Abstract
Twenty-nine ellagitannin derivatives and ellagic acid (EA) metabolites have been chosen to calculate the aqueous and DMSO acidity constants (pKa) and proton affinities (PA) as criterions for estimating antioxidant activity. The calculations have been performed using density functional theory (DFT) and MP2 methods in conjugation with SMD continuum model. The pKa values calculated with the MP2 method are in agreement with the experimental pKa values of EA with low percentage errors. The results show significant differences in the acidic content of several OH phenolic groups of each metabolite. A reliable relationship is observed between the pKa (also PA) values and the minimum of electrostatic potential (Vmin) in the vicinity of acidic sites. The OH group located at the position 5 of urolithin M5 (UM5) is the most acidic site through the effect of intramolecular hydrogen bonding. The glucuronide substituent increases the acidity of metabolites in water and DMSO solvents. Isourolithin A3-glucuronide is the most acidic metabolites among the methyl and glucuronide-conjugated metabolites in both solvents. According to the results, the EA metabolites are good lipophilic antioxidant, as well as EA itself.
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Mazzone G, Toscano M, Russo N (2013) Density functional predictions of antioxidant activity and UV spectral features of nasutin a, isonasutin, ellagic acid, and one of its possible derivatives. J Agric Food Chem 61:9650–9657
Clifford MN, Scalbert A (2000) Ellagitannins – nature, occurrence and dietary burden. J Sci Food Agric 80:1118–1125
Sharma M, Li L, Celver J, Killian C, Kovoor A, Seeram NP (2010) Effects of fruit ellagitannin extracts, ellagic acid, and their colonic metabolite, urolithin a, on wnt signaling. J Agric Food Chem 58:3965–3969
Vrhovsek U, Giongo L, Mattivi F, Viola R (2008) A survey of ellagitannin content in raspberry and blackberry cultivars grown in Trentino (Italy). Eur Food Res Technol 226:817–824
Häkkinen S, Heinonen M, Kärenlampi SO, Mykkänen HM, Ruuskanen J, Törrönen R (1999) Screening of selected flavonoids and phenolic acids in 19 berries. Food Res Int 32:345–353
García-Villalba R, Espín JC, Aaby K, Alasalvar C, Heinonen M, Jacobs G, Voorspoels S, Koivumäki T, Kroon PA, Pelvan E, Saha S, Tomás-Barberán FA (2015) Validated method for the characterization and quantification of extractable and nonextractable ellagitannins after acid hydrolysis in pomegranate fruits, juices, and extracts. J Agric Food Chem 63:6555–6566
González-Barrio R, Truchado P, Ito H, Espín JC, Tomás-Barberán FA (2011) UV and MS identification of urolithins and nasutins, the bioavailable metabolites of ellagitannins and ellagic acid in different mammals. J Agric Food Chem 59:1152–1162
Tomás-Barberán FA, García-Villalba R, González-Sarrías A, Selma MV, Espín JC (2014) Ellagic acid metabolism by human gut microbiota: consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status. J Agric Food Chem 62:6535–6538
Cerdá B, Periago P, Espín JC, Tomás-Barberán FA (2005) Identification of urolithin a as a metabolite produced by human colon microflora from ellagic acid and related compounds. J Agric Food Chem 53:5571–5576
García-Villalba R, Beltrán D, Espín JC, Selma MV, Tomás-Barberán FA (2013) Time course production of urolithins from ellagic acid by human gut microbiota. J Agric Food Chem 61:8797–8806
Cerdá B, Espín JC, Parra S, Martínez P, Tomás-Barberán FA (2004) The potent in vitro antioxidant ellagitannins from pomegranate juice are metabolized into bioavailable but poor antioxidant hydroxy-6H-dibenzopyran-6-one derivatives by the colonic microflora of healthy humans. Eur J Nutr 43:205–220
Espín JC, González-Barrio R, Cerdá B, López-Bote C, Rey AI, Tomás-Barberán FA (2007) Iberian pig as a model to clarify obscure points in the bioavailability and metabolism of ellagitannins in humans. J Agric Food Chem 55:10476–10485
Seeram NP, Henning SM, Zhang Y, Suchard M, Li Z, Heber D (2006) Pomegranate juice ellagitannin metabolites are present in human plasma and some persist in urine for up to 48 hours. J Nutr 136:2481–2485
Bialonska D, Kasimsetty SG, Khan SI, Ferreira D (2009) Urolithins, intestinal microbial metabolites of pomegranate ellagitannins, exhibit potent antioxidant activity in a cell-based assay. J Agric Food Chem 57:10181–10186
Heber D, Schulman RN, Seeram NP (2006) Pomegranates: ancient roots to modern medicine. Taylor & Francis, Boca Raton
Mertens-Talcott SU, Jilma-Stohlawetz P, Rios J, Hingorani L, Derendorf H (2006) Absorption, metabolism, and antioxidant effects of pomegranate (Punica granatum L.) polyphenols after ingestion of a standardized extract in healthy human volunteers. J Agric Food Chem 54:8956–8961
Seeram NP, Aronson WJ, Zhang Y, Henning SM, Moro A, Lee RP, Sartippour M, Harris DM, Rettig M, Suchard MA, Pantuck AJ, Belldegrun A, Heber D (2007) Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland. J Agric Food Chem 55:7732–7737
Gil MI, Tomás-Barberán FA, Hess-Pierce B, Holcroft DM, Kader AA (2000) Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem 48:4581–4589
Henning SM, Seeram NP, Zhang Y, Li L, Gao K, Lee RP, Wang DC, Zerlin A, Karp H, Thames G, Kotlerman J, Li Z, Heber D (2010) Strawberry consumption is associated with increased antioxidant capacity in serum. J Med Food 13:116–122
Priyadarsini KI, Khopde SM, Kumar SS, Mohan H (2002) Free radical studies of ellagic acid, a natural phenolic antioxidant. J Agric Food Chem 50:2200–2206
Galano A, Marquez MF, Pérez- González A (2014) Ellagic acid: an unusually versatile protector against oxidative stress. Chem Res Toxicol 27:904–918
Zhang J, Xiong Y, Peng B, Gao H, Zhou Z (2011) Density functional study on the bioactivity of ellagic acid, its derivatives and metabolite. Comput Theor Chem 963:148–153
Kallio T, Kallio J, Jaakkola M, Mäki M, Kilpeläinen P, Virtanen V (2013) Urolithins display both antioxidant and pro-oxidant activities depending on assay system and conditions. J Agric Food Chem 61:10720–10729
Tiwari MK, Mishra PC (2013) Modeling the scavenging activity of ellagic acid and its methyl derivatives towards hydroxyl, methoxy, and nitrogen dioxide radicals. J Mol Model 19:5445–5456
Marković Z, Milenković D, Ðorović J, Marković JMD, Lučić B, Amić D (2013) A DFT and PM6 study of free radical scavenging activity of ellagic acid. Monatsh Chem - Chem Mon 144:803–812
Nugroho A, Rhim TJ, Choi MY, Choi JS, Kim YC, Kim MS, Park HJ (2014) Simultaneous analysis and peroxynitrite-scavenging activity of galloylated flavonoid glycosides and ellagic acid in Euphorbia supine. Arch Pharm Res 37:890–898
Ambigaipalan P, Camargo A, Shahidi F (2016) Phenolic compounds of pomegranate by-products (outer skin, mesocarp, divider membrane) and their antioxidant activities. J Agric Food Chem 64:6584–6604
Azofeifa G, Quesada S, Boudard F, Morena M, Cristol JP, Pérez AM, Vaillant F, Michel A (2013) Antioxidant and anti-inflammatory in vitro activities of phenolic compounds from tropical highland blackberry (rubus adenotrichos). J Agric Food Chem 61:5798–5805
Sunthankar SR, Yatkar SKK (1938) Electrometric titration of tannic acids part II. Electrometric titration of gallic and gallotannic acids. J Indian Inst Sci 21A:189–208
Queimada AJ, Mota FL, Pinho SP, Macedo EA (2009) Solubilities of biologically active phenolic compounds: measurements and modeling. J Phys Chem B 113:3469–3476
Press RE, Hardcastle D (1969) Some physico-chemical properties of ellagic acid. J Appl Chem 19:247–251
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, Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, 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 O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, revision A.02. Gaussian, Inc., Wallingford
Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652
Lee C, Yang W, Parr RG (1988) Development of the colic-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 37:785–789
Leopoldini M, Russo N, Toscano M (2006) Gas and liquid phase acidity of natural antioxidants. J Agric Food Chem 54:3078–3085
Marenich AV, Cramer CJ, Truhlar DG (2009) Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J Phys Chem B 113:6378–6396
Trummal A, Lipping L, Kaljurand I, Koppel IA, Leito I (2016) Acidity of strong acids in water and dimethyl sulfoxide. J Phys Chem A 120:3663–3670
Reichardt C, Welton T (2011) Solvents and solvent effects in organic chemistry4rd edn. Wiley-VCH, Weinheim
Marcus Y, Kamlet MJ, Taft RW (1988) Linear solvation energy relationships. Standard molar Gibbs free energies and enthalpies of transfer of ions from water into nonaqueous solvents. J Phys Chem 92:3613–3622
Grimme S (2004) Accurate description of van der waals complexes by density functional theory including empirical corrections. J Comput Chem 25:1463–1473
Grimme S, Antony J, Ehrlich S, Krieg H (2010) A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J Chem Phys 132:154104–154123
Møller C, Plesset MS (1934) Note on an approximation treatment for many-Electron systems. Phys Rev 46:618–622
Bader RFW (1990) Atoms in molecules: a quantum theory. Oxford University Press, Oxford
Biegler-könig F, Schönbohm J, Bayles D (2001) AIM2000—a program to analyze and visualize atoms in molecules. J Comput Chem 22:545–559
Lu T, Chen F (2012) Multiwfn: a multifunctional Wavefunction analyzer. J Comput Chem 33:580–592
Breneman CM, Wiberg KB (1990) Determining atom-centered monopoles from molecular electrostatic potentials. The need for high sampling density in Formamide conformational analysis. J Comput Chem 11:361–373
Rimarčík J, Lukeš V, Klein E, Ilčin M (2010) Study of the solvent effect on the enthalpies of homolytic and heterolytic N–H bond cleavage in p-phenylenediamine and tetracyano-p-phenylenediamine. Comput Theor Chem 952:25–30
Atkins PW (1998) Physical chemistry6th edn. Oxford University Press, Oxford
Bader RFW, Essén H (1984) The characterization of atomic interactions. J Chem Phys 80:1943–1960
Granucci G, Hynes JT, Millié P, Tran-Thi TH (2000) A theoretical investigation of excited-state acidity of phenol and cyanophenols. J Am Chem Soc 122:12243–12253
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We thank the University of Sistan and Baluchestan for financial supports and Computational Quantum Chemistry Laboratory for computational facilities.
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Shahraki, A., Ebrahimi, A. Ellagitannin derivatives and some conjugated metabolites: aqueous-DMSO proton affinities and acidity constants. Struct Chem 30, 1343–1351 (2019). https://doi.org/10.1007/s11224-019-1284-8
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DOI: https://doi.org/10.1007/s11224-019-1284-8