Journal of Molecular Modeling

, Volume 16, Issue 5, pp 863–876 | Cite as

Antioxidant mechanisms of Quercetin and Myricetin in the gas phase and in solution – a comparison and validation of semi-empirical methods

  • Gonçalo C. Justino
  • Abel J. S. C. Vieira
Original Paper


Flavonoids have long been recognized for their general health-promoting properties, of which their antioxidant activity may play an important role. In this work we have studied the properties of two flavonols, quercetin and myricetin, using semi-empirical methods in order to validate the application of the recent Parametric Model 6 and to understand the fundamental difference between the two molecules. Their geometries have been optimized and important molecular properties have been calculated. The energetic of the possible antioxidant mechanisms have also been analyzed. The two studied flavonols do not differ significantly in their molecular properties, but the antioxidant mechanisms by which they may act in solution can be rather different. Moreover, we also show that the Parametric Model 6 can produce reliable information for this type of compounds.


Antioxidant mechanism Flavonoids Semi-empirical methods 



G. C. J. would like to acknowledge a post-doctoral grant from Fundação para a Ciência e a Tecnologia (SFRH/BPD/2006/27563). The authors would also like to thank Dr. Marta Corvo and one of the reviewers for very significant discussions.

Supplementary material

894_2009_583_MOESM1_ESM.doc (216 kb)
Esm 1 (DOC 216 kb)


  1. 1.
    Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79:727–747Google Scholar
  2. 2.
    Birt DF, Hendrich S, Wang W (2001) Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther 90:157–177. doi: 10.1016/S0163-7258(01)00137-1 CrossRefGoogle Scholar
  3. 3.
    Bors W, Michel C (2002) Chemistry of the antioxidant effect of polyphenols. Ann N Y Acad Sci 957:57–69. doi: 10.1111/j.1749-6632.2002.tb02905.x CrossRefGoogle Scholar
  4. 4.
    Halliwell B, Rafter J, Jenner A (2005) Health promotion by flavonoids, tocopherols, tocotrienols, and other phenols: direct or indirect effects? Antioxidant or not? Am J Clin Nutr 81(1 Suppl):268S–276SGoogle Scholar
  5. 5.
    Williamson G, Manach C (2005) Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies. Am J Clin Nutr 81(1 Suppl):243S–255SGoogle Scholar
  6. 6.
    Gomes A, Fernandes E, Lima JL, Mira L, Corvo ML (2008) Molecular mechanisms of anti-inflammatory activity mediated by flavonoids. Curr Med Chem 15:1586–1605CrossRefGoogle Scholar
  7. 7.
    Friedman M (2007) Overview of antibacterial, antitoxin, antiviral, and antifungal activities of tea flavonoids and teas. Mol Nutr Food Res 51:116–134. doi: 10.1002/mnfr.200600173 CrossRefGoogle Scholar
  8. 8.
    Biesalski HK (2007) 9: Polyphenols and inflammation: basic interactions. Curr Opin Clin Nutr Metab Care 10:724–728CrossRefGoogle Scholar
  9. 9.
    Wang Y, Yang L, He YQ, Wang CH, Welbeck EW, Bligh SWA, Wang ZT (2008) Characterization of fifty-one flavonoids in a Chinese herbal prescription Longdan Xiegan Decoction by high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry and photodiode array detection. Rapid Commun Mass Spectrom 22:1767–1778. doi: 10.1002/rcm.3536 CrossRefGoogle Scholar
  10. 10.
    Heinrich M (2003) Ethnobotany and natural products: the search for new molecules, new treatments of old diseases or a better understanding of indigenous cultures? Curr Top Med Chem 3:29–42CrossRefGoogle Scholar
  11. 11.
    Arts IC (2008) A review of the epidemiological evidence on tea, flavonoids, and lung cancer. J Nutr 138:1561S–1566SGoogle Scholar
  12. 12.
    Tomar RS, Shiao R (2008) Early life and adult exposure to isoflavones and breast cancer risk. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 26:113–173. doi: 10.1080/10590500802074256 Google Scholar
  13. 13.
    Linseisen J, Rohrmann S (2008) Biomarkers of dietary intake of flavonoids and phenolic acids for studying diet-cancer relationship in humans. Eur J Nutr 47:60–68. doi: 10.1007/s00394-008-2007-x CrossRefGoogle Scholar
  14. 14.
    de Kok TM, van Breda SG, Manson MM (2008) Mechanisms of combined action of different chemopreventive dietary compounds: a review. Eur J Nutr 47(Suppl 2):51–59. doi: 10.1007/s00394-008-2006-y CrossRefGoogle Scholar
  15. 15.
    Manach C, Williamson G, Morand C, Scalbert A, Rémésy C (2005) Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 81(1 Suppl):230S–242SGoogle Scholar
  16. 16.
    Boots AW, Haenen GR, Bast A (2008) Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol 585:325–327. doi: 10.1016/j.ejphar.2008.03.008 CrossRefGoogle Scholar
  17. 17.
    Oyama Y, Fuchs PA, Katayama N, Noda K (1994) Myricetin and quercetin, the flavonoid constituents of Ginkgo biloba extract, greatly reduce oxidative metabolism in both resting and Ca(2+)-loaded brain neurons. Brain Res 635:125–129. doi: 10.1016/0006-8993(94)91431-1 CrossRefGoogle Scholar
  18. 18.
    Gordon MH, Roedig-Penmanm A (1998) Antioxidant activity of quercetin and myricetin in liposomes. Chem Phys Lipids 97:79–85. doi: 10.1016/S0009-3084(98)00098-X CrossRefGoogle Scholar
  19. 19.
    Furuno K, Akasako T, Sugihara N (2002) The contribution of the pyrogallol moiety to the superoxide radical scavenging activity of flavonoids. Biol Pharm Bull 25:19–23. doi: 10.1248/bpb.25.19 CrossRefGoogle Scholar
  20. 20.
    Zhang H-Y, Sun Y-M, Wang X-L (2003) Substituent effects on O-H bond dissociation enthalpies and ionization potentials of catechols: A DFT study and its implications in the rational design of phenolic antioxidants and elucidation of structure-activity relationships for flavonoid antioxidants. Chem Eur J 9:502–508. doi: 10.1002/chem.200390052 CrossRefGoogle Scholar
  21. 21.
    Litwinienko G, Ingold KU (2007) Solvent effects on the rates and mechanisms of reaction of phenols with free radicals. Acc Chem Res 40:222–230. doi: 10.1021/ar0682029 CrossRefGoogle Scholar
  22. 22.
    Mayo SL, Olafson BD, Goddard WA III (1990) DREIDING: a generic force field for molecular simulations. J Phys Chem 94:8897–8909. doi: 10.1021/j100389a010 CrossRefGoogle Scholar
  23. 23.
    Marvin version 5.00 and Calculator Plugins for Marvin 500 2008 ChemAxon (http://wwwchemaxoncom)
  24. 24.
    MOPAC2009 James J P Stewart Stewart Computational Chemistry Version 9034 L. http://OpenMOPACnet
  25. 25.
    Baker J (1986) An algorithm for the location of transition states. J Comp Chem 7:385–395. doi: 10.1002/jcc.540070402 CrossRefGoogle Scholar
  26. 26.
    Dewar MJS, Thiel W (1977) Ground states of molecules. 38. The MNDO method. Approximations and parameters. J Am Chem Soc 99:4899–4907. doi: 10.1021/ja00457a004 CrossRefGoogle Scholar
  27. 27.
    Dewar MJS, Zoebisch EG, Healy EF, Stewart JJP (1985) Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model. J Am Chem Soc 107:3902–3909. doi: 10.1021/ja00299a024 CrossRefGoogle Scholar
  28. 28.
    Rocha GB, Freire RO, Simas AM, Stewart JJP (2006) RM1: A reparameterization of AM1 for H, C, N, O, P, S, F, Cl, Br, and I. J Comp Chem 27:1101–1111. doi: 10.1002/jcc.20425 CrossRefGoogle Scholar
  29. 29.
    Stewart JJP (1989) Optimization of parameters for semiempirical methods I. Method J Comp Chem 10:209–220. doi: 10.1002/jcc.540100208 CrossRefGoogle Scholar
  30. 30.
    Stewart JJP (2007) Optimization of parameters for semiempirical methods V: modification of NDDO approximations and application to 70 elements. J Mol Modeling 13:1173–1213. doi: 10.1007/s00894-007-0233-4 CrossRefGoogle Scholar
  31. 31.
    Klamt A, Schüürmann G (1993) COSMO: a new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient. J Chem Soc Perkin Trans 2:799–805. doi: 10.1039/P29930000799 Google Scholar
  32. 32.
    Antonczak S (2008) Electronic description of four flavonoids revisited by DFT method. THEOCHEM 856:38–45. doi: 10.1016/j.theochem.2008.01.014 CrossRefGoogle Scholar
  33. 33.
    Fiorucci S, Golebiowski J, Cabrol-Bass D, Antonczak S (2007) DFT study of quercetin activated forms involved in antiradical, antioxidant, and prooxidant biological processes. J Agric Food Chem 55:903–911. doi: 10.1021/jf061864s CrossRefGoogle Scholar
  34. 34.
    Klein E, Lukeš V, Ilčin M (2007) DFT/B3LYP study of tocopherols and chromans antioxidant action energetics. Chem Phys 336:51–57. doi: 10.1016/j.chemphys.2007.05.007 CrossRefGoogle Scholar
  35. 35.
    Lide DA (2004) CRC handbook chemistry and physics. CRC Press Inc, Boca Raton, FL, USAGoogle Scholar
  36. 36.
    Parr RG, Szentpály L, Liu S (1999) Electrophilicity index. J Am Chem Soc 121:1922–1924. doi: 10.1021/ja983494x CrossRefGoogle Scholar
  37. 37.
    Mendoza-Wilson AM, Glossman-Mitnik D (2005) CHIH-DFT study of the electronic properties and chemical reactivity of quercetin. THEOCHEM 716:67–72. doi: 10.1016/j.theochem.2004.10.083 CrossRefGoogle Scholar
  38. 38.
    Vasilescu D, Girma R (2002) Quantum molecular modeling of quercetin - simulation of the interaction with the free radical t-BuOO. Int J Quantum Chem 90:888–902. doi: 10.1002/qua.1801 CrossRefGoogle Scholar
  39. 39.
    Russo N, Toscano M, Occella N (2000) Semiempirical molecular modeling into quercetin reactive site: structural, conformational, and electronic features. J Agric Food Chem 48:3232–3237. doi: 10.1021/jf990469h CrossRefGoogle Scholar
  40. 40.
    Leopoldini M, Marino T, Russo N, Toscano M (2004) Antioxidant Properties of Phenolic Compounds: H-Atom versus Electron Transfer Mechanism. J Phys Chem A 108:4916–4922. doi: 10.1021/jp037247d CrossRefGoogle Scholar
  41. 41.
    Leopoldini M, Russo N, Toscano M (2006) Gas and liquid phase acidity of natural antioxidants. J Agric Food Chem 54:3078–3085. doi: 10.1021/jf053180a CrossRefGoogle Scholar
  42. 42.
    Leopoldini M, Marino T, Russo N, Toscano M (2004) Density functional computations of the energetic and spectroscopic parameters of quercetin and its radicals in the gas phase and in solvent. Theor Chem Acc 111:210–216. doi: 10.1007/s00214-003-0544-1 Google Scholar
  43. 43.
    Carpenter JE, Weinhold F (1988) Analysis of the geometry of the hydroxymethyl radical by the “different hybrids for different spins” natural bond orbital procedure. THEOCHEM 169:41–62. doi: 10.1016/0166-1280(88)80248-3 CrossRefGoogle Scholar
  44. 44.
    Carpenter JE, Reed WF, AE WF (1985) Natural localized molecular orbitals. J Chem Phys 83:1736–1740. doi: 10.1063/1.449360 CrossRefGoogle Scholar
  45. 45.
    Cornard JP, Merlin JC, Boudet AC, Vrielynck L (1997) Structural study of quercetin by vibrational and electronic spectroscopies combined with semiempirical calculations. Biospectroscopy 3:183–193. doi: 10.1002/(SICI)1520-6343(1997)3:3<183::AID-BSPY2>3.0.CO;2-7 CrossRefGoogle Scholar
  46. 46.
    van Acker SABE, de Groot MJ, van den Berg M-J, Tromp MNJL, den Kelder GD-O, Vijgh WJF, Bast A (1996) A quantum chemical explanation of the antioxidant activity of flavonoids. Chem Res Toxicol 9:1305–1312. doi: 10.1021/tx9600964 CrossRefGoogle Scholar
  47. 47.
    Yates PC (1991) Semi-empirical molecular orbital calculations on tyrosine kinase inhibitors and structurally related compounds. THEOCHEM 231:201–213. doi: 10.1016/0166-1280(91)85218-V CrossRefGoogle Scholar
  48. 48.
    Erlejman AG, Verstraeten SV, Fraga CG, Oteiza PI (2004) The interaction of flavonoids with membranes: potential determinant of flavonoid antioxidant effects. Free Radic Res 38:1311–1320. doi: 10.1080/10715760400016105 CrossRefGoogle Scholar
  49. 49.
    Olivero-Verbel J, Pacheco-Londoño L (2002) Structure − Activity Relationships for The Anti-HIV Activity of Flavonoids. J Chem Inf Comput Sci 42:1241–1246. doi: 10.1021/ci020363d Google Scholar
  50. 50.
    Bonin KD, Kresin VV (1997) Electric-Dipole Polarizabilities of Atoms Molecules and Clusters. World Scientific, SingaporeGoogle Scholar
  51. 51.
    Foresman JB, Frisch AE (1996) Exploring Chemistry with Electronic Structure Methods. Gaussian, Pittsburgh PA, USAGoogle Scholar
  52. 52.
    Lewars E (2003) Computational Chemistry—Introduction to the Theory and Applications of Molecular and Quantum Mechanics. Kluwer Academic Publishers, Norwell MA, USAGoogle Scholar
  53. 53.
    Hatch FT, Lightstone FC, Colvein ME (2000) Quantitative structure-activity relationship of flavonoids for inhibition of heterocyclic amine mutagenicity. Environ Mol Mutagen 35:279–299. doi: 10.1002/1098-2280(2000)35:4<279::AID-EM3>3.0.CO;2-9 CrossRefGoogle Scholar
  54. 54.
    Rasulev BF, Abdullaev ND, Syrov VN, Leszczynski J (2005) A quantitative structure-activity relationship (QSAR) study of the antioxidant activity of flavonoids. QSAR Combin. Sci 24:1056–1065. doi: 10.1002/qsar.200430013 CrossRefGoogle Scholar
  55. 55.
    Chaudière J, Ferrari-Iliou R (1999) Intracellular antioxidants: from chemical to biochemical mechanisms. Food Chem Toxicol 37:949–962. doi: 10.1016/S0278-6915(99)00090-3 CrossRefGoogle Scholar
  56. 56.
    Martins HFP, Fernandez MT, Lopes VHC, Cordeiro MNDS (2004) Toward the prediction of the activity of antioxidants: experimental and theoretical study of the gas-phase acidities of flavonoids. J Am Soc Mass Spectrom 15:848–861. doi: 10.1016/j.jasms.2004.02.007 CrossRefGoogle Scholar
  57. 57.
    Li MJ, Liu L, Fu Y, Guo QX (2007) Accurate bond dissociation enthalpies of popular antioxidants predicted by the ONIOM-G3B3 method. THEOCHEM 815:1–9. doi: 10.1016/j.theochem.2007.03.012 CrossRefGoogle Scholar
  58. 58.
    Trouillas P, Marsal P, Siri D, Lazzaroni R, Duroux JL (2006) A DFT study of the reactivity of OH groups in quercetin and taxifolin antioxidants: the specificity of the 3-OH site. Food Chem 97:679–688. doi: 10.1016/j.foodchem.2005.05.042 CrossRefGoogle Scholar
  59. 59.
    Wolfe KL, Liu RH (2008) Structure − activity relationships of flavonoids in the cellular antioxidant activity assay. J Agric Food Chem 56:8404–8411. doi: 10.1021/jf8013074 CrossRefGoogle Scholar
  60. 60.
    Munoz-Munoz JL, Garcia-Molina F, Molina-Alarcón M, Tudela J, Carcía-Cánovas F, Rodríguez-López JN (2008) Kinetic characterization of the enzymatic and chemical oxidation of the catechins in green tea. J Agric Food Chem 56:9215–9224. doi: 10.1021/jf8012162 CrossRefGoogle Scholar
  61. 61.
    Tsimogiannis DI, Oreopoulou V (2005) The contribution of flavonoid C-ring on the DPPH free radical scavenging efficiency. A kinetic approach for the 3′,4′-hydroxy substituted members. Innov Food Sci Emerg Technol 7:140–146. doi: 10.1016/j.ifset.2005.09.001 CrossRefGoogle Scholar
  62. 62.
    Wang LF, Zhang HY (2004) Unexpected role of 5-OH in DPPH radical-scavenging activity of 4-thiaflavans. Revealed by theoretical calculations. Bioorg Med Chem Lett 14:2609–2611. doi: 10.1016/j.bmcl.2004.02.066 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Requimte/CQFB – Departamento de QuímicaFaculdade de Ciências e Tecnologia, Universidade Nova de LisboaCaparicaPortugal

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