Hybrid-increased radical-scavenging activity of resveratrol derivatives by incorporating a chroman moiety of vitamin e

Article abstract of DOI:10.1002/chem.201002020

A winning combination: Resveratrol derivatives incorporating a chroman moiety of vitaminE were constructed, resulting in the remarkable enhancement in tris(2,4,6-trichloro-3,5-dinitrophenyl)methyl radical (HNTTM)-scavenging activity as compared with the parent molecules (see scheme). Reaction kinetic analysis, oxidative product identification, and redox potential determination demonstrate that the reaction is governed by a sequential proton-loss electron-transfer (SPLET) mechanism.

Full text of DOI:10.1002/chem.201002020

DOI: 10.1002/chem.201002020
Hybrid-Increased Radical-Scavenging Activity of Resveratrol Derivatives by
Incorporating a Chroman Moiety of Vitamin E
Jie Yang, Guo-Yun Liu, Dong-Liang Lu, Fang Dai, Yi-Ping Qian, Xiao-Ling Jin, and
Bo Zhou*[a]
Excessive production of reactive oxygen species (ROS),
oxidative stress, has been implicated as a causative mecha-
nism in several degenerative diseases, including cancer,[1]
thus using dietary antioxidants has become an attractive
strategy to prevent and control cancer.[2] Of the various diet-
ary antioxidants, resveratrol (3,5,4’-trihydroxy-trans-stilbene)
(Scheme 1), a natural polyphenol found in large amounts in
grapes, stands out as the molecule with the most potential in
cancer chemoprevention[3] and as a promising lead com-
pound in designing more active antioxidants[4] and cancer
chemopreventive agents.[5] The structure feature responsible
for the antioxidant activity of resveratrol is the 4’-OH in the
stilbene scaffold.[4a,6] Recently, we found that introduction of
electron-donating substituents in the ortho- or para-position
of the 4’-OH could significantly enhance its antioxidant ac-
tivity,[7] prooxidant activity on DNA damage in the presence
of CuII ions,[8] and cytotoxicity on human promeolocytic leu-
kemia cells.[9]
The hybrid approach has recently attracted much atten-
tion in medicinal chemistry and design of hybrid molecules
encompassing two pharmacophores in one molecular scaf-
fold is a niche area in a large field of drug discovery.[10] In
C
Scheme 1. Structures of resveratrol, PMC, a-tocopherol, and HNTTM .
view of the fact that a-tocopherol (vitamin E) (Scheme 1) is
known as a natural and chroman-based antioxidant of lipo-
proteins and biomembranes,[11] Koufaki and co-workers re-
ported the synthesis of a trihydroxydihydrostilbene–chro-
man hybrid, which was proven to be a strong neuroprotec-
tant against oxidative stress.[12] However, from an antioxi-
dant point of view, the double bond in the stilbene scaffold
is necessary to resonance stabilize the resulting phenoxyl
radical. Therefore, we describe herein the synthesis of a set
of novel hydroxylated resveratrol–chroman hybrids, which
incorporate skeletons of two kinds of molecules (stilbene
and chroman) with the aim to improve antioxidant activity
and to investigate the antioxidant mechanism.
The overall strategy for the synthesis of hydroxylated stil-
bene–chroman hybrids (11a–11c) is outlined in Scheme 2.
Under an inert atmosphere, the trifluoroacetic acid (TFA)
catalyzed coupling of phenol 1 with 2-methylbut-3-en-2-ol
followed by cyclization resulted in the formation of
[a] J. Yang, G.-Y. Liu, D.-L. Lu, Dr. F. Dai, Y.-P. Qian, Dr. X.-L. Jin,
Prof. Dr. B. Zhou
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, 222 Tianshui Street S.
Lanzhou 730000 (P.R. China)
Fax : (+86)931-8915557
E-mail: bozhou@lzu.edu.cn
2,2,5,7,8-pentamethyl-6-hydroxychroman
(2,
PMC;
Scheme 1), an a-tocopherol analogue in which the polyiso-
prenoid chain is replaced by a methyl group. Bromination of
2 followed by protection of the phenolic OH with an acetyl
group gave 4, which was oxidized with N-methylmorpho-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002020.
12808
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 12808 – 12813

COMMUNICATION
and unique carbon-centered
radical and has been successful-
ly applied to the evaluation of
the electron-transfer ability of
phenolic antioxidants by Juliꢁ
and co-workers.[13] Unlike 2,2-
diphenyl-1-picrylhydrazyl radi-
C
cal (DPPH ), it cannot directly
abstract hydrogen atoms from
phenolic antioxidants due to
the great steric hindrance.[13]
C
The ability of HNTTM to be
reduced by an electron-transfer
reaction to its stable triphenyl-
carbanion HNTTMꢀ, as detect-
ed by spectroscopy, has made it
possible to compare the elec-
tron-transfer ability of antioxi-
dants.[13] By use of this radical,
an intriguing observation that
the electron-transfer capacity of
catechin derivatives correlates
well with cell-cycle-arrest activi-
ty and apoptosis-inducing activ-
ity in HT29 cells, was ob-
tained.[14] Thus, HNTTM was
C
selected to evaluate the radical-
scavenging property of hy-
droxylated
stilbene–chroman
hybrids (11a–11c) and their
corresponding parent molecules
resveratrol and PMC. When
11b was added to the chloro-
form/methanol solution, the
rapid disappearance of the visi-
ble
absorption
band
of
C
HNTTM centered at 387 nm
was accompanied by the ap-
pearance of a peak at 497 nm
due to the formation of the cor-
responding anion HNTTMꢀ
(Figure 1),[13] indicating that the
Scheme 2. Synthesis of hydroxylated stilbene–chroman hybrids (11a–11c).
C
line-N-oxide (NMMO), to obtain the acetyl aldehyde 5.
After deprotection of the phenolic OH with NH4OAc, the
hydroxylated aldehyde 6 was methylated with CH3I to
afford the methoxy aldehyde 7. Wittig–Horner reaction of 7
and the corresponding phosphonate 9 in the presence of
NaH in dry DMF gave exclusively the trans-isomers, the me-
thoxyl hybrids 10a–10c, followed by demethylation with a
large excess of EtSNa in DMF to furnish 11a–11c, which
electron-transfer reaction from 11b to HNTTM took place.
Three possible electron-transfer reaction mechanisms of
phenolic antioxidants with free radicals have been docu-
mented, that is, sequential proton loss electron transfer
(SPLET mechanism, Equation (1), the electron donor is
ArOꢀ), electron transfer then proton transfer (ETPT mech-
anism, Equation (2), the electron donor is ArOH), and
proton-coupled electron transfer [PCET mechanism,
Eq. (3)].[13d,15] The relative contribution of these processes
depends not only on the nature of the solvent and acidity of
the phenolic hydroxyl groups, but also on the redox poten-
tials of the species involved.[7,13d,15a,c,f]
1
were characterized with HRMS (ESI) and H and 13C NMR
spectroscopy (see the Supporting Information), and were
stable in either solid or solution form under air.
It has been admitted that the main characteristic responsi-
ble for the antioxidant activity of a phenolic compound is its
ability to scavenge free radicals. Tris(2,4,6-trichloro-3,5-dini-
ꢀHþ
X
Hþ
C
ꢀ
C
C
ArOH
ArOꢀ
ArO þ X
ArO þ XH
ð1Þ
ƒƒ!
ƒ!
ƒ!
C
trophenyl)methyl radical (HNTTM ) (Scheme 1) is a stable
Chem. Eur. J. 2010, 16, 12808 – 12813
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12809

B. Zhou et al.
þ
ArOH þ CH3OH Ð CH3 O H2 þ ArOꢀ
ð4Þ
To get more of an insight into the detailed electron-trans-
C
fer mechanism, the rate of HNTTM -scavenging reaction of
the hybrids and their parent molecules was measured in
chloroform/methanol (with various ratios of 49:1, 9:1, and
4:1, v/v) by monitoring the decrease in absorbance of
C
387 nm due to HNTTM by using stopped-flow UV/Vis spec-
troscopy at 258C (see the inset of Figure 1C). The reaction
of the hybrids and PMC obeyed second-order kinetics with
C
the ratio of [hybrids or PMC]/ACUTHTNGRNENU[G HNTTM ] being 1:1 (see the
Supporting Information), and their second-order rate con-
stants (k2) are summarized in Table 1. The activity order is
C
Table 1. Observed rate constants and nHNTTM values for the reactions of
C
the hydroxylated hybrids with HNTTM in chloroform/methanol at 258C.
[a]
[a,b]
C
ArOH
k2 [Lmolꢀ1 sꢀ1
chloroform/methanol (v/v)
9:1 49:1
]
nHNTTM
4:1
(9.8ꢃ0.74)ꢂ104
(5.1ꢃ0.19)ꢂ105
(4.6ꢃ0.09)ꢂ105
(6.2ꢃ0.19)ꢂ104
11a
11b
11c
2 (PMC)
resveratrol
G
A
ACHTUNGTRENNUNG
E
A
ACHTUNGTRENNUNG
N
A
ACHTUNGTRENNUNG
E
E
A
[c]
[c]
[c]
[c]
–
–
–
–
[a] Data are expressed as the mean ꢃSD for three determinations.
C
[b] nHNTTM values were measured in chloroform/methanol (2:1, v/v). [c] Re-
sveratrol is inactive in the reaction.
11b>11c>11a>PMC. It is worth noting that the
C
HNTTM -scavenging activity of the hybrids is significantly
higher than that of the parent molecule PMC, an a-toco-
pherol analogue, which exhibits more effective antioxidant
activity than a-tocopherol in some reaction system,[16]
whereas the other parent molecule resveratrol is inactive. In
particular, the k2 value (8.4ꢂ104 Lmolꢀ1 sꢀ1) of 11b in
chloroform/methanol (9:1, v/v) is about 500-fold larger than
that of PMC (1.6ꢂ102 Lmolꢀ1 sꢀ1), which clearly indicates
that the hybrid approach is feasible in antioxidant drug
design. The present observations that the reaction rates of
the hybrids increase with increasing the content of methanol
(Table 1), and that the increase of methanol ratio makes the
peak of HNTTMꢀ more obvious (Figure 1), suggest that in
ionizable methanol, the phenolic hybrid (ArOH) is partially
ionized to the corresponding anion (ArOꢀ) [Eq. (4)], which
is a much stronger electron donor than the parent molecule
(ArOH). The increase of ArOꢀ concentration with the in-
crease of methanol ratio facilitates electron-transfer reaction
Figure 1. Spectral changes of HNTTM (60 mmolLꢀ1
) in the absence
C
(solid line) and presence (dashed line) of the hydroxylated hybrid 11b
(60 mmolLꢀ1) in chloroform/methanol with various volume ratios of 49:1
(A), 9:1 (B), and 4:1 (C) at 258C (the interval: 1 min). The inset in A
shows the enlargement of absorbance in the range l=420–600 nm. The
C
with HNTTM (SPLET reaction) and thus leads to a faster
inset in C shows decay of HNTTM (30 mmolLꢀ1) at 387 nm in the pres-
C
reaction rate. Furthermore, the anodic potentials of the hy-
brids and PMC, and their corresponding anion, as well as
ence of 11b (30 mmolLꢀ1) in chloroform/methanol (4:1, v/v) using the
stopped-flow UV/Vis spectroscopy at 258C.
C
the cathodic peak potential of HNTTM in chloroform/
methanol (9:1, v/v) were determined using cyclic voltamme-
try (Table 2). It is seen that the anodic peak potentials of hy-
brids 11a–11c and PMC are higher than the cathodic peak
ArOH þ X ! ArOH þ Xꢀ ! ArO þ XH
ð2Þ
ð3Þ
C
Cþ
C
ArOH þ X ! ½ArOH ꢁ ꢁ ꢁ X ꢂ! ½ArOH ꢁ ꢁ ꢁ Xꢀꢂ
C
C
Cþ
C
potential of HNTTM (0.50 V vs. SCE), demonstrating that
C
! ArO þ XH
the electron-transfer reaction between the parent molecule
12810
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Chem. Eur. J. 2010, 16, 12808 – 12813

Hybrid-Increased Radical-Scavenging Activity of Resveratrol Derivatives
Table 2. Cyclic voltammetry parameters for the oxidation of the hybrids
COMMUNICATION
C
HNTTM reduced per molecule of the hybrids or PMC, that
C
and PMC and for the reduction of HNTTM in chloroform/methanol
C
is, the stoichiometric factor (nHNTTM ) was determined with a
large excess of HNTTM by UV/Vis spectroscopy. Excellent
linear correlations of concentration versus absorbance were
obtained for all the compounds tested (see the Supporting
Information). The nHNTTM values can be obtained from the
(9:1, v/v).[a]
C
Ep [V][b] (Ep [V][c], anion)
Eo [V][d ](Ep [V][e]
ACHTUNGTERNNUNG )
HNTTM
2 (PMC)
11a
0.55 (0.50)
0.81 (0.50)
0.79 (–)[f]
C
slope of the straight line (Table 1). Indeed, the catechol de-
11b
0.73 (0.20)
0.59 (0.16)
C
rivative 11c has the highest nHNTTM value among the com-
11c
C
pounds tested, and hence possesses the highest HNTTM -
scavenging ability.
[a] The potential was measured versus a saturated calomel electrode
(SCE). [b] Anodic peak potentials. [c] Anodic peak potentials of PMC,
11b and 11c with an excess of tetrabutylammonium hydroxide of 2, 4,
and 4 mmolLꢀ1, respectively. [d] Standard redox potentials. [e] Cathodic
peak potentials. [f] The anodic peak potential of the phenolate anion for
11a could not be determined probably due to the quick and irreversible
side reactions in the alkaline condition (see the Supporting Information).
The SPLET mechanism was also supported by identifying
the oxidation products of the hybrids in chloroform/metha-
nol (2:1, v/v) at room temperature. It was found that
C
HNTTM completely converted 11b and 11c to the corre-
sponding benzofuran derivatives 12b and 12c (Scheme 3) by
characterization with HRMS (ESI) and 1D and 2D NMR
spectroscopy (see the Supporting Information). The forma-
tion of 12 can be easily rationalized by sequential proton
loss from the 4’-OH and electron transfer between the phe-
C
and HNTTM is not thermodynamically feasible. However,
the anodic peak potentials of the phenolate anion for 11b
and 11c (0.20 and 0.16 V, respectively) are much lower than
C
C
the cathodic peak potential of HNTTM , providing unambig-
nolate anion and HNTTM , giving the phenoxyl radical 13,
uous evidence that the actual electron donor is the pheno-
late anion instead of the parent molecule, and a SPLET
mechanism [Eq. (1)] does operate in chloroform/methanol.
Generally speaking, the molecules with a catechol moiety
possess higher activity than those with no such moiety due
to the intramolecular hydrogen-bonding interaction of the
oxidative intermediate, the ortho-hydroxy phenoxyl radi-
cal.[17] Although the k2 value of 11b is slightly larger than
the catechol derivative 11c in the various solvent mixtures,
their values are very close and fall within the error range of
10%. The possible reason is that the anodic peak potentials
of the phenolate anions for 11b and 11c are very close (0.20
and 0.16 V, respectively). Furthermore, the total number of
followed by disproportionation and intramolecular nucleo-
philic attack to give 12 with restoration of aromaticity as the
driving force of the reaction as exemplified in Scheme 3.
Notably, the oxidative products, 12b and 12c were obtained
C
with 1.5 equivalent of HNTTM . If a large excess of
C
HNTTM was used, the oxidative product would further
C
contribute to the HNTTM -scavenging reaction, the end
C
result being that the nHNTTM values of 11b and 11c would be
larger than 2. In the case of the catechol derivative 11c, the
C
nHNTTM value is 4.29 and is larger than the available number
of hydroxyl groups. This could be due to further reaction
products, such as dimers and quinones.[18] On the other
hand, a protic solvent, such as the alcohol molecule, can re-
C
Scheme 3. The HNTTM -scavenging reaction mechanism by 11b or 11c in chloroform/methanol.
Chem. Eur. J. 2010, 16, 12808 – 12813
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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12811

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C
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against
2,2’-azobis(2-amidinopropane)
hydrochloride
(AAPH)-induced peroxidation of linoleic acid in tert-butyl
alcohol/water (3:1, v/v) solution by measuring the oxygen
consumption (see the Supporting Information). Preliminary
studies showed that all of the hybrids almost completely in-
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hausted, and were more effective chain-breaking antioxi-
dants than the parent molecules in the above experimental
system (see the Supporting Information). Further investiga-
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antioxidant activities in biological systems, cytotoxic and
apoptosis-inducing activities against cancer cells, are cur-
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Acknowledgements
This work was supported by the National Natural Science Foundation of
China (Grant No. 20972063), the 111 Project, and Program for New Cen-
tury Excellent Talents in University (NCET-06-0906).
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Received: July 17, 2010
Published online: October 7, 2010
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