Generic placeholder image

Current Organic Synthesis


ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

Review Article

The History of the Glycosidase Inhibiting Hyacinthacine C-type Alkaloids: From Discovery to Synthesis.

Author(s): Anthony W. Carroll* and Stephen G. Pyne*

Volume 16, Issue 4, 2019

Page: [498 - 522] Pages: 25

DOI: 10.2174/1570179416666190126100312


Background: The inherent glycosidase inhibitory activity and potentially therapeutic value of the polyhydroxylated pyrrolizidine alkaloids containing a hydroxymethyl substituent at the C-3 position have been well documented. Belonging to this class, the naturally occurring hyacinthacine C-type alkaloids are of general interest among iminosugar researchers. Their selective micromolar α -glycosidase inhibitory ranges (10 – 100 μM) suggest that these azasugars are potential leads for treating type II diabetes. However, the structures of hyacinthacine C1, C3 and C4 are insecure with hyacinthacine C5 being recently corrected.

Objective: This review presents the hyacinthacine C-type alkaloids: their first discovery to the most recent advancements on the structures, biological activities and total synthesis.

Conclusion: The hyacinthacine C-type alkaloids are of exponentially increasing interest and will undoubtedly continue to be reported as synthetic targets. They represent a challenging but rewarding synthetic feat for the community of those interested in accessing biologically active iminosugars. Since 2009, ten total syntheses have been employed towards accessing similarly related products but only three have assessed the glycosidase inhibitory activity of the final products. This suggests the need for an accessible and universal glycosidase inhibitory assay so to accurately determine the structure-activity relationship of how the hyacinthacine C-type alkaloids inhibit specific glycosidases. Confirming the correct structures of the hyacinthacine C-type alkaloids as well as accessing various analogues continues to strengthen the foundation towards a marketable treatment for type II diabetes and other glycosidase related illnesses.

Keywords: Iminosugars, pyrrolizidine, hyacinthacine, alkaloids, total synthesis, natural product, glycosidase inhibition.

Graphical Abstract
Robins, D.J. The Pyrrolizidine Alkaloids. In: Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products; Herz, W.; Grisebach, H.; Kirby, G.W., Eds.; Springer Vienna: Vienna, 1982; Vol. 41, pp. 115-202.
Pass, D.A.; Hogg, G.G.; Russell, R.G.; Edgar, J.A.; Tence, I.M.; Rikard-Bell, L. Poisoning of chickens and ducks by pyrrolizidine alkaloids of Heliotropium europaeum. Aust. Vet. J., 1979, 55, 284-288.
Bull, L.B.; Culvenor, C.C.J.; Dick, A.T. The pyrrolizidine Alkaloids: Their Chemistry-Pathogenicity and Other Biological Properties; North-Holland Pub. Co: Amsterdam, 1968.
Huxtable, R.J. New aspects of the toxicology and pharmacology of pyrrolizidine alkaloids. Gen. Pharmacol- Vasc. Sys., 1979, 10, 159-167.
Allen, J.R.; Hsu, I.C.; Carstens, L.A. Dehydroretronecine-induced rhabdomyosarcomas in rats. Cancer Res., 1975, 35, 997-1002.
Schoental, R.A. Sensitive analytical method for pyrrolizidine alkaloids. The mass spectra of retronecine derivatives. Cancer Res., 1975, 35, 2020-2024.
Deinzer, M.; Thomson, P.; Griffin, D.; Dickinson, E. A sensitive analytical method for pyrrolizidine alkaloids. The mass spectra of retronecine derivatives. Biomed. Mass Spectrom., 1978, 5, 175-179.
Dickinson, J.O.; Cooke, M.P.; King, R.R.; Mohamed, P.A. Milk transfer of pyrrolizidine alkoloids in cattle. J. Am. Vet. Med. Assoc., 1976, 169, 1192-1196.
Tandon, H.D.; Tandon, B.N.; Mattocks, A.R. An epidemic of veno-occlusive disease of the liver in Afghanistan. Pathologic features. Am. J. Gastroenterol., 1978, 70, 607-613.
Robertson, K.A.; Seymour, J.L.; Hsia, M-T.; Allen, J.R. Covalent interaction of dehydroretronecine, a carcinogenic metabolite of the pyrrolizidine alkaloid monocrotaline, with cysteine and glutathione. Cancer Res., 1977, 37, 3141-3144.
Schoental, R. Alkylation of coenzymes and the acute effects of alkylating hepatotoxins. FEBS Lett., 1976, 61, 111-114.
Kovach, J.S.; Ames, M.M.; Powis, G.; Moertel, C.G.; Hahn, R.G.; Creagan, E.T. Toxicity and pharmacokinetics of a pyrrolizidine alkaloid, indicine N-oxide, in humans. Cancer Res., 1979, 39, 4540-4544.
Atal, C.K. Semisynthetic derivatives of pyrrolizidine alkaloids of pharmacodynamic importance: A review. Lloydia, 1978, 41, 312-326.
Nash, R.J.; Fellows, L.E.; Dring, J.V.; Fleet, G.W.J.; Derome, A.E.; Hamor, T.A.; Scofield, A.M.; Watkin, D.J. Isolation from alexaleiopetala and X-ray crystal structure of alexine, (1r,2r,3r,7s,8s)-3-hydroxymethyl-1,2,7-tri-hydroxypyrrolizidine [(2r,3r,4r,5s,6s)-2-hydroxymethyl-1-azabicyclo[3.3.0] octan-3,4,6-triol], a unique pyrrolizidine alkaloid. Tetrahedron Lett., 1988, 29, 2487-2490.
Molyneux, R.J.; Benson, M.; Wong, R.Y.; Tropea, J.E.; Elbein, A.D. Australine, a Novel Pyrrolizidine Alkaloid Glucosidase Inhibitor from Castanospermum australe. J. Nat. Prod., 1988, 51, 1198-1206.
Nash, R.J.; Fellows, L.E.; Dring, J.V.; Fleet, G.W.J.; Girdhar, A.; Ramsden, N.G.; Peach, J.M.; Hegarty, M.P.; Scofield, A.M. Two alexines [3-hydroxymethyl-1,2,7-trihydroxypyrrolizidines] from Castanospermum australe. Phytochemistry, 1990, 29, 111-114.
Nash, R.J.; Fellows, L.E.; Plant, A.C.; Fleet, G.W.J.; Derome, A.E.; Baird, P.D.; Hegarty, M.P.; Scofield, A.M. Isolation from castanospermum australe and x-ray crystal structure of 3,8-diepialexine, (1r,2r,3s,7s,8r)-3-hydroxymethyl-1,2,7-trihydroxypyrrolizidine [(2s,3r,4r,5s,6r)-2-hydroxy-methyl-1-azabicyclo[3.3.0]octan-3,4,6-triol]. Tetrahedron, 1988, 44, 5959-5964.
Kato, A.; Kano, E.; Adachi, I.; Molyneux, R.J.; Watson, A.A.; Nash, R.J.; Fleet, G.W.J.; Wormald, M.R.; Kizu, H.; Ikeda, K.; Asano, N. Australine and related alkaloids: Easy structural confirmation by 13C NMR spectral data and biological activities. Tetrahedron, 2003, 14, 325-331.
Jones, L.; Hollinshead, J.; Fleet, G.W.J.; Thompson, A.L.; Watkin, D.J.; Gal, Z.A.; Jenkinson, S.F.; Kato, A.; Nash, R.J. Isolation of the pyrrolizidine alkaloid 1-epialexine from Castanospermum australe. Phytochem. Lett., 2010, 3, 133-135.
Asano, N.; Nash, R.J.; Molyneux, R.J.; Fleet, G.W.J. Sugar-mimic glycosidase inhibitors: natural occurrence, biological activity and prospects for therapeutic application. Tetrahedron, 2000, 11, 1645-1680.
Asano, N. Alkaloidal Sugar Mimetics: Biological Activities and Therapeutic Applications. J. Enzyme Inhib. Med. Chem., 2000, 15, 215-234.
Tropea, J.E.; Molyneux, R.J.; Kaushal, G.P.; Pan, Y.T.; Mitchell, M.; Elbein, A.D. Australine, a pyrrolizidine alkaloid that inhibits amyloglucosidase and glycoprotein processing. Biochemistry, 1989, 28, 2027-2034.
Taylor, D.L.; Nash, R.; Fellows, L.E.; Kang, M.S.; Tyms, A.S. Naturally occurring pyrrolizidines: Inhibition of α-glucosidase 1 and anti-HIV activity of one steroisomer. Antivir. Chem. Chemother., 1992, 3, 273-277.
Simmonds, M.S.J.; Blaney, W.M.; Fellows, L.E. Behavioral and electrophysiological study of antifeedant mechanisms associated with polyhydroxy alkaloids. J. Chem. Ecol., 1990, 16, 3167-3196.
Fellows, L.E.; Evans, S.V.; Nash, R.J.; Bell, E.A. Polyhydroxy plant alkaloids as glycosidase inhibitors and their possible ecological role. ACS Symp. Ser., 1986, 296, 72-78.
Nash, R.J.; Thomas, P.I.; Waigh, R.D.; Fleet, G.W.J.; Wormald, M.R. de Q. Lilley, P.M.; Watkin, D.J. Casuarine: A very highly oxygenated pyrrolizidine alkaloid. Tetrahedron Lett., 1994, 35, 7849-7852.
Chopra, R.N.; Nayar, S.L. Glossary of Indian Medicinal Plants; Council of Scientific and Industrial Research: New Delhi, 1956.
Wormald, M.; Nash, R.; Watson, A.; Bhadoria, B.; Langford, R.; Sims, M.; Fleet, G. Casuarine-6-α-D-glucoside from Casuarina equisetifolia and Eugenia jambolana. Carbohydr. Lett., 1996, 2, 169-174.
Davis, A.S.; Pyne, S.G.; Skelton, B.W.; White, A.H. Synthesis of Putative Uniflorine A. J. Org. Chem., 2004, 69, 3139-3143.
Matsumura, T.; Kasai, M.; Hayashi, T.; Arisawa, M.; Momose, Y.; Arai, I.; Amagaya, S.; Komatsu, Y. α-Glucosidase inhibitors from paraguayan natural medicine, nangapiry, the leaves of Eugenia uniflora. Pharm. Biol., 2000, 38, 302-307.
Ritthiwigrom, T.; Pyne, S.G. Synthesis of (+)-uniflorine a: A structural reassignment and a configurational assignment. Org. Lett., 2008, 10, 2769-2771.
Davis, A.S.; Ritthiwigrom, T.; Pyne, S.G. Synthetic and spectroscopic studies on the structures of uniflorines A and B: Structural revision to 1,2,6,7-tetrahydroxy-3-hydroxymethylpyrrolizidine alkaloids. Tetrahedron, 2008, 64, 4868-4879.
Karanjule, N.S.; Markad, S.D.; Dhavale, D.D. Synthesis of pentahydroxy indolizidine alkaloids using ring closing metathesis: Attempts to find the correct structure of uniflorine A. J. Org. Chem., 2006, 71, 6273-6276.
Zhao, Z.; Song, L.; Mariano, P.S. A concise sequential photochemical-metathesis approach for the synthesis of (+)-castanospermine and possible uniflorine-A stereoisomers. Tetrahedron, 2005, 61, 8888-8894.
Bell, A.A.; Pickering, L.; Watson, A.A.; Nash, R.J.; Griffiths, R.C.; Jones, M.G.; Fleet, G.W.J. 2-Hydroxycastanospermines (dihydroxy-L-swainsonines) from octonolactones: Inhibition of naringinase (L-rhamnosidase). Tetrahedron Lett., 1996, 37, 8561-8564.
Ameijde, J.V.; Horne, G.; Wormald, M.R.; Dwek, R.A.; Nash, R.J.; Jones, P.W.; Evinson, E.L.; Fleet, G.W.J. Isolation synthesis and glycosidase inhibition profile of 3-epi-casuarine. Tetrahedron Asymmetry, 2006, 17, 2702-2712.
The Angiosperm Phylogeny Group. An update of the Angiosperm Phylogeny Group classification for the orders and families of flowering plants: APG III. Bot. J. Linn. Soc., 2009, 161, 105-121.
Nash, R.; Watson, A.A.; Asano, N. Alkaloids: Chemical and biological Perspectives; Elsevier: Oxford, 1996, Vol. 11, .
Thursby-Pelham, R.H. Suspected Scilla non-scripta (bluebell) poisoning in cattle. Vet. Rec., 1967, 80, 709-710.
Watson, A.A.; Nash, R.J.; Wormald, M.R.; Harvey, D.J.; Dealler, S.; Lees, E.; Asano, N.; Kizu, H.; Kato, A.; Griffiths, R.C.; Cairns, A.J.; Fleet, G.W.J. Glycosidase-inhibiting pyrrolidine alkaloids from Hyacinthoides non- scripta. Phytochemistry, 1997, 46, 255-259.
Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda, K.; Komae, T.; Kizu, H.; Kameda, Y.; Watson, A.A.; Nash, R.J.; Wormald, M.R.; Fleet, G.W.J.; Asano, N. Polyhydroxylated pyrrolidine and pyrrolizidine alkaloids from Hyacinthoides non-scripta and Scilla campanulata. Carbohydr. Res., 1999, 316, 95-103.
Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda, Y.; Kato, A.; Adachi, I.; Watson, A.A.; Nash, R.J.; Fleet, G.W.J. New polyhydroxylated pyrrolizidine alkaloids from Muscari armeniacum: Structural determination and biological activity. Tetrahedron Asymmetry, 2000, 11, 1-8.
Mehta, A.; Zitzmann, N.; Rudd, P.M.; Block, T.M.; Dwek, R.A. α-Glucosidase inhibitors as potential broad based anti-viral agents. FEBS Lett., 1998, 430, 17-22.
Watson, A.A.; Fleet, G.W.; Asano, N.; Molyneux, R.J.; Nash, R.J. Polyhydroxylated alkaloids - natural occurrence and therapeutic applications. Phytochemistry, 2001, 56, 265-295.
Platt, F.M.; Neises, G.R.; Reinkensmeier, G.; Townsend, M.J.; Perry, V.H.; Proia, R.L.; Winchester, B.; Dwek, R.A.; Butters, T.D. Prevention of lysosomal storage in tay-sachs mice treated with N-butyldeoxynojirimycin. Science, 1997, 276, 428-431.
Cox, T.; Lachmann, R.; Hollak, C.; Aerts, J.; van Weely, S.; Hrebícek, M.; Platt, F.; Butters, T.; Dwek, R.; Moyses, C.; Gow, I.; Elstein, D.; Zimran, A. Novel oral treatment of Gaucher’s disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet, 2000, 355, 1481-1485.
Fan, J-Q.; Ishii, S.; Asano, N.; Suzuki, Y. Accelerated transport and maturation of lysosomal α-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat. Med., 1999, 5, 112-115.
Yamashita, T.; Yasuda, K.; Kizu, H.; Kameda, Y.; Watson, A.A.; Nash, R.J.; Fleet, G.W.J.; Asano, N. New polyhydroxylated pyrrolidine, piperidine, and pyrrolizidine alkaloids from Scilla sibirica. J. Nat. Prod., 2002, 65, 1875-1881.
Asano, N.; Ikeda, K.; Kasahara, M.; Arai, Y.; Kizu, H. Glycosidase-inhibiting pyrrolidines and pyrrolizidines with a long side chain in Scilla peruviana. J. Nat. Prod., 2004, 67, 846-850.
Kato, A.; Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G.W.J.; Kuriyama, C.; Ikeda, K.; Asano, N.; Nash, R.J. Isolation of glycosidase-inhibiting hyacinthacines and related alkaloids from Scilla socialis. J. Nat. Prod., 2007, 70, 993-997.
Chabaud, L.; Landais, Y.; Renaud, P. Total synthesis of hyacinthacine A1 and 3-epi-hyacinthacine A1. Org. Lett., 2005, 7, 2587-2590.
Rambaud, L.; Compain, P.; Martin, O.R. First total synthesis of (+)-hyacinthacine A2. Tetrahedron Asymmetry, 2001, 12, 1807-1809.
Izquierdo, I.; Plaza, M.T.; Franco, F. Polyhydroxylated pyrrolizidines. Part 2: The first total synthesis of (+)-hyacinthacine A3. Tetrahedron, 2002, 13, 1581-1585.
Zhang, T-X.; Zhou, L.; Cao, X-P. First Total synthesis of hyacinthacine a6 from the protected derivative of polyhydroxylated pyrrolidine. Chem. Res. Chin. Univ., 2008, 24, 469-472.
Donohoe, T.J.; Thomas, R.E.; Cheeseman, M.D.; Rigby, C.L.; Bhalay, G.; Linney, I.D. Flexible strategy for the synthesis of pyrrolizidine alkaloids. Org. Lett., 2008, 10, 3615-3618.
Izquierdo, I.; Plaza, M.T.; Tamayo, J.A.; Yáñez, V.; Lo Re, D.; Sánchez-Cantalejo, F. First total synthesis and absolute configuration of naturally occurring (−)-hyacinthacine A7 and its (−)-1-epi-isomer. Tetrahedron, 2008, 64, 4613-4618.
Sengoku, T.; Satoh, Y.; Oshima, M.; Takahashi, M.; Yoda, H. First asymmetric synthesis of pyrrolizidine alkaloids, (+)-hyacinthacine B1 and (+)-B2. Tetrahedron, 2008, 64, 8052-8058.
Au, C.W.G.; Nash, R.J.; Pyne, S.G. Synthesis of hyacinthacine B3 and purported hyacinthacine B7. Chem. Commun., 2010, 46, 713-715.
Savaspun, K.; Au, C.W.G.; Pyne, S.G. Total synthesis of hyacinthacines B3, B4, and B5 and purported hyacinthacine B7, 7-epi-hyacinthacine B7, and 7a-epi-hyacinthacine B3 from a common precursor. J. Org. Chem., 2014, 79, 4569-4581.
Sengoku, T.; Satoh, Y.; Takahashi, M.; Yoda, H. Total synthesis of the proposed structures of hyacinthacines C2, C3, and their C5-epimers. Tetrahedron Lett., 2009, 50, 4937-4940.
Zhang, W.; Sato, K.; Kato, A.; Jia, Y-M.; Hu, X-G.; Wilson, F.X.; van Well, R.; Horne, G.; Fleet, G.W.J.; Nash, R.J.; Yu, C-Y. Synthesis of fully substituted polyhydroxylated pyrrolizidines via cope–house cyclization. Org. Lett., 2011, 13, 4414-4417.
Tamayo, J.A.; Franco, F.; Sánchez-Cantalejo, F. Synthesis of the proposed structure of pentahydroxylated pyrrolizidine hyacinthacine C5 and Its C6,C7 epimer. Eur. J. Org. Chem., 2011, 35, 7182-7188.
Pecchioli, T.; Cardona, F.; Reissig, H-U.; Zimmer, R.; Goti, A. alkoxyallene-based stereodivergent syntheses of (−)-hyacinthacine B4 and of putative hyacinthacine C5 epimers: Proposal of hyacinthacine C5 structure. J. Org. Chem., 2017, 82, 5835-5844.
Carroll, A.W.; Savaspun, K.; Willis, A.C.; Hoshino, M.; Kato, A.; Pyne, S.G. Total synthesis of natural hyacinthacine C5 and six related hyacinthacine C5 epimers. J. Org. Chem., 2018, 83, 5558-5576.
Muniraju, C.; Rao, M.V.; Rajender, A.; Rao, B.V. A common approach to the total synthesis of l-1-deoxyallonojirimycin, l-homo-1-deoxyazaallose and triacetyl derivative of 5-epi-hyacinthacine A5. Tetrahedron Lett., 2016, 57, 1763-1766.
Izquierdo, I.; Plaza, M.T.; Tamayo, J.A.; Sánchez-Cantalejo, F. Total synthesis of the 5-epimers of naturally occurring (-)-hyacinthacine A5 and unnatural (+)-hyacinthacine A4. Tetrahedron, 2007, 18, 2211-2217.
Robertson, J.; Stevens, K. Pyrrolizidine alkaloids. Nat. Prod. Rep., 2014, 31, 1721-1788.
Robertson, J.; Stevens, K. Pyrrolizidine alkaloids: Occurrence, biology, and chemical synthesis. Nat. Prod. Rep., 2017, 34, 62-89.
Tamariz, J.; Burgueño-Tapia, E.; Vázquez, M.A.; Delgado, F. Pyrrolizidine Alkaloids. In: The Alkaloids: Chemistry and Biology; Knölker, H-J., Ed.; Academic Press, 2018; Vol. 80, pp. 1-314.
Ritthiwigrom, T.; Au, W.G.C.; Pyne, G.S. Structure, biological activities and synthesis of hyacinthacine alkaloids and their stereoisomers. Curr. Org. Synth., 2012, 9, 583-612.
Tamayo, J.A.; Franco, F.; Re, D.L.; Sánchez-Cantalejo, F. Synthesis of pentahydroxylated pyrrolizidines and indolizidines. J. Org. Chem., 2009, 74, 5679-5682.
Tamayo, J.A.; Franco, F.; Sánchez-Cantalejo, F. Synthesis of unnatural pentahydroxylated pyrrolizidines: 5-epi- and 5,7a-di-epi-hyacinthacine C1. Tetrahedron, 2010, 66, 7262-7267.
Izquierdo, I.; Plaza, M.T.; Tamayo, J.A.; Franco, F.; Sánchez-Cantalejo, F. Total synthesis of natural (+)-hyacinthacine A6 and non-natural (+)-7a-epi-hyacinthacine A1 and (+)-5,7a-di-epi-hyacinthacine A6. Tetrahedron, 2010, 66, 3788-3794.
Beňadiková, D.; Medvecký, M.; Filipová, A.; Moncol, J.; Gembický, M.; Prónayová, N.; Fischer, R. New synthetic approach to C5-hydroxymethyl-substituted polyhydroxylated pyrrolizidines. Synlett, 2014, 25, 1616-1620.
Lahiri, R.; Palanivel, A.; Kulkarni, S.A.; Vankar, Y.D. Synthesis of isofagomine–pyrrolidine hybrid sugars and analogues of (−)-steviamine and (+)-hyacinthacine C5 using 1,3-dipolar cycloaddition reactions. J. Org. Chem., 2014, 79, 10786-10800.
Palanivel, A.; Dharuman, S.; Vankar, Y.D. Synthesis of analogues of hyacinthacines, casuarine and uniflorine A from C-2 formyl galactal. Tetrahedron, 2016, 27, 1088-1100.
Appel, R. Tertiary phosphane/tetrachloromethane, a versatile reagent for chlorination, dehydration, and P-N linkage. Angew. Chem. Int. Ed. Engl., 1975, 14, 801-811.
Jasiński, M.; Moreno-Clavijo, E.; Reissig, H-U. Synthesis of a series of enantiopure polyhydroxylated bicyclic N-heterocycles from an L-erythrose-derived nitrone and alkoxyallenes. Eur. J. Org. Chem., 2014, 2, 442-454.

© 2024 Bentham Science Publishers | Privacy Policy