This is an open access article published under an ACS AuthorChoice License, which permits
copying and redistribution of the article or any adaptations for non-commercial purposes.
Article
Cite This: ACS Omega 2019, 4, 8222−8230
http://pubs.acs.org/journal/acsodf
An Efficient Synthesis of Deoxyrhapontigenin-3‑O‑β‑D‑glucuronide,
a Brain-Targeted Derivative of Dietary Resveratrol, and Its Precursor
4′‑O‑Me-Resveratrol
 ngelo de Fátima,*,†,‡ Maite Docampo-Palacios,† Anislay Alvarez-Hernandez,† Giulio M. Pasinetti,§
and Richard A. Dixon*,†
Downloaded via 107.174.52.114 on August 22, 2019 at 18:13:52 (UTC).
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
†
BioDiscovery Institute and Department of Biological Sciences, University of North Texas, 1155 Union Circle #311428, Denton,
Texas 76203-5017, United States
‡
Department of Chemistry, Universidade Federal de Minas Gerais, Avenida Presidente Antônio Carlos 6627, Campus Pampulha,
Belo Horizonte, Minas Gerais 31270-901, Brazil
§
Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, P.O. Box 1230, New York, New
York 10029, United States
S Supporting Information
*
ABSTRACT: Bioactive dietary polyphenols have health benefits against a
variety of disorders, but some benefits of polyphenols may be not directly
related to them but rather to their metabolites. Recently, we have identified
the brain-available phenol glucuronide metabolite deoxyrhapontigenin-3-O-βD-glucuronide (5) in perfused rat brains following subacute treatment with
the stilbene resveratrol (1). However, the role of such a metabolite in the
neuroprotective activity of resveratrol (1) is not understood, in part due to
the noncommercial availability of 5 for performing biological evaluation in
animal models of Alzheimer’s disease or other neurological disorders. Here,
we describe a concise chemical synthesis of deoxyrhapontigenin-3-O-β-Dglucuronide (5) and its precursor 4-O-Me-resveratrol (2), accomplished in
four and six steps with 74 and 21% overall yields, respectively, starting from
commercially available 3,5-dihydroxybenzaldehyde. Pivotal reactions employed in the synthesis include the palladium-catalyzed C−C coupling
between 3,5-di-tert-butyldiphenylsilyloxystyrene and p-iodoanisole in the presence of tributylamine and the acid-catalyzed
glucuronidation between the trichloroacetimidate-activated glucuronic acid and 4-O-Me-resveratrol.
metabolites 2−4 (Figure 1) in the colorectum,37 and
metabolite 4 inhibited colon cancer cell proliferation and led
to an accumulation of cells in the S phase.38 Remarkably, the
mixture of such metabolites induced a synergistic effect.38
Furthermore, resveratrol metabolites 3 and 4 (Figure 1)
induced similar delipidating effects to resveratrol in maturing
pre-adipocytes, and both glucuronide metabolites 2 and 3
showed a depleting effect, although lower than that of
resveratrol, in mature adipocytes.39 These findings suggest
that both resveratrol and resveratrol metabolites are involved,
to greater or lesser extents, in the anti-obesity effects of these
polyphenols,39 and the literature shows that the activity of
resveratrol and/or resveratrol metabolites depends on their
distribution and concentration in different tissues and the
species used for in vivo studies.9,40−42
Flavonoids have been known for some time to impact brain
function,43 and our laboratory and others have shown that
1. INTRODUCTION
Bioactive dietary polyphenols are receiving increasing interest
due to their reported health benefits against a variety of
disorders1−7 arising from intestinal absorption, metabolism,
and subsequent interactions with target tissues.8−12 Additionally, some polyphenol metabolites from dietary sources might
have more profound biological activities than their precursors.10,13−16
Resveratrol (1; Figure 1), a polyphenol naturally produced
by several plants, is widely reported to be beneficial for human
health as an anticancer,17−19 antidiabetic,20−22 anti-obesity,20,23,24 anti-oxidant,25−28 anti-inflammatory,29−31 and
anti-Alzheimer’s disease (AD)32−35 agent, among others.
However, some of these beneficial properties may be not
directly related to this polyphenol but rather be a result of its
phase II metabolism. For instance, the resveratrol metabolites
2 and 3 (Figure 1) were shown to inhibit the growth of human
adenocarcinoma (Caco-2) cells by 80 and 86%, respectively,
whereas resveratrol (1) at the same concentration impaired the
growth by 52%.36 Patients with colorectal cancer and receiving
oral resveratrol (0.5 to 1.0 g/day for 8 days) have high levels of
© 2019 American Chemical Society
Received: March 20, 2019
Accepted: April 18, 2019
Published: May 7, 2019
8222
DOI: 10.1021/acsomega.9b00722
ACS Omega 2019, 4, 8222−8230
ACS Omega
Article
Figure 1. Chemical structures of resveratrol (1) and its metabolites resveratrol 3-O-β-D-glucuronide (2), resveratrol 4′-O-β-D-glucuronide (3),
resveratrol 3-sulfate (sodium salt) (4), and deoxyrhapontigenin-3-O-β-D-glucuronide (5).
were detected using KMnO4 (0.5 g) dissolved in 1 N NaOH
(100 mL) or H2SO4 (5% in water). Column chromatographic
purification was performed using 230−400 mesh silica gel,
unless otherwise noted. The proton and carbon nuclear
magnetic resonance (1H-NMR and 13C-NMR, respectively)
spectra were recorded using a Varian-INOVA 500 NMR
spectrometer (Varian, CA, USA) at 500 and 125 MHz,
respectively. For the NMD analysis, the synthesized substances
were dissolved in a specific deuterated solvent [CD3OD
(99.6% atom D; Sigma, St. Louis, MO); acetone-d6 (99.9%
atom D; Sigma, St. Louis, MO); CDCl3 (99.8% atom D; Acros
Organics, Morris Plains, NJ)] and then transferred to a 5 mm
Shigemi tube (Wilmad Glass, Vineland, NJ). Preparative highperformance liquid chromatography (HPLC) was performed
on an Agilent HP1200 HPLC, monitoring at 280 nm. The
HPLC with ChemStation software version B.02.01.SRI was
equipped with a G1322A degasser, G1311A quaternary pump,
G1367B autosampler, G1316A thermostatic column compartment, and G1315C diode array detector. A Phenomenx Luna
10 μm C18(2) 250 × 21.2 mm column was used for
preparative HPLC on the Agilent HPLC system. The column
was eluted with an isocratic mixture of acetonitrile and water
with formic acid (0.1%) (28:72, v/v), and the flow rate was set
at 8 mL/min. The detection of newly synthesized metabolites
was achieved using a hybrid triple quadrupole/ion trap mass
spectrometer QTRAP 5500 from AB Sciex. Each compound
was injected individually and directly into the mass
spectrometer at a flow rate of 7 μL/min using electrospray
ionization. Full and product ion scan modes were utilized to
assess precursor ion mass and MS/MS spectrum, respectively.
LC−MS/MS data were recorded and processed using Analyst
1.7 software (AB Sciex). Melting points were measured in
open capillary tubes on an Electrothermal IA9000 Series
apparatus and are uncorrected.
2.2. Synthesis of 4′-O-Me-Resveratrol (11). 2.2.1. 3,5Dihydroxystyrene (7). 3,5-Dihydroxystyrene (7) was prepared
according to the literature procedure.53 Sodium hydride
(NaH) (320 mg, 8.0 mmol) was dissolved in 6 mL of
anhydrous DMSO, and the mixture was stirred under a
nitrogen atmosphere for 1 h at 70 °C. The mixture was then
cooled in an ice bath, and a solution of CH3P(C6H5)Br (2.85
g, 8.0 mmol) in anhydrous DMSO (5 mL) was added
dropwise under vigorous stirring. The mixture was then stirred
grape seed extracts (GSE) and red wine are able to modulate
AD phenotypes by modulating multiple disease-modifying
modalities via both β-amyloid-dependent and β-amyloidindependent mechanisms.44−51 By assessing the accumulation
of polyphenols in the brains of rats treated with oral dosage of
Cabernet Sauvignon red wine and testing the identified braintargeted polyphenols for potential beneficial AD diseasemodifying activities, we identified quercetin-3-O-β-D-glucuronide as a novel anti-Alzheimer agent.16 Our results showed
that quercetin-3-O-β-D-glucuronide may simultaneously modulate multiple independent AD disease-modifying mechanisms
and, as such, may contribute to the benefits of dietary
supplementation with red wines in AD models.16 We have also
identified resveratrol 3-O-β-D-glucuronide (2) and deoxyrhapontigenin-3-O-β-D-glucuronide (5; Figure 1) in perfused rat
brains following subacute treatment with resveratrol (1) (300
mg/kg/day for 10 days) (unpublished data). The presence of
such metabolites in the rat brain suggests that they can
penetrate the blood−brain barrier (BBB) and may thereby play
an important role in the anti-AD effect of resveratrol (1). It is
therefore important to determine if and how these metabolites
(2 and 5) are involved in the modulation of AD by resveratrol
(1). However, only the resveratrol 3-O-β-D-glucuronide (2) is
commercially available, and there is no chemical synthetic
approach described for obtaining deoxyrhapontigenin-3-O-β-Dglucuronide (5). To the best of our knowledge, there is only
one microbial synthesis of deoxyrhapontigenin-3-O-β-Dglucuronide (5) described using Streptomyces sp. M52104.52
Here, we report the first chemical synthesis of deoxyrhapontigenin-3-O-β-D-glucuronide (5) and the synthesis of its
precursor 4′-O-Me-resveratrol (2). The 4′-O-Me-resveratrol
(2) and deoxyrhapontigenin-3-O-β-D-glucuronide (5) were
synthesized in four and six steps with 74 and 21% overall
yields, respectively.
2. MATERIALS AND METHODS
2.1. General Information. High-performance liquid
chromatography (HPLC)-grade solvents were purchased
from Fisher Scientific. Chemicals and solvents were of reagent
grade and obtained from commercial sources without further
purification. All reactions were monitored by thin-layer
chromatography (TLC) on aluminum-backed precoated silica
gel 60 F254 plates (Sigma, St. Louis, MO), and compounds
8223
DOI: 10.1021/acsomega.9b00722
ACS Omega 2019, 4, 8222−8230
ACS Omega
Article
Table 1. 1H-NMR (500 MHz) and 13C-NMR (125 MHz), in Acetone-d6, of 4′-O-Me-Resveratrol (11)a
1
13
H-NMR (δ ppm, J Hz)
atom #
1
2
3
4
5
6
7
8
1′
2′
3′
4′
5′
6′
OCH3
OH
C-NMR (δ ppm)
b
(500 MHz)
lit. (500 MHz)
6.55, d, J = 2.2
6.54, d, J = 3.0
6.28, t, J = 2.2
6.31, t, J = 2.4
6.55, d, J = 2.2
6.95, d, J = 15.9
7.05, d, J = 15.9
6.54, d, J = 3.0
6.82, d, J = 16.0
6.96, d, J = 16.0
7.52, d, J = 8.4
6.94, d, J = 8.4
7.41, d, J = 8.4
6.88, s
6.94,
7.52,
3.81,
8.20,
6.88,
7.41,
3.80,
7.94,
d, J = 8.4
d, J = 8.4
s
br s
s
d, J = 8.4
s
br s
(125 MHz)
lit.b (125 MHz)
140.7
105.7
159.6
102.8
159.6
105.7
127.5
128.8
131.0
128.6
114.9
160.4
114.9
128.8
55.6
140.5
105.8
159.2
102.8
159.2
105.8
127.4
128.8
130.7
128.5
114.8
160.1
114.8
128.5
55.8
a
Reagents and reaction conditions: (a) (i) 1.1 equiv of 2,3,4-tri-O-acetyl-α-D-glucuronic acid methyl ester, tricholoroacetamidate, 0.25 equiv of
TMSOTf, DCM, 4 Å molecular sieves, 0 °C, 3 h (30%) or (ii) 1.2 equiv of 2,3,4-tri-O-acetyl-α-D-glucuronic acid methyl ester,
tricholoroacetamidate, 0.70 equiv of BF3·Et2O, DCM, 4 Å molecular sieves, 0 °C, 5 h (35%); (b) MeONa/MeOH (5.4 M), NaOH (1.0 M),
THF/MeOH (4:1, v/v), 0 °C, 3.5 h (80%). bRef 52.
Ph-H), 6.42 (2× s, 2H, H4 and H8), 6.37 (dd, J = 10.9, 17.6
Hz, 1H, H2), 6.15 (t, J = 2.2 Hz, 1H, H6), 5.33 (dd, J = 1.0,
17.6, 1H, Htrans-1a), 5.04 (dd, J = 1.0, 10.9 Hz, 1H, Hcis-1b),
1.04 (s, 18H, 2× (CH3)3). 13C-NMR (125 MHz, CDCl3): δ
156.4, 139.0, 136.7, 135.6, 133.0, 129.9, 127.8, 113.8, 111.3,
111.1, 26.7, 19.6.
2.2.3. p-Iodoanisole (10). p-Iodoanisole (10) was prepared
according to the literature procedure.54 A mixture of 4iodophenol (9) (264 mg, 1.2 mmol), methyl iodide (170 mg,
1.2 mmol), and K2CO3 (828 g, 6.0 mmol) in 10 mL of acetone
was stirred at 60 °C for 24 h. After cooling to room
temperature, the mixture was poured into 100 mL of water and
extracted with diethyl ether (3 × 40 mL). The combined
organic phase was evaporated under vacuum to remove the
solvent. The residue was subjected to silica gel column
chromatography, eluting with hexane to give p-iodoanisole
(10) as white crystals (258 mg, 92%). 1H-NMR (500 MHz,
CDCl3): δ 7.56 (d, J = 9.0 Hz, 2H), 6.68 (d, J = 9.0 Hz, 2H),
3.78 (s, 3H, CH3). 13C-NMR (125 MHz, CDCl3): δ 159.5,
138.3, 116.5, 82.8, 55.4.
2.2.4. 4′-O-Me-Resveratrol (11). To a stirred solution of
3,5-di-tert-butyldiphenylsilyloxystyrene (8) (240 mg, 0.39
mmol) and p-iodoanisole (10) (110 mg, 0.47 mmol) in
anhydrous dimethylformamide (5 mL) at room temperature
under a nitrogen atmosphere were added benzyltriethylammonium chloride (90 mg, 0.39 mmol), tributylamine (241 μL,
1.01 mmol), and palladium (II) acetate (5 mg, 5 mol %). The
resulting pale orange solution was stirred at 110 °C for 30 min
and then allowed to cool to room temperature. The mixture
was poured onto water (150 mL) and then extracted with
diethyl ether (3 × 50 mL). The combined organic phase was
washed with water (2 × 50 mL), then dried over anhydrous
MgSO4, and filtered, and the solvent evaporated under
at room temperature for 10 min, and a solution of 3,5dihydroxybenzaldehyde (274 mg, 2.0 mmol) in anhydrous
DMSO (7 mL) was added dropwise under vigorous stirring
and a nitrogen atmosphere for 1 h. The reaction was quenched
by addition of 60 mL of diethyl ether and 100 g of ice. The
organic phase was separated, and the aqueous phase extracted
with diethyl ether (3 × 40 mL). The combined organic phase
was dried over anhydrous MgSO4 and filtered, and the solvent
was evaporated under vacuum. The residue was subjected to
silica gel column chromatography, eluting with hexane/diethyl
ether (1:3) to give 3,5-dihydroxystyrene (7) as a colorless oil
(248 mg, 91%). 1H-NMR (500 MHz, DMSO-d6): δ 9.22 (s,
2H, 2× OH), 6.53 (dd, J = 10.8, 17.6 Hz, 1H, H2), 6.30 (2× s,
2H, H4 and H8), 6.15 (s, 1H, H6), 5.62 (dd, J = 1.0, 17.6 Hz,
1H, Htrans-1a), 5.15 (dd, J = 1.0, 10.8 Hz, 1H, Hcis-1b). 13CNMR (125 MHz, DMSO-d6): δ 158.5, 138.9, 137.2, 113.2,
104.3, 102.4.
2.2.2. 3,5-Di-tert-butyldiphenylsilyloxystyrene (8). Imidazole (953 mg, 14.0 mmol) was added to a solution of 3,5dihydroxystyrene (7) (238 mg, 1.75 mmol) in dimethylformamide (2.6 mL), and the mixture was stirred under a nitrogen
atmosphere for 15 min at room temperature. The silyl chloride
(1.82 mL, 7.0 mmol) was added, and the light yellow solution
was stirred for 18 h. The mixture was dissolved in diethyl ether
(50 mL), and water (100 mL) was added. The organic phase
was separated, and the aqueous phase was extracted with
diethyl ether (3 × 50 mL). The combined organic phase was
washed with brine (2 × 50 mL) and dried over anhydrous
MgSO4, and the solvent was evaporated under vacuum. The
residue was subjected to silica gel column chromatography,
eluting with hexane/ethyl acetate (15:1) to give 3,5-di-tertbutyldiphenylsilyloxystyrene (8) as a colorless oil (1.02 g,
95%). 1H-NMR (500 MHz, CDCl3): δ 7.60−7.30 (m, 20H,
8224
DOI: 10.1021/acsomega.9b00722
ACS Omega 2019, 4, 8222−8230
ACS Omega
Article
2.3.2. Deoxyrhapontigenin-3-O-β-D-glucuronide (5). To a
stirred solution of (E)-1-[3-hydroxy-5-O-(2,3,4-tri-O-acetyl-βD-glucopyranoside)phenyl]-2-(4′-methoxy) ethene methyl
ester (12) (45 mg, 0.08 mmol) in tetrahydrofuran (THF)
and methanol (4:1, v/v) (15 mL) at 0 °C under a nitrogen
atmosphere was added sodium methoxide [5.4 M (30 wt.%) in
methanol] (0.65 mL, 3.51 mmol). After stirring for 1 h at 0 °C,
sodium hydroxide (1.0 M in water) (13.3 mL, 1.3 mmol) was
added to the reaction mixture. The resulting pale-yellow
solution was stirred at 0 °C for 2.5 h. Amberlyst 15 hydrogen
form was then added to adjust the reaction mixture to pH 4.
The resin was filtered off and washed with methanol (3 × 20
mL), and the solvent was evaporated under air flow to a thick
brown oil. The oil was subjected to preparative HPLC to give
deoxyrhapontigenin-3-O-β-D-glucuronide (5) as a white solid
(27 mg, 80%). The 1H-NMR and 13C-NMR data are presented
in Table 2. Melting point of 5: decomposes without melting
above 250 °C. Preparative HPLC was performed on an Agilent
HP1200 HPLC, monitoring at 280 nm. HPLC with
ChemStation software version B.02.01.SRI was equipped
with a G1322A degasser, G1311A quaternary pump, a
vacuum. The residue was subjected to silica gel column
chromatography, eluting with hexane/ethyl acetate (15:1) to
give 3,5-di-tert-butyldiphenylsilyloxy-4′-O-Me-resveratrol as a
pale brown crystal (276 mg, 98%). 1H-NMR (500 MHz,
acetone-d6): δ 7.63−7.36 (m, 20H, Ph-H), 7.38 (d, J = 8.8 Hz,
2H, H2′ and H6′), 6.89 (d, J = 8.8 Hz , 2H, H3′ and H5′),
6.76 (d, J = 16.4 Hz, 1H, H8), 6.73 (d, J = 16.4 Hz, 1H, H7),
6.61 (2× s, 2H, H2 and H6), 6.16 (t, J = 2.2 Hz, 1H, H4), 3.78
(s, 3H, OCH3), 1.02 (s, 18H, (2× (CH3)3). 13C-NMR (125
MHz, acetone-d6): δ 160.4, 157.3, 140.4, 136.2, 136.2, 133.4,
130.8, 128.7, 128.6, 126.6, 114.9, 111.9, 111.3, 55.5, 26.9, 19.9.
The next step involved the deprotection of the TBDPS groups
of 3,5-di-tert-butyldiphenylsilyloxy-4′-O-Me-resveratrol. To
achieve that, TBAF trihydrate (1.0 M in THF) (1.9 mL,
1.88 mmol) was added to a cold (0 °C) and stirred solution of
3,5-di-tert-butyldiphenylsilyloxy-4′-O-Me-resveratrol (337 mg,
0.47 mmol) in THF (8 mL). After stirring for 1 h at 0 °C,
saturated aqueous NH4Cl solution (50 mL) was poured into
the reaction mixture. The resultant mixture was extracted with
ethyl acetate (3 × 150 mL). The combined organic phase was
washed with saturated aqueous NH4Cl solution (2 × 50 mL)
and brine (2 × 50 mL). The aqueous phases were extracted
with ethyl acetate (2 × 100 mL), and the combined organic
phases were dried over MgSO4. The solvent was evaporated
under vacuum, and the residue was subjected to silica gel
column chromatography, eluting with hexane/ethyl acetate
(2:1) to give 4′-O-Me-resveratrol (11) as a pale brown crystal
(109 mg, 96%). The 1H-NMR and 13C-NMR data are
presented in Table 1.
2.3. Synthesis of Deoxyrhapontigenin-3-O-β-D-glucuronide (5). 2.3.1. (E)-1-[3-Hydroxy-5-O-(2,3,4-tri-O-acetylβ-D-glucopyranoside)phenyl]-2-(4′-methoxy) Ethene Methyl
Ester (12). A suspension of the dried 4′-O-Me-resveratrol (11)
(120 mg, 0.49 mmol), 2,3,4-tri-O-acetyl-α-D-glucuronic acid
methyl ester, tricholoroacetamidate (296 mg, 0.59 mmol), and
4 Å MS (2.0 g) in anhydrous CH2Cl2 (10 mL) was vigorously
stirred at room temperature for 30 min. The suspension was
then cooled to 0 °C, and a solution of the Lewis acid
[TMSOTf (22 μL in 1.4 mL of CH2Cl2) or BF3·OEt2 (42 μL
in 2.7 mL of CH2Cl2)] was slowly added. The resulting
suspension was continuously stirred at 0 °C for 3 h (in the case
of TMSOTf) or 5 h (in the case of BF3·OEt2). Then, the
reaction was quenched with three drops of Et3N and filtered
under Celite, and the solvent was removed under vacuum. The
residue was purified by silica gel column chromatography,
eluting with hexane/ethyl acetate (4:5) to give (E)-1-[3hydroxy-5-O-(2,3,4-tri-O-acetyl-β-D-glucopyranoside)phenyl]2-(4′-methoxy) ethene methyl ester (12) as a colorless oil [83
mg, 30% (TMSOTf) and 97 mg, 35% (BF3·OEt2)]. 4′-O-MeResveratrol (11) was recovered from both reaction conditions
[78 mg (TMSOTf) and 60 mg (BF3·OEt2)]. 1H-NMR (500
MHz, acetone-d6): δ 8.36 (d, J = 8.7 Hz, 2H, H2′ and H6′),
7.96 (d, J = 16.4 Hz, 1H, H8), 7.83 (d, J = 16.4 Hz, 1H, H7),
7.80 (d, J = 8.7 Hz, 2H, H3′ and H5′), 7.64 and 7.62 (dt, 2H, J
= 1.7 Hz, H2 and H6), 7.31 (t, J = 2.2 Hz, 1H, H4), 6.41 (d,
1H, H1″), 6.32 (t, 1H), and 6.05−6.09 (m, 3H, H2″, H3″,
H4″), 5.46 (d, 1H, H5″), 4.67 (s, 3H, C4′OCH3), 4.55 (s, 3H,
OCH3-glucuronic moiety), 2.89, 2.86, 2.85 (3× s, 3× (3H),
OAc-glucuronic moiety).13C-NMR (125 MHz, acetone-d6): δ
170.2, 169.9, 169.7, 167.9, 160.5, 159.5, 159.2, 141.1, 130.7,
129.7, 128.7, 126.7, 114.9, 109.1, 106.7, 103.9, 99.2, 72.8, 72.5,
71.8, 70.3, 55.6, 53.0, 20.6, 20.5, 20.4.
Table 2. 1H-NMR (500 MHz) and 13C-NMR (125 MHz), in
MeOD-d4, of Deoxyrhapontigenin-3-O-β-D-glucuronide (5)
1
13
H-NMR (δ ppm, J Hz)
atom #
1
2
3
4
5
6
7
8
1′
2′
3′
4′
5′
6′
OCH3
1″
2″
3″
4″
5″
6″
OH
C-NMR (δ ppm)
a
(500 MHz)
lit.
6.78, br. t
6.78, br.t
6.50, t, J = 2.1
6.45, t, J = 1.9
6.64, br. t
6.92, d, J = 16.3
7.02, d, J = 16.3
6.65, br.t
6.89, d, J = 16.5
7.04, d, J = 16.5
7.45, d, J = 8.8
6.91, d, J = 8.9
7.45, d, J = 8.5
6.89, d, J = 8.5
6.91, d, J = 8.9
7.45, d, J = 8.8
3.80, s
4.92c
3.53−3.47, m
3.53−3.47, m
3.57, m
3.83, d, J = 9.6
6.89,
7.45,
3.80,
4.96,
3.50,
3.51,
3.79,
4.00,
d, J = 8.5
d, J = 8.5
s
d, J = 7.2
m
t, d, J = 9.1
m
d, d, J = 9.5
(125 MHz)
lit.a
141.2
107.5
160.5
104.4
159.9
108.4
127.4
129.6
131.4
128.8
115.1
160.9
115.1
128.8
55.7
102.6
74.7d
77.7d
73.4
76.6
167.4
141.1
107.2
159.2
104.1
159.8
108.7
127.4
129.6
b
130.8
128.4
114.9
160.5
114.9
128.4
55.6
102.5
76.9
74.4
72.5
76.5
8.31, s
Ref 52. bThe 13C-NMR for H1′ was not furnished by the authors,
potentially leading to misplaced assignments. cThe signal for the
anomeric hydrogen (H1″) was partially superimposed on the solvent
signal. dThese signals may be inverted due to the uncertainty of
assignment.
a
8225
DOI: 10.1021/acsomega.9b00722
ACS Omega 2019, 4, 8222−8230
ACS Omega
Article
Figure 2. Synthetic route to 4′-O-Me-resveratrol (11) by Heck coupling between 3,5-dihydroxybenzaldehyde (6) and p-iodoanisole (10). Reagents
and reaction conditions: (a) NaH, CH3P(C6H5)3Br, DMSO, 70 °C (1 h), then r.t. (1 h) (91%); (b) imidazole, tert-butyl(chloro)diphenylsilane
(TBDPSCl) (8), DMF, 18 h (95%); (c) CH3I, K2CO3, acetone, 60 °C, 24 h (92%); (d) BnEt3NCl, Bu3N, Pd(OAc)2, DMF, 110 °C, 30 min
(98%); (e) TBAF trihydrate (1.0 M in THF), THF, 0 °C (96%).
Figure 3. Preparation of deoxyrhapontigenin-3-O-β-D-glucuronide (5) from 4′-O-Me-resveratrol (11).
between 8 and 10 furnished 3,5-di-tert-butyldiphenylsilyloxy4′-O-Me-resveratrol with 98% yield, and no non-TBDPSprotected adducts and/or (Z)-isomer were isolated from the
reaction medium. The yield of the Heck reaction (98%) was
more than 2-fold higher than obtained by Farina et al.53 and
Hoshino et al.,58 who used the 3,5-di-tert-butyldimethylsilyloxystyrene (a TBDMS analogue of 8) as the olefin and
acetyliodophenol (an acetyl analogue of 10) for the reaction.
Finally, the deprotection of the TBDPS protection groups
using 1.0 M TBAF trihydrate solution in THF-furnished 4-OMe-resveratrol (11) with 96% yield.
Using our synthetic approach, the 4-O-Me-resveratrol (11)
was stereoselectively obtained from 3,5-dihydroxybenzaldehyde (6) in four steps, 81% yield and excellent purity (HPLC,
>98%; Figure 20SA, Supporting Information). To the best of
our knowledge, our synthetic approach is one of the most
efficient routes to prepare 4-O-Me-resveratrol (11). For
example, Mizuni et al.59 reported the preparation of 4-O-Meresveratrol (11) using a Wittig reaction as the key step.
Compound 11 was obtained in three steps, however, with only
7% overall yield.59 Under the Wittig reaction conditions, the
(E)-isomer of 11 was formed as the minor regioisomer
(1.0:2.8, E/Z),59 similar to the 1.0:2.3 E/Z ratio reported by
Orsini et al.60 but considerably higher than the 1.0:9.0 E/Z
ratio described by Pettit et al.61 Š midrkal et al.62 reported a
highly stereoselective synthesis of 4-O-Me-resveratrol (11)
[only the (E)-isomer was observed] in seven steps. These
authors employed the Wittig−Horner reaction, a well-known
reaction for producing predominantly E-alkenes, as the key
step for obtaining the desired compound 11; however, the
overall yield for 11 was very low (4%).62 The Wittig−Horner
G1367B autosampler, G1316A thermostatic column compartment, and G1315C diode array detector. A Phenomenx Luna
10 μm C18(2) 250 × 21.2 mm column was used for
preparative HPLC on the Agilent HPLC system. The column
was eluted with an isocratic mixture of acetonitrile and water
with formic acid (0.1%) (28:72, v/v). The flow rate was set at
8 mL/min, and the peak related to deoxyrhapontigenin-3-O-βD-glucuronide (5) was detected at 37 min.
3. RESULTS AND DISCUSSION
To ultimately address biological mechanisms whereby brainbioavailable deoxyrhapontigenin-3-O-β-D-glucuronide (5) may
impact the development of AD, we investigated the synthesis
of 5 from 4-O-Me-resveratrol (11) (Figures 2 and 3).
4-O-Me-Resveratrol (11) was obtained through the Heck
coupling between the 3,5-di-tert-butyldiphenylsilyloxystyrene
(8) and p-iodoanisole (10) (Figure 2). Styrene 8 was prepared,
with 86% yield (two steps), through Wittig reaction between
3,5-dihydroxybenzaldehyde (6) and methyltriphenylphosphonium bromide according to the methodology developed by
Farina et al.,53 followed by the protection of hydroxyl groups
with tert-butyl(chloro)diphenylsilane (TBDPSCl) (Figure 2).
Protection of the hydroxyl groups of 7 was necessary, but it is
well known that if styrenes are unprotected, or protected with
acetyl or tert-butyldimethylsilyl (TBDMS), desired products
are obtained with low yields.53,55 For this reason, we selected
tert-butyldiphenylsilyl (TBDPS) as a protecting group since
this group is known to be more stable than TBDMS under
both alkaline and acid conditions.56,57 Synthesis of piodoanisole (10) was achieved with 92% yield as described
by Chen et al.54 To our satisfaction, the Heck coupling
8226
DOI: 10.1021/acsomega.9b00722
ACS Omega 2019, 4, 8222−8230
ACS Omega
Article
ence (HMQC) and heteronuclear multiple bond coherence
(HMBC) (Table 2) and are in accordance to those previously
described by Marvalin and Azerad,52 except for some of the
13
C-NMR assignments (Table 2). The 1H-NMR spectrum of
5, in comparison with that of 11, showed that H2 and H6,
which are identical in 11, became discriminated in the
glucuronide 5, as indicated by the multiplicity of the signals
at 6.78 and 6.64 ppm for H2 and H6, respectively (Table 2),
suggesting that the glucuronidation broke the symmetry of the
molecule. The J7,8 value of 16.3 Hz for 5 confirmed the E
stereochemistry of the stilbene bridge and agrees with the
value reported by Marvalin and Azerad52 (J7,8 = 16.5 Hz) and
Lucas et al.70 (J7,8 = 16.4 Hz). The anomeric hydrogen H1″
(δH 4.92 ppm) was partially superimposed on the solvent
signal; however, it was possible to determine its anomeric
carbon C3 at δC 160.5 ppm. Both assignments are consistent
with those reported by Marvalin and Azerad.52 The main
discrepancies between our 13C-NMR data and those reported
by Marvalin and Azerad52 are related to the assignments for
the carbon of the aromatic ring that bears the OMe group (C1′
to C6′) and the glucuronic acid unit (C1″ to C6″) (Table 2).
The anomeric carbon (C1″) of the glucuronic acid moiety
appears around δC 102 ppm, consistent with the literature
data;68−70 however, this is very different from the δC 55.6 ppm
reported by Marvalin and Azerad.52 The assignments of
proton-bearing carbons (OCH3, C2, C6, C4, C2′, C3′, C5′,
C6′, C1″, C2″, C3″, C4″, and C5″) were achieved using
HMQC. The assignments of the ipso carbons C1, C3, C5, C1′,
and C4′ were accomplished using HMBC. Specifically, C1 was
assigned based on its three-bond coupling with H8, whereas
C3 and C5 were assigned based on their two-bond correlation
with H2/H4 and H4/H6, respectively. It is worth mentioning
that C3, to which the O-glucuronic acid residue is attached,
also has a three-bond long-range coupling with the anomeric
H1″. C1′ was assigned on the basis of its three-bond coupling
with H3′, H5′, and H7, whereas C4′ was assigned on the basis
of its three-bond coupling with H2′ and H6′. In addition, C4′
showed strong three-bond coupling with the methyl hydrogen
(δH 3.80 ppm). Thus, by the combination of HSQC and
HMBC, all carbons could be assigned unambiguously.
reaction was used as a key step for synthesis of 4-O-Meresveratrol (11) from 3,5-dihydroxybenzoic acid. The authors
obtained 4-O-Me-resveratrol (11) in six steps, with 24% overall
yield and 100% stereoselectivity for the (E)-isomer.63,64
The 1H-nuclear magnetic resonance (1H-NMR) and 13CNMR spectra for all synthesized compounds shown in Figure 2
are available as Figures 1S−10S (Supporting Information).
The 1H-NMR and 13C-NMR and liquid chromatography
coupled to mass spectrometry (LC/MS) data derived from 4′O-Me-resveratrol (11) were in complete accordance with the
assigned structure of 11 and those already published in the
literature (Table 1).52 The geometry of the double bond was
assigned as E for 11 based on the coupling constant of the
signals for the olefinic protons H7 and H8 (J7,8 = 15.9 Hz).
This value is consistent with those reported elsewhere by Pettit
et al.61 (J7,8 = 15.9 Hz), Orsini et al.60 (J7,8 = 16.4 Hz), and Lee
et al.64 (J7,8 = 16.5 Hz). Finally, the LC−MS analysis of 4′-OMe-resveratrol (11) (Figure 20SB, Supporting Information)
showed the expected quasimolecular ion at m/z 241.1 [M −
H]− (calcd for 11, 241.2).
The next step was the glucuronidation of 4′-O-Meresveratrol (11), which can be difficult because of the very
low reactivity of phenolic hydroxyl groups as a glucuronic acid
acceptor.60 First, we tried to perform the glucuronidation of 11
under two different basic conditions: (i) acetobromo-α-Dglucuronic acid methyl ester, Ag2O, piridine, 3 Å molecular
sieves, 0 °C, 48 h65 or (ii) acetobromo-α-D-glucuronic acid
methyl ester, Ag2CO3, THF, 4 Å molecular sieves, 0 °C, 24 h.66
However, under both conditions, the desired glucuronide 12
was not formed, and unreacted 4′-O-Me-resveratrol (11) was
recovered from the reaction mixture. Due to the lack of success
in obtaining 12 using basic conditions, we attempted to
perform the glucuronidation of 11 (Figure 3) using
trimethylsilyltrifluoromethanesulfonate (TMSOTf) and boron
trifluoride diethyl etherate (BF3·OEt2), two Lewis acids that
are well known to catalyze the glucuronidation of phenolic
compounds.67,68 Under these acidic conditions, the desired
glucuronide 12 was obtained in approximately 30 and 35%
yields when TMSOTf or BF3·OEt2 were used as Lewis acid,
respectively (Figure 3). Thereafter, deprotection of the acetyl
groups, as well as the hydrolysis of the methyl ester, was easily
achieved using a mixture of 5.4 M MeONa in MeOH and 1.0
M NaOH in water at 0 °C for 3.5 h (Figure 3). Acid workup
using Amberlyst 15 hydrogen form to adjust the pH to 3.0,
followed by evaporation of the solvent and purification of the
residue by preparative HPLC, furnished deoxyrhapontigenin-3O-β-D-glucuronide (5) with 80% yield and excellent purity
(HPLC, >99%; Figure 1S, Supporting Information) from 5.
Overall, our synthetic approach furnished the deoxyrhapontigenin-3-O-β-D-glucuronide (5) from 3,5-dihydroxybenzaldehyde (6) in six steps, 21% yield, and excellent purity.
Deoxyrhapontigenin-3-O-β-D-glucuronide (5) showed a
quasimolecular ion at m/z 417.0 [M − H]− (calcd for 5,
417.2). A fragment at m/z 241 for 5 (Figure 22SB, Supporting
Information) was also observed, corresponding to the neutral
loss of 176 Da (the glucuronic moiety) from the
quasimolecular precursor ions m/z 417 [M − H]−, indicating
that 5 is a glucuronide conjugate of 11. The same pattern of
fragmentation was observed for dihydroresveratrol-3-O-β-Dglucuronide, an analogue of 5.69
Complete assignments of the hydrogen and carbon atoms of
both the aromatic rings and glucuronic acid moiety were
accomplished using heteronuclear multiple quantum coher-
4. CONCLUSIONS
As outlined here, we described the synthesis of 4-O-Meresveratrol (2) in four steps with 74% overall yield and present
what we believe to be the first report of the chemical synthesis
of deoxyrhapontigenin-3-O-β-D-glucuronide (5), obtained in
six steps with 21% overall yield. The robust synthetic approach
for 5 will allow us and others to evaluate the mechanism of
action of this brain-targeted bioactive dietary glucuronide in
the modulation of AD and other neurological disorders by
resveratrol (1).
■
ASSOCIATED CONTENT
S Supporting Information
*
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acsomega.9b00722.
1
H-NMR and 13C-NMR spectra of 3,5-dihydroxystyrene,
H-NMR and 13C-NMR spectra of 3,5-di-tert-butyldiphenylsilyloxystyrene, 1H-NMR and 13C-NMR spectra
of p-iodoanisole, 1H-NMR and 13C-NMR spectra of (E)(5-(4-methoxystyryl)-1,3-phenylene)bis1
8227
DOI: 10.1021/acsomega.9b00722
ACS Omega 2019, 4, 8222−8230
ACS Omega
Article
(methyldiphenylsilane), 1H-NMR and 13C-NMR spectra
of 4′-O-Me-resveratrol, 1H-NMR and 13C-NMR spectra
of (E)-1-[3-hydroxy-5-O-(2,3,4-tri-O-acetyl-β- D glucopyranoside)phenyl]-2-(4′-methoxy) ethene methyl
ester, 1H-NMR and 13C-NMR spectra of deoxyrhapontigenin-3-O-β-D-glucuronide, HMQC-NMR spectra of
deoxyrhapontigenin-3-O-β-D-glucuronide, HMBC-NMR
spectra of deoxyrhapontigenin-3-O-β-D-glucuronide,
LC−MS/MS analysis of 4′-O-Me-resveratrol, LC−MS/
MS analysis of deoxyrhapontigenin-3-O-β-D-glucuronide,
and MS and MS/MS spectra of deoxyrhapontigenin-3O-β-D-glucuronide (PDF)
■
Ribes, J.; Williamson, G.; Astley, S. B. Bioavailability and metabolism.
Mol. Aspects Med. 2002, 23, 39−100.
(9) Walle, T. Bioavailability of resveratrol. Ann. N. Y. Acad. Sci. 2011,
1215, 9−15.
(10) Chiou, Y. S.; Wu, J. C.; Huang, Q.; Shahidi, F.; Wang, Y. J.; Ho,
C. T.; Pan, M. H. Metabolic and colonic microbiota transformation
may enhance the bioactivities of dietary polyphenols. J. Funct. Foods
2014, 7, 3−25.
(11) De Vries, K.; Strydom, M.; Steenkamp, V. Bioavailability of
resveratrol: Possibilities for enhancement. J. Herb. Med. 2018, 11, 71−
77.
(12) Pannu, N.; Bhatnagar, A. Resveratrol: From enhanced
biosynthesis and bioavailability to multitargeting chronic diseases.
Biomed. Pharmacother. 2019, 109, 2237−2251.
(13) Scalbert, A.; Williamson, G. Dietary intake and bioavailability of
polyphenols. J. Nutr. 2000, 130, 2073S−2085S.
(14) Monagas, M.; Urpi-Sarda, M.; Sánchez-Patán, F.; Llorach, R.;
Garrido, I.; Gómez-Cordovés, C.; Andres-Lacueva, C.; Bartolomé, B.
Insights into the metabolism and microbial biotransformation of
dietary flavan-3-ols and the bioactivity of their metabolites. Food
Funct. 2010, 1, 233−253.
(15) Delmas, D.; Aires, V.; Limagne, E.; Dutartre, P.; Mazué, F.;
Ghiringhelli, F.; Latruffe, N. Transport, stability, and biological
activity of resveratrol. Ann. N. Y. Acad. Sci. 2011, 1215, 48−59.
(16) Ho, L.; Ferruzzi, M. G.; Janle, E. M.; Wang, J.; Gong, B.; Chen,
T. Y.; Lobo, J.; Cooper, B.; Wu, Q. L.; Talcott, S. T.; Percival, S. S.;
Simon, J.E.; Pasinetti, G. M. Identification of brain-targeted bioactive
dietary quercetin-3-O-glucuronide as a novel intervention for
Alzheimer’s disease. FASEB J. 2013, 27, 769−781.
(17) Fulda, S. Resveratrol and derivatives for the prevention and
treatment of cancer. Drug Discovery Today 2010, 15, 757−765.
(18) Alamolhodaei, N. S.; Tsatsakis, A. M.; Ramezani, M.; Hayes, A.
W.; Karimi, G. Resveratrol as MDR reversion molecule in breast
cancer: An overview. Food Chem. Toxicol. 2017, 103, 223−232.
(19) Elshaer, M.; Chen, Y.; Wang, X.J.; Tang, X. Resveratrol: An
overview of its anti-cancer mechanisms. Life Sci. 2018, 207, 340−349.
(20) Szkudelska, K.; Szkudelski, T. Resveratrol, obesity and diabetes.
Eur. J. Pharmacol. 2010, 635, 1−8.
(21) Szkudelski, T.; Szkudelska, K. Resveratrol and diabetes: From
animal to human studies. Biochim. Biophys. Acta 2015, 1852, 1145−
1154.
(22) Ö ztürka, E.; Arslan, A. K. K.; Yerer, M. B.; Bishayee, A.
Resveratrol and diabetes: A critical review of clinical studies. Biomed.
Pharmacother. 2017, 95, 230−234.
(23) Kim, S.; Jin, Y.; Choi, Y.; Park, T. Resveratrol exerts antiobesity effects via mechanisms involving down-regulation of
adipogenic and inflammatory processes in mice. Biochem. Pharmacol.
2011, 81, 1343−1351.
(24) de Ligt, M.; Timmers, S.; Schrauwen, P. Resveratrol and
obesity: Can resveratrol relieve metabolic disturbances? Biochim.
Biophys. Acta 2015, 1852, 1137−1144.
(25) Mahal, H. S.; Mukherjee, T. Scavenging of reactive oxygen
radicals by resveratrol: Antioxidant effect. Res. Chem. Intermed. 2006,
32, 59−71.
(26) Gülçin, I. Antioxidant properties of resveratrol: A structureactivity insight. Innovative Food Sci. Emerging Technol. 2010, 11, 210−
218.
(27) Hussein, M. A. A convenient mechanism for the free radical
scavenging activity of resveratrol. Int. J. Phytomed. 2011, 3, 459−469.
(28) Gerszon, J.; Rodacka, A.; Puchała, M. Antioxidant properties of
resveratrol and its protective effects in neurodegenerative diseases.
Adv. Cell Biol. 2014, 4, 97−117.
(29) Alarcon De La Lastra, C.; Villegas, I. Resveratrol as an antiinflammatory and anti-aging agent: Mechanisms and clinical
implications. Mol. Nutr. Food Res. 2005, 49, 405−430.
(30) Udenigwe, C. C.; Ramprasath, V. R.; Aluko, R. E.; Jones, P. J.
Potential of resveratrol in anticancer and anti-inflammatory therapy.
Nutr. Rev. 2008, 66, 445−454.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: adefatima@qui.ufmg.br (A.d.F.).
*E-mail: Richard.Dixon@unt.edu (R.A.D).
ORCID
 ngelo de Fátima: 0000-0003-2344-5590
Giulio M. Pasinetti: 0000-0002-1524-5196
Richard A. Dixon: 0000-0001-8393-9408
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This study was supported by grant number P50 AT008661-01
from the NCCIH and the ODS and by the University of North
Texas. G.M.P. holds a Senior VA Career Scientist Award.
A.d.F. acknowledges the Brazilian National Council for
Scientific and Technological Development (CNPq) for the
scholarship received during his sabbatical year (process
#204106/2017-6) at the University of North Texas, Denton,
TX, USA. The authors acknowledge the BioAnalytical Facility
at the University of North Texas for the support with mass
spectrometry analyses during this work. We acknowledge that
the contents of this study do not represent the views of the
NCCIH, the ODS, the NIH, the U.S. Department of Veterans
Affairs, or the United States Government.
■
■
REFERENCES
(1) Ness, A. R.; Powles, J. W. Fruit and vegetables, and
cardiovascular disease: A review. Int. J. Epidemiol. 1997, 26, 1−13.
(2) Kris-Etherton, P. M.; Hecker, K. D.; Bonanome, A.; Coval, S. M.;
Binkoski, A.E.; Hilpert, K. F.; Griel, A. E.; Etherton, T. D. Bioactive
compounds in foods: Their role in the prevention of cardiovascular
disease and cancer. Am. J. Med. 2002, 113, 71−88.
(3) Yao, L. H.; Jiang, Y. M.; Shi, J.; Tomas-Barberan, F. A.; Datta,
N.; Singanusong, R.; Chen, S. S. Flavonoids in food and their health
benefits. Plant Foods Hum. Nutr. 2004, 59, 113−122.
(4) Shao, Y.; Bao, J. Polyphenols in whole rice grain: Genetic
diversity and health benefits. Food Chem. 2015, 180, 86−97.
(5) Costa, C.; Tsatsakis, A.; Mamoulakis, C.; Teodoro, M.;
Briguglio, G.; Caruso, E.; Dimitris, T.; Margina, D.; Dardiotis, E.;
Kouretas, D.; Fenga, C. Current evidence on the effect of dietary
polyphenols intake on chronic diseases. Food Chem. Toxicol. 2017,
110, 286−299.
(6) Gürbüz, N.; Uluişik, S.; Frary, A.; Frary, A.; Doğanlar, S. Health
benefits and bioactive compounds of eggplant. Food Chem. 2018, 268,
602−610.
(7) Sanlier, N.; Atik, I.;̇ Atik, A. A minireview of effects of white tea
consumption on diseases. Trends Food Sci. Technol. 2018, 82, 82−88.
(8) Stahl, W.; van den Berg, H.; Arthur, J.; Bast, A.; Dainty, J.;
Faulks, R. M.; Gärtner, C.; Haenen, G.; Hollman, P.; Holst, B.; Kelly,
F. J.; Polidori, M. C.; Rice-Evans, C.; Southons, S.; van, V. T.; Viña8228
DOI: 10.1021/acsomega.9b00722
ACS Omega 2019, 4, 8222−8230
ACS Omega
Article
(31) Poulsen, M. M.; Fjeldborg, K.; Ornstrup, M. J.; Kjær, T. N.;
Nøhr, M. K.; Pedersen, S. B. Resveratrol and inflammation:
Challenges in translating pre-clinical findings to improved patient
outcomes. Biochim. Biophys. Acta 2015, 1852, 1124−1136.
(32) Anekonda, T. S. Resveratrol - A boon for treating Alzheimer’s
disease? Brain Res. Rev. 2006, 52, 316−326.
(33) Villaflores, O. B.; Chen, Y. J.; Chen, C. P.; Yeh, J. M.; Wu, T. Y.
Curcuminoids and resveratrol as anti-Alzheimer agents. Taiwanese J.
Obstetr. Gynecol. 2012, 51, 515−525.
(34) Bastianetto, S.; Ménard, C.; Quirion, R. Neuroprotective action
of resveratrol. Biochim. Biophys. Acta 2015, 1852, 1195−1201.
(35) Drygalski, K.; Fereniec, E.; Koryciński, K.; Chomentowski, A.;
Kiełczewska, A.; Odrzygózd́ ź, C.; Modzelewska, B. Resveratrol and
Alzheimer’s disease. From molecular pathophysiology to clinical trials.
Exp. Gerontol. 2018, 113, 36−47.
(36) Storniolo, C. E.; Moreno, J. J. Resveratrol metabolites have an
antiproliferative effect on intestinal epithelial cancer cells. Food Chem.
2012, 134, 1385−1391.
(37) Patel, K. R.; Brown, V. A.; Jones, D. J.; Britton, R. G. Clinical
pharmacology of resveratrol and its metabolites in colorectal cancer
patients. Cancer Res. 2010, 70, 7392−7399.
(38) Aires, V.; Limagne, E.; Cotte, A. K.; Latruffe, N.; Ghiringhelli,
F.; Delmas, D. Resveratrol metabolites inhibit human metastatic colon
cancer cells progression and synergize with chemotherapeutic drugs to
induce cell death. Mol. Nutr. Food Res. 2013, 57, 1170−1181.
(39) Lasa, A.; Churruca, I.; Eseberri, I.; Andrés-Lacueva, C.; Portillo,
M. P. Delipidating effect of resveratrol metabolites in 3T3-L1
adipocytes. Mol. Nutr. Food Res. 2012, 56, 1559−1568.
(40) Kaldas, M. I.; Walle, U. K.; Walle, T. Resveratrol transport and
metabolism by human intestinal Caco-2 cells. J. Pharm. Pharmacol.
2003, 55, 307−312.
(41) Walle, T.; Hsieh, F.; DeLegge, M. H.; Oatis, J. E.; Walle, K.
High absorption but very low BIOAVAILABILITY of oral resveratrol
in humans. Drug Metab. Dispos. 2004, 32, 1377−1382.
(42) Juan, M. E.; Maijó, M.; Planas, J. M. Quantification of transresveratrol and its metabolites in rat plasma and tissues by HPLC. J.
Pharm. Biomed. Anal. 2010, 51, 391−398.
(43) Spencer, J. P. The impact of flavonoids on memory:
physiological and molecular considerations. Chem. Soc. Rev. 2009,
38, 1152−1161.
(44) Rezai-Zadeh, K.; Shytle, D.; Sun, N.; Mori, T.; Hou, H.;
Jeanniton, D.; Ehrhart, J.; Townsend, K.; Zeng, J.; Morgan, D.; Hardy,
J.; Town, T.; Tan, J. Green tea epigallocatechin-3-gallate (EGCG)
modulates amyloid precursor protein cleavage and reduces cerebral
amyloidosis in Alzheimer transgenic mice. J. Neurosci. 2005, 25,
8807−8814.
(45) Hartman, R. E.; Shah, A.; Fagan, A. M.; Schwetye, K. E.;
Parsadanian, M.; Schulman, R. N.; Finn, M. B.; Holtzman, D. M.
Pomegranate juice decreases amyloid load and improves behavior in a
mouse model of Alzheimer’s disease. Neurobiol. Dis. 2006, 24, 506−
515.
(46) Wang, J.; Ho, L.; Zhao, Z.; Seror, I.; Humala, N.; Dickstein, D.
L.; Thiyagarajan, M.; Percival, S. S.; Talcott, S. T.; Pasinetti, G. M.
Moderate consumption of Cabernet Sauvignon attenuates Aβ
neuropathology in a mouse model of Alzheimer’s disease. FASEB J.
2006, 20, 2313−2320.
(47) Vingtdeux, V.; Dreses-Werringloer, U.; Zhao, H.; Davies, P.;
Marambaud, P. Therapeutic potential of resveratrol in Alzheimer’s
disease. BMC Neurosci. 2008, 9, S6.
(48) Wang, J.; Ho, L.; Zhao, W.; Ono, K.; Rosensweig, C.; Chen, L.;
Humala, N.; Teplow, D. B.; Pasinetti, G. M. Grape-derived
polyphenolics prevent A Oligomerization and attenuate cognitive
deterioration in a mouse model of Alzheimer’s disease. J. Neurosci.
2008, 28, 6388−6392.
(49) Thomas, P.; Wang, Y. J.; Zhong, J. H.; Kosaraju, S.;
O’Callaghan, N. J.; Zhou, X. F.; Fenech, M. Grape seed polyphenols
and curcumin reduce genomic instability events in a transgenic mouse
model for Alzheimer’s disease. Mutat. Res., Fund. Mol. Mech. Mutagen.
2009, 661, 25−34.
(50) Pasinetti, G. M. Novel role of red wine-derived polyphenols in
the prevention of Alzheimer’s disease dementia and brain pathology:
Experimental approaches and clinical implications. Planta Med. 2012,
78, 1614−1619.
(51) Wang, J.; Bi, W.; Cheng, A.; Freire, D.; Vempati, P.; Zhao, W.;
Gong, B.; Janle, E. M.; Chen, T. Y.; Ferruzi, M. G.; Schmeider, J.; Ho,
L.; Pasinetti, G. M. Targeting multiple pathogenic mechanisms with
polyphenols for the treatment of Alzheimer’s disease - Experimental
approach and therapeutic implications. Front. Aging Neurosci. 2014, 6,
42.
(52) Marvalin, C.; Azerad, R. Microbial glucuronidation of
polyphenols. J. Mol. Cat. B: Enzym. 2011, 73, 43−52.
(53) Farina, A.; Ferranti, C.; Marra, C. An improved synthesis of
resveratrol. Nat. Prod. Res. 2007, 20, 247−252.
(54) Chen, J.; Ko, S.; Liu, L.; Sheng, Y.; Han, H.; Li, X. The effect of
different alkyl chains on the photovoltaic performance of D-π-A
porphyrin-sensitized solar cells. New J. Chem. 2015, 39, 3736−3746.
(55) Learmonth, D. A. A concise synthesis of the 3-O-β-D- and 4‘-Oβ-d-Glucuronide conjugates oftrans-Resveratrol. Bioconjugate Chem.
2003, 14, 262−267.
(56) Hanessian, S.; Lavallee, P. The preparation and synthetic Utility
oftert-Butyldiphenylsilyl ethers. Can. J. Chem. 1975, 53, 2975−2977.
(57) Torisawa, Y.; Shibasaki, M.; Ikegami, S. Novel reactivities on
tert-butyldimethylsilyl and tert-butyldiphenylsilyl ethers; Application
to the synthesis of 11‑epi‑PGF2.ALPHA. Chem. Pharm. Bull. 1983, 31,
2607−2615.
(58) Hoshino, J.; Park, E.-J.; Kondratyuk, T. P.; Marler, L.; Pezzuto,
J. M.; van Breemen, R. B.; Mo, S.; Li, Y.; Cushman, M. Selective
synthesis and biological evaluation of sulfate-conjugated resveratrol
metabolites. J. Med. Chem. 2010, 53, 5033−5043.
(59) Mizuno, C. S.; Ma, G.; Khan, S.; Patny, A.; Avery, M. A.;
Rimando, A. M. Design, synthesis, biological evaluation and docking
studies of pterostilbene analogs inside PPARα. Bioorg. Med. Chem.
2008, 16, 3800−3808.
(60) Orsini, F.; Pelizzoni, F.; Bellini, B.; Miglierini, G. Synthesis of
biologically active polyphenolic glycosides (combretastatin and
resveratrol series). Carbohydr. Res. 1997, 301, 95−109.
(61) Pettit, G. R.; Grealish, M. P.; Jung, M. K.; Hamel, E.; Pettit, R.
K.; Chapuis, J.-C.; Schmidt, J. M. Antineoplastic agents. 465,
Structural modification of resveratrol: Sodium resverastatin phosphate. J. Med. Chem. 2002, 45, 2534−2542.
(62) S̆ midrkal, J.; Harmatha, J.; Buděsí̌ nský, M.; Vorác,̌ K.; Zídek, Z.;
Kmoníčková, E.; Merkl, R.; Filip, V. Modified approach for preparing
(E)-stilbenes related to resveratrol, and evaluation of their potential
immunobiological effects. Collect. Czech. Chem. Commun. 2010, 75,
175−186.
(63) Han, S. Y.; Lee, H. S.; Choi, D. H.; Hwang, J. W.; Yang, D. M.;
Jun, J.-G. Efficient total synthesis of piceatannol via (E)-selective
Wittig-Horner reaction. Synth. Commun. 2009, 39, 1425−1432.
(64) Lee, H. S.; Lee, B. W.; Kim, M. R.; Jun, J.-G. Syntheses of
resveratrol and its hydroxylated derivatives as radical scavenger and
tyrosinase inhibitor. Bull. Korean Chem. Soc. 2010, 31, 971−975.
(65) Needs, P. W.; Kroon, P. A. Convenient syntheses of
metabolically important quercetin glucuronides and sulfates. Tetrahedron 2006, 62, 6862−6868.
(66) Wang, L.-X.; Heredia, A.; Song, H.; Zhang, Z.; Yu, B.; Davis,
C.; Redfield, R. Resveratrol glucuronides as the metabolites of
resveratrol in humans: Characterization, synthesis, and anti-HIV
activity. J. Pharm. Sci. 2004, 93, 2448−2457.
(67) Zhang, Z.; Yu, B.; Schmidt, R. R. Synthesis of mono- and di-Oβ-D-glucopyranoside conjugates of (E)-resveratrol. Synthesis 2006,
2006, 1301−1306.
(68) Zhang, M.; Jagdmann, G. E., Jr.; Zandt, M. V.; Sheeler, R.;
Beckett, P. Chemical synthesis and characterization of epicatechin
glucuronides and sulfates: Bioanalytical standards for epicatechin
metabolite identification. J. Nat. Prod. 2013, 76, 157−169.
(69) Radko, Y.; Christensen, K. B.; Christensen, L. P. Semipreparative isolation of dihydroresveratrol-3-O-β-D-glucuronide and
four resveratrol conjugates from human urine after oral intake of a
8229
DOI: 10.1021/acsomega.9b00722
ACS Omega 2019, 4, 8222−8230
ACS Omega
Article
resveratrol-containing dietary supplement. J. Chromatogr. B: Biomed.
Sci. Appl. 2013, 930, 54−61.
(70) Lucas, R.; Alcantara, D.; Morales, J. C. A concise synthesis of
glucuronide metabolites of urolithin-B, resveratrol, and hydroxytyrosol. Carbohydr. Res. 2009, 344, 1340−1346.
8230
DOI: 10.1021/acsomega.9b00722
ACS Omega 2019, 4, 8222−8230