search for simple, readily accessible, and efficient glycosidase inhibitors [25–27], we designed, prepared, and assayed a series of structurally simple 1-thio-β-D-glucosides. 2. Results and Discussion 2.1. Synthesis of 1-Thio-β-D-glucopyranosides A series of aryl and alkyl 1-thio-β-D-glucopyranosides 2a–2i was synthesized according to Scheme 1. In addition to the model compounds 2a–2f with simple aryl and alkyl aglycones, we included the phenanthroline derivative 2g, which was found to possess activity towards some glycosidases [27]. Compounds 2h–2i？？were designed as disaccharide analogues in view of the significant inhibitory activity of the 1,2-cyclohexanedicarboxylic acid derivatives towards fungal glycosidases [25, 26]. Scheme 1: Preparation of 1-thio- β-D-glucopyranosides 2a–2i. The structures of all products and intermediates were determined from the data of 1H NMR and 13C NMR, including COSY and HMQC techniques. Thanks to a bias of the conformational equilibria towards the all-equatorial form of the pyranose ring, the configurational assignment was rather straightforward: large spin-spin coupling constants (9–11？Hz) indicated a trans-diaxial orientation of the corresponding vicinal protons, while all other relative positions (axial-equatorial and equatorial-equatorial) resulted in small couplings between them (2–4？Hz). 2.2. Glycosidase Inhibitory Activity The synthesized compounds have been assayed for enzyme inhibitory activity against several glycosidases in multienzyme complexes isolated from fungi Penicillium canescens and Aspergillus oryzae [28–32]. The multienzyme complex from P. canescens
References
[1]
R. K. H. Kinne and F. Castaneda, “SGLT inhibitors as new therapeutic tools in the treatment of diabetes,” Handbook of Experimental Pharmacology, vol. 203, pp. 105–126, 2011.
[2]
A. Dondoni and A. Marra, “Calixarene and calixresorcarene glycosides: their synthesis and biological applications,” Chemical Reviews, vol. 110, no. 9, pp. 4949–4977, 2010.
[3]
F. Castaneda, A. Burse, W. Boland, and R. K. H. Kinne, “Thioglycosides as inhibitors of hSGLT1 and hSGLT2: potential therapeutic agents for the control of hyperglycemia in diabetes,” International Journal of Medical Sciences, vol. 4, no. 3, pp. 131–139, 2007.
[4]
Q. V. Vo, C. Trenerry, S. Rochfort, J. Wadeson, C. Leyton, and A. B. Hughes, “Synthesis and anti-inflammatory activity of aromatic glucosinolates,” Bioorganic and Medicinal Chemistry, vol. 21, no. 19, pp. 5945–5954, 2013.
[5]
J. Rodrigue, G. Ganne, B. Blanchard et al., “Aromatic thioglycoside inhibitors against the virulence factor LecA from Pseudomonas aeruginosa,” Organic and Biomolecular Chemistry, vol. 11, no. 40, pp. 6906–6918, 2013.
[6]
E. S. H. El Ashry, E. S. H. El Tamany, M. E. D. A. El Fattah, A. T. A. Boraei, and H. M. Abd El-Nabi, “Regioselective synthesis, characterization and antimicrobial evaluation of S-glycosides and S,N-diglycosides of 1,2-Dihydro-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione,” European Journal of Medicinal Chemistry, vol. 66, pp. 106–113, 2013.
[7]
H. A. El-Sayed, A. H. Moustafa, and A. E. Z. Haikal, “Synthesis, antiviral, and antimicrobial activity of 1,2,4-triazole thioglycoside derivatives,” Phosphorus, Sulfur and Silicon and the Related Elements, vol. 188, no. 5, pp. 649–662, 2013.
[8]
A. J. Cagnoni, O. Varela, J. Kovensky, and M. L. Uhrig, “Synthesis and biological activity of divalent ligands based on 3-deoxy-4-thiolactose, an isosteric analogue of lactose,” Organic and Biomolecular Chemistry, vol. 11, no. 33, pp. 5500–5511, 2013.
[9]
E. Repetto, C. Marino, and O. Varela, “Synthesis of the (1→6)-linked thiodisaccharide of galactofuranose: inhibitory activity against a β-galactofuranosidase,” Bioorganic and Medicinal Chemistry, vol. 21, no. 11, pp. 3327–3333, 2013.
[10]
I. L. Rogers, D. W. Gammon, and K. J. Naidoo, “Conformational preferences of plumbagin with phenyl-1-thioglucoside conjugates in solution and bound to MshB determined by aromatic association,” Carbohydrate Research, vol. 371, pp. 52–60, 2013.
[11]
S. V. Pestova, D. V. Sudarikov, S. A. Rubtsova, and A. V. Kutchin, “Synthesis and asymmetric oxidation of thioglycosides derived from neomenthanethiol and α-D-galactose,” Russian Journal of Organic Chemistry, vol. 49, no. 3, pp. 366–373, 2013.
[12]
T. Terauchi, Y. Koyama, S. Machida, T. Kasumi, and S. Komba, “Synthesis of novel thioglycoside analogs as the substrates and/or the inhibitors of cellobiohydrolases,” Journal of Applied Glycoscience, vol. 59, no. 1, pp. 11–19, 2012.
[13]
C. Stanetty, A. Wolkerstorfer, H. Amer et al., “Synthesis and antiviral activities of spacer-linked 1-thioglucuronide analogs of glycyrrhizin,” Beilstein Journal of Organic Chemistry, vol. 8, pp. 705–711, 2012.
[14]
R. Dettmann and T. Ziegler, “Synthesis of octyl S-glycosides of tri- to pentasaccharide fragments related to the GPI anchor of Trypanosoma brucei,” Carbohydrate Research, vol. 346, no. 15, pp. 2348–2361, 2011.
[15]
H. N. Hafez, H. A. R. Hussein, and A.-R. B. A. El-Gazzar, “Synthesis of substituted thieno[2,3-d]pyrimidine-2,4-dithiones and their S-glycoside analogues as potential antiviral and antibacterial agents,” European Journal of Medicinal Chemistry, vol. 45, no. 9, pp. 4026–4034, 2010.
[16]
M. Poláková, M. Beláňová, L. Petru？, and K. Miku？ová, “Synthesis of alkyl and cycloalkyl α-D-mannopyranosides and derivatives thereof and their evaluation in the mycobacterial mannosyltransferase assay,” Carbohydrate Research, vol. 345, no. 10, pp. 1339–1347, 2010.
[17]
R. Caraballo, M. Sakulsombat, and O. Ramstr？m, “Towards dynamic drug design: identification and optimization of β-galactosidase inhibitors from a dynamic hemithioacetal system,” ChemBioChem, vol. 11, no. 11, pp. 1600–1606, 2010.
[18]
I. F. Nassar, “Synthesis and antitumor activity of new substituted mercapto-1,2,4-triazine derivatives, their thioglycosides, and acyclic thioglycoside analogs,” Journal of Heterocyclic Chemistry, vol. 50, no. 1, pp. 129–134, 2013.
[19]
I. García-álvarez, H. Groult, J. Casas et al., “Synthesis of antimitotic thioglycosides: in vitro and in vivo evaluation of their anticancer activity,” Journal of Medicinal Chemistry, vol. 54, no. 19, pp. 6949–6955, 2011.
[20]
M. A. Abu-Zaied, E. M. El-Telbani, G. H. Elgemeie, and G. A. M. Nawwar, “Synthesis and in vitro anti-tumor activity of new oxadiazole thioglycosides,” European Journal of Medicinal Chemistry, vol. 46, no. 1, pp. 229–235, 2011.
[21]
M. A. Jermyn, “Fungal cellulases. XV. Acceptor specificity of the aryl beta-glucosidase of Stachybotrys atra.,” Australian Journal of Biological Sciences, vol. 19, no. 5, pp. 903–917, 1966.
[22]
T. Kuntothom, M. Raab, I. Tvaro？ka et al., “Binding of β-d-glucosides and β-d-mannosides by rice and barley β-d-glycosidases with distinct substrate specificities,” Biochemistry, vol. 49, no. 40, pp. 8779–8793, 2010.
[23]
M. Schnabelrauch, A. Vasella, and S. G. Withers, “Synthesis and evaluation as irreversible glycosidase inhibitors of mono- and oligo(glycosylthio)benzoquinones,” Helvetica Chimica Acta, vol. 77, no. 3, pp. 778–799, 1994.
[24]
C.-S. Kuhn, J. Lehmann, and J. Steck, “Syntheses and properties of some photolabile β-thioglycosides: potential photoaffinity reagents for β-glycoside hydrolases,” Tetrahedron, vol. 46, no. 9, pp. 3129–3134, 1990.
[25]
B. Brazdova, N. S. Tan, N. M. Samoshina, and V. V. Samoshin, “Novel easily accessible glucosidase inhibitors: 4-hydroxy-5-alkoxy-1,2-cyclohexanedicarboxylic acids,” Carbohydrate Research, vol. 344, no. 3, pp. 311–321, 2009.
[26]
N. S. Tan, B. Brazdova, N. M. Samoshina, and V. V. Samoshin, “Novel inhibitors for fungal glycosidases based on cyclohexane-1, 2-dicarboxylic acids,” Journal of Undergraduate Chemistry Research, vol. 6, no. 4, pp. 186–192, 2007.
[27]
I. A. Dotsenko, M. Curtis, N. M. Samoshina, and V. V. Samoshin, “Convenient synthesis of 5-aryl(alkyl)sulfanyl-1,10-phenanthrolines from 5,6-epoxy-5,6-dihydro-1,10-phenanthroline, and their activity towards fungal β-d-glycosidases,” Tetrahedron, vol. 67, no. 39, pp. 7470–7478, 2011.
[28]
M. M. Gomarteli, A. K. Kulikova, A. K. Tsereteli, A. M. Bezborodov, and G. I. Kvesitadze, “beta-Galactosidase from Penicillium canescens st. 20171,” Applied Biochemistry and Microbiology, vol. 24, no. 1, pp. 16–22, 1988.
[29]
N. M. Samoshina, L. V. Yugova, P. H. Gross, G. B. Bravova, A. A. Shishkova, and V. V. Samoshin, “Partial purification and characterization of glycosidases from Aspergillus oryzae and Penicillium canescens,” in Proceedings of the 219th National Meeting of the American Chemical Society, p. 160, The American Chemical Society, San Francisco, Calif, USA, 2000.
[30]
O. S. Korneeva, N. A. Zherebtsov, and I. V. Cheryomushkina, “Identification of catalytically active groups of Penicillium canescens F-436 beta-galactosidase,” Biochemistry, vol. 66, no. 3, pp. 334–339, 2001.
[31]
O. A. Sinitsyna, F. E. Bukhtoyarov, A. V. Gusakov et al., “Isolation and properties of major components of Penicillium canescens extracellular enzyme complex,” Biochemistry, vol. 68, no. 11, pp. 1200–1209, 2003.
[32]
I. M. Gracheva and A. Y. Krivova, The Technology of Enzyme Preparations, Elevar, Moscow, Russia, 2000.
[33]
A. B. Pardee, F. Jacob, and J. Monod, “The genetic control and cytoplasmic expression of inducibility in the synthesis of β-galactosidase by Escherichia coli,” Journal of Molecular Biology, vol. 1, pp. 165–178, 1959.
[34]
C. Riou, J. Salmon, M. Vallier, Z. Günata, and P. Barre, “Purification, characterization, and substrate specificity of a novel highly glucose-tolerant β-glucosidase from Aspergillus oryzae,” Applied and Environmental Microbiology, vol. 64, no. 10, pp. 3607–3614, 1998.
[35]
X. Bian, X. Fan, C. Ke, Y. Luan, G. Zhao, and A. Zeng, “Synthesis and α-glucosidase inhibitory activity evaluation of N-substituted aminomethyl-β-d-glucopyranosides,” Bioorganic and Medicinal Chemistry, vol. 21, no. 17, pp. 5442–5450, 2013.
[36]
K. Duskova, L. Gude, and M.-S. Arias-Pérez, “N-Phenanthroline glycosylamines: synthesis and copper(II) complexes,” Tetrahedron, vol. 70, no. 5, pp. 1071–1076, 2014.
[37]
T. M. Wrodnigg and A. E. Stütz, “The two faces of iminoalditols: powerful inhibitors trigger glycosidase activation,” Current Enzyme Inhibition, vol. 8, no. 1, pp. 47–99, 2012.
[38]
Y. Nakagawa, S. Sehata, S. Fujii, H. Yamamoto, A. Tsuda, and K. Koumoto, “Mechanistic study on the facilitation of enzymatic hydrolysis by α-glucosidase in the presence of betaine-type metabolite analogs,” Tetrahedron, vol. 70, no. 35, pp. 5895–5903, 2014.
[39]
N. M. Samoshina and V. V. Samoshin, “The Michaelis constants ratio for two substrates with a series of fungal (mould and yeast) β-galactosidases,” Enzyme and Microbial Technology, vol. 36, no. 2-3, pp. 239–251, 2005.
[40]
E. Alverson-Banks Avegno, S. J. Hasty, A. R. Parameswar, G. S. Howarth, A. V. Demchenko, and L. D. Byers, “Reactive thioglucoside substrates for β-glucosidase,” Archives of Biochemistry and Biophysics, vol. 537, no. 1, pp. 1–4, 2013.
[41]
A. E. Stutz, Ed., Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond, Wiley-VCH, Weinheim, Germany, 1999.
[42]
P. Compain and O. R. Martin, Eds., Iminosugars: From Synthesis to Therapeutic Applications, John Wiley & Sons, Chichester, UK, 2007.
[43]
P. Compain, V. Chagnault, and O. R. Martin, “Tactics and strategies for the synthesis of iminosugar C-glycosides: a review,” Tetrahedron Asymmetry, vol. 20, no. 6-8, pp. 672–711, 2009.
[44]
G. M. Aerts, O. van Opstal, and C. K. de Bruyne, “Mixed inhibition of β-d-glucosidase from Stachybotrys atra by substrate analogues,” Carbohydrate Research, vol. 138, pp. 127–134, 1985.
[45]
V. Gopalan, L. B. Daniels, R. H. Glew, and M. Claeyssens, “Kinetic analysis of the interaction of alkyl glycosides with two human β-glucosidases,” Biochemical Journal, vol. 262, no. 2, pp. 541–548, 1989.
[46]
M. S. Cheng, Q. L. Wang, Q. Tian et al., “Total synthesis of methyl protodioscin: a potent agent with antitumor activity,” The Journal of Organic Chemistry, vol. 68, no. 9, pp. 3658–3662, 2003.
[47]
S. Weng, “Diastereoselective thioglycosylation of peracetylated glycosides catalyzed by in situ generated iron(III) iodide from elemental iodine and iron,” Tetrahedron Letters, vol. 50, no. 46, pp. 6414–6417, 2009.
[48]
J. Kuhn, E. M. Pettersson, B. K. Feld et al., “Sequestration of plant-derived phenolglucosides by larvae of the leaf beetle Chrysomela lapponica: thioglucosides as mechanistic probes,” Journal of Chemical Ecology, vol. 33, no. 1, pp. 5–24, 2007.
[49]
E. M. Montgomery, N. K. Richtmyer, and C. S. Hudson, “Attempts to find new antimalarials. VIII. Phenyl β-D-glucothiosides, diphenyl disulfides, phenyl thiocyanates, and related compounds,” Journal of Organic Chemistry, vol. 11, no. 3, pp. 301–306, 1946.
[50]
W. T. Haskins, R. M. Hann, and C. S. Hudson, “Relations between rotatory power and structure in the sugar group. XXXV. Some 2′-naphthyl 1-thioglycopyranosides and their acetates,” Journal of the American Chemical Society, vol. 69, no. 7, pp. 1668–1672, 1947.
[51]
S. A. Galema, J. B. F. N. Engberts, and H. A. van Doren, “Synthesis, purification and liquid-crystalline behaviour of several alkyl 1-thio-D-glycopyranosides,” Carbohydrate Research, vol. 303, no. 4, pp. 423–434, 1997.
[52]
H. Lineweaver and D. Burk, “The determination of enzyme dissociation constants,” Journal of the American Chemical Society, vol. 56, no. 3, pp. 658–666, 1934.
[53]
I. H. Segel, Biochemical Calculations, John Wiley & Sons, New York, NY, USA, 1976.
