Advertisement

Phytochemistry Reviews

, Volume 13, Issue 2, pp 471–498 | Cite as

Natural products and their derivatives as inhibitors of glycogen phosphorylase: potential treatment for type 2 diabetes

  • Joseph M. Hayes
  • Anastassia L. Kantsadi
  • Demetres D. Leonidas
Article

Abstract

Glycogen phosphorylase (GP) (EC 2.4.1.1) is an important therapeutic target for the potential treatment of type 2 diabetes. The search for potent, selective and drug-like GP inhibitors which may eventually lead to hypoglycaemic agents has to date uncovered a number of natural product inhibitors with both pharmaceutical and nutraceutical potential. GP is an allosteric protein with at least six different ligand binding sites that modulate its enzymatic activity. Hence, inhibitors with considerable structural diversity can be designed. This review is focused on advances in the discovery of natural products and their derivatives as GP inhibitors.

Keywords

Diabetes Flavonoids Glucose analogues Indirubins Pentacyclic triterpenes 

Notes

Acknowledgments

A.L.K. and D.D.L. would like to acknowledge the support of the “ARISTEIA” Action of the “Operational Programme Education and Lifelong Learning” co-funded by the European Social Fund (ESF) and National Resources. This work was also supported in part by the Postgraduate Programmes ‘‘Biotechnology-Quality assessment in Nutrition and the Environment”, ‘‘Application of Molecular Biology-Molecular Genetics-Molecular Markers”, Department of Biochemistry and Biotechnology, University of Thessaly.

References

  1. Agius L (2010) Physiological control of liver glycogen metabolism: lessons from novel glycogen phosphorylase inhibitors. Mini Rev Med Chem 10:1175–1187PubMedGoogle Scholar
  2. Andersen B, Rassov A, Westergaard N, Lundgren K (1999) Inhibition of glycogenolysis in primary rat hepatocytes by 1,4-dideoxy-1,4-imino-D-arabinitol. Biochem J 342(Pt 3):545–550PubMedCentralPubMedGoogle Scholar
  3. Asano N, Yamashita T, Yasuda K, Ikeda K, Kizu H, Kameda Y, Kato A, Nash RJ, Lee HS, Ryu KS (2001) Polyhydroxylated alkaloids isolated from mulberry trees (Morus alba L.) and silkworms (Bombyx mori L.). J Agric Food Chem 49:4208–4213PubMedGoogle Scholar
  4. Barford D, Johnson LN (1989) The allosteric transition of glycogen phosphorylase. Nature 340:609–616PubMedGoogle Scholar
  5. Barford D, Hu SH, Johnson LN (1991) Structural mechanism for glycogen phosphorylase control by phosphorylation and AMP. J Mol Biol 218:233–260PubMedGoogle Scholar
  6. Benltifa M, Vidal S, Fenet B, Msaddek M, Goekjian PG, Praly J-P, Brunyanszki A, Docsa T, Gergely P (2006) In search of glycogen phosphorylase inhibitors: 5-substituted 3-C-glucopyranosyl-1,2,4-oxadiazoles from β-D-glucopyranosyl cyanides upon cyclization of O-acylamidoxime intermediates. Eur J Org Chem 18:4242–4256Google Scholar
  7. Benltifa M, Hayes JM, Vidal S, Gueyrard D, Goekjian PG, Praly J-P, Kizilis G, Tiraidis C, Alexacou KM, Chrysina ED, Zographos SE, Leonidas DD, Archontis G, Oikonomakos NG (2009) Glucose-based spiro-isoxazolines: a new family of potent glycogen phosphorylase inhibitors. Bioorg Med Chem 17:7368–7380PubMedGoogle Scholar
  8. Bergans N, Stalmans W, Goldmann S, Vanstapel F (2000) Molecular mode of inhibition of glycogenolysis in rat liver by the dihydropyridine derivative, BAY R3401: inhibition and inactivation of glycogen phosphorylase by an activated metabolite. Diabetes 49:1419–1426PubMedGoogle Scholar
  9. Bokor E, Docsa T, Gergely P, Somsak L (2010) Synthesis of 1-(D-glucopyranosyl)-1,2,3-triazoles and their evaluation as glycogen phosphorylase inhibitors. Bioorg Med Chem 18:1171–1180PubMedGoogle Scholar
  10. Bokor E, Docsa T, Gergely P, Somsak L (2013) C-Glucopyranosyl-1,2,4-triazoles As new potent inhibitors of glycogen phosphorylase. ACS Med Chem Lett 4:47–50Google Scholar
  11. Butler MS (2005) Natural products to drugs: natural product derived compounds in clinical trials. Nat Prod Rep 22:162–195PubMedGoogle Scholar
  12. Chen J, Liu J, Gong YC, Zhang LY, Hua WY, Sun HB (2006a) Synthesis and biological evaluation of urosolic acid derivatives as novel inhibitors of glycogen phosphorylase. J China Pharm Univ 37:397–402Google Scholar
  13. Chen J, Liu J, Zhang LY, Wu GZ, Hua WY, Wu XM, Sun HB (2006b) Pentacyclic triterpenes. Part 3: synthesis and biological evaluation of oleanolic acid derivatives as novel inhibitors of glycogen phosphorylase. Bioorg Med Chem Lett 16:2915–2919PubMedGoogle Scholar
  14. Chen J, Gong YC, Liu J, Hua WY, Zhang LY, Sun HB (2008) Synthesis and biological evaluation of novel pyrazolo[4,3-b]oleanane derivatives as inhibitors of glycogen phosphorylase. Chem Biodivers 5:1304–1312PubMedGoogle Scholar
  15. Cheng K, Liu J, Liu X, Li H, Sun H, Xie J (2009) Synthesis of glucoconjugates of oleanolic acid as inhibitors of glycogen phosphorylase. Carbohydr Res 344:841–850PubMedGoogle Scholar
  16. Cheng K, Liu J, Sun H, Bokor E, Czifrak K, Konya B, Toth M, Docsa T, Gergely P, Somsak L (2010a) Tethered derivatives of D-glucose and pentacyclic triterpenes for homo/heterobivalent inhibition of glycogen phosphorylase. New J Chem 34:1450–1464Google Scholar
  17. Cheng KG, Liu J, Sun HB, Xie J (2010b) Synthesis of oleanolic acid dimers as inhibitors of glycogen phosphorylase. Chem Biodivers 7:690–697PubMedGoogle Scholar
  18. Cheng KG, Wang C, Liu J, Xie J, Sun HB (2010c) Synthesis and evaluation of C-28 oleanolic acid derivatives as inhibitors of glycogen phosphorylase. Lett Drug Des Discov 7:116–121Google Scholar
  19. Chinese Pharmacopoeia Editorial Committee (1995) Vol 1. People’s Health Publisher, BeijingGoogle Scholar
  20. Chrysina ED (2010) The prototype of glycogen phosphorylase. Mini Rev Med Chem 10:1093–1101PubMedGoogle Scholar
  21. Chrysina ED, Bokor E, Alexacou KM, Charavgi MD, Oikonomakos GN, Zographos SE, Leonidas DD, Oikonomakos NG, Laszlo S (2009) Amide-1, 2, 3-triazole bioisosterism: the glycogen phosphorylase case. Tetrahedron: Asymm 20:733–740Google Scholar
  22. Cohen P (2006) The twentieth century struggle to decipher insulin signalling. Nat Rev Mol Cell Biol 7:867–873PubMedGoogle Scholar
  23. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, Lin JK, Farzadfar F, Khang YH, Stevens GA, Rao M, Ali MK, Riley LM, Robinson CA, Ezzati M (2011) National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 9785:31–40Google Scholar
  24. Daview TG, Tunnah P, Meijer L, Marko D, Eisenbrand G, Endicott JA, Noble MEM (2001) Inhibitor binding to active and inactive CDK2: the crystal structure of CDK2-Cyclin A/Indirubin-5-sulphonate. Structure 9:389–397Google Scholar
  25. Docsa T, Czifrak K, Huse C, Somsak L, Gergely P (2011) Effect of glucopyranosylidene-spiro-thiohydantoin on glycogen metabolism in liver tissues of streptozotocin-induced and obese diabetic rats. Mol Med Rep 4:477–481PubMedGoogle Scholar
  26. Felföldi N (2009) Department of Chemistry, PhD. University of Debrecen, DebrecenGoogle Scholar
  27. Fosgerau K, Westergaard N, Quistorff B, Grunnet N, Kristiansen M, Lundgren K (2000) Kinetic and functional characterization of 1,4-dideoxy-1, 4-imino-d-arabinitol: a potent inhibitor of glycogen phosphorylase with anti-hyperglyceamic effect in ob/ob mice. Arch Biochem Biophys 380:274–284PubMedGoogle Scholar
  28. Furukawa S, Murakami K, Nishikawa M, Nakayama O, Hino M (2005) FR258900, a novel glycogen phosphorylase inhibitor isolated from fungus no. 138354. II. Anti-hyperglycemic effects in diabetic animal models. J Antibiot (Tokyo) 58:503–506Google Scholar
  29. Gershell L (2005) Type 2 diabetes market. Nat Rev Drug Discov 4:367–368PubMedGoogle Scholar
  30. Goldsmith EJ, Fletterick RJ, Withers SG (1987) The three-dimensional structure of Acarbose bound to glycogen phosphorylase. J Biol Chem 262:1449–1455PubMedGoogle Scholar
  31. Goyard D, Baron M, Skourti PV, Chajistamatiou AS, Docsa T, Gergely P, Chrysina ED, Praly J-P, Vidal S (2012) Synthesis of 1,2,3-triazoles from xylosyl and 5-thioxylosyl azides: evaluation of the xylose scaffold for the design of potential glycogen phosphorylase inhibitors. Carbohyd Res 364:28–40Google Scholar
  32. Gyorgydeak Z, Hadady Z, Felfoldi N, Krakomperger A, Nagy V, Toth M, Brunyanszki A, Docsa T, Gergely P, Somsak L (2004) Synthesis of N-(β-D-glucopyranosyl)- and N-(2-acetamido-2-deoxy-β-D-glucopyranosyl) amides as inhibitors of glycogen phosphorylase. Bioorg Med Chem 12:4861–4870PubMedGoogle Scholar
  33. Habash M, Taha MO (2011) Ligand-based modelling followed by synthetic exploration unveil novel glycogen phosphorylase inhibitory leads. Bioorg Med Chem 19:4746–4771PubMedGoogle Scholar
  34. Hampson LJ, Arden C, Agius L, Ganotidis M, Kosmopoulou MN, Tiraidis C, Elemes Y, Sakarellos C, Leonidas DD, Oikonomakos NG (2006) Bioactivity of glycogen phosphorylase inhibitors that bind to the purine nucleoside site. Bioorg Med Chem 14:7835–7845PubMedGoogle Scholar
  35. Hao J, Zhang P, Wen XA, Sun HB (2008) Efficient access to 2-isobetulinic acid, 2-isooleanolic acid, and 2-isoursolic acid. J Org Chem 73:7405–7408PubMedGoogle Scholar
  36. Hayes JM, Leonidas DD (2010) Computation as a tool for glycogen phosphorylase inhibitor design. Mini Rev Med Chem 10:1156–1174PubMedGoogle Scholar
  37. Hayes JM, Skamnaki VT, Archontis G, Lamprakis C, Sarrou J, Bischler N, Skaltsounis AL, Zographos SE, Oikonomakos NG (2011) Kinetics, in silico docking, molecular dynamics, and MM-GBSA binding studies on prototype indirubins, KT5720, and staurosporine as phosphorylase kinase ATP-binding site inhibitors: the role of water molecules examined. Proteins Struct Func Bioinf 79:703–719Google Scholar
  38. Hellerstein MK, Neese RA, Linfoot P, Christiansen M, Turner S, Letscher A (1997) Hepatic gluconeogenic fluxes and glycogen turnover during fasting in humans. A stable isotope study. J Clin Invest 100:1305–1319PubMedCentralPubMedGoogle Scholar
  39. Holton S, Merckx A, Burgess D, Doerig C, Noble M, Endicott J (2003) Structures of P. falciparum PfPK5 test the CDK regulation paradigm and suggest mechanisms of small molecule inhibition. Structure 11:1329–1337PubMedGoogle Scholar
  40. Hoover DJ, Lefkowitz-Snow S, Burgess-Henry JL, Martin WH, Armento SJ, Stock IA, McPherson RK, Genereux PE, Gibbs EM, Treadway JL (1998) Indole-2-carboxamide inhibitors of human liver glycogen phosphorylase. J Med Chem 41:2934–2938PubMedGoogle Scholar
  41. Horne G, Wilson FX, Tinsley J, Williams DH, Storer R (2011) Iminosugars past, present and future: medicines for tomorrow. Drug Discov Today 16:107–118PubMedGoogle Scholar
  42. Hudson JW, Golding GB, Crerar MM (1993) Evolution of allosteric control in glycogen-phosphorylase. J Mol Biol 234:700–721PubMedGoogle Scholar
  43. Irwin JJ, Shoichet BK (2005) ZINC-a free database of commercially available compounds for virtual screening. J Chem Inf Model 45:177–182PubMedCentralPubMedGoogle Scholar
  44. Jacob JR, Mansfield K, You JE, Tennant BC, Kim YH (2007) Natural iminosugar derivatives of 1-deoxynojirimycin inhibit glycosylation of hepatitis viral envelope proteins. J Microbiol 45:431–440PubMedGoogle Scholar
  45. Jakobs S, Fridrich D, Hofem S, Pahlke G, Eisenbrand G (2006) Natural flavonoids are potent inhibitors of glycogen phosphorylase. Mol Nutr Food Res 50:52–57PubMedGoogle Scholar
  46. Jautelat R, Brumby T, Schafer M, Briem H, Eisenbrand G, Schwahn S, Kruger M, Lucking U, Prien O, Siemeister G (2005) From the insoluble dye indirubin towards highly active, soluble CDK2-inhibitors. ChemBioChem 6:531–540PubMedGoogle Scholar
  47. Johnson LN (1992) Glycogen phosphorylase: control by phosphorylation and allosteric effectors. FASEB J 6:2274–2282PubMedGoogle Scholar
  48. Johnson LN, Snape P, Martin JL, Acharya KR, Barford D, Oikonomakos NG (1993) Crystallographic binding studies on the allosteric inhibitor glucose-6-phosphate to T state glycogen phosphorylase b. J Mol Biol 232:253–267PubMedGoogle Scholar
  49. Jones RM (2012) New therapeutic strategies for type 2 diabetes: small molecule approaches. RSC drug discovery series no 27, Cambridge, UKGoogle Scholar
  50. Kaiser A, Nishi K, Gorin FA, Walsh DA, Bradbury EM, Schnier JB (2001) The cyclin-dependent kinase (CDK) inhibitor flavopiridol inhibits glycogen phosphorylase. Arch Biochem Biophys 386:179–187PubMedGoogle Scholar
  51. Kalra EK (2003) Nutraceutical-definition and introduction. AAPS PharmSci 5:E25PubMedGoogle Scholar
  52. Kamiyama O, Sanae F, Ikeda K, Higashi Y, Minami Y, Asano N, Adachi I, Kato A (2010) In vitro inhibition of α-glucosidases and glycogen phosphorylase by catechin gallates in green tea. Food Chem 122:1061–1066Google Scholar
  53. Kantsadi AL, Hayes JM, Manta S, Skamnaki VT, Kiritsis C, Psarra AM, Koutsogiannis Z, Dimopoulou A, Theofanous S, Nikoleousakos N, Zoumpoulakis P, Kontou M, Papadopoulos G, Zographos SE, Komiotis D, Leonidas DD (2012a) The sigma-hole phenomenon of halogen atoms forms the structural basis of the strong inhibitory potency of C5 halogen substituted glucopyranosyl nucleosides towards glycogen phosphorylase b. ChemMedChem 7:722–732PubMedGoogle Scholar
  54. Kantsadi AL, Manta S, Psarra AM, Dimopoulou A, Kiritsis C, Parmenopoulou V, Skamnaki VT, Zoumpoulakis P, Zographos SE, Leonidas DD, Komiotis D (2012b) The binding of C5-alkynyl and alkylfurano[2,3-d]pyrimidine glucopyranonucleosides to glycogen phosphorylase b: synthesis, biochemical and biological assessment. Eur J Med Chem 54:740–749PubMedGoogle Scholar
  55. Kantsadi AL, Apostolou A, Theofanous S, Stravodimos GA, Kyriakis E, Gorgogietas VA, Chatzileontiadou DSM, Pegiou K, Skamnaki VT, Stagos D, Kouretas D, Psarra A-MG, Haroutounian SA, Leonidas DD (2014) Biochemical and biological assessment of the inhibitory potency of extracts from vinification by products of Vitis vinifera extracts against glycogen phosphorylase. Food Chem Toxicol 67:35–43PubMedGoogle Scholar
  56. Kasvinsky PJ, Madsen NB, Fletterick RJ, Sygusch J (1978a) X-ray crystallographic and kinetic studies of oligosaccharide binding to phosphorylase. J Biol Chem 253:1290–1296PubMedGoogle Scholar
  57. Kasvinsky PJ, Madsen NB, Sygusch J, Fletterick RJ (1978b) Regulation of glycogen phosphorylase-a by nucleotide derivatives—kinetic and X-ray crystallographic studies. J Biol Chem 253:3343–3351PubMedGoogle Scholar
  58. Kato A, Nasu N, Takebayashi K, Adachi I, Minami Y, Sanae F, Asano N, Watson AA, Nash RJ (2008a) Structure-activity relationships of flavonoids as potential inhibitors of glycogen phosphorylase. J Agric Food Chem 56:4469–4473PubMedGoogle Scholar
  59. Kato A, Minoshima Y, Yamamoto J, Adachi I, Watson AA, Nash RJ (2008b) Protective effects of dietary chamomile tea on diabetic complications. J Agric Food Chem 56:8206–8211PubMedGoogle Scholar
  60. Kato A, Kamiyama O, Sanae F, Ikeda K, Higashi Y, Minami Y, Asano N, Adachi I (2010) In vitro inhibition of α-glucosidases and glycogen phosphorylase by catechin gallates in green tea. Food Chem 122:1061–1066Google Scholar
  61. Klabunde T, Wendt KU, Kadereit D, Brachvogel V, Burger HJ, Herling AW, Oikonomakos NG, Kosmopoulou MN, Schmoll D, Sarubbi E, von Roedern E, Schonafinger K, Defossa E (2005) Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. J Med Chem 48:6178–6193PubMedGoogle Scholar
  62. Kosmopoulou MN, Leonidas DD, Chrysina ED, Bischler N, Eisenbrand G, Sakarellos CE, Pauptit R, Oikonomakos NG (2004) Binding of the potential antitumour agent indirubin-5-sulphonate at the inhibitor site of rabbit muscle glycogen phosphorylase b—comparison with ligand binding to pCDK2-cyclin A complex. Eur J Biochem 271:2280–2290PubMedGoogle Scholar
  63. Kosmopoulou MN, Leonidas DD, Chrysina ED, Eisenbrand G, Oikonomakos NG (2005) Indirubin-3′-aminooxy-acetate inhibits glycogen phosphorylase by binding at the inhibitor and the allosteric site. Broad specificities of the two sites. Lett Drug Des Discov 2:377–390Google Scholar
  64. Krimm I, Lancelin J-M, Praly J-P (2012) Binding evaluation of fragment-based scaffolds for probing allosteric enzymes. J Med Chem 55:1287–1295PubMedGoogle Scholar
  65. Kun S, Bokor É, Varga G, Szőcs B, Páhi A, Czifrák K, Tóth M, Juhász L, Docsa T, Gergely P, Somsák L (2014) New synthesis of 3-(β-D-glucopyranosyl)-5-substituted-1,2,4-triazoles, nanomolar inhibitors of glycogen phosphorylase. Eur J Med Chem 76:567–579PubMedGoogle Scholar
  66. Kuriyama C, Kamiyama O, Ikeda K, Sanae F, Kato A, Adachi I, Imahori T, Takahata H, Okamoto T, Asano N (2008) In vitro inhibition of glycogen-degrading enzymes and glycosidases by six-membered sugar mimics and their evaluation in cell cultures. Bioorg Med Chem 16:7330–7336PubMedGoogle Scholar
  67. Lahlou M (2007) Screening of natural products for drug discovery. Expert Opin Drug Discov 2:697–705PubMedGoogle Scholar
  68. Latsis T, Andersen B, Agius L (2002) Diverse effects of two allosteric inhibitors on the phosphorylation state of glycogen phosphorylase in hepatocytes. Biochem J 368:309–316PubMedCentralPubMedGoogle Scholar
  69. Leonidas DD, Oikonomakos NG, Papageorgiou AC, Xenakis A, Cazianis CT, Bem F (1990) The ammonium sulfate activation of phosphorylase b. FEBS Lett 261:23–27PubMedGoogle Scholar
  70. Liang Z, Zhang L, Li L, Liu J, Li H, Chen L, Cheng K, Zheng M, Wen X, Zhang P, Hao J, Gong Y, Zhang X, Zhu X, Chen J, Liu H, Jiang H, Luo C, Sun H (2011) Identification of pentacyclic triterpenes derivatives as potent inhibitors against glycogen phosphorylase based on 3D-QSAR studies. Eur J Med Chem 46:2011–2021PubMedGoogle Scholar
  71. Lorenzo C, Wagenknecht LE, D’Agostino RB Jr, Rewers MJ, Karter AJ, Haffner SM (2010) Insulin resistance, β-cell dysfunction, and conversion to type 2 diabetes in a multiethnic population: the insulin resistance atherosclerosis study. Diabetes Care 33:67–72PubMedCentralPubMedGoogle Scholar
  72. Loughlin WA (2010) Recent advances in the allosteric inhibition of glycogen phosphorylase. Mini Rev Med Chem 10:1139–1155PubMedGoogle Scholar
  73. Lu Z, Bohn J, Bergeron R, Deng Q, Ellsworth KP, Geissler WM, Harris G, McCann PE, McKeever B, Myers RW, Saperstein R, Willoughby CA, Yao J, Chapman K (2003) A new class of glycogen phosphorylase inhibitors. Bioorg Med Chem Lett 13:4125–4128PubMedGoogle Scholar
  74. Madsen NB, Shechosky S, Fletterick RJ (1983) Site-site interactions in glycogen phosphorylase b probed by ligands specific for each site. Biochemistry 22:4460–4465PubMedGoogle Scholar
  75. Manta S, Xipnitou A, Kiritsis C, Kantsadi AL, Hayes JM, Skamnaki VT, Lamprakis C, Kontou M, Zoumpoulakis P, Zographos SE, Leonidas DD, Komiotis D (2012) 3′-Axial CH(2) OH substitution on glucopyranose does not increase glycogen phosphorylase inhibitory potency. QM/MM-PBSA calculations suggest why. Chem Biol Drug Des 79:663–673PubMedGoogle Scholar
  76. Martin JL, Veluraja K, Ross K, Johnson LN, Fleet GWJ, Ramsden NG, Bruce I, Orchard MG, Oikonomakos NG, Papageorgiou AC, Leonidas DD, Tsitoura HS (1991) Glucose analogue inhibitors of glycogen phosphorylase: the design of potential drugs for diabetes. Biochemistry 30:10101–10116PubMedGoogle Scholar
  77. Martin WH, Hoover DJ, Armento SJ, Stock IA, McPherson RK, Danley DE, Stevenson RW, Barrett EJ, Treadway JL (1998) Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo. Proc Natl Acad Sci USA 95:1776–1781PubMedCentralPubMedGoogle Scholar
  78. Martinez-Castro E, Gonzalez-Benjumea A, Lopez O, Maya I, Alvarez E, Fernandez-Bolanos JG (2012) Intramolecular cyclization of alkoxyaminosugars: access to novel glycosidase inhibitor families. Org Biomol Chem 10:4220–4228PubMedGoogle Scholar
  79. McKay DL, Blumberg JB (2006) A review of the bioactivity and potential health benefits of chamomile tea (Matricaria recutita L.). Phytother Res 20:519–530PubMedGoogle Scholar
  80. Middleton E Jr, Kandaswami C, Theoharides TC (2000) The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 52:673–751PubMedGoogle Scholar
  81. Minami Y, Kuriyama C, Ikeda K, Kato A, Takebayashi K, Adachi I, Fleet GW, Kettawan A, Okamoto T, Asano N (2008) Effect of five-membered sugar mimics on mammalian glycogen-degrading enzymes and various glucosidases. Bioorg Med Chem 16:2734–2740PubMedGoogle Scholar
  82. Murata GH, Duckworth WC, Hoffman RM, Wendel CS, Mohler MJ, Shah JH (2004) Hypoglycemia in type 2 diabetes: a critical review. Biomed Pharmacother 58:551–559PubMedGoogle Scholar
  83. Nagy V, Benltifa M, Vidal S, Berzsenyi E, Teilhet C, Czifrak K, Batta G, Docsa T, Gergely P, Somsak L, Praly J-P (2009) Glucose-based spiro-heterocycles as potent inhibitors of glycogen phosphorylase. Bioorg Med Chem 17:5696–5707PubMedGoogle Scholar
  84. Nagy V, Felfoldi N, Konya B, Praly JP, Docsa T, Gergely P, Chrysina ED, Tiraidis C, Kosmopoulou MN, Alexacou KM, Konstantakaki M, Leonidas DD, Zographos SE, Oikonomakos NG, Kozmon S, Tvaroska I, Somsak L (2012) N-(4-Substituted-benzoyl)-N′-(β-d-glucopyranosyl)ureas as inhibitors of glycogen phosphorylase: synthesis and evaluation by kinetic, crystallographic, and molecular modelling methods. Bioorg Med Chem 20:1801–1816PubMedGoogle Scholar
  85. Nagy L, Docsa T, Szanto M, Brunyanszki A, Hegedus C, Marton J, Konya B, Virag L, Somsak L, Gergely P, Bai P (2013) Glycogen phosphorylase inhibitor N-(3,5-dimethyl-benzoyl)-N′-(β-D-glucopyranosyl)urea improves glucose tolerance under normoglycemic and diabetic conditions and rearranges hepatic metabolism. Plos One 8:e69420Google Scholar
  86. Nash RJ, Kato A, Yu CY, Fleet GW (2011) Iminosugars as therapeutic agents: recent advances and promising trends. Fut Med Chem 3:1513–1521Google Scholar
  87. Ogawa AK, Willoughby CA, Bergeron R, Ellsworth KP, Geissler WM, Myers RW, Yao J, Harris G, Chapman KT (2003) Glucose-lowering in a db/db mouse model by dihydropyridine diacid glycogen phosphorylase inhibitors. Bioorg Med Chem Lett 13:3405–3408PubMedGoogle Scholar
  88. Oikonomakos NG (2002) Glycogen phosphorylase as a molecular target for type 2 diabetes therapy. Curr Prot Pept Sci 3:561–586Google Scholar
  89. Oikonomakos NG, Somsak L (2008) Advances in glycogen phosphorylase inhibitor design. Curr Opin Investig Drugs 9:379–395PubMedGoogle Scholar
  90. Oikonomakos NG, Zographos SE, Johnson LN, Papageorgiou AC, Acharya KR (1995) The binding of 2-deoxy-D-glucose 6-phosphate to glycogen phosphorylase b: kinetic and crystallographic studies. J Mol Biol 254:900–917PubMedGoogle Scholar
  91. Oikonomakos NG, Schnier JB, Zographos SE, Skamnaki VT, Tsitsanou KE, Johnson LN (2000) Flavopiridol inhibits glycogen phosphorylase by binding at the inhibitor site. J Biol Chem 275:34566–34573PubMedGoogle Scholar
  92. Oikonomakos NG, Kosmopoulou M, Zographos SE, Leonidas DD, Chrysina ED, Somsak L, Nagy V, Praly JP, Docsa T, Toth B, Gergely P (2002a) Binding of N-acetyl-N′-β-d-glucopyranosyl urea and N-benzoyl-N′-β-d-glucopyranosyl urea to glycogen phosphorylase b. Eur J Biochem 269:1684–1696PubMedGoogle Scholar
  93. Oikonomakos NG, Zographos SE, Skamnaki VT, Archontis G (2002b) The 1.76 Å resolution crystal structure of glycogen phosphorylase b complexed with glucose, and CP320626, a potential antidiabetic drug. Bioorg Med Chem 10:1313–1319PubMedGoogle Scholar
  94. Oikonomakos NG, Kosmopoulou MN, Chrysina ED, Leonidas DD, Kostas ID, Wendt KU, Klabunde T, Defossa E (2005) Crystallographic studies on acyl ureas, a new class of glycogen phosphorylase inhibitors, as potential antidiabetic drugs. Prot Sci 14:1760–1771Google Scholar
  95. Oikonomakos NG, Kosmopoulou MN, Leonidas DD., Chrysina ED, Tiraidis C, Bischler N, Tsitsanou KE, Zographos SE, Kostas ID, Eisenbrand G (2006a) Indirubin and indigo analogues as potential inhibitors of glycogenolysis: structural basis of glycogen phosphorylase inhibition. In: Meijer L, Guyard N, Skaltsounis L, Eisenbrand G (eds) Indirubin, the red shade of indigo. Life in progress editions, Roscoff, France, pp 177–189Google Scholar
  96. Oikonomakos NG, Tiraidis C, Leonidas DD, Zographos SE, Kristiansen M, Jessen CU, Norskov-Lauritsen L, Agius L (2006b) Iminosugars as potential inhibitors of glycogenolysis: structural insights into the molecular basis of glycogen phosphorylase inhibition. J Med Chem 49:5687–5701PubMedGoogle Scholar
  97. Pan D, Tseng Y, Hopfinger AJ (2003) Quantitative structure-based design: formalism and application of receptor-dependent RD-4D-QSAR analysis to a set of glucose analogue inhibitors of glycogen phosphorylase. J Chem Inf Comput Sci 43:1591–1607PubMedGoogle Scholar
  98. Pan DH, Liu JZ, Senese C, Hopfinger AJ, Tseng Y (2004) Characterization of a ligand-receptor binding event using receptor dependent four-dimensional quantitative structure-activity relationship analysis. J Med Chem 47:3075–3088Google Scholar
  99. Parmenopoulou V, Kantsadi AL, Tsirkone VG, Chatzileontiadou DSM, Manta S, Zographos SE, Kollatos N, Archontis G, Agius L, Hayes JM, Leonidas DD, Komiotis D (2014) Structure based inhibitor design targeting glycogen phosphorylase b. Virtual screening, synthesis, biochemical and biological assessment of novel N-(β-D-glucopyranosyl) amides (submitted)Google Scholar
  100. Paterson I, Anderson EA (2005) Chemistry. The renaissance of natural products as drug candidates. Science 310:451–453PubMedGoogle Scholar
  101. Pautsch A, Stadler N, Wissdorf O, Langkopf E, Moreth W, Streicher R (2008) Molecular recognition of the protein phosphatase 1 glycogen targeting subunit by glycogen phosphorylase. J Biol Chem 283:8913–8918PubMedGoogle Scholar
  102. Pinotsis N, Leonidas DD, Chrysina ED, Oikonomakos NG, Mavridis IM (2003) The binding of β- and γ-cyclodextrins to glycogen phosphorylase b: kinetic and crystallographic studies. Protein Sci 12:1914–1924PubMedCentralPubMedGoogle Scholar
  103. Polyak M, Varga G, Szilagyi B, Juhasz L, Docsa T, Gergely P, Begum J, Hayes JM, Somsak L (2013) Synthesis, enzyme kinetics and computational evaluation of N-(β-D-glucopyranosyl) oxadiazolecarboxamides as glycogen phosphorylase inhibitors. Bioorg Med Chem 21:5738–5747PubMedGoogle Scholar
  104. Polychronopoulos P, Magiatis P, Skaltsounis AL, Myrianthopoulos V, Mikros E, Tarricone A, Musacchio A, Roe SM, Pearl L, Leost M, Greengard P, Meijer L (2004) Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases. J Med Chem 47:935–946PubMedGoogle Scholar
  105. Praly J-P, Vidal S (2010) Inhibition of glycogen phosphorylase in the context of type 2 diabetes, with focus on recent inhibitors bound at the active site. Mini Rev Med Chem 10:1102–1126PubMedGoogle Scholar
  106. Rath VL, Ammirati M, Danley DE, Ekstrom JL, Gibbs EM, Hynes TR, Mathiowetz AM, McPherson RK, Olson TV, Treadway JL, Hoover DJ (2000) Human liver glycogen phosphorylase inhibitors bind at a new allosteric site. Chem Biol 7:677–682PubMedGoogle Scholar
  107. Rosauer KG, Ogawa AK, Willoughby CA, Ellsworth KP, Geissler WM, Myers RW, Deng QL, Chapman KT, Harris G, Moller DE (2003) Novel 3,4-dihydroquinolin-2(1H)-one inhibitors of human glycogen phosphorylase a. Bioorg Med Chem Lett 13:4385–4388PubMedGoogle Scholar
  108. Skamnaki VT, Kantsadi AL, Chatzileontiadou DSM, Stravodimos G, Leonidas DD (2013) Glycogen metabolism enzymes as molecular targets for drug development. In: Weiss PL, Faulkner BD (eds) Glycogen structure, functions in the body and role in disease. Nova Science Publishers Inc, New York, pp 109–135Google Scholar
  109. Socaci C, Hayes JM, Sovantzis D, Hadjiloi T, Mamais M, Lazoura E, Grammatopoulos P, Panagopoulos D, Stathis D, Oikonomakos GN, Zographos SE, Leonidas DD, Oikonomakos NG, Chrysina ED, Gimisis T (2014) Synthesis, X-ray and computational studies of β-D-glucopyranosyl-pyrimidine derivatives as glycogen phosphorylase inhibitors: the role of ligand ionization/tautomeric states (in preparation)Google Scholar
  110. Somsak L (2011) Glucose derived inhibitors of glycogen phosphorylase. C R Chim 14:211–223Google Scholar
  111. Somsak L, Kovacs L, Toth M, Osz E, Szilagyi L, Gyorgydeak Z, Dinya Z, Docsa T, Toth B, Gergely P (2001) 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 44:2843–2848PubMedGoogle Scholar
  112. Somsak L, Czifrak K, Toth M, Bokor E, Chrysina ED, Alexacou KM, Hayes JM, Tiraidis C, Lazoura E, Leonidas DD, Zographos SE, Oikonomakos NG (2008) New inhibitors of glycogen phosphorylase as potential antidiabetic agents. Curr Med Chem 15:2933–2983PubMedGoogle Scholar
  113. Sprang S, Fletterick R, Stern M, Yang D, Madsen N, Sturtevant J (1982) Analysis of an allosteric binding site: the nucleoside inhibitor site of phosphorylase alpha. Biochem 21:2036–2048Google Scholar
  114. Sprang SR, Acharya KR, Goldsmith EJ, Stuart DI, Varvill K, Fletterick RJ, Madsen NB, Johnson LN (1988) Structural-changes in glycogen-phosphorylase induced by phosphorylation. Nature 336:215–221PubMedGoogle Scholar
  115. Sprang SR, Withers SG, Goldsmith EJ, Fletterick RJ, Madsen NB (1991) Structural basis for the activation of glycogen phosphorylase-b by adenosine-monophosphate. Science 254:1367–1371PubMedGoogle Scholar
  116. Srivastava JK, Gupta S (2007) Antiproliferative and apoptotic effects of chamomile extract in various human cancer cells. J Agric Food Chem 55:9470–9478PubMedGoogle Scholar
  117. Toth M, Kun S, Bokor E, Benltifa M, Tallec G, Vidal S, Docsa T, Gergely P, Somsak L, Praly J-P (2009) Synthesis and structure-activity relationships of C-glycosylated oxadiazoles as inhibitors of glycogen phosphorylase. Bioorg Med Chem 17:4773–4785PubMedGoogle Scholar
  118. Treadway JL, Mendys P, Hoover DJ (2001) Glycogen phosphorylase inhibitors for treatment of type 2 diabetes mellitus. Expert Opin Investig Drugs 10:439–454PubMedGoogle Scholar
  119. Tsirkone VG, Tsoukala E, Lamprakis C, Manta S, Hayes JM, Skamnaki VT, Drakou C, Zographos SE, Komiotis D, Leonidas DD (2010) 1-(3-Deoxy-3-fluoro-β-D-glucopyranosyl) pyrimidine derivatives as inhibitors of glycogen phosphorylase b: kinetic, crystallographic and modelling studies. Bioorg Med Chem 18:3413–3425PubMedGoogle Scholar
  120. Tsitsanou KE, Hayes JM, Keramioti M, Mamais M, Oikonomakos NG, Kato A, Leonidas DD, Zographos SE (2013) Sourcing the affinity of flavonoids for the glycogen phosphorylase inhibitor site via crystallography, kinetics and QM/MM-PBSA binding studies: comparison of chrysin and flavopiridol. Food Chem Toxicol 61:14–27PubMedGoogle Scholar
  121. Wagman AS, Nuss JM (2001) Current therapies and emerging targets for the treatment of diabetes. Curr Pharm Des 7:417–450PubMedGoogle Scholar
  122. Watson KA, Mitchell EP, Johnson LN, Gruciani G, Son JC, Bichard CJF, Fleet GWJ, Oikonomakos NG, Kontou M, Zographos SE (1995) Glucose analogue inhibitors of glycogen phosphorylase: from crystallographic analysis to drug prediction using GRID force-field and GOLPE variable selection. Acta Crystallogr D51:458–472Google Scholar
  123. Wen X, Zhang P, Liu J, Zhang L, Wu X, Ni P, Sun H (2006) Pentacyclic triterpenes. Part 2: synthesis and biological evaluation of maslinic acid derivatives as glycogen phosphorylase inhibitors. Bioorg Med Chem Lett 16:722–726PubMedGoogle Scholar
  124. Wen X, Xia J, Cheng K, Zhang L, Zhang P, Liu J, Ni P, Sun H (2007) Pentacyclic triterpenes. Part 5: synthesis and SAR study of corosolic acid derivatives as inhibitors of glycogen phosphorylases. Bioorg Med Chem Lett 17:5777–5782PubMedGoogle Scholar
  125. Wen X, Sun H, Liu J, Cheng K, Zhang P, Zhang L, Hao J, Ni P, Zographos SE, Leonidas DD, Alexacou KM, Gimisis T, Hayes JM, Oikonomakos NG (2008) Naturally occurring pentacyclic triterpenes as inhibitors of glycogen phosphorylase: synthesis, structure-activity relationships, and X-ray crystallographic studies. J Med Chem 51:3540–3554PubMedGoogle Scholar
  126. Wen XA, Zhang XY, Liu J, Zhang LY, Ni PZ, Sun HB (2010) Synthesis and biological activity of heterocycle-fused derivatives of pentacylic triterpenes as glycogen phosphorylase inhibitors. J Chin Pharm Univ 40:491–496Google Scholar
  127. Whitman M (2001) Understanding the perceived need for complementary and alternative nutraceuticals: lifestyle issues. Clin J Oncol Nurs 5:190–194PubMedGoogle Scholar
  128. Wu LY, Juan CC, Ho LT, Hsu YP, Hwang LS (2004) Effect of green tea supplementation on insulin sensitivity in Sprague-Dawley rats. J Agric Food Chem 52:643–648PubMedGoogle Scholar
  129. Zhang P, Hao J, Liu J, Lu Q, Sheng HM, Zhang LY, Sun HB (2009a) Synthesis of 3-deoxypentacyclic triterpene derivatives as inhibitors of glycogen phosphorylase. J Nat Prod 72:1414–1418PubMedGoogle Scholar
  130. Zhang LY, Chen J, Gong YC, Liu J, Zhang LY, Hua WY, Sun HB (2009b) Synthesis and biological evaluation of asiatic acid derivatives as inhibitors of glycogen phosphorylase. Chem Biodivers 6:864–874PubMedGoogle Scholar
  131. Zhang L, Li H, Zhu Q, Liu J, Chen L, Leng Y, Jiang H, Liu H (2009c) Benzamide derivatives as dual-action hypoglycemic agents that inhibit glycogen phosphorylase and activate glucokinase. Biorg Med Chem 17:7301–7312Google Scholar
  132. Zhang L, Chen X, Liu J, Zhu Q, Leng Y, Luo X, Jiang H, Liu H (2012) Discovery of novel dual-action antidiabetic agents that inhibit glycogen phosphorylase and activate glucokinase. Eur J Med Chem 58:624–639PubMedGoogle Scholar
  133. Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414:782–787PubMedGoogle Scholar
  134. Zographos SE, Oikonomakos NG, Tsitsanou KE, Leonidas DD, Chrysina ED, Skamnaki VT, Bischoff H, Goldmann S, Watson KA, Johnson LN (1997) The structure of glycogen phosphorylase b with an alkyldihydropyridine-dicarboxylic acid compound, a novel and potent inhibitor. Structure 5:1413–1425PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Division of Chemistry, Centre for Materials ScienceUniversity of Central LancashirePrestonUK
  2. 2.Department of Biochemistry and BiotechnologyUniversity of ThessalyLarissaGreece

Personalised recommendations