Synthesis and antioxidant evaluation of (S,S)- and (R,R)- secoisolariciresinol diglucosides (SDGs)

Article abstract of DOI:10.1016/j.bmcl.2013.07.062

Secoisolariciresinol diglucosides (SDGs) (S,S)-SDG-1 (major isomer in flaxseed) and (R,R)-SDG-2 (minor isomer in flaxseed) were synthesized from vanillin via secoisolariciresinol (6) and glucosyl donor 7 through a concise route that involved chromatographic separation of diastereomeric diglucoside derivatives (S,S)-8 and (R,R)-9. Synthetic (S,S)-SDG-1 and (R,R)-SDG-2 exhibited potent antioxidant properties (EC₅₀ = 292.17 ± 27.71 μM and 331.94 ± 21.21 μM, respectively), which compared well with that of natural (S,S)-SDG-1 (EC₅₀ = 275.24 ± 13.15 μM). These values are significantly lower than those of ascorbic acid (EC₅₀ = 1129.32 ± 88.79 μM) and α-tocopherol (EC₅₀ = 944.62 ± 148.00 μM). Compounds (S,S)-SDG-1 and (R,R)-SDG-2 also demonstrated powerful scavenging activities against hydroxyl [natural (S,S)-SDG-1: 3.68 ± 0.27; synthetic (S,S)-SDG-1: 2.09 ± 0.16; synthetic (R,R)-SDG-2: 1.96 ± 0.27], peroxyl [natural (S,S)-SDG-1: 2.55 ± 0.11; synthetic (S,S)-SDG-1: 2.20 ± 0.10; synthetic (R,R)-SDG-2: 3.03 ± 0.04] and DPPH [natural (S,S)-SDG-1: EC₅₀ = 83.94 ± 2.80 μM; synthetic (S,S)-SDG-1: EC₅₀ = 157.54 ± 21.30 μM; synthetic (R,R)-SDG-2: EC₅₀ = 123.63 ± 8.67 μM] radicals. These results confirm previous studies with naturally occurring (S,S)-SDG-1 and establish both (S,S)-SDG-1 and (R,R)-SDG-2 as potent antioxidants and free radical scavengers for potential in vivo use.

Full text of DOI:10.1016/j.bmcl.2013.07.062

Bioorganic & Medicinal Chemistry Letters 23 (2013) 5325–5328
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antioxidant evaluation of (S,S)- and
(R,R)-secoisolariciresinol diglucosides (SDGs)
Om P. Mishra a, , Nicholas Simmons b, , Sonia Tyagi a, Ralph Pietrofesa a, Vladimir V. Shuvaev c,
Roman A. Valiulin b, Philipp Heretsch b,e, K. C. Nicolaou b,d,e, , Melpo Christofidou-Solomidou a,
⇑
⇑
a Department of Medicine, Pulmonary Allergy and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
b Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
c Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
d Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA
e Department of Chemistry, BioScience Research Collaborative, Rice University, Houston, TX 77005, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Secoisolariciresinol diglucosides (SDGs) (S,S)-SDG-1 (major isomer in flaxseed) and (R,R)-SDG-2 (minor
isomer in flaxseed) were synthesized from vanillin via secoisolariciresinol (6) and glucosyl donor 7
through a concise route that involved chromatographic separation of diastereomeric diglucoside deriva-
tives (S,S)-8 and (R,R)-9. Synthetic (S,S)-SDG-1 and (R,R)-SDG-2 exhibited potent antioxidant properties
Received 4 June 2013
Revised 23 July 2013
Accepted 25 July 2013
Available online 2 August 2013
(EC50 = 292.17 27.71
natural (S,S)-SDG-1 (EC50 = 275.24 13.15
bic acid (EC50 = 1129.32 88.79 M) and
l
M and 331.94 21.21
M). These values are significantly lower than those of ascor-
-tocopherol (EC50 = 944.62 148.00 M). Compounds (S,S)-
lM, respectively), which compared well with that of
l
a
Keywords:
Antioxidant
SDG
Free radical scavenger
Flaxseed lignans
ROS
l
l
SDG-1 and (R,R)-SDG-2 also demonstrated powerful scavenging activities against hydroxyl [natural
(S,S)-SDG-1: 3.68 0.27; synthetic (S,S)-SDG-1: 2.09 0.16; synthetic (R,R)-SDG-2: 1.96 0.27], peroxyl
[natural (S,S)-SDG-1: 2.55 0.11; synthetic (S,S)-SDG-1: 2.20 0.10; synthetic (R,R)-SDG-2: 3.03 0.04]
and DPPH [natural (S,S)-SDG-1: EC50 = 83.94 2.80
lM; synthetic (S,S)-SDG-1: EC50 = 157.54 21.30
l
M; synthetic (R,R)-SDG-2: EC50 = 123.63 8.67 M] radicals. These results confirm previous studies
l
with naturally occurring (S,S)-SDG-1 and establish both (S,S)-SDG-1 and (R,R)-SDG-2 as potent antioxi-
dants and free radical scavengers for potential in vivo use.
Ó 2013 Elsevier Ltd. All rights reserved.
Secoisolariciresinol diglucoside [SDG, (S,S)-SDG-1] is a major
component of the lignans in flaxseed (Fig. 1).1 Previous studies
have shown that flaxseed (S,S)-SDG-1 is a potent antioxidant
in vitro and in vivo,2–6 and a powerful in vitro scavenging agent
against hydroxyl free radicals.7 Increased generation of reactive
oxygen species (ROS) such as superoxide anion (O2ꢀ), hydroxyl
radical (ꢁOH), and hydrogen peroxide leads to tissue damage under
various pathological conditions.8–10 These species result in cellular
damage through oxidative modification of cellular membrane lip-
ids, proteins, and the genomic DNA.11 Therefore, SDG as an antiox-
idant may have therapeutic potential under various experimental
and disease conditions that are associated with oxidative tissue
damage, such as in cancer patients undergoing radiotherapy.
Ionizing radiation inflicts damage to biological systems through
generation of reactive oxygen and nitrogen species (e.g., peroxida-
tion of membrane lipids, oxidation and nitration of proteins, DNA
and RNA strand breaks).12 Antioxidant compounds that scavenge
free radicals, enhance endogenous antioxidant enzyme levels,
and boost DNA repair may be useful in countering radiation dam-
age. Despite extensive research efforts toward the development of
synthetic compounds as radioprotectors, there is still a need for
safe and more effective agents. In view of their properties, natural
products and their analogs are increasingly considered as promis-
ing leads for the discovery and development of radioprotectors.
Plants contain a plethora of secondary metabolites with wide-
ranging pharmacological properties. Phenolic acids, flavonoids,
and phenylpropanoids are the most prominent metabolite classes
known for antioxidant activity.13 Dietary and medicinal plants pos-
sessing antioxidant properties have been shown to play an impor-
tant role in preventing many human diseases associated with
oxidative stress.14,15
In previous studies, we have investigated the role of whole
grain dietary flaxseed in radiation-induced damage.16–18 Flaxseed
ameliorated the radiation-induced inflammation and oxidative
stress in mice, and irradiated mice fed with flaxseed diets enriched
with (S,S)-SDG-1 showed improved hemodynamic indices and
survival over the control. Importantly, a flaxseed diet enriched in
⇑
Corresponding authors. Tel.: +1 713 348 8860 (K.C.N.), Tel.: +1 215 573 9917;
fax: +1 215 573 4469 (M.C.).
E-mail addresses: kcn@rice.edu (K.C. Nicolaou), melpo@mail.med.upenn.edu
(M. Christofidou-Solomidou).
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.07.062

5326
O. P. Mishra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5325–5328
OH
OH
condensation19 has been used to prepare racemic secoisolaricires-
inol, and enantioenriched secoisolariciresinols have been prepared
from aldol reactions on chiral
-butyrolactones20 as well as diaste-
reoselective alkylation of Evans auxiliary appended hydroferulic
acid derivatives.21 In a recent report the synthesis of (S,S)-SDG-1
was claimed.3
The synthesis of secoisolariciresinol diglucosides (S,S)-SDG-1
and (R,R)-SDG-2 proceeded from vanillin (3) as shown in Figure 2.
Thus, following a modified literature procedure,19 3 was subjected
to Stobbe condensation with dimethyl succinate in the presence of
lithium wire in refluxing methanol, and the resulting mixture of
carboxylic acids was esterified with methanol under acidic condi-
tions to furnish dimethyl ester 4 in 70% overall yield (single isomer,
OH
OH
OH
OH
O
O
c
O
O
MeO
HO
OH
O
MeO
HO
OH
O
(R)
(S)
(R)
(S)
OH
OH
OH
O
O
(S,S)-SDG-1
(R,R)-SDG-2
OH
MeO
HO
MeO
HO
OH
OH
OH
OH
Figure 1. Molecular structures of secoisolariciresinol diglucosides (S,S)-SDG-1 and
(R,R)-SDG-2.
unassigned olefin geometry).
A second Stobbe condensation
involving product 4 with vanillin under the same lithium-medi-
ated conditions, followed by esterification with methanol under
the same acidic conditions, led to diene 5 in 61% overall yield (sin-
gle isomer, unassigned olefin geometry). The latter compound
underwent diastereoselective hydrogenation (Pd/C, H2, 84% yield),
phenolic benzylation (NaH, BnBr, 95% yield), and ester reduction
(LiAlH4, 93% yield) to provide bis-benzyl secoisolariciresinol 6.
The relative stereochemistry of 6 was confirmed by X-ray crystal-
lographic analysis (see Fig. 3 for ORTEP representation). Attempts
to attach the glucose moieties onto 6 employing peracetyl-pro-
tected glucosyl donors led predominately to acetylation of the pri-
mary hydroxyl groups of the substrate. The glycosidation of 6 was
finally achieved through the use of the perbenzoyl-protected tri-
chloroacetimidate 722 under the influence of TMSOTf, furnishing
a diastereomeric mixture of inseparable bis-b-glucosides (88%
combined yield, 1:1 dr). Cleavage of the benzyl ethers by hydrog-
enolysis provided a mixture of diastereomeric bis-phenols (86%
yield, 1:1 dr) which proved separable by preparative thin layer
chromatography (PTLC, multiple elutions) to afford pure (S,S)-8
and (R,R)-9. Each perbenzoylated bis-glucoside was treated with
NaOMe in MeOH to give the corresponding secoisolariciresinol dig-
lucoside (S,S)-SDG-1 (88% yield) and (R,R)-SDG-2 (81% yield),
whose spectral data matched those previously reported for these
compounds.23
As antioxidants, polyphenols and other lignan components have
been reported to modulate the activity and expression of enzymes
involved in reactive oxygen species detoxification, quench free
Figure 2. Synthesis of secoisolariciresinol diglucosides (S,S)-SDG-1 and (R,R)-SDG-
2. For details see Supplementary data.
(S,S)-SDG-1 also improved polymorphonuclear cell infiltration and
decreased lung inflammation, demonstrating its protective effects
against radiation-induced lung damage in vivo.
Secoisolariciresinol (the aglycon of (S,S)-SDG-1 and (R,R)-SDG-
2) has been of interest to several synthetic groups. A double Stobbe
Figure 3. ORTEP representation of dihydroxy compound 6 (CCDC-940963).

O. P. Mishra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5325–5328
5327
radicals, and chelate transition metals, resulting in complexes
which are redox inactive in the Fenton reaction.24 Since such a
compound may have diverse antioxidant properties, we chose to
evaluate our synthetic agents using various assays.25 In light of
these observations, we proceeded to evaluate the reducing power
of synthesized (S,S)-SDG-1 and (R,R)-SDG-2 as well as their free
radical scavenging activity against hydroxyl, peroxyl, and DPPH
free radicals.
substrate concentration was observed at lower concentrations
(1–100 M), allowing regression line equations to be established
for the five compounds. This allowed the half maximal effective
concentration (EC50) for reducing power to be calculated (Fig. 5).
The EC50 (mean std. dev.) values for (S,S)-SDG-1 and (R,R)-SDG-
l
2 were 292.17 27.71
These values were comparable to that of natural (S,S)-SDG-1
(EC50 = 275.24 13.15 M) but approximately threefold higher
than that exhibited by ascorbic acid (EC50 = 1129.32 88.79 M)
and -tocopherol (EC50 = 944.62 148.00 M).
lM and 331.94 21.21 lM, respectively.
l
The reducing power of synthetic (S,S)-SDG-1, synthetic (R,R)-
l
SDG-2, natural (S,S)-SDG-1, ascorbic acid, and
a
-tocopherol was
a
l
determined by the reduction of K3FeCN6 in the presence of FeCl3,
as measured by the absorbance of the resulting ferric-ferrous com-
plex (Fig. 4).26 The reducing power of synthetic (S,S)-SDG-1, syn-
thetic (R,R)-SDG-2, and natural (S,S)-SDG-1 was significantly
concentration-dependent at higher concentrations; however, at
all concentrations tested, the SDGs had comparable or higher
reducing power than known antioxidants ascorbic acid and
The ability of synthetic (S,S)-SDG-1 and (R,R)-SDG-2 to scavenge
hydroxyl and peroxyl radicals as manifested by their inhibition of
the oxidation of fluorescein was assessed by the Hydroxyl Radical
Antioxidant Capacity (HORAC, gallic acid standard) and Oxygen
Radical Antioxidant Capacity assays (ORAC, Trolox standard),
respectively (Table 1). Fluorescein oxidation by hydroxyl radicals
was decreased by synthetic (S,S)-SDG-1 and synthetic (R,R)-SDG-
2 in a concentration-dependent manner and was found to be two-
fold higher than gallic acid. However, synthetic (S,S)-SDG-1 activity
differed from natural (S,S)-SDG-1, likely due to trace impurities.
Fluorescein oxidation by peroxyl radicals generated using 2,20-azo-
bis(2-amidinopropane) dihydrochloride (AAPH) was greatly re-
duced in the presence of synthetic (S,S)-SDG-1, (R,R)-SDG-2 and
natural (S,S)-SDG-1, with a twofold increase in potency over the
Trolox standard (Table 1).
a-tocopherol, with a notable increase in potency in the 200–
500 M range. A linear relationship between reducing power and
l
1.40
1.20
1.00
0.80
0.60
0.40
0.20
0.00
natural (S,S)-SDG-1
synthetic (R,R)-SDG-2
synthetic (S,S)-SDG-1
ascorbic acid
**
**
The free radical scavenging activities of synthetic (S,S)-SDG-1
and (R,R)-SDG-2 were determined using a 2,2-diphenyl-1-pic-
rylhydrazyl (DPPH) free radical scavenging assay and were
compared to those of natural (S,S)-SDG-1, ascorbic acid, and
α-tocopherol
*
*
a
-tocopherol (Fig. 6). At low (5–25
(50–100 M) ranges, the SDGs exhibited similar scavenging poten-
tials; however, at higher concentrations (250–500 M), the inhibi-
lM) and mid-concentration
*
*
l
*
*
*
*
*
*
l
tion by synthetic (S,S)-SDG-1 was significantly lower than those
exerted by (R,R)-SDG-2 and natural (S,S)-SDG-1. Establishing
regression lines for the potentials at low- and mid-concentration
0
1
25
50
100
250
500
Concentration (µM)
ranges (5–100
of these compounds to be determined. As shown in Figure 7, syn-
thetic (R,R)-SDG-2 (123.63 8.67 M) and synthetic (S,S)-SDG-1
(157.54 21.30 M) were not significantly different. These values
were similar to those exhibited by natural (S,S)-SDG-1 (83.94
2.80 M) and -tocopherol (132.81 12.57 M) but considerably
M). These
lM) allowed the free radical EC50 scavenging activity
Figure 4. Reducing power of synthetic (S,S)-SDG-1 and (R,R)-SDG-2. The increase in
absorbance at 700 nm indicates increase in reducing power. The results are
presented as mean standard deviation (n = 3). ⁄p <0.05 significantly lower than
natural (S,S)-SDG-1, synthetic (R,R)-SDG-2, and synthetic (S,S)-SDG-1; ⁄⁄p <0.05
significantly higher than synthetic (R,R)-SDG-2, synthetic (S,S)-SDG-1, ascorbic acid
and a-tocopherol. The somewhat higher potency of natural (S,S)-SDG-1 may be due
to an unknown impurity in our samples, however the NMR spectra of both natural
and synthetic (S,S)-SDG-1 did not reveal major impurities.
l
l
l
a
l
lower than that shown by ascorbic acid (439.56 11.81
l
results are comparable to those recently reported for SDG.3
In summary, we have synthesized (S,S)-SDG-1 and (R,R)-SDG-2
and characterized their antioxidant properties. Both possess strong
reducing power and high free radical scavenging activity for hydro-
1400
*
1200
*
1000
800
600
400
200
0
Table 1
Antioxidant capacity of synthetic and natural SDGs
Entry
Antioxidant
Against hydroxyla
radicals (GAE)c
Against peroxylb
radicals (TE)d
1
2
3
Natural (S,S)-SDG-1
Synthetic (R,R)-SDG-2
Synthetic (S,S)-SDG-1
3.68 0.27
1.96 0.27
2.09 0.16
2.55 0.11
2.20 0.10
3.03 0.04
Antioxidant capacity of synthetic (S,S)-SDG-1 and (R,R)-SDG-2. Hydroxyl radicals
were generated from hydrogen peroxide by Fenton reaction. Peroxyl radicals were
generated by AAPH (2,20-azobis(2-amidinopropane) dihydrochloride). Oxidation of
fluorescein was measured. Calculations used SDG concentrations that fitted the
linear part of the calibration curve. The results are presented as mean standard
deviation (n = 3). The somewhat higher potency of natural (S,S)-SDG-1 may be due
to an unknown impurity in our samples, however the NMR spectra of both natural
and synthetic (S,S)-SDG-1 did not reveal impurities.
Figure 5. Reducing power of synthetic (S,S)-SDG-1 and (R,R)-SDG-2. The rate of
reaction is linear in the concentration range of 1ꢀ100
lM. Equation of the linear
a
Determined by HORAC assay.
Determined by ORAC assay.
Gallic acid equivalents.
regression was used to determine EC50. The results are presented as mean stan-
dard deviation (n = 3). Natural (S,S)-SDG-1, synthetic (R,R)-SDG-2, and synthetic
(S,S)-SDG-1 were not significantly different from each other. ⁄p <0.05 significantly
higher than natural (S,S)-SDG-1, synthetic (R,R)-SDG-2, and synthetic (S,S)-SDG-1.
b
c
d
Trolox equivalents.

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O. P. Mishra et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5325–5328
Acknowledgments
natural (S,S)-SDG-1
synthetic (R,R)-SDG-2
synthetic (S,S)-SDG-1
ascorbic acid
90
80
70
60
50
40
30
20
10
0
We thank Drs. D.H. Huang, L. Pasternack, and R. Chadha for
NMR spectroscopic and X-ray crystallographic assistance. This
work was funded in part by The Skaggs Institute for Research,
the National Science Foundation (graduate fellowship to N.S.),
Merck (postdoctoral fellowship to R.A.V.), the Deutsche Akademie
der Naturforscher Leopoldina (postdoctoral fellowship to P.H.),
NIH-R01 CA133470 (M.C.S.), NIH-RC1AI081251 (M.C.S.), the Uni-
versity of Pennsylvania Research Foundation (M.C.S.) and by pilot
project support from 1P30 ES013508-02 awarded to M.C.S. (its
contents are solely the responsibility of the authors and do not
necessarily represent the official views of the NIEHS, NIH).
α-tocopherol
*
*
**
**
**
*
**
*
*
Supplementary data
5
10
25
50
100
250
500
Concentration (µM)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.07.
062.
Figure 6. DPPH free radical scavenging activity of natural (S,S)-SDG-1, synthetic
(S,S)-SDG-1 and (R,R)-SDG-2, ascorbic acid, and -tocopherol. The radical scaveng-
a
ing activity was measured as a decrease in the absorbance of DPPH at 517 nm. The
results are presented as mean standard deviation (n = 3). ⁄p <0.05 significantly
lower than all other compounds, ⁄⁄p <0.05 significantly lower than natural (S,S)-
SDG-1.
References and notes
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Figure 7. DPPH free radical scavenging activity of natural (S,S)-SDG-1, synthetic
(S,S)-SDG-1 and (R,R)-SDG-2, ascorbic acid, and
regression was used to determine EC50 The rate of reaction is linear in the
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and
-tocopherol were not significantly different. ⁄p <0.05 significantly higher than
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a-tocopherol. Equation of the linear
.
l
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xyl, peroxyl and DPPH free radicals. Synthetic (S,S)-SDG-1 and
(R,R)-SDG-2 have been shown to be promising agents for use in
modulating cellular redox states and for scavenging oxygen free
radicals in vivo. Efforts are currently underway to develop scalable
synthetic routes to (S,S)-SDG-1, (R,R)-SDG-2 and related analogs.
Further in vitro and in vivo studies to determine the mechanism
of action and usefulness of the SDGs as antioxidants and protectors
against radiation-induced tissue damage are in progress.