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. Author manuscript; available in PMC: 2024 Mar 1.
Published in final edited form as: Photochem Photobiol. 2022 Sep 15;99(2):672–679. doi: 10.1111/php.13704

Singlet Oxygen Quenching by Resveratrol Derivatives†

Charlotte G Monsour 1, Abegail B Tadle 1, Bliss J Tafolla-Aguirre 1, Nidhi Lakshmanan 1, Jin Hyeok Yoon 1, Rhemrose B Sabio 1, Matthias Selke 1,*
PMCID: PMC9971345  NIHMSID: NIHMS1833306  PMID: 36031343

Abstract

We investigated singlet oxygen quenching ability of several derivatives of trans-resveratrol which have been reported to have significant antioxidant ability, including photoprotective activity. We measured the total rate constants of singlet oxygen removal (kT) by the methylated resveratrol derivative 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene, and the partially methylated resveratrol derivatives 4-((E)-2-(3,5-dimethoxyphenyl)ethenyl)phenol (pterostilbene), 5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene-1,3-diol, and (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one (dihydromyricetin). A protic solvent system results in higher kT values, except for the completely methylated derivative. We also investigated the ability of trans-resveratrol to directly act as a photosensitizer (rather than via secondary photoproducts resulting from other primary photochemical reactions) for the production of singlet oxygen, but found that neither resveratrol nor any of its derivatives are able to do so. We then studied the chemical reactions of the methylated derivative with singlet oxygen. The main pathway consists of a [4+2] cycloaddition reaction involving the trans-double bond and the para-substituted benzene ring similar to what has been observed for trans-resveratrol. Unlike for trans-resveratrol, the primary singlet oxygen product undergoes a second [4+2] cycloaddition with singlet oxygen leading to formation of diendoperoxides. A second reactivity pathway for both trans-resveratrol and the methylated derivative leads to formation of aldehydes via cleavage of a transient dioxetane.

Graphical Abstract

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While Trans-resveratrol and its methylated and partially methylated derivatives do not sensitize the production of singlet oxygen, they are moderately strong quenchers of singlet oxygen. Methylation of the hydroxy groups decreases the total rate of singlet oxygen scavenging (kT) while a protic solvent system results in higher kT values, except for the completely methylated derivative.

INTRODUCTION

Singlet oxygen is a reactive oxygen species generated by the excitation of ground state (triplet) oxygen. It is most commonly generated through the transfer of energy from a photoexcited photosensitizer to ground-state (triplet) oxygen, although it can also be generated intracellularly by neutrophils using NADPH oxidase and myeloperoxidase (1–4). Once generated, singlet oxygen can react with fatty acids, amino acids, and the DNA base guanine (5–9). Unlike many other reactive oxygen species (ROS), singlet oxygen is not a radical; instead, it is strongly electrophilic due to its low lying LUMO. The intracellular lifetime of singlet oxygen is roughly 3 μs, and it has a spherical spatial domain in the cell of about 100 nm (10–12).

It is one of the most common ROS involved in metastasis (13,14). It is also implicated in Alzheimer’s disease, Parkinson’s disease, and some cancers because of the damage it causes to DNA bases (15,16).

Due to singlet oxygen’s reactivity with biomolecules in the cellular environment, the ability of antioxidants to remove (i.e., quench) singlet oxygen has been a topic of considerable interest. The health benefits of trans-resveratrol (1, 5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol), a compound found in red wine grapes, cranberries, blueberries, and peanuts, have been extensively discussed in the literature (17–24). Resveratrol has been said to ameliorate diabetes, protect folate from UV-mediated damage, and act as an antioxidant, potentially through synergistically assisting β-carotene (25–28). However, recent work has called into question resveratrol’s ability to act as an antioxidant against free radical oxidations, and it has even been shown to be cytotoxic and genotoxic under certain conditions (17,28,29). There is, however, evidence of resveratrol’s potential activity as an antioxidant against singlet oxygen in its potential ability to prevent photooxidative damage to the retina. Fluorophore A2E, a part of the retina, may act as a sensitizer for singlet oxygen, which can subsequently cause damage to the epithelial cells. Several studies have reported that resveratrol may prevent epithelial cell damage of the eyes by quenching singlet oxygen before it interacts with fluorophore A2E (30–33).

Fotiou et al. found that, upon irradiation with UVC light, resveratrol undergoes isomerization from its trans to its cis form. During this process, resveratrol reportedly transfers its excitation energy to triplet oxygen, generating singlet oxygen (19). However, the generation of singlet oxygen was measured indirectly through detecting changes in chemiluminescence resulting from oxidative damage to DNA. While other ROS may cause oxidative damage to DNA, the authors noted that the addition of mannitol (a hydroxyl radical scavenger) and superoxide dismutase (which removes superoxide from the cell) did not affect the chemiluminescence measurements, providing evidence that singlet oxygen may indeed have been the oxidant. Trigos et al. also reported the generation of singlet oxygen by resveratrol after irradiation. In this case, resveratrol was used as photosensitizer for the photooxidation of ergosterol via a [4+2] cycloaddition (34). In contrast to the above studies, Liang et al. did not find evidence that resveratrol was able to directly act as a photosensitizer for the production of singlet oxygen: Based on steady-state irradiation of trans-resveratrol with UV B light (which is at the maximum absorption of trans-resveratrol), the sole primary photoproduct was observed to be the cis-isomer. None of the photoproducts obtained upon reaction of trans-resveratrol with externally generated singlet oxygen (i.e. via the photosensitizer Methylene Blue) were observed when trans-resveratrol was directly irradiated without an external photosensitizer until isomerization to the cis-isomer was complete. Liang et al. proposed that after the isomerization of trans-resveratrol to cis-resveratrol under UV B irradiation, the cis-resveratrol would undergo a photocyclization reaction to form 2,4,6-phenanthrenetriol, which is able to act as a photosensitizer (18). A benzofuran compound, 2-(4-hydroxyphenyl)-5,6-benzofurandione was also formed upon UVB irradiation of trans-resveratrol. The authors postulated that the latter compound formed through reaction with singlet oxygen which would have been generated by the phenanthrene compound with resveratrol. This reaction would initially form an endoperoxide that would undergo further rearrangement into the observed benzofuran in a mechanism similar to the Moracin M synthesis reported by the Selke group in 2011. Thus, it remains uncertain if resveratrol can produce singlet oxygen either directly or indirectly from secondary photoproducts. Furthermore, no quantum yield measurements to determine how much singlet oxygen (if any) is produced from trans-resveratrol have been reported (19,29).

Singlet oxygen can be removed from a system in two ways: physical quenching, which includes several processes that result in the regeneration of triplet oxygen without changing the structure of the quenching compound; and chemical quenching, in which singlet oxygen reacts with the quencher compound to generate new product(s). The sum of the physical (kq) and chemical (kr) quenching rate constants is the total rate of singlet oxygen removal (kT). The effectiveness of a molecule as a singlet oxygen quencher depends on several factors. One important factor is the relative reaction rates of the quencher with singlet oxygen compared to those of relevant biomolecules with singlet oxygen. More effective quenchers will have quenching rates that are significantly higher than the rates of reaction of biomolecules with singlet oxygen. For example, the kT value for quenching by the carbon-carbon double bond in fatty acids in CD3OD is roughly 1–5 × 104 M−1 s−1, and in CD3OD resveratrol has a kT value of 1.5 × 106 M−1 s−1 (17,35). Comparing these values, we can see that resveratrol could potentially protect against fatty acid degradation. However, compared with other well-known singlet oxygen quenchers such as α-tocopherol and β-carotene, which have (in vitro) kT values of 6.7 × 108 M−1 s−1 and 1.0 × 1010 M−1 s−1, respectively, resveratrol does not appear to be a particularly good quencher (17,28,36).

Another important factor to be considered when determining the efficacy of a potential antioxidant is the nature of any reaction products that may form during reactions with ROS. In the case of resveratrol, we have previously reported that chemical reaction with singlet oxygen, which accounts for roughly 25% of the total quenching, proceeds through either [4+2] or [2+2] cycloadditions. The [4+2] product, which accounts for 60% of chemical reaction products, forms an endoperoxide, whereas the [2+2] reaction produces a transient dioxetane that cleaves to form aldehydes (17). Aldehydes have been shown to be implicated in cytotoxicity and genotoxicity and are also involved in modulating signaling pathways essential to cell survival (37–40). If the reaction between resveratrol and singlet oxygen produces potentially toxic aldehydes (and that chemical reaction accounts for a significant proportion of resveratrol’s reactivity), the use of resveratrol as an antioxidant against singlet oxygen would be of questionable benefit.

The [4+2] addition reaction between singlet oxygen and resveratrol involves the ring bearing the para-hydroxy group. Other groups have also noted that the para-hydroxy group is more reactive than the meta-hydroxy groups (41,42) but quantitative data of how substitution at the various hydroxy groups affects singlet oxygen quenching and reactivity is unknown. We therefore determined singlet oxygen quenching ability of various methylated derivatives of resveratrol, namely the completely methylated derivative 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene (2), pterostilbene which is methylated at the resorcinol ring (3, 4-((E)-2-(3,5-dimethoxyphenyl)ethenyl)phenol), and 5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene-1,3-diol (4) which is methylated at the para-position. Determination of the kT values for compounds 2-4 allows us to determine the effects of placing hydroxy groups at the para- vs. meta-positions on the stilbenoid. We also investigated singlet oxygen quenching by the related antioxidant (+)-dihydromyricetin (5, (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one) which has several additional hydroxy groups on the ring containing the reactive para-hydroxy group. The structures of the resveratrol derivatives investigated in this study are depicted in Fig. 1 below.

Figure 1.

Figure 1.

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Chemical structures of resveratrol (1), methylated and partially methylated derivatives 2-4, and (+)-dihydromyricetin (5).

Compound 3 (pterostilbene) has been reported to exhibit antioxidant activity through reducing ROS production (including that of singlet oxygen) and oxidative damage, as well as reducing inflammation (43–46). The fully methylated compound 2, while less genotoxic than resveratrol, has been shown to be an ineffective antioxidant against free radicals (21,43,47,48). Methylation of the para-hydroxy group has been reported to enhance the ability of 2 and 4 to inhibit cytochrome P450 (49,50). 5 has also been reported to exhibit antioxidant activity as a free radical scavenger and in its ability to reduce lipid peroxidation (51–54). None of these reports have reported quantitative data for singlet oxygen removal.

MATERIALS AND METHODS

Trans-resveratrol (1) and the methylated derivatives 2-4 were purchased from Sigma Aldrich. (+)-Dihydromyricetin (5) was purchased from Arctom Scientific. All deuterated solvents were purchased from Cambridge Isotope Laboratories. Compounds 1-5 were used as received, after their purity was verified by 1H NMR (400 MHz Bruker Avance).

Singlet Oxygen Luminescence Quenching Experiments

The singlet oxygen (1O2) luminescence quenching experiments involve the preparation of a photosensitizer and quencher solution. Either Methylene Blue (MB) or Rose Bengal (RB) were used as external photosensitizers for singlet oxygen production. In preparing the photosensitizer solution, 6 mL of the solvent system was added to a securely capped vial. A small amount of photosensitizer (MB or RB) was added to that solvent solution so that an absorbance of 0.2–0.3 was obtained at λex = 532 nm. 2 mL of the photosensitizer solution was then added to a fluorescence grade quartz cuvette. Stock solutions of the quencher (resveratrol and its derivatives, i.e. compounds 1-5) were prepared in either d3-acetonitrile, or a 1:1 mixture of d3-acetonitrile : d4-methanol. Between 0.3–0.57 mg of the quencher was added to 1 mL of solvent in a 1 mL volumetric flask, resulting in a starting concentration range of 2.0–2.5 × 10−6 M.

A 400 V Nd: YAG laser (New Wave Research Mini-Lase II) was used for the pulsed irradiation (2 ns) of each cuvette. We employed a thermoelectric cooled near-infrared photomultiplier tube (NIR-PMT, Hamamatsu H10330B-45) to detect the singlet oxygen NIR emission signal. The initial measurement was taken upon excitation of the 2 mL photosensitizer solution which yields the decay of singlet oxygen without added quencher. 20 μL of the quencher stock solution was then added for every subsequent data point collection. All measurements were taken in air-saturated solutions. The luminescence signals from each run were analyzed via OriginPro software. Using I = Ioe−kt, the observed rate constant of the decay kobs of 1O2 for each data point was calculated. The observed rate constant kobs was plotted against the quencher concentration; the slope of this plot yields the rate constant kT, i.e. the total rate constant of 1O2 quenching.

Photooxidation of 1,3-Dimethoxy-5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene (2)

1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene (2, 1.85 mM to 21.9 mM) was dissolved in 1 mL of CD3CN containing methylene blue. The mixture was placed into an NMR tube where a slow stream of oxygen gas was bubbled through the solution during the photooxidation studies. A 200 W tungsten-halogen lamp was used as a light source. The time frame of irradiation of the samples ranged from 0–10 hours. Wavelengths below 493 nm were blocked using a filter for the light source to prevent trans to cis isomerization. The reaction was monitored by 1H-NMR on a Bruker 400 MHz instrument. The new aldehyde peaks appearing at 9.86 ppm and 9.89 ppm were compared with the spectra of authentic samples of 4-methoxybenzaldehyde and 3,5-dimethoxybenzaldehyde (Sigma-Aldrich).

Analyses of Photooxidation Products of 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl) ethenyl]benzene (2) by Electrospray Ionization Mass Spectrometry

Electrospray Ionization Mass Spectrometry was used to characterize the photooxidation product of 2 with singlet oxygen. The mass spectra were recorded on a linear ion trap mass spectrometer (Thermo Fisher, San Jose, CA) equipped with an electrospray ionization (ESI) source. Samples were diluted 100 fold with 50/50 water/acetonitrile with 0.1% formic acid. Samples were introduced into the mass spectrometer at a flow rate of 20 μL/min. Electrospray ionization MS was conducted in the positive ion mode at a spray voltage of 4 kV and capillary temperature was at 250 °C. The sheath and auxiliary gases were set to 15 and 3 psi, respectively. Samples from 0, 2, 5, 7, and 10 hours of irradiation were analyzed.

Analyses of Photooxidation Products of 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl) ethenyl]benzene (2) by Liquid Chromatography - Mass Spectrometry

A Thermo Fisher Acella UHPLC system (Thermo Fisher Scientific, San Jose, CA) coupled to a photodiode array detector and a high-resolution mass spectrometer (Exactive) was used to analyze the photooxidation products of the reaction of singlet oxygen with 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl) ethenyl]benzene (2). Separation was performed using a Kinetex C18 column (1.7 μm, 2.1 mm × 50 mm, 100 Å) from Phenomenex (Torrance, CA) at a flow rate of 0.5 mL/min at 40 °C and eluted species were detected at 254 nm. The mobile phase contained water, acetonitrile, and 0.1% formic acid. The gradient elution for all samples was ramped from 5% to 95% acetonitrile over 7 min and then back down to 5% in 0.5 min, and then was held for 2.5 min. Electrospray ionization-MS was conducted in the positive ion mode at a spray voltage of 4 kV and capillary temperature was at 350 °C. The sheath and auxiliary gases were set to 55 and 7 psi, respectively.

RESULTS AND DISCUSSION

Singlet Oxygen Quenching by Resveratrol Derivatives

In a previous communication, we have reported the values for the total singlet oxygen quenching rate constant (kT value) of resveratrol in deuterated acetonitrile as well as in a 3:2 CD3OD-D2O mixture and in D2O at pH 10 (17) using time-resolved singlet oxygen luminescence spectroscopy. We now report the kT values for the methylated resveratrol derivative 2 (Fig. 2) as well as for the partially methylated derivatives 3 and 4 and dihydromyricetin (5). Singlet oxygen was generated by flash excitation of Rose Bengal at 532 nm. Compounds 1-5 were studied in both protic (1:1 mixture of deuterated acetonitrile and deuterated methanol) and aprotic (deuterated acetonitrile) solvent systems; results are summarized below (Table 1) and additional sample plots of kobsd vs. the concentration of the quencher for compounds 1-5 are shown in the Supporting Information, Figures S1–S5.

Figure 2.

Figure 2.

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Quenching of singlet oxygen by 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)ethenyl]-benzene (2) in CD3CN.

Table 1.

Total rate constant (kT) of singlet oxygen removal for compounds 1–5.

Compound Solvent kT (M−1 s−1)
1 (5-[(E)-2-(4-hydroxyphenyl) ethenyl]benzene-1,3-diol) CD3CNa (1.6 ± 0.1) × 106
1 CD3CN-CD3OD (1:1)b (2.1 ± 0.1) × 106
1 CD3OD-D2O (3:2)a (9.2 ± 0.2) × 106
1 D2O (pH=10)a (3.7 ± 0.2) × 108
2 (1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene) CD3CNb (5.8 ± 0.3) × 105
2 CD3CN-CD3OD (1:1)b (3.5 ± 0.2) × 105
3 (4-((E)-2-(3,5-dimethoxyphenyl)ethenyl)phenol) CD3CNb (1.3 ± 0.1) × 106
3 CD3CN-CD3OD (1:1)b (1.4 ± 0.4) × 106
4 (5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene-1,3-diol) CD3CNb (1.2 ± 0.1) × 106
4 CD3CN-CD3OD (1:1)b (2.2 ± 0.1) × 106
5 ((2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one) CD3CNb (1.8 ± 0.1) × 106
5 CD3CN-CD3OD (1:1)b (2.6 ± 0.2) × 106
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a

Values from Ref. (17).

b

This work. Average of three to five plots; error is one standard deviation.

Our results show that in general methylation of the hydroxy groups decreases the singlet oxygen scavenging ability of the resveratrol derivatives. Thus, compound 2, in which all the hydroxy groups are replaced by methoxy groups, has the lowest kT value. The effect is, however, rather modest, and even though 3 has one fewer hydroxy group than compound 4, their kT values are very similar. Likewise, the results for compounds 3 and 4 in CD3CN indicate that the location of the methoxy substitutions does not have a significant effect on the kT values. Interestingly, compound 5 which possesses additional hydroxy groups on the aromatic ring bearing the para-hydroxy group but lacks the central double bond has a very similar value of kT as compared to compounds 1, 3 and 4.

The addition of protic solvents somewhat increased the kT values of these derivatives, with the exceptions of the completely methylated derivative 2 and partially methylated derivative 3 (in which the two meta-hydroxy groups are methylated). We suggest that this could be due to the higher ionizing ability of the CD3CN-CD3OD mixture, as we had previously reported that resveratrol in D2O at pH 10 has a kT value more than two orders of magnitude higher than in CD3CN (17). Consistent with this hypothesis, derivative 2, which has no hydroxy groups, actually has a smaller kT value in the CD3CN-CD3OD mixture.

Photosensitizer Effects on Observed Quenching Behavior

During our initial singlet oxygen quenching (kT) measurements, we observed that the use of Methylene Blue (instead of Rose Bengal) as a photosensitizer led to a slight upward (i.e. non-linear behavior) curvature of plots of kobsd vs. concentration of the quencher. This effect was observed for compounds 1 and 4. Similar non-linear plots were observed in our recent work studying the photooxidation of tryptophan with and without cation-π interaction when Methylene Blue was used as the photosensitizer. We hypothesize that this results from electron transfer from the quencher to the excited cationic methylene blue photosensitizer, i.e., a type I photooxidation process (55). In our previous work, we had been studying a tryptophan model complex. Reducing the electron-donating ability of the quencher (i.e., via presence of a cation-π interaction) resulted in the generation of linear kT plots. Other groups have made similar observations when using Methylene Blue as a photosensitizer. The McNeill group demonstrated that phenolic compounds react with Methylene Blue through a proton-coupled electron transfer (PCET) mechanism, and that more acidic compounds react faster with Methylene Blue (56), which would be consistent with the methylated compound 2 not showing this effect. Similarly, Jiang et al. compared the photooxidation of two fatty acid chains: one that contained two conjugated π bonds (and therefore had a region with more electron density) and one that contained two π bonds that were separated by an sp3 carbon (57). The conjugated compound was shown to bleach methylene blue at a faster rate than the non-conjugated compound. These results suggest that the use of Methylene Blue as a photosensitizer for electron-rich substrates may result in competing Type I photooxidation reactions. Use of Rose Bengal as a photosensitizer in our kT experiments resulted in linear plots of kobsd vs. concentration of the quencher in all cases.

Singlet Oxygen Production by Trans-Resveratrol and Derivatives

As discussed in the introduction, several groups have suggested that resveratrol may be capable of acting as a photosensitizer to generate singlet oxygen while others have suggested that singlet oxygen is only formed from secondary photoproducts formed upon irradiation of trans-resveratrol. In all of these examples, singlet oxygen was detected by indirect (i.e., trapping) methods. Therefore, we decided to determine whether trans-resveratrol and the various derivatives produced singlet oxygen through direct measurement of the singlet oxygen near-infrared (NIR) luminescence by laser flash excitation of 1-5. We excited compounds 1-5 with the third harmonic of an Nd:YAG laser (355 nm, A355 = 0.20 to 0.33 in 1:1 CD3OD-CD3CN) and in all cases did not observe any singlet oxygen production, i.e. no signal of the characteristic 1O2 NIR luminescence was detected. Liang et al. also found that the primary photoproduct formed upon direct steady-state excitation of trans-resveratrol (in the absence of an external photosensitizer) is the cis isomer, without concomitant formation of singlet oxygen products. Taken together with our results from the NIR luminescence experiments, we conclude that the photooxidation products reported in the literature formed upon irradiation of resveratrol must be due to singlet oxygen production from secondary photoproducts, as suggested by Liang et al. (18).

Product Studies of the Reaction of Methylated Resveratrol with Singlet Oxygen

Chemical reactions of singlet oxygen quenchers may limit their utility; this is especially the case if the resulting products are toxic and/or highly reactive. In our previous communication (17), we reported that trans-resveratrol undergoes two chemical reactions with singlet oxygen leading to an endoperoxide as well as aldehyde products. Detailed characterization of these products by NMR can be found in the supporting information of our previous paper. These reactions account for roughly 25% of the total quenching. The endoperoxide is formed via a [4+2] cycloaddition pathway, whereas the aldehydes are formed via a [2+2] addition of singlet oxygen to the trans double bond which produces a transient dioxetane (17). The [4+2] cycloaddition involves the trans-double bond and the benzene ring bearing the 4’-hydroxy group. This product readily tautomerizes leading to formation of the corresponding ketone (Fig. 3a). Methylation at the 4’-hydroxy group should prevent this tautomerization, leading instead to a potentially reactive diene as a primary product of the [4+2] cycloaddition. Thus, methylation of the 4’ hydroxy group could lead to two sequential [4+2] cycloaddition reactions with singlet oxygen with the second one being faster than the initial one. To test this hypothesis, we decided to study the photooxidation products of the methylated resveratrol derivative 2. Samples of 2 (ca. 20 mM) were irradiated in CD3CN in the presence of Methylene Blue or Rose Bengal. Wavelengths below 493 nm were blocked using a cut-off filter to prevent excitation of 2 and possible trans to cis isomerization. The reaction was initially followed by 1H-NMR. The reaction of 2 with singlet oxygen is exceedingly slow, and even after ten hours of irradiation, 1H NMR analyses indicates that most of the starting material is still present, in addition to a complex mixture of products (Figure S6a). All attempts to separate the various products by column chromatography led to their decomposition. We were therefore unable to quantify which product may predominate. Two new peaks observed at 9.86 and 9.89 ppm (Figure S6b) are consistent with formation of 4-methoxybenzaldehyde and 3,5-dimethoxybenzaldehyde, respectively, as the aldehyde peaks were not present in the initial solution prior to photooxidation. Addition of authentic samples of 4-methoxybenzaldehyde and 3,5-dimethoxybenzaldehyde (Sigma-Aldrich) to the product mixture led to an increase of both of these peaks confirming their identity. Formation of these aldehydes is consistent with [2+2] addition at the trans double bond followed by dioxetane cleavage, very similar to what has been observed as one of the two reaction pathways for trans-resveratrol. We used Electrospray Ionization Mass Spectrometry (ESI-MS) to further characterize the products of the reaction of 2 with singlet oxygen. ESI-MS was conducted in the positive ion mode at a spray voltage of 4 kV and capillary temperature of 250 °C. The sample prior to irradiation showed the presence of the starting material at m/z= 271.13349 (calculated molecular weight=270.32). Upon irradiation (from two to ten hours; shorter irradiation times than two hours did not allow us to detect any products), a peak for addition of two molecules of O2 was observed (m/z= 335.11394, calculated molecular weight=334.32). This peak is consistent with two sequential [4+2] cycloaddition reactions leading to formation of diendoperoxides. A similar pathway of two sequential [4+2] cycloaddition reactions has been observed for the photooxidation of 4-propenyl anisole by Greer et al. (58). To further support the assignment of the peaks obtained from ESI-MS spectrometry, we performed liquid chromatography mass-spectrometry (LC-MS) experiments. The LC trace again revealed a complex mixture of products (Figure S7). After the separation of the photooxidation products by LC, products were analyzed by a high-resolution mass spectrometer (Exactive, Thermo Fisher). The retention time of the starting material at m/z=271.12787 was at 5.43 min (Figure S8). We were able to observe a small peak at 4.20 min retention time with a m/z value of 303.1227 (Figure S9). This peak could be the initial [4+2] cycloaddition product. The largest peaks of the photooxidation products had retention times of 3.81 and 4.00 min. Both of these peaks had m/z values of 335.10753 (Figure S10). This appears to be consistent with our assignment of this peak in the ESI-MS as the double [4+2] cycloaddition adduct, since the second [4+2] cycloaddition reaction should result in the formation of a mixture of diastereomers. Finally, a peak at 2.87 min was found have a m/z value of 137.059791 which corresponds to 4-methoxybenzaldehyde. We were unable to identify the second aldehyde cleavage product (3,5-dimethoxybenzaldehyde) by LC-MS.

Figure 3.

Figure 3.

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(a) Reactivity pathways of [(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol, (trans-resveratrol, 1) (b) Reactivity pathways of 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl) ethenyl]benzene (2) with singlet oxygen leading to formation of a diendoperoxide.

Figure 3b shows a possible reaction pathway for the sequential [4+2] additions of 2 with singlet oxygen. It would be of interest to determine the fraction of chemical reaction (kr) vs kT for compound 2, but the fact that the primary singlet oxygen product is more reactive with singlet oxygen than the starting compound precludes use of competition kinetics with a known singlet oxygen acceptor to determine the value of kr (59).

CONCLUSIONS

While trans-resveratrol and its methylated derivatives do not sensitize the production of singlet oxygen, they are moderately strong singlet oxygen quenchers. Methylation of the hydroxy groups of trans-resveratrol leads to a decrease in the singlet oxygen scavenging ability of this class of antioxidants. The rate constants of singlet oxygen removal for these compounds are one to two orders of magnitude below that of α-tocopherol (36), but are one to two orders of magnitude higher than the rate constants for reaction of singlet oxygen with unsaturated fatty acids (35). Thus these compounds may possess some modest photoprotective ability as far as lipid peroxidation by singlet oxygen is concerned. However, chemical reaction of singlet oxygen with resveratrol and its methylated derivative leads to formation of aldehydes as well as endoperoxides. In the case of the methylated resveratrol derivative 2, a diendoperoxide is formed upon two sequential [4+2] cycloaddition reactions with singlet oxygen. Such reactions may well limit the utility of these compounds to function as photoprotective agents against singlet oxygen.

Supplementary Material

supinfo

Figure S1. Quenching of singlet oxygen by trans-resveratrol (1, 5-[(E)-2-(4-hydroxyphenyl)-ethenyl]benzene-1,3-diol) in 1:1 CD3CN-CD3OD, photosensitizer = Rose Bengal.

Figure S2. Quenching of singlet oxygen by 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2) in 1:1 CD3CN-CD3OD, photosensitizer = Rose Bengal.

Figure S3. Quenching of singlet oxygen by pterosilbene (3, 4-((E)-2-(3,5-dimethoxyphenyl)-ethenyl)phenol), in 1:1 CD3CN-CD3OD, photosensitizer = Rose Bengal.

Figure S4. Quenching of singlet oxygen by 5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene-1,3-diol (4) in 1:1 CD3CN-CD3OD, photosensitizer = Rose Bengal.

Figure S5. Quenching of singlet oxygen by (+)-dihydromyricetin (5, (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one) in 1:1 CD3CN-CD3OD, photosensitizer = Rose Bengal.

Figure S6. (a) Aromatic region of 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2), initial reaction mixture and after 10 hours of steady state photooxidation (sensitizer = methylene blue) in CD3CN. (b) Aldehyde region of 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2) after 10 hours of steady state photooxidation (sensitizer = methylene blue) in CD3CN.

Figure S7. LC of photooxidation product mixture of the reaction of singlet oxygen with 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2), irradiation time 10 hours.

Figure S8. LC-MS of 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2), retention time 5.43 min.

Figure S9. LC-MS of [4+2] photooxidation product of the reaction of singlet oxygen with 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2), retention time 4.20 min.

Figure S10. LC-MS of double [4+2] photooxidation product (diendoperoxide) of the reaction of singlet oxygen with 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2), retention time 4.00 min.

Acknowledgements.

B.T.-A. acknowledges support from the NIH-NIGMS MARC program No. T34 GM08228. Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institute of Health under Award Number R25GM061331. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health. M.S. acknowledges partial support from the NSF-CREST program (No. DRM-1547723) for upgrading and maintaining the singlet oxygen luminescence quenching set-up.

Footnotes

SUPPORTING INFORMATION

Additional supporting information may be found online in the Supporting Information section at the end of the article:

†

This article is part of a Special Issue celebrating the 50th Anniversary of the American Society for Photobiology.

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Associated Data

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Supplementary Materials

supinfo

Figure S1. Quenching of singlet oxygen by trans-resveratrol (1, 5-[(E)-2-(4-hydroxyphenyl)-ethenyl]benzene-1,3-diol) in 1:1 CD3CN-CD3OD, photosensitizer = Rose Bengal.

Figure S2. Quenching of singlet oxygen by 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2) in 1:1 CD3CN-CD3OD, photosensitizer = Rose Bengal.

Figure S3. Quenching of singlet oxygen by pterosilbene (3, 4-((E)-2-(3,5-dimethoxyphenyl)-ethenyl)phenol), in 1:1 CD3CN-CD3OD, photosensitizer = Rose Bengal.

Figure S4. Quenching of singlet oxygen by 5-[(E)-2-(4-methoxyphenyl)ethenyl]benzene-1,3-diol (4) in 1:1 CD3CN-CD3OD, photosensitizer = Rose Bengal.

Figure S5. Quenching of singlet oxygen by (+)-dihydromyricetin (5, (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-2,3-dihydrochromen-4-one) in 1:1 CD3CN-CD3OD, photosensitizer = Rose Bengal.

Figure S6. (a) Aromatic region of 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2), initial reaction mixture and after 10 hours of steady state photooxidation (sensitizer = methylene blue) in CD3CN. (b) Aldehyde region of 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2) after 10 hours of steady state photooxidation (sensitizer = methylene blue) in CD3CN.

Figure S7. LC of photooxidation product mixture of the reaction of singlet oxygen with 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2), irradiation time 10 hours.

Figure S8. LC-MS of 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2), retention time 5.43 min.

Figure S9. LC-MS of [4+2] photooxidation product of the reaction of singlet oxygen with 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2), retention time 4.20 min.

Figure S10. LC-MS of double [4+2] photooxidation product (diendoperoxide) of the reaction of singlet oxygen with 1,3-dimethoxy-5-[(E)-2-(4-methoxyphenyl)-ethenyl]benzene (2), retention time 4.00 min.

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