Pyranoid Spirosugars as Enzyme Inhibitors

Barbara       La Ferla; Giuseppe       D’Orazio
Abstract

Background: Pyranoid spirofused sugar derivatives represent a class of compounds with a significant impact in the literature. From the structural point of view, the rigidity inferred by the spirofused entity has made these compounds object of interest mainly as enzymatic inhibitors, in particular, carbohydrate processing enzymes. Among them glycogen phosphorylase and sodium glucose co-transporter 2 are important target enzymes for diverse pathological states. Most of the developed compounds present the spirofused entity at the C1 position of the sugar moiety; nevertheless, spirofused entities can also be found at other sugar ring positions. The main spirofused entities encountered are spiroacetals/thioacetals, spiro-hydantoin and derivatives, spiro-isoxazolines, spiro-aminals, spiro-lactams, spiro-oxathiazole and spiro-oxazinanone, but also others are present.
Objectives: The present review focuses on the most explored synthetic strategies for the preparation of this class of compounds, classified according to the position and structure of the spirofused moiety on the pyranoid scaffold. Moreover, the structures are correlated to their main biological activities or to their role as chiral auxiliaries.
Conclusion: It is clear from the review that, among the different derivatives, the spirofused structures at position C1 of the pyranoid scaffold are the most represented and possess the most relevant enzymatic inhibitor activities. Nevertheless, great efforts have been devoted to the introduction of the spirofused entity also in the other positions, mainly for the preparation of biologically active compounds but also for the synthesis of chiral auxiliaries useful in asymmetric reactions; examples of such auxiliaries are the spirofused chiral 1,3-oxazolidin-2-ones and 1,3-oxazolidine-2-thiones.
Keywords: Glycomimetics, spirofused, enzyme inhibitors, pyranoid structure, sugar derivatives, spiro-isoxazolines.
Graphical Abstract

[1] 
Sanofi.. Sanofi and regeneron to present alirocumab clinical data at american college of cardiology 63rd annual scientific session. Paris, France and
Tarrytown, NY, March 27, 2014.
[2] 
Oku, A.; Ueta, K.; Arakawa, K.; Ishihara, T.; Nawano, M.; Kuronuma, Y.; Matsumoto, M.; Saito, A.; Tsujihara, K.; Anai, M.; Asano, T.; Kanai, Y.; Endou, H. T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes,  1999, 48(9), 1794-1800.
[http://dx.doi.org/10.2337/diabetes.48.9.1794] [PMID:  10480610] 
[3] 
Palazzo, M.; Gariboldi, S.; Zanobbio, L.; Selleri, S.; Dusio, G.F.; Mauro, V.; Rossini, A.; Balsari, A.; Rumio, C. Sodium-dependent glucose transporter-1 as a novel immunological player in the intestinal mucosa. J. Immunol.,  2008, 181(5), 3126-3136.
[http://dx.doi.org/10.4049/jimmunol.181.5.3126] [PMID:  18713983] 
[4] 
(a)La Ferla, B.; Spinosa, V.; D’Orazio, G.; Palazzo, M.; Balsari, A.; Foppoli, A.A.; Rumio, C.; Nicotra, F. Dansyl C-glucoside as a novel agent against endotoxic shock. ChemMedChem,  2010, 5(10), 1677-1680.
[http://dx.doi.org/10.1002/cmdc.201000282] [PMID: 20726031] 
(b)Cardani, D.; Sardi, C.; La Ferla, B.; D’Orazio, G.; Sommariva, M.; Marcucci, F.; Olivero, D.; Tagliabue, E.; Koepsell, H.; Nicotra, F.; Balsari, A.; Rumio, C. Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis. Mol. Cancer,  2014, 13(1), 23.
[http://dx.doi.org/10.1186/1476-4598-13-23] [PMID:  24495286] 
[5] 
Meng, W.; Ellsworth, B.A.; Nirschl, A.A.; McCann, P.J.; Patel, M.; Wu, G.; Sher, P.M.; Morrison, E.P.; Biller, S.A.; Zahler, R.; Deshpande, P.P.; Pullockaran, A.; Hagan, D.L.; Morgan, N.; Taylor, J.R.; Obermeier, M.T.; Humphreys, W.G.; Khanna, A.; Discenza, L.; Robertson, J.G.; Wang, A.; Han, S.; Wetterau, J.R.; Janovitz, E.B.; Flint, O.P.; Whaley, J.M.; Washburn, W. Discovery of dapagliflozin: A potent, selective renal sodium-dependent glucose cotransporter 2 (sglt2) inhibitor for the treatment of type 2 diabetes. N. J. Med. Chem.,  2008, 51, 1145.
[http://dx.doi.org/10.1021/jm701272q] 
[6] 
Gougoutas, J.Z. WO 02/083066. Chem. Abstr.,  2002, 137311199
[7] 
Lv, B.; Xu, B.; Feng, Y.; Peng, K.; Xu, G.; Du, J.; Zhang, L.; Zhang, W.; Zhang, T.; Zhu, L.; Ding, H.; Sheng, Z.; Welihinda, A.; Seed, B.; Chen, Y. Exploration of O-spiroketal C-arylglucosides as novel and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors. Bioorg. Med. Chem. Lett.,  2009, 19(24), 6877-6881.
[http://dx.doi.org/10.1016/j.bmcl.2009.10.088] [PMID:  19896374] 
[8] 
Xu, B.; Lv, B.; Feng, Y.; Xu, G.; Du, J.; Welihinda, A.; Sheng, Z.; Seed, B.; Chen, Y. O-Spiro C-aryl glucosides as novel sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors. Bioorg. Med. Chem. Lett.,  2009, 19(19), 5632-5635.
[http://dx.doi.org/10.1016/j.bmcl.2009.08.030] [PMID:  19700318] 
[9] 
Murakata, M.; Ikeda, T.; Kimura, N.; Kawase, A.; Nagase, M.; Kimura, M.; Maeda, K.; Honma, A.; Shimizu, H. The regioselective bromine-lithium exchange reaction of alkoxymethyldibromobenzene: A new strategy for the synthesis of tofogliflozin as a SGLT2 inhibitor for the treatment of diabetes. Tetrahedron,  2017, 73, 655-660.
[http://dx.doi.org/10.1016/j.tet.2016.12.028] 
[10] 
Ohtake, Y.; Emura, T.; Nishimoto, M.; Takano, K.; Yamamoto, K.; Tsuchiya, S.; Yeu, S-Y.; Kito, Y.; Kimura, N.; Takeda, S.; Tsukazaki, M.; Murakata, M.; Sato, T. Development of a scalable synthesis of tofogliflozin. J. Org. Chem.,  2016, 81(5), 2148-2153.
[http://dx.doi.org/10.1021/acs.joc.5b02734] [PMID:  26871504] 
[11] 
Murakata, M.; Kawase, A.; Kimura, N.; Ikeda, T.; Nagase, M.; Koizumi, M.; Kuwata, K.; Maeda, K.; Shimizu, H. Synthesis of tofogliflozin as an sglt2 inhibitor via construction of dihydroisobenzofuran by intramolecular [4 + 2] cycloaddition. Org. Process Res. Dev.,  2019, 23(4), 548-557.
[http://dx.doi.org/10.1021/acs.oprd.8b00400] 
[12] 
Wang, Y.; Lou, Y.; Wang, J.; Li, D.; Chen, H.; Zheng, T.; Xia, C.; Song, X.; Dong, T.; Li, J.; Li, J.; Liu, H. Design, synthesis and biological evaluation of 6-deoxy O-spiroketal C-arylglucosides as novel renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes. Eur. J. Med. Chem.,  2019, 180, 398-416.
[http://dx.doi.org/10.1016/j.ejmech.2019.07.032] [PMID:  31325786] 
[13] 
Md. M. Ahmed; G. A. O Doherty. De novo enantioselective syntheses of galacto-sugars and deoxy sugars via the iterative dihydroxylation of dienoate. Tetrahedron Lett.,  2005, 46, 4151-4155.
[14] 
Mainkar, P.S.; Johny, K.; Rao, T.P.; Chandrasekhar, S. Synthesis of O-spiro-C-aryl glycosides using organocatalysis. J. Org. Chem.,  2012, 77(5), 2519-2525.
[http://dx.doi.org/10.1021/jo202353r] [PMID:  22309409] 
[15] 
(a)Pérez, P.; Varona, R.; Garcia-Acha, I.; Durán, A. FEBS Lett.,  1981, 129, 249-252.
[http://dx.doi.org/10.1016/0014-5793(81)80176-7] 
(b)Varona, R.; Pérez, P.; Durán, A. FEMS Microbiol. Lett.,  1983, 20, 243-247.
(c)Baguley, B.C.; Römmele, G.; Gruner, J.; Wehrli, W.; Papulacandin, B. an
inhibitor of glucan synthesis in yeast spheroplasts. Eur. J. Biochem.,  1979, 97(2), 345-351.
[http://dx.doi.org/10.1111/j.1432-1033.1979.tb13120.x] [PMID: 380990] 
(d)Debono, M.; Gordee, R.S. Antibiotics that inhibit fungal cell wall development.,  Annu. Rev. Microbiol.,  1994, 48, 471-497.
[http://dx.doi.org/10.1146/annurev.mi.48.100194.002351] [PMID: 7826015] 
(e)Schmatz, D.M.; Romancheck, M.A.; Pittarelli, L.A.; Schwartz, R.E.; Fromtling, R.A.; Nollstadt, K.H.; Vanmiddlesworth, F.L.; Wilson, K.E.; Turner, M.J. Treatment of Pneumocystis carinii pneumonia with 1,3-betaglucan synthesis inhibitors.  Proc. Natl. Acad. Sci. USA,  1990, 87(15), 5950-5954.
[http://dx.doi.org/10.1073/pnas.87.15.5950] [PMID: 2198575] 
(f)Kanai, Y.; Lee, W.S.; You, G.; Brown, D.; Hediger, M.A. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J. Clin. Invest.,  1994, 93(1), 397-404.
[http://dx.doi.org/10.1172/JCI116972] [PMID:  8282810] 
[16] 
Martín, A.; Salazar, J.A.; Suárez, E. Synthesis of Chiral Spiroacetals from Carbohydrates. J. Org. Chem.,  1996, 61(12), 3999-4006.
[http://dx.doi.org/10.1021/jo960060g] [PMID:  11667274] 
[17] 
Martín, A.; Quintanal, L.M.; Suárez, E. Effect of papulacandin B and aculeacin A on β‐(1,3) glucan‐synthase from geotrichum lactis. Tetrahedron Lett.,  2007, 48, 5507-5511.
[http://dx.doi.org/10.1016/j.tetlet.2007.05.166] 
[18] 
Paterson, D.E.; Griffin, F.K.; Alcaraz, M.L.; Taylor, R.J.K. A ramberg−bäcklund approach to the synthesis of c‐glycosides, c‐linked disaccharides, and c‐glycosyl amino acids. Eur. J. Org. Chem.,  2002, 1323-1336.
[http://dx.doi.org/10.1002/1099-0690(200204)2002:7<1323:AID-EJOC1323>3.0.CO;2-8] 
[19] 
Main, C.A.; Rahman, S.S.; Hartley, R.C. Synthesis of spiroacetals using functionalised titanium carbenoids. Tetrahedron Lett.,  2008, 49, 4771-4774.
[http://dx.doi.org/10.1016/j.tetlet.2008.05.094] 
[20] 
Lin, H-C.; Chen, Y-B.; Lin, Z-P.; Wong, F.F.; Lin, C-H.; Lin, S-K. Synthesis of 1,7-dioxaspiro[5.5]undecanes and 1-oxa-7-thiaspiro[5.5]undecanes from exo-glycal. Tetrahedron,  2010, 66, 5229-5234.
[http://dx.doi.org/10.1016/j.tet.2010.04.075] 
[21] 
Corbet, M.; Bourdon, B.; Gueyrard, D.; Goekjian, P.G. A Julia olefination approach to the synthesis of functionalized enol ethers and their transformation into carbohydrate-derived spiroketals. Tetrahedron Lett.,  2008, 49, 750-754.
[http://dx.doi.org/10.1016/j.tetlet.2007.11.207] 
[22] 
Schneider, T.F.; Werz, D.B. Ring-enlargement reactions of donor-acceptor-substituted cyclopropanes: which combinations are most efficient? Org. Lett.,  2011, 13(7), 1848-1851.
[http://dx.doi.org/10.1021/ol200355f] [PMID:  21388123] 
[23] 
van Hooft, P.A.V.; Leeuwenburgh, M.A.; Overkleeft, H.S.; van der Marel, G.A.; van Boeckel, C.A.A.; van Boom, J.H. A novel and flexible synthesis of pyranose spiroacetal derivatives. Tetrahedron Lett.,  1998, 39, 6061-6064.
[http://dx.doi.org/10.1016/S0040-4039(98)01247-7] 
[24] 
van Boom, J.H.; Leeuwenburgh, M.A. Synthesis and elaboration of functionalised carbohydrate-derived spiroketals. Org. Biomol. Chem.,  2004, 2, 1395-1403.
[http://dx.doi.org/10.1039/b401699h] [PMID:  15105932] 
[25] 
(a)Liu, G.; Wurst, J.M.; Tan, D.S. Stereoselective synthesis of benzannulated spiroketals: influence of the aromatic ring on reactivity and conformation. Org. Lett.,  2009, 11(16), 3670-3673.
[http://dx.doi.org/10.1021/ol901437f] [PMID: 19634891] 
(b)Moilanen, S.B.; Potuzak, J.S.; Tan, D.S. Stereocontrolled synthesis of spiroketals via Ti(Oi-Pr)4-mediated kinetic spirocyclization of glycal epoxides with retention of configuration. J. Am. Chem. Soc.,  2006, 128(6), 1792-1793.
[http://dx.doi.org/10.1021/ja057908f] [PMID:  16464069] 
[26] 
Nakajima, M.; Itoi, K.; Takamatsu, Y.; Kinoshita, T.; Okazaki, T.; Kawakubo, K.; Shindo, M.; Honma, T.; Tohjigamori, M.; Haneishi, T. Hydantocidin: a new compound with herbicidal activity from Streptomyces hygroscopicus. J. Antibiot. (Tokyo),  1991, 44(3), 293-300.
[http://dx.doi.org/10.7164/antibiotics.44.293] [PMID:  2026555] 
[27] 
Takallasi, S.; Nakajima, M.; Kinoshita, T.; Harayama, T.; Sugai, S.; Honma, T.; Sato, S.; Haneishi, T. Hydantocidin and cornexistin. ACS Syrup. Ser.,  1994, 551, 74.
[28] 
Bichard, C.J.F.; Mitchell, E.P.; Wormald, M.R.; Watson, K.A.; Johnson, L.N.; Zographos, S.E.; Koutra, D.D.; Oikonomakosd, N.G.; Fleet, G.W.J. Potent inhibition of glycogen phosphorylase by a spirohydantoin of glucopyranose: First pyranose analogues of hydantocidin. Tetrahedron Lett.,  1995, 36, 2145-2148.
[http://dx.doi.org/10.1016/0040-4039(95)00197-K] 
[29] 
Krulle, T.M.; Fuente, C.; Watson, K.A.; Gregoriou, M.; Johnson, L.N.; Tsitsanou, K.E.; Zographos, S.E.; Oikonomakos, N.G.; Fleet, G.W.J. Stereospecific synthesis of spirohydantoins of β-glucopyranose: inhibitors of glycogen phosphorylase. Synlett,  1997, 211-213.
[http://dx.doi.org/10.1055/s-1997-736] 
[30] 
Fuente, C. KruÈlle, T.M.; Watson, K.A.; Gregoriou, M.; Johnson, L.N.; Tsitsanou, K.E.; Zographos, S.E.; Oikonomakos, N.G.; Fleet, G W.J. Glucopyranose spirohydantoins: Specific inhibitors of glycogen phosphorylase. Synlett,  1997, 485-487.
[31] 
Watson, K.A.; Chrysina, E.D.; Tsitsanou, K.E.; Zographos, S.E.; Archontis, G.; Fleet, G.W.J.; Oikonomakos, N.G. Kinetic and crystallographic studies of glucopyranose spirohydantoin and glucopyranosylamine analogs inhibitors of glycogen phosphorylase. Proteins,  2005, 61(4), 966-983.
[http://dx.doi.org/10.1002/prot.20653] [PMID:  16222658] 
[32] 
Ősz, E.; Somsák, L.; Szilágyi, L.; Kovács, L.; Docsa, T.; Tóth, B.; Gergely, P. Efficient inhibition of muscle and liver glycogen phosphorylases by a new glucopyranosylidene-spiro-thiohydantoin. Bioorg. Med. Chem. Lett.,  1999, 9, 1385-1390.
[PMID: 10360741] 
[33] 
Docsa, T.; Czifrák, K.; Hüse, C.; Somsák, L.; Gergely, P. Effect of glucopyranosylidene-spiro-thiohydantoin on glycogen metabolism in liver tissues of streptozotocin-induced and obese diabetic rats. Mol. Med. Rep.,  2011, 4(3), 477-481.
[PMID:  21468595] 
[34] 
Docsa, T.; Marics, B.; Németh, J.; Hüse, C.; Somsák, L.; Gergely, P.; Peitl, B. Insulin sensitivity is modified by a glycogen phosphorylase inhibitor: Glucopyranosylidene-spiro-thiohydantoin in streptozotocin-induced diabetic rats. Curr. Top. Med. Chem.,  2015, 15(23), 2390-2394.
[http://dx.doi.org/10.2174/1568026615666150622091407] [PMID:  26095241] 
[35] 
Gyémánt, G.; Kandra, L.; Nagy, V.; Somsák, L. Inhibition of human salivary alpha-amylase by glucopyranosylidene-spiro-thiohydantoin. Biochem. Biophys. Res. Commun.,  2003, 312(2), 334-339.
[http://dx.doi.org/10.1016/j.bbrc.2003.10.119] [PMID:  14637141] 
[36] 
Kandra, L.; Remenyik, J.; Batta, G.; Somsák, L.; Gyémánt, G.; Park, K.H. Enzymatic synthesis of a new inhibitor of alpha-amylases: Acarviosinyl-isomaltosyl-spiro-thiohydantoin. Carbohydr. Res.,  2005, 340(7), 1311-1317.
[http://dx.doi.org/10.1016/j.carres.2005.03.003] [PMID:  15854600] 
[37] 
Szabó, K.; Kandra, L.; Gyémánt, G. Studies on the reversible enzyme reaction of rabbit muscle glycogen phosphorylase b using isothermal titration calorimetry. Carbohydr. Res.,  2019, 477, 58-65.
[http://dx.doi.org/10.1016/j.carres.2019.03.014] [PMID:  31005807] 
[38] 
Somsák, L. Nagy. A new, scalable preparation of a glucopyranosylidene-spiro-thiohydantoin: one of the best inhibitors of glycogen phosphorylases. Tetrahedron Asymmetry,  2000, 11, 1719-1727.
[39] 
Somsák, L.; Kovács, L.; Tóth, M.; Ősz, E.; Szilágyi, L.; Györgydeák, Z.; Dinya, Z.; Docsa, T.; Tóth, B.; Gergely, P. Synthesis of and a comparative study on the inhibition of muscle and liver glycogen phosphorylases by epimeric pairs of d-gluco- and d-xylopyranosylidene-spiro-(thio)hydantoins and N-(d-glucopyranosyl) amides. J. Med. Chem.,  2001, 44(17), 2843-2848.
[http://dx.doi.org/10.1021/jm010892t] [PMID:  11495595] 
[40] 
Páhi, A.; Czifrák, K.; Kövér, K.E.; Somsák, L. Anomeric spirocycles by solvent incorporation: reactions of O-peracylated (glyculopyranose and glyculopyranosyl bromide)onamide derivatives with ketones. Carbohydr. Res.,  2015, 403, 192-201.
[http://dx.doi.org/10.1016/j.carres.2014.04.003] [PMID:  24933234] 
[41] 
Ősz, E.; Szilágyi, L.; Somsák, L.; Bényei, A. Syntheses of novel glycosylidene-spiro-heterocycles related to hydantocidin. Tetrahedron,  1999, 55, 2419-2430.
[http://dx.doi.org/10.1016/S0040-4020(99)00034-4] 
[42] 
Zhang, D.; Ye, D.; Feng, E.; Wang, J.; Shi, J.; Jiang, H.; Liu, H. Highly alpha-selective synthesis of sialyl spirohydantoins by regiospecific domino condensation/O-->N acyl migration/N-sialylation of carbodiimides with peracetylated sialic acid. J. Org. Chem.,  2010, 75(11), 3552-3557.
[http://dx.doi.org/10.1021/jo100016k] [PMID:  20462259] 
[43] 
Pal, A.P.J.; Kadigachalam, P.; Mallick, A.; Doddi, V.R.; Vankar, Y.D. Synthesis of sugar-derived spiroaminals via lactamization and metathesis reactions. Org. Biomol. Chem.,  2011, 9(3), 809-819.
[http://dx.doi.org/10.1039/C0OB00555J] [PMID:  21107447] 
[44] 
Martín, A.; Pérez-Martín, I.; Suárez, E. Intramolecular hydrogen abstraction promoted by amidyl radicals. Evidence for electronic factors in the nucleophilic cyclization of ambident amides to oxocarbenium ions. Org. Lett.,  2005, 7(10), 2027-2030.
[http://dx.doi.org/10.1021/ol050526u] [PMID:  15876046] 
[45] 
Pal, A.P.J.; Gupta, P.; Suman Reddy, Y.; Vankar, Y.D. Synthesis of dihydroxymethyl dihydroxypyrrolidines and steviamine analogues from c-2 formyl glycals. Eur. J. Org. Chem.,  2010, 36, 6957-6966.
[46] 
Pal, A.P.J.; Vankar, Y.D. Azidation of anomeric nitro sugars: Application in the synthesis of spiroaminals as glycosidase inhibitors. Tetrahedron Lett.,  2010, 51(18), 2519-2524.
[http://dx.doi.org/10.1016/j.tetlet.2010.03.003] 
[47] 
Goyard, D.; Kónya, B.; Chajistamatiou, A.S.; Chrysina, E.D.; Leroy, J.; Balzarin, S.; Tournier, M.; Tousch, D.; Petit, P.; Duret, C.; Maurel, P.; Somsák, L.; Docsa, T.; Gergely, P.; Praly, J-P.; Azay-Milhau, J.; Vidal, S. Glucose-derived spiro-isoxazolines are anti-hyperglycemic agents against type 2 diabetes through glycogen phosphorylase inhibition. Eur. J. Med. Chem.,  2016, 108, 444-454.
[http://dx.doi.org/10.1016/j.ejmech.2015.12.004] [PMID:  26708111] 
[48] 
Benltifa, M.; Hayes, J.M.; Vidal, S.; Gueyrard, D.; Goekjian, P.G.; Praly, J.P.; Kizilis, G.; Tiraidis, C.; Alexacou, K.M.; Chrysina, E.D.; Zographos, S.E.; Leonidas, D.D.; Archontis, G.; Oikonomakos, N.G. Glucose-based spiro-isoxazolines: A new family of potent glycogen phosphorylase inhibitors. Bioorg. Med. Chem.,  2009, 17(20), 7368-7380.
[http://dx.doi.org/10.1016/j.bmc.2009.08.060] [PMID:  19781947] 
[49] 
Benltifa, M.; Vidal, S.; Gueyrard, D.; Goekjian, P.G.; Msaddek, M.; Praly, J-P. 1,3-Dipolar cycloaddition reactions on carbohydrate-based templates: Synthesis of spiro-isoxazolines and 1,2,4-oxadiazoles as glycogen phosphorylase inhibitors. Tetrahedron Lett.,  2006, 47(34), 6143-6147.
[http://dx.doi.org/10.1016/j.tetlet.2006.06.058] 
[50] 
Goyard, D.; Telligmann, S.M.; Goux-Henry, C.; Boysen, M.M.K.; Framery, E.; Gueyrard, D.; Vidal, S. Carbohydrate-based spiro bis(isoxazolines): Synthesis and evaluation in asymmetric catalysis. Tetrahedron Lett.,  2010, 51, 374.
[http://dx.doi.org/10.1016/j.tetlet.2009.11.028] 
[51] 
Li, X.; Takahashi, H.; Ohtake, H.; Ikegami, S. Synthesis of ketosyl spiro-isoxazolidine by 1,3-dipolar cycloaddition of 1-methylenesugars with nitrones -A new access to c-glycosyl amino acids. Heterocycles,  2003, 59, 547-571.
[http://dx.doi.org/10.3987/COM-02-S52] 
[52] 
Li, X.; Takahashi, H.; Ohtake, H.; Ikegami, S. A new, scalable preparation of a glucopyranosylidene-spiro-thiohydantoin: one of the best inhibitors of glycogen phosphorylases. Tetrahedron Lett.,  2004, 45, 4123.
[http://dx.doi.org/10.1016/j.tetlet.2004.03.155] 
[53] 
Somsák, L.; Bokor, É.; Czibere, B.; Czifrák, K.; Koppány, C.; Kulcsár, L.; Kun, S.; Szilágyi, E.; Tóth, M.; Docsa, T.; Gergely, P. Synthesis of C-xylopyranosyl- and xylopyranosylidene-spiro-heterocycles as potential inhibitors of glycogen phosphorylase. Carbohydr. Res.,  2014, 399, 38-48.
[http://dx.doi.org/10.1016/j.carres.2014.05.020] [PMID:  25081322] 
[54] 
Zhang, P-Z.; Li, X-L.; Chen, H.; Li, Y-N.; Wang, R. The synthesis and biological activity of novel spiro-isoxazoline C-disaccharides based on 1,3-dipolar cycloaddition of exo-glycals and sugar nitrile oxides. Tetrahedron Lett.,  2007, 48(44), 7813-7816.
[http://dx.doi.org/10.1016/j.tetlet.2007.09.007] 
[55] 
Somsák, L.; Nagy, V.; Vidal, S.; Czifrák, K.; Berzsényi, E.; Praly, J-P. Novel design principle validated: glucopyranosylidene-spiro-oxathiazole as new nanomolar inhibitor of glycogen phosphorylase, potential antidiabetic agent. Bioorg. Med. Chem. Lett.,  2008, 18(20), 5680-5683.
[http://dx.doi.org/10.1016/j.bmcl.2008.08.052] [PMID:  18793852] 
[56] 
Nagy, V.; Benltifa, M.; Vidal, S.; Berzsényi, E.; Teilhet, C.; Czifrák, K.; Batta, G.; Docsa, T.; Gergely, P.; Somsák, L.; Praly, J.P. Glucose-based spiro-heterocycles as potent inhibitors of glycogen phosphorylase. Bioorg. Med. Chem.,  2009, 17(15), 5696-5707.
[http://dx.doi.org/10.1016/j.bmc.2009.05.080] [PMID:  19574053] 
[57] 
Gregoriou, M.; Noble, M.E.M.; Watson, K.A.; Garman, E.F.; Krulle, T.M.; de la Fuente, C.; Fleet, G.W.J.; Oikonomakos, N.G.; Johnson, L.N. The structure of a glycogen phosphorylase glucopyranose spirohydantoin complex at 1.8 A resolution and 100 K: the role of the water structure and its contribution to binding. Protein Sci.,  1998, 7(4), 915-927.
[http://dx.doi.org/10.1002/pro.5560070409] [PMID:  9568898] 
[58] 
Brochard, L.; Joseph, B.; Viaud, M.C.; Rollin, P. 1,3-Dipolar cycloaddition of exo-methylenesugars with nitrone: Approach to new amino-C-ketosyl disaccharides. Synth. Commun.,  1994, 24(10), 1403-1414.
[http://dx.doi.org/10.1080/00397919408011744] 
[59] 
Praly, J.P.; Faure, R.; Joseph, B.; Kiss, L.; Rollin, P. Synthesis, structure and enzymatic evaluation of new spiro oxathiazole sugar derivatives. Tetrahedron,  1994, 50(22), 6559-6568.
[http://dx.doi.org/10.1016/S0040-4020(01)89686-1] 
[60] 
Elek, R.; Kiss, L.; Praly, J.P.; Somsák, L. beta-D-Galactopyranosyl-thiohydroximates and D-galactopyranosylidene-spiro-oxathiazoles: Synthesis and enzymatic evaluation against E. colid-galactosidase. Carbohydr. Res.,  2005, 340(7), 1397-1402.
[http://dx.doi.org/10.1016/j.carres.2005.02.021] [PMID:  15854612] 
[61] 
Goyard, D.; Kónya, B.; Czifrák, K.; Larini, P.; Demontrond, F.; Leroy, J.; Balzarin, S.; Tournier, M.; Tousch, D.; Petit, P.; Duret, C.; Maurel, P.; Docsa, T.; Gergely, P.; Somsák, L.; Praly, J-P.; Azay-Milhau, J.; Vidal, S. Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition. Org. Biomol. Chem.,  2020, 18(5), 931-940.
[http://dx.doi.org/10.1039/C9OB01190K] [PMID:  31922157] 
[62] 
Czifrák, K.; Páhi, A.; Deák, S.; Kiss-Szikszai, A.; Kövér, K.E.; Docsa, T.; Gergely, P.; Alexacou, K-M.; Papakonstantinou, M.; Leonidas, D.D.; Zographos, S.E.; Chrysina, E.D.; Somsák, L. Glucopyranosylidene-spiro-iminothiazolidinone, a new bicyclic ring system: synthesis, derivatization, and evaluation for inhibition of glycogen phosphorylase by enzyme kinetic and crystallographic methods. Bioorg. Med. Chem.,  2014, 22(15), 4028-4041.
[http://dx.doi.org/10.1016/j.bmc.2014.05.076] [PMID:  25009003] 
[63] 
Szabó, K.E.; Kun, S.; Mándi, A.; Kurtán, T.; Somsák, L. Glucopyranosylidene-spiro-thiazolinones: Synthetic studies and determination of absolute configuration by tddft-ecd calculations. Molecules,  2017, 22, 1760.
[http://dx.doi.org/10.3390/molecules22101760] 
[64] 
Szabó, K.E.; Kyriakis, E.; Psarra, A.G.; Karra, A.G.; Sipos, Á.; Docsa, T.; Stravodimos, G.A.; Katsidou, E.; Skamnaki, V.T.; Liggri, P.G.V.; Zographos, S.E.; Mándi, A.; Király, S.B.; Kurtán, T.; Leonidas, D.D.; Somsák, L. Glucopyranosylidene-spiro-imidazolinones, a new ring system: Synthesis and evaluation as glycogen phosphorylase inhibitors by enzyme kinetics and x-ray crystallography. J. Med. Chem.,  2019, 62(13), 6116-6136.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00356] [PMID:  31251604] 
[65] 
Stathi, A.; Mamais, M.; Chrysina, E.D.; Gimisis, T. Anomeric spironucleosides of β-d-glucopyranosyl uracil as potential inhibitors of glycogen phosphorylase. Molecules,  2019, 24(12), 2327.
[http://dx.doi.org/10.3390/molecules24122327] [PMID:  31242546] 
[66] 
Tite, T.; Tomas, L.; Docsa, T.; Gergely, P.; Kovensky, J.; Gueyrard, D.; Wadouachi, A. Synthesis of N-aryl spiro-sulfamides as potential glycogen phosphorylase inhibitors. Tetrahedron Lett.,  2012, 53(8), 959-961.
[http://dx.doi.org/10.1016/j.tetlet.2011.12.049] 
[67] 
Benltifa, M.; De Kiss, M.; Garcia-Moreno, M.I.; Mellet, C.O.; Gueyrard, D.; Wadouachi, A. Regioselective synthesis and biological evaluation of spiro-sulfamidate glycosides from exo-glycals. Tetrahedron Asymmetry,  2009, 20(15), 1817-1823.
[http://dx.doi.org/10.1016/j.tetasy.2009.07.012] 
[68] 
Toumieux, S.; Compain, P.; Martin, O.R. Intramolecular metal-catalyzed amination of pseudo-anomeric C–H bonds. Tetrahedron Lett.,  2005, 46(28), 4731-4735.
[http://dx.doi.org/10.1016/j.tetlet.2005.05.043] 
[69] 
Li, X.; Wang, R.; Wang, Y.; Chen, H.; Li, Z.; Ba, C.; Zhang, J. Stereoselective synthesis and biological activity of novel spiro-oxazinanone-C-glycosides. Tetrahedron,  2008, 64(42), 9911-9920.
[http://dx.doi.org/10.1016/j.tet.2008.08.002] 
[70] 
Lambu, M.R.; Hussain, A.; Sharma, D.K.; Yousuf, S.K.; Singh, B.; Tripathi, A.K.; Mukherjee, D. Synthesis of C-spiro-glycoconjugates from sugar lactones via zinc mediated Barbier reaction. RSC Advances,  2014, 4(22), 11023-11028.
[71] 
Chen, G.; Fei, Z.; Huang, X.; Xie, Y.; Xu, J.; Gola, J.; Steng, M.; Praly, J. Ring‐closing olefin metathesis of 3,3′‐(d‐glycopyranosylidene)bis(1‐propene) compounds as a route to anomeric spiro sugars. Eur. J. Org. Chem.,  2001, 2939-2946.
[http://dx.doi.org/10.1002/1099-0690(200108)2001:15<2939:AID-EJOC2939>3.0.CO;2-H] 
[72] 
Kun, S.; Kánya, N.; Galó, N.; Páhi, A.; Mándi, A.; Kurtán, T.; Makleit, P.; Veres, S.; Sipos, Á.; Docsa, T.; Somsák, L.J. Ring‐closing olefin metathesis of 3,3′‐(d‐glycopyranosylidene)bis(1‐propene) compounds as a route to anomeric spiro sugars. Agr. Food Chem.,  2019, 67(24), 6884-6891.
[http://dx.doi.org/10.1021/acs.jafc.9b00443] 
[73] 
Yu, J.X.; Zhang, S.; Li, Z.J.; Lu, W.J.; Zhang, L.J.; Zhou, R.; Liu, Y.T.; Cai, M.S. Synthesis, x-ray diffraction, and nmr analysis of (2s, 3a′r, 6′s, 7a′r)-3-acetyl-2′, 2′, 2″, 2″-tetramethyl-5-phenyl-2, 3-dihydro-1, 3, 4-oxadiazole-2-spiro-7′-1′, 3′-dioxolano [4, 5-c] pyrano-6′-spiro-4″-(1″, 3″-dioxolane). J. Carbohydr. Chem.,  2001, 20(9), 877-884.
[http://dx.doi.org/10.1081/CAR-100108664] 
[74] 
Alho, M.A.M.; D’Accorso, N.B. Synthesis and NMR analysis of spiranic heterocycles from carbohydrate derivatives. J. Heterocycl. Chem.,  2007, 44(4), 901-907.
[http://dx.doi.org/10.1002/jhet.5570440425] 
[75] 
Pan, Y.; Song, Q.L.; Lin, Y.H.; Lu, N.; Yu, H.M.; Li, X.J. GLB prevents tumor metastasis of Lewis lung carcinoma by inhibiting tumor adhesion actions. Acta Pharmacol. Sin.,  2005, 26(7), 881-886.
[http://dx.doi.org/10.1111/j.1745-7254.2005.00125.x] [PMID:  15960897] 
[76] 
Dong, H.; Xiang-Bao, M.; Lin-Na, W.; Hong, L.; Yun, Y.; Zhuo, W.; Zhen-Jun, Y.; Zhen-Min, L.; Zhong-Jun, L. Efficient synthesis of a series of novel fructose-based 3-acetyl-5-alkyl-2,3-dihydro-1,3,4-oxadiazole derivatives and studies of the reaction mechanism. Tetrahedron Asymmetry,  2009, 20, 399-410.
[http://dx.doi.org/10.1016/j.tetasy.2008.12.033] 
[77] 
Tardy, S.; Vicente, J.L.; Tatibouet, A.; Dujardin, G.; Rollin, P. Epoxides of d-fructose and l-sorbose: A convenient class of “click” functionality for the synthesis of a rare family of amino- and thio-sugars. Synthesis,  2008, 19, 3108-3120.
[78] 
Silva, S.; Tardy, S.; Routier, S.; Suzenet, F.; Tatibouet, A.; Rauter, A.P.; Rollin, P. 1,3-Oxazoline- and 1,3-oxazolidine-2-thiones as substrates in direct modified Stille and Suzuki cross-coupling. Tetrahedron Lett.,  2008, 49(39), 5583-5586.
[http://dx.doi.org/10.1016/j.tetlet.2008.07.023] 
[79] 
Zhang, F.; Liu, H.; Li, Y-F.; Liu, H-M. Novel synthesis of methyl 4,6-O-benzylidenespiro[2-deoxy-alpha-D-arabino-hexopyranoside-2,2′-imidazolidine] and its homologue and sugar-gamma-butyrolactam derivatives from methyl 4,6-O-benzylidene-alpha-D-arabino-hexopyranosid-2-ulose. Carbohydr. Res.,  2010, 345(6), 839-843.
[http://dx.doi.org/10.1016/j.carres.2010.01.004] [PMID:  20138258] 
[80] 
Postel, D.; Van Nhien, A.N.; Villa, P.; Ronco, G. Novel spirohydantoins of d-allose and d-ribose derived from glyco-α-aminonitriles. Tetrahedron Lett.,  2001, 42, 1499-1502.
[http://dx.doi.org/10.1016/S0040-4039(00)02294-2] 
[81] 
Gash, C.; Merino-Montiel, P.; López, O.; Fernández-Bolaños, J.G.; Fuentes, J. Spiranic d-gluco-configured N-substituted thiohydantoins as potential enzymatic inhibitors. Tetrahedron,  2010, 66, 9964-9973.
[http://dx.doi.org/10.1016/j.tet.2010.09.109] 
[82] 
Merino-Montiel, P.; Lopez, O.; Fernandez-Bolanos, J.G. Spiranic d-gluco-configured N-substituted thiohydantoins as potential enzymatic inhibitors. RSC Advances,  2012, 2(30), 11326-11335.
[83] 
Shibata, K.; Hiruma, K.; Kanie, O.; Wong, C-H. Synthesis of 1,1-linked galactosyl mannosides carrying a thiazine ring as mimetics of sialyl Lewis X antigen: investigation of the effect of carboxyl group orientation on P-selectin inhibition. J. Org. Chem.,  2000, 65(8), 2393-2398.
[http://dx.doi.org/10.1021/jo991556b] [PMID:  10789451] 
[84] 
Plewe, M.; Sandhoff, K.; Schmidt, R.R. Synthesis of 4‐epoxy‐4‐c‐methyleneglycosylceramides, potential glycosyltransferase inhibitors. Liebigs Ann. Chem.,  1992, 7, 699-708.
[http://dx.doi.org/10.1002/jlac.1992199201118] 
[85] 
Zacharias, C.; van Echten-Deckert, G.; Plewe, M.; Schmidt, R.R.; Sandhoff, K. A truncated epoxy-glucosylceramide uncouples glycosphingolipid biosynthesis by decreasing lactosylceramide synthase activity. J. Biol. Chem.,  1994, 269(18), 13313-13317.
[PMID: 8175761] 
[86] 
Freire, R.; Martin, A.; Perez-Martin, I.; Suarez, E. Synthesis of oxa-aza spirobicycles by intramolecular hydrogen abstraction promoted by N-radicals in carbohydrate systems. Tetrahedron Lett.,  2002, 43(29), 5113-5116.
[http://dx.doi.org/10.1016/S0040-4039(02)00983-8] 
[87] 
Amigues, E.J.; Greenberg, M.L.; Ju, S.; Chen, Y.; Migaud, M.E. Synthesis of cyclophospho-glucoses and glucitols. Tetrahedron,  2007, 63(40), 10042-10053.
[http://dx.doi.org/10.1016/j.tet.2007.07.027] 
[88] 
Robinson, R.P.; Mascitti, V.; Boustany-Kari, C.M.; Carr, C.L.; Foley, P.M.; Kimoto, E.; Leininger, M.T.; Lowe, A.; Klenotic, M.K.; Macdonald, J.I.; Maguire, R.J.; Masterson, V.M.; Maurer, T.S.; Miao, Z.; Patel, J.D.; Préville, C.; Reese, M.R.; She, L.; Steppan, C.M.; Thuma, B.A.; Zhu, T. C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization. Bioorg. Med. Chem. Lett.,  2010, 20(5), 1569-1572.
[http://dx.doi.org/10.1016/j.bmcl.2010.01.075] [PMID:  20149653] 
[89] 
Hammoud, J.; Joosten, A.; Lecourt, T. Functionalization of glucopyranosides at position 5 by 1,5 c-h insertion of rh(ii)-carbenes: Dramatic influence of the anomeric configuration. Carbohydr. Res.,  2019, 486107834
[http://dx.doi.org/10.1016/j.carres.2019.107834] [PMID:  31689578] 
[90] 
Shaw, M.; Kumar, A. Visible-light-mediated β-c(sp3)-h amination of glycosylimidates: En Route to oxazoline-fused/spiro nonclassical bicyclic sugars. Org. Lett.,  2019, 21(9), 3108-3113.
[http://dx.doi.org/10.1021/acs.orglett.9b00763] [PMID:  30998381] 
Cite As
Current Organic Synthesis

Pyranoid Spirosugars as Enzyme Inhibitors

Abstract

Graphical Abstract
