Delphinidin, one of the natural anthocyanin pigments was theoretically (at M05-2X/6-311+G(d,p) level of theory) investigated for its ability scavange potentially highly damaging hydroxyl and superoxide anion radicals. Theoretical calculations point to HAT and SPLET mechanisms as operative for delphinidin in all solvents under investigations.Teoretski (na M05-2X/6-311+G(d,p) nivou teorije) je ispitivana sposobnost delfinidina, prirodnog antocijaninskog pigmenta, da reaguje sa potencijalno veoma štetnim hidroksi i superoksid anjon radikalima. Proračuni su pokazali da su HAT i SPLET mogući mehanizmi u svim rastvaračima

Dimitrić-Marković, Jasmina

Marković, Zoran

Milenković, Dejan

Mojović, Miloš

English

Delphinidin, one of the natural anthocyanin pigments was theoretically (at
M05-2X/6-311+G(d,p) level of theory) investigated for its ability scavange potentially
highly damaging hydroxyl and superoxide anion radicals. Theoretical calculations point
to HAT and SPLET mechanisms as operative for delphinidin in all solvents under
investigations.Teoretski (na M05-2X/6-311+G(d,p) nivou teorije) je ispitivana sposobnost
delfinidina, prirodnog antocijaninskog pigmenta, da reaguje sa potencijalno veoma
štetnim hidroksi i superoksid anjon radikalima. Proračuni su pokazali da su HAT i
SPLET mogući mehanizmi u svim rastvaračima

Markovic, Zoran

Milenkovic, Dejan

Dimitric Markovic, Jasmina

Mojovic, Milos

CaSA NaRA

Teorijsko ispitivanje antiradikalske aktivnosti delfinidina

AgroSpace

“XX  SAVETOVANJE  O  BIOTEHNOLOGIJI”                      Zbornik radova, Vol. 20.(22), 2015.  373 THEORETICAL INVESTIGATION OF ANTIRADICAL ACTIVITY OF DELPHINIDIN   Zoran Marković, Dejan Milenković, Jasmina Dimitrić Marković, Miloš Mojović  Abstract: Delphinidin, one of the natural anthocyanin pigments was theoretically (at M05-2X/6-311+G(d,p) level of theory) investigated for its ability scavange potentially highly damaging hydroxyl and superoxide anion radicals.  Theoretical calculations point to HAT and SPLET mechanisms as operative for delphinidin in all solvents under investigations.   Key words: delphinidin, hyrdoxyl radical, superoxide anion radical, HAT and SPLET mechanisms  Introduction  Anthocyanins are natural pigments widely distributed in nature (Delgado-Vargas & Paredes-López, 2003). These compounds are flavonoids that belong to the family of polyphenols. Delphinidin (2-(3,4,5-Trihydroxyphenyl)chromenylium-3,5,7-triol) (Fig.1) is an  natural anthocyanin pigment that can be found in cranberries and Concord grapes as well as pomegranates (Ribéreau-Gayon & Ribéreau-Gayon, 1958).  The present paper aims to provide quantitative tools to thoroughly and comprehensively determine antiradical mechanisms of delphinidin by calculating the energy requirements of the reactions of delphinidin and selected radical species in different media. Calculated energy requirements may indicate which radical scavenging mechanism is thermodynamically preferred and point out active sites for radical inactivation.  Material and methods  The majority of theoretical investigation of delphinidin is focused on the all rings, where OH groups are located. Geometry optimizations for all species involved in radical scavenging mechanisms have been carried out using density functional method (M05-2X),                                                        Zoran Marković, Department of Chemical-Technological Sciences, State  University of  Novi Pazar, Vuka Karadžića bb, 36300 Novi Pazar, Republic of Serbia (zmarkovic@kg.ac.rs)       Dejan Milenković, Bioengineering Research and Development Center , Prvoslava Stojanovića 6, 34000 Kragujevac, Republic of Serbia (deki82@kg.ac.rs)      Jelena Đorović, Bioengineering Research and Development Center , Prvoslava Stojanovića 6, 34000 Kragujevac, Republic of Serbia (jelena.djorovic@kg.ac.rs)       Svetlana Jeremić, Department of Chemical-Technological Sciences, State  University of  Novi Pazar, Vuka Karadžića bb, 36300 Novi Pazar, Republic of Serbia (jeremics@kg.ac.rs)       Jasmina Dimitrić Marković, Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Republic of Serbia (markovich@ffh.bg.ac.rs)       Miloš Mojović, Faculty of Physical Chemistry, University of Belgrade, Studentskitrg 12-16, 11000 Belgrade, Republic of Serbia (milos@ffh.bg.ac.rs) “XX  SAVETOVANJE  O  BIOTEHNOLOGIJI”                      Zbornik radova, Vol. 20.(22), 2015.  374developed by the Truhlar group (Zhao and Truhlar, 2008) and 6-311+G(d,p) basis set implemented in the Gaussian 09 package (Frisch et al., 2009). The influence of water, dimethylsulfooxide (DMSO), ethanol and dimethylformamide (DMF) as solvents was approximated by (SMD) solvation model (Marenich et al., 2009).  Geometries were fully optimized without imposing any restriction. Local minima were confirmed by the absence of imaginary frequencies. Thermodynamic corrections at 298.15 K were included in the calculation of relative energies.    Slika 1. Hemijska struktura delfinidina Figure 1. Chemical structure of  delphinidin  Results and discussion  In order to examine the influence of different radicals to an antiradical mechanism of delphinidin (Fig.1), the reactive particles RO• were used. In the present paper RO• particle represents hydroxyl and superoxide anion radicals. In HAT mechanism, the hydrogen atom is transferred from phenolic compound to the free radical RO: D−OH + RO → D−O + ROH                         (1) ΔHBDE for the HAT mechanism can be calculated using the following equation: ΔHBDE=H( DO) + H(ROH) - H( D−OH) - H(RO)                       (2) where the H( DO), H(ROH), H( D−OH), and H(RO) are the enthalpies of the phenolic radical, molecule obtained after hydrogen atom abstraction from the phenolic compound, starting phenolic compound, and reactive radical species, respectively.  The first step in the SET-PT mechanism is transfer of an electron from phenolic compound to free radical species, yielding the phenolic radical cation Ph−OH+ and corresponding anion.    D−OH + RO →  D−OH++ RO−                                                                                                     (3) ΔHIP for the first step of the SET-PT mechanism can be calculated as follows: ΔHIP= H( D−OH+) + H(RO−) - H( D−OH) - H(RO)         (4) where the H( D−OH+) and H(RO−) are the enthalpies of the radical cation of initial phenolic compound and anion generated from the corresponding initial radical. The second step of this mechanism is deprotonation of  D−OH+ by RO−: “XX  SAVETOVANJE  O  BIOTEHNOLOGIJI”                      Zbornik radova, Vol. 20.(22), 2015.  375D−OH++ RO− →  D−O + ROH                                                                     (5) ΔHPDE can be calculated using the following equation:  ΔHPDE= H( D−O) + H(ROH) - H(D−OH+) - H(RO−)         (6) The first step in the SPLET mechanism is deprotonation of phenolic compound by RO− or other base. The outcome of this reaction is the formation of the phenoxide anion  D−O−: D−OH + RO− →  D−O−  + ROH                                                                      (7) ΔHPA can be calculated as follows: ΔHPA = H(D−O−) + H(ROH) - H( D−OH) - H(RO−)                                      (8) In the next step electron transfer from  D−O− to RO takes place: D−O− + RO →  D−O + RO−                                                                                                                  (9)  ΔHETE can be determined by the equation: ΔHETE = H(D−O) + H(RO−) - H(D−O−) - H(RO)                                       (10)  The potential antiradical activity of delphinidin, for each reactive site (OH group), is simulated in the reactions with hydroxyl (OH) and superoxide anion (OO−) radicals. They are among the biologically relevant radicals that have been detected by spin trapping techniques using electron paramagnetic resonance (EPR) spectroscopy and synthetic nitrones (Villamena et al., 2005). Reaction enthalpies for the reaction of delphinidin with selected radicals, related to three mechanisms of free radical scavenging activity (HAT, SET-PT and SPLET), were calculated using M05-2X/6-311+G(d,p) model. Calculations were performed in the aqueous phase, DMSO, ethanol and DMF. The preferred mechanism of antiradical activity of delphidin can be estimated from ΔHBDE, ΔHIP, and ΔHPA values. The lowest of these values indicates which mechanism is favorable. The reaction enthalpies of these two radicals with delphidin are presented in Table 1.  Tabela 1. Izračunate reakcione entalpije (kJ/mol) za reakciju delfidina sa hidroksi radikalom i superoksid radikal anjonom Table 1. Calculated reaction enthalpies (kJ/mol) for the reactions of delphidin with hydroxyl radical and  superoxide radical anion  M05-2X/6-311+G(d,p)  Voda ε=78.35 Water ε=78.35 DMSO ε=46.83 DMSO ε=46.83 delfinidin delphinidin HAT SET-PT SPLET HAT SET-PT SPLET  ΔHBDE ΔHIP ΔHPDE ΔHPA ΔHETE ΔHBDE ΔHIP ΔHPDE ΔHPA ΔHETE   99     125    DOH-3 + .OH -130  -228 -145 15 -136  -260 -145 10 DOH-3` + .OH -130  -229 -129 -1 -136  -261 -121 -15 DOH-4` + .OH -157  -255 -163 6 -166  -290 -176 11 DOH-5` + .OH -132  -231 -128 -4 -138  -262 -119 -19 DOH-5 + .OH -117  -216 -151 34 -121  -245 -152 31 DOH-7 + .OH -111  -210 -151 40 -113  -237 -153 41   417     448    DOH-3 + .OO- 93  -325 -16 109 86  -362 -16 103 “XX  SAVETOVANJE  O  BIOTEHNOLOGIJI”                      Zbornik radova, Vol. 20.(22), 2015.  376DOH-3` + .OO- 92  -326 0 92 86  -362 8 78 DOH-4` + .OO- 66  -352 -34 99 57  -391 -47 104 DOH-5` + .OO- 90  -327 1 89 85  -363 11 74 DOH-5 + .OO- 105  -312 -22 127 102  -346 -23 124 DOH-7 + .OO- 111  -306 -22 133 110  -338 -24 134  Etanol ε=24.85 Ethanol ε=24.85 DMF ε=37.22 DMF ε=37.22   118     129    DOH-3 + .OH -129  -247 -153 24 -135  -264 -148 12 DOH-3` + .OH -129  -247 -133 4 -136  -265 -123 -13 DOH-4` + .OH -156  -274 -171 16 -165  -294 -176 11 DOH-5` + .OH -131  -249 -131 0 -137  -266 -121 -17 DOH-5 + .OH -115  -233 -159 44 -120  -249 -154 34 DOH-7 + .OH -109  -227 -159 50 -112  -241 -156 43   452     455    DOH-3 + .OO- 94  -358 -23 117 87  -368 -18 105 DOH-3` + .OO- 93  -358 -3 96 86  -369 7 80 DOH-4` + .OO- 67  -385 -41 108 57  -398 -46 104 DOH-5` + .OO- 92  -360 -1 93 85  -370 9 76 DOH-5 + .OO- 108  -344 -28 136 102  -353 -25 127 DOH-7 + .OO- 114  -338 -28 142 110  -345 -26 136  On the basis of the thermodynamically values (ΔHBDE, and ΔHPA) from Table 1, it is clear that delphinidin reacts with hydroxyl radical via both, HAT and SPLET mechanisms in all solvents under investigations. As can be seen from Table 1, the C4’−OH group of delphinidin is the most favoured site for homolytic and heterolytic O−H breaking in all solvents.  In the case of the superoxide anion radical the reaction representing HAT mechanisam, for delphidin, is endothermic in all solvents see Table 1. On the other hand the small negative values of ΔHPA indicate SPLET mechanisam as possible, but not much probable one. This could explain no antiradical activity of Dp towards superoxide anion radical.  Conclusion  The ΔHBDE, ΔHIP, and ΔHPA values were used to investigate antioxidative capacity of delphinidin in the presence of  •OH, and •OO−. SET-PT is not a plausible mechanism for delphinidin, due to high ΔHIP values for the reactions with all radicals in all solvents. Reaction enthalpies (ΔHBDE and ΔHPA), calculated using the M052X/6-311+G(d,p) level of theory, are exothermic in all solvents. The obtained resultas shows that delphinidin reacts with hydroxyl radical via both, HAT and SPLET mechanisms in all solvents under investigations. The C4’−OH group of delphinidin is the most favoured site for homolytic and heterolytic O−H breaking in all solvents. Obtained results also show that delphinidin reacts with •OO− via the SPLET mechanism (reaction is egzothermic – ΔHPA < 0), while HAT is no mechanism suitable “XX  SAVETOVANJE  O  BIOTEHNOLOGIJI”                      Zbornik radova, Vol. 20.(22), 2015.  377for the reaction of delphinidin with superoxide anion radical, because the reaction is endothermic in all solvents (ΔHBDE > 0). Acknowledgment  The authors acknowledge financial support of the Ministry of Science of the Republic of Serbia, grants No. 172015 and 174028.        References  Delgado-Vargas F., Paredes-López O. (2003). Natural Colorants for Food and Nutraceutical Uses, CRC Press, Boca Raton, FL. Frisch M. J., Trucks G. W., Schlegel H. B., et al. (2010). Gaussian 09, Revision C.01, Gaussian, Inc.,  Wallingford, CT, USA. Marenich A.V., Cramer C.J.,Truhlar D.G. (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. Journal of Physical Chemistry B. 113: 6378-6396. Ribéreau-Gayon J.; Ribéreau-Gayon P. (1958). The Anthocyans and Leucoanthocyans of Grapes and Wines. American Journal of Enology and Viticulture. 9: 1–9. Villamena F. A., Hadad C. M., Zweier J. L. (2005). Comparative DFT Study of the Spin Trapping of Methyl, Mercapto, Hydroperoxy, Superoxide, and Nitric Oxide Radicals by Various Substituted Cyclic Nitrones. Journal of Physical Chemistry A, 109: 1662-1674. Zhao Y., Truhlar D.G. (2008). The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theoretical Chemistry Accounts. 120 (1-3): 215-241.   TEORIJSKO ISPITIVANJE ANTIRADIKALSKE AKTIVNOSTI DELFINIDINA  Zoran Marković, Dejan Milenković, Jelena Đorović, Svetlana Jeremić, Jasmina Dimitrić Marković  Izvod: Teoretski (na M05-2X/6-311+G(d,p) nivou teorije) je ispitivana sposobnost delfinidina, prirodnog antocijaninskog pigmenta, da reaguje sa potencijalno veoma štetnim hidroksi i superoksid anjon radikalima.  Proračuni su pokazali da su HAT i SPLET mogući mehanizmi u svim rastvaračima.   Ključne reči: delfinidin, hidroksi radikal, superoksid radikal anjon, HAT i SPLET mehanizmi.  

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Teorijsko ispitivanje antiradikalske aktivnosti delfinidina

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