Skip to main content
SpringerLink
Log in

Bond dissociation enthalpies calculated by the PM3 method confirm activity cliffs in radical scavenging of flavonoids

  • Full Length Paper
  • Published:
Molecular Diversity Aims and scope Submit manuscript

An Erratum to this article was published on 27 November 2008

Abstract

Radical scavenging potency of flavonoids is associated with activity cliffs, i.e., small chemical modifications on flavonoid core can have a significant effect on activity. The presence or absence of the 3′,4′-diOH and/or 3-OH group may serve as an activity switch for radical scavenging. The physicochemical background of such an indicator variable, defined previously (Amić et al. (2003) Croat Chem Acta 76:55–61), is confirmed by computation of bond dissociation enthalpies and selecting the minimal of all values relating to flavonoid OH groups. Bond dissociation enthalpies for hydrogen abstraction from OH groups for 29 flavonoids were calculated by the PM3 method. Minimal bond dissociation enthalpy values were obtained for OH groups attached to C-3, C-3′ and C-4′ positions, and they correspond to the previously introduced indicator variable. Taking into account some driving forces of the radical scavenging mechanism, it is possible to relate structural characteristics of flavonoids to their radical scavenging potency as well as to develop reliable structure-activity models.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

RSA:

Radical scavenging activity

ROS:

Reactive oxygen species

BDE:

Bond dissociation enthalpy

LOO:

Leave-one-out

CV:

Cross-validation

QSAR:

Quantitative structure–activity relationship

SAR:

Structure–activity relationship

References

  1. Hermans N, Cos P, Maes L et al (2007) Challenges and pitfalls in antioxidant research. Curr Med Chem 14: 417–430. doi:10.2174/092986707779941005

    Article  PubMed  CAS  Google Scholar 

  2. Heim KE, Tagliaferro AR, Bobilya DJ (2002) Flavonoid antioxidants: chemistry, metabolism and structure–activity relationships. J Nutr Biochem 13: 572–584. doi:10.1016/S0955-2863(02)00208-5

    Article  PubMed  CAS  Google Scholar 

  3. Bors W, Heller W, Michel K et al (1996) Flavonoids and polyphenols: chemistry and biology. In: Cadenas E, Packer L (eds) Handbook of antioxidants. Marcel Dekker Inc., New York, pp 409–466

    Google Scholar 

  4. Havsteen BH (2002) The biochemistry and medical significance of the flavonoids. Pharmacol Ther 96: 67–202. doi:10.1016/S0163-7258(02)00298-X

    Article  PubMed  CAS  Google Scholar 

  5. Zhang H-Y, Ji H-F (2006) How vitamin E scavenges DPPH radicals in polar protic media. N J Chem 30: 503–504. doi:10.1039/b600025h

    Article  CAS  Google Scholar 

  6. Leopoldini M, Marino T, Russo N et al (2004) Antioxidant properties of phenolic compounds: H-Atom versus electron transfer mechanism. J Phys Chem A 108: 4916–4922. doi:10.1021/jp037247d

    Article  CAS  Google Scholar 

  7. Amić D, Davidović-Amić D, Bešlo D et al (2007) SAR and QSAR of the antioxidant activity of flavonoids. Curr Med Chem 14: 827–845. doi:10.2174/092986707780090954

    Article  PubMed  Google Scholar 

  8. Bors W, Heller W, Michel C et al (1990) Flavonoids as antioxidants: determination of radical-scavenging efficiencies. In: Packer L, Glazer AN (eds) Methods in enzymology, vol 186. Academic Press, San Diego, pp 343–355

    Google Scholar 

  9. Rice-Evans CA, Miller NJ, Paganga G (1996) Structure–antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20: 933–956. doi:10.1016/0891-5849(95)02227-9

    Article  PubMed  CAS  Google Scholar 

  10. Maggiora GM (2006) On outliers and activity cliffs—Why QSAR often disappoints. J Chem Inf Model 46: 1535. doi:10.1021/ci060117s

    Article  PubMed  CAS  Google Scholar 

  11. Johnson SR (2008) The trouble with QSAR (or How I learned to stop worrying and embrace fallacy). J Chem Inf Model 48: 25–26. doi:10.1021/ci700332k

    Article  PubMed  CAS  Google Scholar 

  12. Cai Y-Z, Sun M, Xing J, Luo Q, Corke H (2006) Structure–radical scavenging activity relationships of phenolic compounds from traditional Chinese medicinal plants. Life Sci 78: 2872–2888. doi:10.1016/j.lfs.2005.11.004

    Article  PubMed  CAS  Google Scholar 

  13. Lučić B, Amić D, Trinajstić N (2009) Antioxidant QSAR modeling as exemplified on polyphenols. In: Armstrong D (eds) Advanced protocols in oxidative stress I, Series: methods in molecular biology, vol 477. Humana Press, New York (in press)

    Google Scholar 

  14. Amić D, Davidović-Amić D, Bešlo D, Trinajstić N (2003) Structure–radical scavenging activity relationships of flavonoids. Croat Chem Acta 76: 55–61

    Google Scholar 

  15. Burda S, Oleszek W (2001) Antioxidant and antiradical activities of flavonoids. J Agric Food Chem 49: 2774–2779. doi:10.1021/jf001413m

    Article  PubMed  CAS  Google Scholar 

  16. Tetko IV, Gasteiger J, Todeschini R et al (2005) Virtual computational chemistry laboratory—design and description. J Comput Aided Mol Des 14: 453–463. doi:10.1007/s10822-005-8694-y

    Article  Google Scholar 

  17. Dewar MJS, Zoebisch Z, Healy EF et al (1985) AM1: a new general purpose quantum mechanical molecular model. J Am Chem Soc 107: 3902–3909. doi:10.1021/ja00299a024

    Article  CAS  Google Scholar 

  18. Stewart JJP (1989) Optimization of parameters for semi-empirical methods. I. Method. J Comput Chem 10: 209–220. doi:10.1002/jcc.540100208

    Article  CAS  Google Scholar 

  19. Schmidt MW, Baldridge KK, Boatz JA et al (1993) General atomic and molecular electronic structure system (GAMESS). J Comput Chem 14: 1347–1363. doi:10.1002/jcc.540141112

    Article  CAS  Google Scholar 

  20. Lučić B, Trinajstić N (1999) Multivariate regression outperforms several robust architectures of neural networks in QSAR modeling. J Chem Inf Comput Sci 39: 121–132. doi:10.1021/ci980090f

    Google Scholar 

  21. Cronin MTD, Schultz TW (2003) Pitfalls in QSAR. J Mol Struct THEOCHEM 622: 39–51. doi:10.1016/S0166-1280(02)00616-4

    Article  CAS  Google Scholar 

  22. Netzeva TI, Worth AP, Aldenberg T et al (2005) Current status of methods for defining the applicability domain of (quantitative) structure–activity relationships. ATLA 33: 155–173

    PubMed  CAS  Google Scholar 

  23. Gramatica P (2007) Principles of QSAR models validation: internal and external. QSAR Comb Sci 26: 694–701. doi:10.1002/qsar.200610151

    Article  CAS  Google Scholar 

  24. Kondo K, Kurihara M, Miyata N et al (1999) Mechanistic studies of catechins as antioxidants against radical oxidation. Arch Biochem Biophys 362: 79–86. doi:10.1006/abbi.1998.1015

    Article  PubMed  CAS  Google Scholar 

  25. Zhang H-Y, Wang L-F (2002) Are allylic hydrogens in catechins more abstractable than catecholic hydrogens? J Am Oil Chem Soc 79: 943–944. doi:10.1007/s11746-002-0583-6

    Article  CAS  Google Scholar 

  26. Kancheva V, Dinchev D, Tsimidou M et al (2007) Antioxidative properties of Tribulus terrestris from Bulgaria and radical scavenging activity of its flavonoid components. Riv Ital Sost Grasse 84: 210–219

    CAS  Google Scholar 

  27. Wright JS, Johnson ER, DiLabio GA (2001) Predicting the activity of phenolic antioxidants: theoretical method, analysis of substituent effects, and application to major families of antioxidants. J Am Chem Soc 123: 1173–1183. doi:10.1021/ja002455u

    Article  PubMed  CAS  Google Scholar 

  28. 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

    Article  CAS  Google Scholar 

  29. Zhang H-Y (2005) Structure-activity relationships and rational design strategies for radical-scavenging antioxidants. Curr Comp-Aided Drug Des 1: 257–273. doi:10.2174/1573409054367691

    Article  CAS  Google Scholar 

  30. Pannala AS, Chan TS, O’Brien PJ et al (2001) Flavonoid B-ring chemistry and antioxidant activity: fast reaction kinetics. Biochem Biophys Res Commun 282: 1161–1168. doi:10.1006/bbrc.2001.4705

    Article  Google Scholar 

  31. Trouillas P, Marsal P, Siri D et al (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

    Article  CAS  Google Scholar 

  32. Li M-J, Liu L, Fu Y et al (2007) Accurate bond dissociation enthalpies of popular antioxidants predicted by the ONIOM-G3B3 method. J Mol Struct THEOCHEM 815: 1–9. doi:10.1016/j.theochem.2007.03.012

    Article  CAS  Google Scholar 

  33. Yoo KM, Kim D-O, Lee CY (2007) Evaluation of different methods of antioxidant measurement. Food Sci Biotechnol 16: 177–182

    CAS  Google Scholar 

  34. Rasulev BF, Abdullaev ND, Syrov VN et al (2005) A quantitative structure-activity relationship (QSAR) study of the antioxidant activity of flavonoids. QSAR Comb Sci 24: 1056–1065. doi:10.1002/qsar.200430013

    Article  CAS  Google Scholar 

  35. Om A, Kim JH (2008) A quantitative structure–activity relationship model for radical scavenging activity of flavonoids. J Med Food 11: 29–37. doi:10.1089/jmf.2007.048

    Article  PubMed  CAS  Google Scholar 

  36. Todeschini R, Consonni V (2000) Hand book of molecular descriptors. Wiley-VCH, Weinheim

    Google Scholar 

  37. Nagar S, Islam MA, Das S et al (2008) Pharmacophore mapping of flavone derivatives for aromatase inhibition. Mol Diversity 12: 65–76. doi:10.1007/s11030-008-9077-9

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Agriculture, The Josip Juraj Strossmayer University, P.O. Box 719, 31107, Osijek, Croatia

    Dragan Amić

  2. The Rugjer Bošković Institute, P.O. Box 180, 10002, Zagreb, Croatia

    Bono Lučić, Goran Kovačević & Nenad Trinajstić

Authors
  1. Dragan Amić
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bono Lučić
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Goran Kovačević
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nenad Trinajstić
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dragan Amić.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s11030-008-9102-z

Rights and permissions

Reprints and permissions

About this article

Cite this article

Amić, D., Lučić, B., Kovačević, G. et al. Bond dissociation enthalpies calculated by the PM3 method confirm activity cliffs in radical scavenging of flavonoids. Mol Divers 13, 27–36 (2009). https://doi.org/10.1007/s11030-008-9095-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-008-9095-7

Keywords

Search

Navigation