Chrysin flavonoid adsorbed on B₁₂N₁₂ nanocage - A novel antioxidant nanomaterial

Cite this paper: Vietnam J. Chem., 2021, 59(2), 211-220 Article DOI: 10.1002/vjch.202000168 211 Wiley Online Library © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH Chrysin flavonoid adsorbed on B12N12 nanocage - A novel antioxidant nanomaterial Atefeh Khalili 1 , Mohammad T. Baei 2* , Seyed Hossein Hosseini Ghaboos 1 1 Department of Food Science and Technology, Azadshahr Branch, Islamic Azad University, Azadshahr, Golestan, Iran, postal code: 49617-89985 2 Department of Chemistry, Azadshahr Branch, Islamic Azad University, Azadshahr, Golestan, Iran Submitted September 29, 2020; Accepted January 8, 2021 Abstract Antioxidative activity of chrysin (CYS) on the B12N12 nanocage has been evaluated by density functional theory with B3PW91-D3 and M06-2X-D3 methods. Adsorption behavior and study of topologies demonstrated that the CYS has chemisorbed to the nanocage and shows notable changes in the electronic properties of B12N12. The antioxidant properties of the CYS and CYS/B12N12 systems have been studied in the different environments by the M06-2X-D3 method. The findings demonstrated that in the vacuum phase and water, benzene, and ethanol solvents, the BDE (5O- H), PDE, PA values of CYS/B12N12 are smaller than those of CYS system. The current study implied that B12N12 nanocage can increase the antioxidative properties of the CYS. Keywords. Chrysin, antioxidative activity, antiradical mechanisms, B12N12, DFT. 1. INTRODUCTION Flavonoids have been accepted as one of the largest and most widespread bioactive materials, and subset of phenolic compounds that can be found in vegetables, plants, and fruits. [1] Flavonoids showed potent scavenger activity against reactive nitrogen and oxygen species. They can transfer hydrogen’s and electrons to RONS which stabilizes them providing relatively permanent flavonoid radicals. Furthermore, flavonoids can chelate to metals for the prevention of radicals generation as well as activating antioxidant enzymes in deactivating free radicals. They are used in food products of the packaging in order to enhance the products' shelf-life and bioactive compound content due to their oxygen-sensitivity as an active antioxidant material. [2] Chrysin is a flavonoid and an analog of apigenin included in natural products (Pleurotus ostreatus, [3] propolis, [4] honey, [5] etc.) and many plants (Passiflora caerulea, [6] Passiflora incarnate, [7] Oroxylum indicum, [8] etc.). It has the high remedial power of transferring the intestinal membrane and also can be used to afford a wide variety of pharmacological activities particularly anti-inflammatory and antioxidant [8] properties. In late years, there has been an increasing attachment in using boron nitride nanotubes and other boron nitride nanostructures as promising materials for therapeutic agents [9-10] with significant prominence in cancer therapy. Boron nitride (BN) has distinguishing features containing substantial electrical-insulating performance, high resistance to oxidation, high Young’s modulus high thermal conductivity and stability, and high chemical inertness. [11] BN fullerenes were characterized by electron irradiation or arc-melting methods, with their chemical compositions and cage-like structures were examined by transmission electron microscopy (TEM) and time-of-flight mass spectrometry (TOFMS). [12] BNNPs have become an important topic in this field because of the wide availability of boron nitride and its inherent features of low toxicity, biodegradability and biocompatibility. [13] Also, in the last few decades, the potential of boron nitride for biomedical uses in the medic field, such as drug delivery, imaging and cellule stimulation was increased. [14] Hence, adsorption of chrysin on appropriate surfaces can be used as an election to increase its lifetime. There are several kinds of research focused on the chrysin adsorption on different substrates. [15] Moreover, boron nitride nanostructures have been widely used for the detection and sorption of drugs. [16,17] On the other hand, in late years, research into boron-including compounds has notably increased in pharmaceutical chemistry. [18] Also, it has been widely used for the detection and absorption of noble gases. [19] It Vietnam Journal of Chemistry Mohammad T. Baei et al. © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 212 is, therefore, significant to comprehend the influence of B12N12 nanocage on the antiradical activity of chrysin in order to deliver new clues to the development of antioxidants. Moreover, we evaluated the efficacy of the polar and non-polar solvents on the antioxidative activity of the systems. 2. COMPUTATIONAL METHODS We evaluated the improvement of antiradical activity of the CYS through the interaction with B12N12 nanocage by DFT calculations. Geometries, charge transfer characteristics (QT) between CYS and the nanocage, density of states (DOS), molecular electrostatic potential (MEP), and frontier molecular orbital (FMO) of the considered systems are computed with B3PW91- GD3BJ and M06-2X- D3 methods. The M06-2X method [20] is usually used to be the most appropriate one for main groups in chemistry and noncovalent interactions. [21] Therefore, geometry calculations and vibration frequencies were carried out on the nanocage, all molecules, ions, and various chrysin/B12N12 systems by the M06-2X/6-31G* [22,23] method with an empirical dispersion term (M06-2X-D3) in the Gaussian 09 program. [24] Then, the vibrational frequencies for the optimized geometries were computed at the M06-2X-D3 level combined with the 6-311+G* basis set for thermodynamic parameters. For the systems, the basis set superposition error (BSSE) and the dispersion interaction effects were calculated. Solvent effects were checked out by using the SMD continuum solvent model on the energies of all studied species. [25] For the relaxed systems, the adsorption energy (Ead) of chrysin on the B12N12 surface is obtained using the following equation: Ead = ECYS - B12N12 - (ECYS + E B12N12) + EBSSE (1) where ECYS - B12N12 is the energy of CYS/B12N12 system. E B12N12 and ECYS are the energies of the pure B12N12 and chrysin. The phenolic antioxidants show a significant role in the oxidative process mainly through three accepted radical scavenging mechanisms. [26] In this research, the antioxidative activity of the phenolic compounds were investigated using the bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA) and electron transfer enthalpy (ETE). [27] For the hydrogen atom transfer (HAT), antioxidative activity of phenolic antioxidant (ArOH) can evaluate by electron transfer from the phenolic system to the free radical. It can be shown as follows: ArOH + R º → RH + ArOº (2) The HAT in equation (2) is defined by the BDE of the O-H bond. [28] The molecules with a lower BDE value illustrate the greater antioxidant capacity of the systems. The BDE value can be specified by the following equation: BDE = ΔH (ArOº) + ΔH (Hº) – ΔH (ArOH) (3) In the single electron transfer-proton transfer (SET-PT) method, an electron is transferred from the antioxidant to a free radical and forming a cation radical as computed from equation of 4: Rº + ArOH → R− + ArOH+º (4) The IP and PDE are related to the first and second steps of SET-PT mechanism. R − + ArOH+º → RH + ArOº (5) The IP and PDE values were determined from the following equation: IP = ΔH (ArOH+º) + ΔH (e−) – ΔH (ArOH) (6) PDE = ΔH (ArOº) + ΔH (H+) – ΔH (ArOH+º) (7) And in the last step, sequential proton loss electron transfer (SPLET) method was calculated from the following equation: ArOH → ArO− + H+ (8) ArO − + Rº → ArOº + R− (9) The PA and ETE values were calculated from the following equation: PA = ΔH (ArO−) + ΔH (H+) – ΔH (ArOH) (10) ETE = ΔH (ArOº) + ΔH (e−) – ΔH (ArO−) (11) The calculated values of gas and solvent phase of H (H+), H (e−) and H (H.) were determined from Refs. [29] and [30]. 3. RESULTS AND DISCUSSION 3.1. Adsorption behavior of Chrysin on B12N12 nanocage Figures 1 and 2 display the relaxed structures, MEP and FMO plots of the B12N12 nanocage and chrysin in the vacuum environment. The nonpolar B12N12 nanocage is the smallest stable boron nitride fullerene with Th symmetry which is composed of six 4-membered rings (4-MR) and eight 6- membered rings (6-MR). As depicted in figure 1, the B-N bond lengths in B12N12 are calculated to be 1.44 Å (6-MR) and 1.48 Å (4-MR) in a vacuum environment by the B3PW91-D3 functional. The FMO and MEP plots on B12N12 nanocage is also shown in figure 1. FMO analysis represents that the Vietnam Journal of Chemistry Chrysin flavonoid adsorbed on B12N12 nanocage © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 213 HOMO and LUMO distributions are mostly localized on the boron and nitrogen atoms of the B12N12 nanocage as shown in figure 1. MEP plot of B12N12 represents that the boron atom of nanocage is the most desirable site for the attraction of nucleophilic agent, while the oxygen atom of Figure 1: (a) Geometrical parameters, (b) MEP and (c, d) FMO plots for the optimized structure of B12N12 obtained by the M06-2X method. The distances and angles are in Å and degrees carbonyl group in chrysin (quinolic system) with red color can be the most susceptible site for the electrophilic attack to boron atom of B12N12 in comparison to phenolic system, defined by the distribution of charge density. As shown in figure 2, the CYS has one nucleophilic site containing oxygen atom (-0.560 |e|) because it has a negative electrostatic potential surface. The FMO analysis illustrates that the HOMO and LUMO are mostly localized on the carbon and oxygen atoms of the drug. The lengths of C=O, C5-O, and C7-O bonds for the CYS molecule are computed to be 1.25, 1.33, and 1.35 Å by the B3PW91-D3 and 1.24, 1.33, and 1.35 Å by the M06-2X-D3 method, respectively. In these analyses, the results obtained at the B3PW91- D3 method are similar to the M06-2X-D3 method. As shown in figure 3, CYS molecule is adsorbed from its carbonyl group on boron atom of B12N12 nanocage with the interaction distances about 1.54 Å by the B3PW91-D3 method. The adsorption energy for the CYS/B12N12 system is found to be -32.16 kcal/mol in the vacuum environment. As it can be seen in figure 3, the adsorption of CYS induces a local structural deformation on both the CYS and the B12N12 nanocage. The bond length of C=O of CYS is increased from 1.25 and 1.24 Å in isolated CYS to Vietnam Journal of Chemistry Mohammad T. Baei et al. © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 214 1.29 Å in the CYS/B12N12 system by the B3PW91- D3 and M06-2X-D3, respectively. This behavior is in agreement with the change in the frequency of C=O bond in the structure. The vibratory frequency of the bond is reduced from 1767.71 and 1823.38 cm -1 in free CYS to 1614.71 and 1646 cm -1 in the CYS/B12N12 system by the B3PW91-D3 and M06- 2X-D3, respectively. [31] A natural bond orbital (NBO) charge about 0.12 e transfers from the CYS to the B12N12 nanocage. This can be understood by the fact that the CYS tends to share some electron with the LUMO site of the B12N12 nanocage. The HOMO-LUMO gap (Egap) CYS is found to be about 4.51 eV (B3PW91-D3) and 6.83 eV (M06-2X-D3). After adsorption of CYS on the surface of B12N12 nanocage, the value of Egap was reduced to 3.44 and 5.81 eV by the B3PW91-D3 and M06-2X-D3 methods, respectively (figure 4). The difference in the Egap value in the CYS/B12N12 system was 50.99 (B3PW91-D3) and 54.23 % (M06-2X-D3), respectively. As expected, a significant decrement of Egap is accompanied by the increase in the electrical conductivity of B12N12 nanocage. [32] Hence, B12N12 nanocage can exhibit an electrical noise in the presence of CYS and can be used as biosensor for medical usage. Figure 2: (a) Geometrical parameters, (b) MEP and (c, d) FMO plots for the optimized structure of Chrysin obtained by the M06-2X method. The distances and angles are in Å and degrees 3.2. Antioxidative mechanisms of CSY on B12N12 nanocage 3.2.1. HAT mechanism In the HAT mechanism, the strength of a phenolic antioxidant to exist as stable radical species when breaking a hydrogen atom from its phenolic OH group was measured that can be characterized by the BDE. The lower values of BDE represent an easier reaction and the greater antioxidant activity of the configuration. The BDE and ΔBDE values, where ΔBDE = BDE (CYS/B12N12 system) – BDE (CSY) for the O-H of CYS and CYS/B12N12 system in vacuum environment in addition in the different solvents (water, ethanol and benzene) are computed Vietnam Journal of Chemistry Chrysin flavonoid adsorbed on B12N12 nanocage © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 215 at the M06-2X-D3 level as listed in table 1. For CYS, the lowest BDE is at 7O-H and the BDE value in 7O-H in the environments is lower than that of 5O-H, because 5O-H situation taking part in inter hydrogen bond so, 7O-H of CYS is the most effective for OH radical attack. In the previous report, [33] for CYS in water and DMSO phases, 7O- H is also more suitable for radical attack, because the BDE value of 7O-H in these two solvents is lower than that of 5O-H. Also, as can be showed in table 1, the lowest BDE value for the CYS/B12N12 complex at situation 7-OH of the systems in the vacuum and benzene environments. In truth, it can be assumed that for the systems the 7-OH group undergoes the HAT mechanism with the most possibility. On the other hand, the BDE values (5O- H) of CYS/B12N12 complex in the vacuum, water, benzene, and ethanol environments are lower than BDE values of CYS. Therefore, the ΔBDE values (BDE CYS/B12N12 –BDE CYS) in the environments for 5O-H are negative. Nevertheless, negative value of ΔBDE for the systems represent that CYS adsorption on B12N12 nanocage in the HAT analysis with lower BDEs may present stronger antioxidant activity in comparison to CYS in the reported structures. Figure 3: Calculated geometries (a), MEP (b), and FMO (c, d) for CSY/B12N12 system Table 1: Bond dissociation enthalpy (BDE) and ΔBDE in kcal/mol of O-H obtained by the M062X-D3 functional Solvent BDE ΔBDE CYS B12N12-CYS system 5O-H 7O-H 5O-H 7O-H 5O-H 7O-H Vacuum 100.44 89.42 98.42 92.90 -2.02 3.48 Benzene 98.65 89.60 95.59 93.06 -3.06 3.46 Ethanol 94.61 91.92 92.45 93.78 -2.16 1.86 Water 94.82 92.91 92.80 95.55 -2.02 2.64 Vietnam Journal of Chemistry Mohammad T. Baei et al. © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 216 Figure 4: Calculated TDOS plots for CSY (a), B12N12 (b), and CSY/B12N12 (c) systems 3.2.2. SET-PT mechanism analysis In this mechanism an electron is transferred from the antioxidant to a free radical and forming a cation radical that is characterized by IP, then, a proton donation carried out from the cation radical and is governed by PDE. A stronger the electron-donating ability and the proton donation ability is expected upon having lower values of IP and PDE. The effects of substituents (phenols and chromans), [34] several substituted anilines [35] on the IP value were reported in the literature. In this paper, we are reporting on the computed values for the IP, ΔIP, PDE, and ΔPDE for the CYS and CYS/B12N12 system in the vacuum and solvent environments through M06-2X-D3 functional (tables 2 and 3). It is noted that the calculated IP and PDE values have an obvious sensitivity towards the polarity changes of the solvents where these values are computed to be lower in polar solvents (ethanol and water) compared to those of the nonpolar (vacuum and benzene) solvents. This shows that polar solvents Table 2: Ionization potential (IP) and ΔIP in kcal/mol calculated by the M062X-D3 level Solvent CYS B12N12-CYS system ΔIP IP IP Vacuum 182.71 185.87 3.16 Benzene 159.57 174.44 14.87 Ethanol 141.09 148.41 7.32 Water 140.59 146.29 5.70 enhance the electron-donating and the proton donation abilities of the CYS and CYS/B12N12 system. Moreover, the ΔIP values (IP CYS/B12N12 –IP CYS) was positive showing that the formation of a cation radical in CYS/B12N12 system is not as easy as those of the CYS and stands for the more activity of the CYS in the first step of the SET-PT mechanism. The sequences of PDEs and BDEs for OH groups of the systems are similar whereas the 7−OH groups Vietnam Journal of Chemistry Chrysin flavonoid adsorbed on B12N12 nanocage © 2021 Vietnam Academy of Science and Technology, Hanoi & Wiley-VCH GmbH www.vjc.wiley-vch.de 217 undergo the mechanisms with the most probability. Herein, it is expected that the 7−OH group of the CYS and CYS/B12N12 system generates the most stable cation among the studied structures. Moreover, the ΔPDE values (PDE CYS/B12N12 –PDE CYS) in the environments were negative. This shows that the proton-donating ability of the cation radical of the CYS/B12N12 system in the environments are stronger than that in the CYS, resulting in a higher antioxidant activity of the CYS/B12N12 system. Table 3: Proton dissociation enthalpy (PDE) and ΔPDE in kcal/mol calculated by the M062X/6-311+G* method Solvent PDE ΔPDE CYS B12N12-CYS system 5O-H 7O-H 5O-H 7O-H 5O-H 7O-H Vacuum 230.54 219.51 225.36 219.21 -5.18 -0.30 Benzene 37.77 28.70 19.83 17.30 -17.94 -11.40 Ethanol 16.10 13.41 6.62 7.97 -9.48 -5.44 Water 21.11 19.20 13.38 16.14 -7.73 -3.06 3.2.3. SPLET mechanism analysis SPLET is known as the other significant mechanism for the antioxidative activity of a given molecule/system. Deprotonation of a flavonoid and forming a flavonoid anion is the first step of the SPLET analysis. PA is herein a significant parameter indicating for the capability of proton donation. In the second step, an electron is transferred from flavonoid anion to free radical (ETE). The calculated PA, ΔPA, ETE, and ΔETE for the CYS and CYS/B12N12 system in the vacuum environment and the different solvents were calculated and shown in tables 4 and 5. Here, the polarity dramatically affects the PAs value obtained by our calculations where the PA values for the CYS and CYS/B12N12 systems are decreased drastically from the vacuum environment to the solvent environments. The sequences of PAs for the OH groups in the structures in these environments also demonstrate that the 7−OH groups almost creates the most acidic hydrogens and the deprotonation of 7−OH groups forms the most stable anion in the calculated structures showing the important role that the 7−OH group of the compounds play in the first step of SPLET mechanism. Moreover, ΔPA values (PACYS/B12N12 –PACYS) in environments were obtained as negative (especially in vacuum and benzene environment), showing that the PA value of the CYS/B12N12 system is smaller than that in the CYS which results in a higher antioxidant activity of the CYS/B12N12 complex. These findings suggest that the interaction of CYS on the B12N12 nanocage enhances the antir