Polyphenol Glycosides as Potential Remedies in Kidney Stones Therapy. Experimental Research Supported by Computational Studies

  • D. ToczekEmail author
  • E. Klepacz
  • S. Roszak
  • R. Gancarz
Part of the Challenges and Advances in Computational Chemistry and Physics book series (COCH, volume 17)


Polyphenol glycosides are potential compounds in the kidney stones therapy. Experimental data indicate the formation of glycoside complexes with calcium ions. Theoretical studies support experimental finding in elucidating the structures of studied complexes. DFT methods constitutes reasonable approach to investigate the strength and structural properties these complexes. The extraction of main structural factors responsible for complexing activity allows to design new ligands for calcium ions, being helpful in the kidney stones treatment.


Kidney stones DFT Polyphenol glycosides Metal complexes Interaction Calcium ions Computer modeling Carbohydrates Sugar complexes 



This work was supported by the statutory activity subsidy from Polish Ministry of Science and Technology of Higher Education for the Faculty of Chemistry of Wroclaw University of Technology. The computations were performed in Wroclaw Supercomputing and Networking Center.


  1. 1.
    Sejersted OM (2011) Calcium controls cardiac function—by all means! J Physiol 589(12):2919–2920. doi:10.1113/jphysiol.2011.210989CrossRefGoogle Scholar
  2. 2.
    Lovelock JE, Porterfield BM (1952) Blood clotting: the function of electrolytes and of calcium. Biochemistry 50:415–420Google Scholar
  3. 3.
    Peacock M (2010) Calcium metabolism in health and disease. Clin J Am Soc Nephrol 5:S23–S30. doi:10.2215/CJN.05910809CrossRefGoogle Scholar
  4. 4.
    Endo M (2006) Calcium ion as a second messenger with special reference to excitation–contraction coupling. J Pharmacol Sci 100:519–524. doi:10.1254/jphs.CPJ06004XCrossRefGoogle Scholar
  5. 5.
    Moe OW (2006) Kidney stones: pathophysiology and medical management. Lancet 367:333–344. doi:10.1016/S0140-6736(06)68071-9CrossRefGoogle Scholar
  6. 6.
    Lewandowski S, Rodgers AL (2004) Idiopathic calcium oxalate urolithiasis: risk factors and conservative treatment. Clin Chim Acta 345:17–34. doi:10.1016/j.cccn.2004.03.009CrossRefGoogle Scholar
  7. 7.
    Coe FL, Evan A, Worcester E (2005) Kidney stone disease. J Clin Invest 115(10):2598–2608. doi:10.1172/JCI26662CrossRefGoogle Scholar
  8. 8.
    Hall PM (2009) Nephrolithiasis: treatment, causes, and prevention. Cleve Clin J Med 76(10):583–591. doi:10.3949/ccjm.76a.09043CrossRefGoogle Scholar
  9. 9.
    Kaufman Katz A, Glusker JP, Beebe SA, Bock CW (1996) Calcium ion coordination: a comparison with that of beryllium, magnesium, and zinc. J Am Chem Soc 118:5752–5763. doi:10.1021/ja953943iCrossRefGoogle Scholar
  10. 10.
    Nakanishi F, Nagasawa Y, Kabaya Y, Sekimoto H, Shimomura K (2005) Characterization of lucidin formation in Rubia tinctorum L. Plant Physiol Biochem 43:921–928. doi:10.1016/j.plaphy.2005.08.005CrossRefGoogle Scholar
  11. 11.
    Gyurcsik B, Nagy L (2000) Carbohydrates as ligands: coordination equilibria and structure of the metal complexes. Coord Chem Rev 203:81–149. doi:10.1016/S0010-8545(99)00183-6CrossRefGoogle Scholar
  12. 12.
    Alekseev YE, Garnovskii AD, Zhdanov YA (1998) Complexes of natural carbohydrates with metal cations. Russ Chem Rev 67(8):649–669.CrossRefGoogle Scholar
  13. 13.
    Bugg CE, Cook WJ (1972) Calcium ion binding to uncharged sugars: crystal structures of calcium bromide complexes of lactose, galactose, and inositol. J Chem Soc Chem Commun 12:727–729. doi:10.1039/C39720000727CrossRefGoogle Scholar
  14. 14.
    Bugg CE (1973) Calcium binding to carbohydrates. Crystal structure of a hydrates calcium bromide complex of lactose. J Am Chem Soc 95:908–913. doi:10.1021/ja00784a046CrossRefGoogle Scholar
  15. 15.
    Saladini M, Menabue L, Ferrari E (2001) Sugar complexes with metal2 + ions: thermodynamic parameters of associations of Ca2 +, Mg2 + and Zn2 + with galactaric acid. Carbohydr Res 336(1):55–61. doi:10.1016/S0008-6215(01)00243-9CrossRefGoogle Scholar
  16. 16.
    Yang L, Su Y, Liu W, Jin X, Wu J (2002) Sugar interaction with metal ions. The coordination behavior of neutral galactitol to Ca(II) and lanthanide ions. Carbohydr Res 337(14):1485–1493. doi:10.1016/S0008-6215(02)00130-1CrossRefGoogle Scholar
  17. 17.
    Angyal SJ (1973) Complex formation between sugars and metal ions. Pure Appl Chem 35(2):131–146. doi:10.1351/pac197335020131CrossRefGoogle Scholar
  18. 18.
    Angyal SJ (1980) Haworth memorial lecture. Sugar–cation complexes—structure and applications. Chem Soc Rev 9(4):415–428. doi:10.1039/CS9800900415CrossRefGoogle Scholar
  19. 19.
    Alvarez AM, Morel-Desrosiers N, Morel J-P (1987) Interactions between cations and sugars. III. Free energies, enthalpies, and entropies of association of Ca2 +, Sr2 +, Ba2 +, La3 +, Gd3 + with D-ribose in water at 25 °C. Can J Chem 65(11):2656–2660. doi:10.1139/v87–439CrossRefGoogle Scholar
  20. 20.
    Angyal SJ (1974) Complexing of polyols with cations. Tetrahedron 30(12):1695–1702. doi:10.1016/S0040-4020(01)90691-XCrossRefGoogle Scholar
  21. 21.
    Hancock RD, Hegetschweiler K (1993) A molecular mechanics study of the complexation of metal ions by inositols. J Chem Soc Dalton Trans 2137–2140. doi:10.1039/DT9930002137Google Scholar
  22. 22.
    Palma M, Pascal YL (1995) Étude théorique de la complexation des cations Pb2 + et Hg2 + par le d-talose. Can J Chem 73(1):22–40. doi:10.1139/v95-005CrossRefGoogle Scholar
  23. 23.
    Dheu-Andries ML, Perez S (1983) Geometrical features of calcium–carbohydrate interactions. Carbohydr Res 124(2):324–332. doi:10.1016/0008-6215(83)88468-7CrossRefGoogle Scholar
  24. 24.
    Beevers CA, Cochran W (1947) The crystal structure of sucrose sodium bromide dihydrate. Proc R Soc London Ser A 190:257–272.CrossRefGoogle Scholar
  25. 25.
    Craig DC, Stephenson NC, Stevens JD (1972) An X-ray crystallographic study of β-d-mannofuranose-CaCl2 · 4H2O. Carbohydr Res 22(2):494–495. doi:10.1016/S0008-6215(00)81309-9CrossRefGoogle Scholar
  26. 26.
    Jeffrey GA, Kim HS (1971) The crystal and molecular structure of epinositol. Acta Crystallogr Sect B: Struct Crystallogr Cryst Chem 27(9):1812–1817. doi:10.1107/S0567740871004837CrossRefGoogle Scholar
  27. 27.
    Tajmir-Riahi H-A (1988) Interaction of d-glucose with alkaline-earth metal ions. Synthesis, spectroscopic, and structural characterization of Mg(II)- and Ca(II)-d-glucose adducts and the effect of metal-ion binding on anomeric configuration of the sugar. Carbohydr Res 183:35–46. doi:10.1016/0008-6215(88)80043-0CrossRefGoogle Scholar
  28. 28.
    Ollis J, James VJ, Angyal SJ, Pojer PM (1978) An X-ray crystallographic study of α-d-allopyranosyl α-d-allopyranoside·CaCl2 · 5H2O (a pentadentate complex). Carbohydr Res 60(2):219–228. doi:10.1016/S0008-6215(78)80029-9CrossRefGoogle Scholar
  29. 29.
    Lu Y, Deng G, Miao F, Li Z (2003) Sugar complexation with calcium ion. Crystal structure and FT-IR study of a hydrated calcium chloride complex of d-ribose. J Inorg Biochem 92:487–492. doi:10.1016/S0162-0134(03)00251-4CrossRefGoogle Scholar
  30. 30.
    Takashi F, Kazuyuki O, Mitsuru T, Tomoya M (2006) Crystal structure of α,α-trehalose–calcium chloride monohydrate complex. J Carbohydr Chem 25(7):521–532. doi:10.1080/07328300600966414CrossRefGoogle Scholar
  31. 31.
    Cook WJ, Bugg CE (1973) Calcium interactions with d-glucans: crystal structure of α,α-trehalose–calcium bromide monohydrate. Carbohydr Res 31:265–275. doi:10.1016/S0008-6215(00)86191-1CrossRefGoogle Scholar
  32. 32.
    Guo J, Lu Y, Whiting R (2012) Metal–ion interactions with sugars. The crystal structure of CaCl2–fructose complex. Bull Korean Chem Soc 33(6):2028–2030. doi:10.5012/bkcs.2012.33.6.2028CrossRefGoogle Scholar
  33. 33.
    Yang L, Su Y, Xu Y, Wang Z, Guo Z, Weng S, Yan C, Zhang S, Wu J (2003) Interactions between metal ions and carbohydrates. Coordination behavior of neutral erythritol to Ca(II) and lanthanide Ions. Inorg Chem 42:5844–5856. doi:10.1021/ic0300464CrossRefGoogle Scholar
  34. 34.
    Yang L, Su Y, Liu W, Jin X, Wu J (2002) Sugar interaction with metal ions. The coordination behavior of neutral galactitol to Ca(II) and lanthanide ions. Carbohydr Res 337(16):1485–1493. doi:10.1016/S0008-6215(02)00130-1CrossRefGoogle Scholar
  35. 35.
    Agulhon P, Markova V, Robitzer M, Quignard F, Mineva T (2012) Structure of alginate gels: interaction of diuronate units with divalent cations from density functional calculations. Biomacromol 13(6):1899–1907. doi:10.1021/bm300420zCrossRefGoogle Scholar
  36. 36.
    Angyal SJ, Davies KP (1971) Complexing of sugars with metal ions. Chem Commun 500–501. doi:10.1039/C29710000500Google Scholar
  37. 37.
    McGavin DG, Natusch DFS, Young JD (1969) Complexes of sugars with metalions. In: Proceedings of the Xllth International Conference on Coordination Chemistry Sydney 134–5 Science Press Marrickville New South Wales AustraliaGoogle Scholar
  38. 38.
    Angyal SJ, Greeves D (1976) Complexes of carbohydrates with metal cations. VII. Lanthanide-induced shifts in the P.M.R. spectra of cyclitols. Aust J Chem 29:1223–1230. doi:10.1071/CH9761223CrossRefGoogle Scholar
  39. 39.
    Angyal SJ, Greeves D, Mills JA (1974) Complexes of carbohydrates with metal cations. III. Conformations of alditols in aqueous solution. Aust J Chem 27:1447–1456. doi:10.1071/CH9741447CrossRefGoogle Scholar
  40. 40.
    Angyal SJ (1973) Shifts induced by lanthanide ions in the N.M.R. spectra of carbohydrates in aqueous solution. Carbohydr Res 26(1):271–273. doi:10.1016/S0008-6215(00)85054-5CrossRefGoogle Scholar
  41. 41.
    Angyal SJ (1972) Complexes of carbohydrates with metal cations. I. Determination of the extent of complexing by N.M.R. spectroscopy. Aust J Chem 25:1957–1966. doi:10.1071/CH9721957CrossRefGoogle Scholar
  42. 42.
    Angyal SJ (1981) Conformational nomenclature for five- and six-membered ring forms of monosaccharides and their derivatives. Pure & Appl Chem 53(10):1901–1905. doi:10.1351/pac198153101901Google Scholar
  43. 43.
    Symons MCR, Benbow JA, Pelmore H (1984) Interactions between calcium ions and a range of monosaccharides studied by hydroxy-proton resonance spectroscopy. J Chem Soc Faraday Trans 80:1999–2016. doi:10.1039/F19848001999CrossRefGoogle Scholar
  44. 44.
    Angyal SJ (1969) The Composition and conformation of sugars in solution. Angew Chem Int Ed Engl 8(3):157–166. doi:10.1002/anie.196901571CrossRefGoogle Scholar
  45. 45.
    Frąckowiak A, Skibiński P, Gaweł W, Zaczyńska E, Czarny A, Gancarz R (2010) Synthesis of glycoside derivatives of hydroxyanthraquinone with ability to dissolve and inhibit formation of crystals of calcium oxalate. Potential compounds in kidney stone therapy Eur J Med Chem 45(3):1001–1007. doi:10.1016/j.ejmech.2009.11.042CrossRefGoogle Scholar
  46. 46.
    Kubas K (2012) Glycosides of polyphenols, hydroxyketones and their derivatives. Sythesis and evaluation their complexing ability toward calcium ions. Doctoral dissertation Wroclaw University of Technology (in polish)Google Scholar
  47. 47.
    Frąckowiak A (2010) Solubility, inhibition of crystallization and microscopic analysis of calcium oxalate crystals in the presence of fractions from Humulus lupulus L. J Cryst Growth 31(23):3525–3532. doi:10.1016/j.jcrysgro.2010.09.040CrossRefGoogle Scholar
  48. 48.
    Das I (2005) In vitro inhibition and dissolution of calcium oxalate by edible plant Trianthema monogyna and pulse Macrotyloma uniflorum extracts. J Cryst Growth 273(3–4):546–554. doi:10.1016/j.jcrysgro.2004.09.038CrossRefGoogle Scholar
  49. 49.
    Das I (2004) Inhibition and dissolution of calcium oxalate crystals by Berberis Vulgaris-Q and other metabolites. J Cryst Growth 267(3–4):654–661. doi:10.1016/j.jcrysgro.2004.04.022CrossRefGoogle Scholar
  50. 50.
    Sillanpaa AJ, Aksela R, Laasonen K (2003) Density functional complexation study of metal ions with (amino) polycarboxylic acid ligands. Phys Chem Chem Phys 5:3382–3393. doi:10.1039/B303234PCrossRefGoogle Scholar
  51. 51.
    Parr RG, Yang W (1995) Density-functional theory of the electronic structure of molecules. Annu Rev Phys Chem 46:701–728. doi:10.1146/annurev.pc.46.100195.003413CrossRefGoogle Scholar
  52. 52.
    Suarez D, Rayon VM, Diaz N, Valdes H (2011) Ab initio benchmark calculations on Ca(II) complexes and assessment of density functional theory methodologies. J Phys Chem A 115:11331–11343. doi: 10.1021/jp205101zCrossRefGoogle Scholar
  53. 53.
    Head-Gordon M, Pople JA, Frisch MJ (1988) Chem Phys Lett 153:503–506CrossRefGoogle Scholar
  54. 54.
    Purvis GD, Bartlett RJ, (1982) A full coupled-cluster singles and doubles model: the inclusion of disconnected triples. J Chem Phys 76:1910–1918. doi: 10.1063/1.443164CrossRefGoogle Scholar
  55. 55.
    Zheng YJ, Ornstein RL, Leary JA (1997) A density functional theory investigation of metal ion binding sites in monosaccharides. J Mol Struc (Theochem) 389(3):233–240. doi:10.1016/S0166-1280(96)04707-0CrossRefGoogle Scholar
  56. 56.
    Wong CHS, Siu FM, Ma NL, Tsang CW (2001) Interaction of Ca2 + with mannose: a density functional study. J Mol Struc (Theochem) 536(2):227–234. doi:10.1016/S0166-1280(00)00634-5CrossRefGoogle Scholar
  57. 57.
    Toczek D, Kubas K, Turek M, Roszak S, Gancarz R (2013) J Mol Model. 19:4209–4214. doi:10.1007/s00894-013-1841-9CrossRefGoogle Scholar
  58. 58.
    Fabian WMF (2007) Metal binding induced conformational interconversions in methyl ß-d-xylopyranoside. Theor Chem Acc 117:223–229. doi:10.1007/s00214-006-0130-4CrossRefGoogle Scholar
  59. 59.
    Toczek D, Kubas K, Roszak S, Gancarz R (in the preparation)Google Scholar
  60. 60.
    Gaussian 09, Revision A.1(2009), Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam NJ, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ Gaussian, Inc., WallingfordGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Organic and Pharmaceutical Technology Group, Chemistry DepartmentWrocław University of Technology (WUT)WrocławPoland
  2. 2.Institute of Physical and Theoretical ChemistryWrocław University of Technology (WUT)WrocławPoland

Personalised recommendations