Efficient synthesis of 6-o-methyl-scutellarein from scutellarin via selective methylation

Article abstract of DOI:10.2174/15701786113109990046

Scutellarin (1) possesses distinguished efficacy in the clinical therapy of cerebral infarction, coronary heart disease, and angina pectoris. Scutellarin (1) is readily converted in vivo, therefore, synthetic methods for the construction of its metabolite

Full text of DOI:10.2174/15701786113109990046

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Letters in Organic Chemistry, 2013, 10, 733-737
733
Efficient Synthesis of 6-O-methyl-scutellarein from Scutellarin via
Selective Methylation
Min-Zhe Shen†,a,b, Zhi-Hao Shi†,a,c, Nian-Guang Lia,b*, Hao-Tanga,b, Qian-Ping Shia,b, Yu-Ping
Tanga*, Jian-Ping Yanga and Jin-Ao Duana*
aJiangsu Key Laboratory for High Technology of TCM Formulae Research, Nanjing University of Chinese Medicine, 138 Xian-
lin Road, Nanjing, Jiangsu 210023, P.R. China; bDepartment of Medicinal Chemistry, Nanjing University of Chinese Medicine,
c
Nanjing, Jiangsu 210023, P.R. China; Department of Organic Chemistry, China Pharmaceutical University, Nanjing, Jiangsu
211198, P.R. China
Received March 23, 2013: Revised July 22, 2013: Accepted August 07, 2013
Abstract: Scutellarin (1) possesses distinguished efficacy in the clinical therapy of cerebral infarction, coronary heart dis-
ease, and angina pectoris. Scutellarin (1) is readily converted in vivo, therefore, synthetic methods for the construction of
its metabolites will be very important in the near future. In this work, an efficient and first synthetic method for 6-O-
methyl-scutellarein (3), one metabolite of scutellarin in vivo, is developed. Dichlorodiphenylmethane in diphenyl ether is
used firstly to protect the dihydroxy groups at C-6 and C-7 in scutellarein (2). Then, benzyl bromide is used to selectively
protect the hydroxy groups at C-4' and C-7 in 10. 6-O-Methyl-scutellarein (3) is obtained in high yield through seven
steps.
Keywords: 6-O-methyl-scutellarein, metabolite, scutellarin, synthesis, regioselective protection.
1. INTRODUCTION
most common route in clinical application. Nonetheless,
therapeutic effects elicited by breviscapine require repeated
injection daily for a long time.
Ischemic cerebrovascular disease, a common and fre-
quently-occurring disease, seriously endangers human
health, and it has been one of the leading causes of death and
disability worldwide [1]. Scutellarin (1) (Fig. 1), which is the
main effective constituent (>85%) of a natural drug brevis-
capine consisting of total flavonoids of Erigeron breviscapus
(Vant.) Hand-Mazz. (Compositae), has been used for the
treatment of cerebral infarction, coronary heart disease, and
angina pectoris with a large market share in China [2].
Pharmacological studies have demonstrated that scutellarin
(1) is associated with a wide range of benefits to brain injury
caused by cerebral ischemia/reperfusion, these benefits are
due to its antioxidant and anticoagulant activities to attenuate
neuronal damage [3-5].
Pharmacokinetic studies on scutellarin (1) in rats [6-8],
dogs [9] and humans [10] showed that the oral bioavailabil-
ity of scutellarin (1) was very poor [11]. One reason was its
poor aqueous solubility and low lipophilicity [12]. Its poor
ability to penetrate cell membranes has long been a major
impediment to its overall effectiveness as an oral drug. The
other reason was that scutellarin (1) is readily converted into
scutellarein (2) (Fig. 1) before absorption in vivo. Scutel-
larein (2) is relatively easily absorbed into the blood and can
metabolite into glucuronidated, sulfated or methylated forms
[13]. Due to the low bioavailability after oral administration,
direct administration of scutellarin (1) by injection is the
In order to improve the bioavailability of scutellarin, our
group has synthesized many scutellarin derivatives [14-16],
some compounds demonstrated stronger anticoagulant activ-
ity, better water solubility and good antioxidant activity
compared with scutellarein. However, very few studies have
focused on 6-O-methyl-scutellarein (3) (Fig. 1), despite the
fact that it was the one of the circulating metabolites of
scutellarin in vivo and might be responsible for the therapeu-
tic effects. This interesting scutellarin metabolite is not
commercially available, as a result, synthetic methods will
be very important for the preparation of large amount in or-
der to further study its bioactivity. Because 6-O-methyl-
scutellarein (3) was a metabolite in vivo, so the biosynthetic
means such as liver microsomal preparation can be used
[17,18], but this is not convenient and efficient for the prepa-
ration of large quantities [19].
In this work dichlorodiphenylmethane in diphenyl ether
is used firstly to protect the dihydroxy groups at C-6 and C-7
in scutellarein (2). Then, benzyl bromide is used to selec-
tively protect the hydroxy groups at C-4' and C-7 in 10, 6-O-
methyl-scutellarein (3) is obtained in high yield through
seven steps.
2. RESULTS AND DISCUSSION
Firstly, our aim was to synthesize 6-O-methyl-
scutellarein (3) based on the different reactive activity of
hydroxyl groups in the preferential order 7 > 4ꢀ > 6 > 5
[19] in the scutellarein (2) skeleton as shown in Scheme 1.
*Address correspondence to these authors at Jiangsu Key Laboratory for
High Technology of TCM Formulae Research, Nanjing University of Chi-
nese Medicine, Nanjing 210023, P.R. China; Tel & Fax: +86-(0)25-
85811916; E-mails: linianguang@ njutcm.edu.cn,
yupingtang@njutcm.edu.cn and dja@njutcm.edu.cn
†Co-first authors.
1875-6255/13 $58.00+.00
© 2013 Bentham Science Publishers

734 Letters in Organic Chemistry, 2013, Vol. 10, No. 10
Shen et al.
3'
6'
OH
OH
OH
OH
2'
O
4'
1
O
8
O
HO
HO
O
O
O
HO
HO
O
O
HO
5'
7
OH
3
HO
H3CO
6
5
OH
OH
OH
O
Scutellarein (2)
3
Scutellarin (1)
Fig. (1). Chemical structures of scutellarin (1), scutellarein (2) and 6-O-methyl-scutellarein (3).
OH
OH
OH
O
O
HO
HO
O
O
O
HO
HO
O
O
i
ii
OH
HO
OH
OH
2
1
OMOM
+
OH
MOMO
O
O
MOMO
HO
O
HO
OH
OH
O
4
5
OMOM
OH
MOMO
H3CO
O
O
HO
O
O
H3CO
OH
OH
3
6
Scheme 1. Reagents and conditions: (i) HCl, EtOH, N2, reflux, 36h, 17%; (ii) MOMCl (3.5 equiv), K2CO3 (3.0 equiv), acetone, reflux, 4h,
45% for 4, 30% for 5.
According to our previous method [14, 15], the scutellarein
(2) was obtained from the hydrolysis of scutellarin (1) by
refluxing it with 6N HCl in 90% ethanol under N2 protection.
There are four hydroxyl groups in the flavone skeleton, how-
ever, the reactive activity of these four hydroxyl groups were
different, and the most reactive hydroxyl group were at C-7
and C-4' [19]. So we decided to use the chloromethyl ether to
protect the hydroxyl groups at C-7 and C-4' in scutellarein
(2), and the treatment of 2 with 3.5 equiv. of chloromethyl
ether in the presence of K2CO3 afforded two products 4 and
5. The location of MOM groups in these two compounds
was confirmed by H NMR and ROESY. The H NMR sig-
nal (in DMSO-d6) at ꢀ 12.76 of 4 suggested that 5-OH re-
mained unchanged. A cross-peak observed in the ROESY
spectrum of 4 between 5.35 (-OCH2) with 6.69 (8-H) indi-
cated that one of the two MOM groups was at C7, other
cross-peaks between 5.22 (-OCH2) with 7.05 (3ꢀ,5ꢀ-H) indi-
cated that the second MOM group was at C4'. 7-OMOM in 5
was also confirmed by ROESY cross-peak between 5.35
(-OCH2) with 6.66 (8-H). However, the polarity of these two
compounds was very close, and they were hardly separated
over silica gel column. Unfortunately, when we added more
or less equiv. of chloromethyl ether in this reaction, the yield
of 4 was not improved, furthermore, the tri-MOM substituted
and tetra-MOM substituted byproducts appeared with more
equiv. of chloromethyl ether, which increased the difficulty
of the separate purification of 4.
Then we turned our attention to the partial synthesis from
scutellarein (2) as shown in (Scheme 2), these reactions rely
on successive and selective protection of the different hy-
droxyl groups in scutellarein (2). Firstly, we employed the
method developed by us [20-22] and treated 2 with 1.5
equiv. of dichlorodiphenylmethane with diphenyl ether as
solvent at 175 °C, after only 30 min, the desired product 7
was obtained in 85% yield. Taken into the account that the
protecting groups of diphenylmethylene ketal and benzyl
groups could be removed by the different reactive condition,
1
1

An Efficient and First Synthesis of 6-O-methyl-scutellarein
Letters in Organic Chemistry, 2013, Vol. 10, No. 10 735
OCH2Ph
OH
OH
O
O
O
O
HO
HO
O
O
O
O
O
O
Ph
Ph
Ph
Ph
i
iii
ii
C
C
OH
OH
OH
7
8
2
OCH2Ph
OCH2Ph
v
OCH2Ph
OH
HO
HO
O
O
PhH2CO
HO
O
O
PhH2CO
H3CO
O
O
HO
H3CO
O
iv
vi
OH
OH
10
OH
11
OH
O
9
3
Scheme 2. Reagents and conditions: (i) a) Ph2CCl2 (1.5 equiv.), Ph2O, 175 °C, 30min, 85%; (ii) PhCH2Br (1.5 equiv), K2CO3 (1.75 equiv),
DMF, 25 °C, 12h, 93%; (iii) HAc: H2O (4:1), reflux, 1.5h, 95%; (iv) PhCH2Br (1.3 equiv), K2CO3 (1.5 equiv), DMF, 25 °C, 12h, 93%; (v)
CH3I (1.2 equiv), K2CO3 (1.4 equiv), DMF, 25 °C, 6h, 94%; (vi) Pd/C (10 wt%), H2 (1 atm), THF/EtOH, 8h, 96%.
tions were transferred via syringe or stainless steel cannula.
Organic solutions were concentrated by rotary evaporation
below 45 °C at approximately 20 mm Hg. All non-aqueous
reactions were carried out under anhydrous conditions using
flame-dried glassware in an argon atmosphere in dry, freshly
distilled solvents, unless otherwise noted. Yields refer to
chromatographically and spectroscopically (1H NMR) ho-
mogeneous materials, unless otherwise stated. Reactions
were monitored by thin-layer chromatography (TLC) carried
out on 0.15–0.20 mm Yantai silica gel plates (RSGF 254)
using UV light as the visualizing agent. Chromatography
was performed on Qingdao silica gel (160–200 mesh) with
petroleum ether (60–90) and ethyl acetate mixtures as eluant.
1H NMR spectra were obtained with a Bruker AV-300 (300
MHz). Chemical shifts are recorded in ppm downfield from
tetramethylsilane. J values are given in Hz. Abbreviations
used are s (singlet), d (doublet), t (triplet), q (quartet), b
(broad) and m (multiplet). ESI-MS spectra were recorded on
a Waters Synapt HDMS spectrometer.
we used 1.5 equiv. benzyl bromide to selectively protect the
hydroxyl group at C-4' in compound 7 in the presence of
K2CO3 afforded 8. From compound 8, we focused on the
selection of the deprotection conditions of diphenylmethyl-
ene ketal, there are two available different methods for the
cleavage of this protecting group: hydrogenolysis or hy-
drolysis. Fortunately, under hydrolysis conditions the
diphenylmethylene ketal was deprotected with HAc in H2O
to give 9 in 95% yield and no side product was detected by
TLC analysis. Selective benzylation of 9 with benzyl bro-
mide and K2CO3 in DMF led to the di-benzyl ether substi-
tuted product 10. The ROESY cross-peak between 5.03 (-
OCH2Ph) with 6.87 (8-H) indicated that one of the two ben-
zyl group was at C7. The ROESY cross-peak between 5.23
(-OCH2Ph) with 7.18 (3ꢁ,5ꢁ-H) indicated that the other benzyl
group was at C4'. Treatment of 10 with 1.2 equiv. of io-
domethane [19] led selectively to 11 with the desired 6-OH
methylated product in 94% yield. Then the deprotection of
di-benzyl groups under hydrogenation conditions using 10%
palladium on carbon as the catalyst in THF/EtOH afforded 3
in 96% yield.
5,6,7-Trihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-
one (2)
3. CONCLUSION
To a stirring mixture of 1 (10.0 g, 20.6 mmol) and con-
centrated hydrochloric acid (120 mL) in ethanol (120 mL)
was added water (10 mL), the reaction mixture was refluxed
under a N2 atmosphere for 36 h. After cooled down to the
room temperature, the mixture was poured into water. The
solid obtained was filtered followed by silica gel column
chromatographic purification of the residue using 50% ethyl
acetate in petroleum ether afforded the compound 2 in 17.0%
In conclusion, we have firstly succeeded in synthesizing
6-O-methyl-scutellarein (3) from scutellarin (1). Our strategy
relies on the selective protection of the catechol group with
dichlorodiphenylmethane using diphenyl ether as a solvent,
and on the selective protection of the different hydroxyl
groups at C-4' and C-7 with benzyl bromide. This efficient
method could be applied to the selective synthesis of other
O-methylflavonoids as well as the other flavonoid sulfate-
and glucuronide-metabolites. These metabolites will assist
the research on the structure activity relationship studies of
flavonoids, and their easily obtained labeled form will give
access to isotopic dilution dosage by LC–MS, and so will
help in the identification of unknown flavonoid metabolites.
1
yield as yellow solid. H NMR (DMSO-d6, 300 MHz) ꢀ
12.78 (s, 1H, 5-OH), 10.44 (s, 1H, 4'-OH), 10.29 (s, 1H, 7-
OH), 8.71 (s, 1H, 6-OH), 7.90 (d, J = 8.8 Hz, 2H, 2',6'-H),
6.91 (d, J = 8.8 Hz, 2H, 3',5'-H), 6.74 (s, 1H, 3-H), 6.57 (s,
1H, 8-H); ESI-MS: m/z 287 [M+H]+.
Synthesis of di-MOM Substituted Product 4 and mono-
MOM Substituted Product 5
4. EXPERIMENTAL SECTION
To a stirring mixture of 2 (2 g, 7 mmol) and K2CO3 (2.90
g, 21 mmol, 3 equiv) in dry acetone at room temperature was
added chloromethyl ether (1.86 mL, 24.5 mmol, 3.5 equiv),
Reagents and solvents were purchased from commercial
sources and used without further purification unless other-
wise specified. Air- and moisture-sensitive liquids and solu-

736 Letters in Organic Chemistry, 2013, Vol. 10, No. 10
Shen et al.
the reaction mixture was refluxed gently for 4 h. After cool-
ing to room temperature, the reaction mixture was filtered.
Removal of the solvent in vacuo followed by purification by
column chromatography on silica gel of the residue with
20% ethyl acetate in petroleum ether afforded 4 (1.14g, 45%)
and 5 (693mg, 30%) as yellow solids.
2-(4-(Benzyloxy)phenyl)-5,6,7-trihydroxy-4H-chromen-4-
one (9)
The solid 8 (150 mg, 0.28 mmol) was dissolved in 20 ml
of HOAc/H2O (4:1) solution and the reaction mixture was
refluxed under a N2 atmosphere for 1.5 h. After cooled down
to the room temperature, the mixture was poured into 100 ml
water, extracted with ethyl acetate (50 mlꢀ3), then the or-
ganic layer was washed with brine (100 ml), dried over
Na2SO4, filtered and concentrated. The crude material was
purified by column chromatography (25% ethyl acetate in
petroleum ether) to yield the 9 (100 mg, 95% yield) as a yel-
low solid. 1H NMR (300 MHz, DMSO-d6) ꢁ 12.69 (s, 1H, 5-
OH), 10.35 (s, 1H, 7-OH), 8.74 (s, 1H, 6-OH), 7.94 (d, 2H, J
= 8.7 Hz, 2ꢂ,6ꢂ-H), 7.51-7.54 (m, 2H, -Ph), 7.35-7.45 (m, 3H,
-Ph), 7.00 (s, 1H, 8-H), 6.92 (d, 2H, J = 8.7 Hz, 3ꢂ,5ꢂ-H),
6.81 (s, 1H, 3-H), 5.28 (s, 2H, -OCH2); ESI-MS: m/z 375
[M-H]-.
5,6-Dihydroxy-7-(methoxymethoxy)-2-(4-(methoxyme-
thoxy)phenyl)-4H-chromen-4-one (4)
1H NMR (300 MHz, DMSO-d6) ꢁ 12.76 (s, 1H, 5-OH),
8.01 (d, 2H, J = 8.6 Hz, 2ꢂ,6ꢂ-H), 7.05 (d, 2H, J = 8.6 Hz,
3ꢂ,5ꢂ-H), 6.69 (s, 1H, 8-H), 6.61 (s, 1H, 3-H), 5.35 (s, 2H, -
OCH2), 5.22 (s, 2H, -OCH2), 3.61 (s, 3H, -OCH3), 3.52 (s,
3H, -OCH3); ESI-MS: m/z 373 [M-H]-.
5,6-Dihydroxy-2-(4-hydroxyphenyl)-7-(methoxyme-
thoxy)-4H-chromen-4-one (5)
1H NMR (300 MHz, DMSO-d6) ꢁ 12.40 (s, 1H, 5-OH),
10.33 (s, 1H, 4ꢂ-OH), 8.02 (d, 2H, J = 8.6 Hz, 2ꢂ,6ꢂ-H), 7.04
(d, 2H, J = 8.6 Hz, 3ꢂ,5ꢂ-H), 6.66 (s, 1H, 8-H), 6.60 (s, 1H, 3-
H), 5.35 (s, 2H, -OCH2), 3.50 (s, 3H, -OCH3); ESI-MS: m/z
329 [M-H]-.
7-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-5,6-dihydroxy-
4H-chromen-4-one (10)
To a stirring solution of 9 (200 mgꢀ0.53 mmol) in dry
DMF (20 ml) was added K2CO3 (109 mg, 0.80 mmol, 1.5
equiv.) and benzyl bromide (0.08 mL, 0.68 mmol, 1.3
equiv.) at 0 °C, then the mixture was warmed to room tem-
perature. After 12 h, the reaction mixture was partitioned
between 100 ml ethyl acetate and 100 ml water. The ethyl
acetate layer was then washed with brine (100 ml), dried
over Na2SO4, filtered and concentrated. The crude material
was purified by column chromatography (25% ethyl acetate
in petroleum ether) to yield dibenzylether 10 (230 mg, 93%
9-Hydroxy-6-(4-hydroxyphenyl)-2,2-diphenyl-8H-[1,3]
dioxolo[4,5-g]chromen-8-one (7)
To a stirring mixture of scutellarein (2) (10 g, 35 mmol)
in diphenyl ether (200 ml) was added dichlorodiphen-
ylmethane (18 g, 52.5 mmol, 1.5 equiv), and the reaction
mixture was heated at 175 °C for 30 min. The mixture was
cooled to room temperature and petroleum ether (1000 ml)
was added to give a solid compound. Then the solid was
filtered and purified by column chromatography (25% ethyl
acetate in petroleum ether) to yield 7 (13.35 g, 85%) as a
yellow solid. 1H NMR (300 MHz, DMSO-d6) ꢁ 12.99 (s, 1H,
5-OH), 10.41 (s, 1H, 4ꢂ-OH), 7.94 (d, 2H, J = 8.7 Hz, 2ꢂ,6ꢂ-
H), 7.58-7.61 (m, 4H, -Ph), 7.47-7.50 (m, 6H, -Ph), 6.96 (d,
2H, J = 8.7 Hz, 3ꢂ,5ꢂ-H), 6.82 (s, 1H, 8-H), 6.69 (s, 1H, 3-H);
ESI-MS: m/z 449 [M-H]-.
1
yield) as yellow solids. H NMR (300 MHz, DMSO-d6) ꢁ
13.11 (s, 1H, 5-OH), 10.82 (s, 1H, 6-OH), 8.04 (d, 2H, J =
8.6 Hz, 2ꢂ,6ꢂ-H), 7.31-7.53 (m, 10H, -Ph), 7.18 (d, 2H, J =
8.6 Hz, 3ꢂ,5ꢂ-H), 6.87 (s, 1H, 8-H), 6.62 (s, 1H, 3-H), 5.23 (s,
2H, -OCH2), 5.03 (s, 2H, -OCH2); ESI-MS: m/z 465 [M-H]-.
7-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-5-hydroxy-6-me-
thoxy-4H-chromen-4-one (11)
To a stirring solution of 10 (84 mg, 0.18 mmol) in dry
DMF (20 ml) was added K2CO3 (48 mg, 0.35 mmol, 1.4
equiv.) and iodomethane (0.014 ml, 0.22 mmol, 1.2 equiv.)
at room temperature. After 12 h, the reaction mixture was
then partitioned between 100 ml ethyl acetate and 100 ml
water. The ethyl acetate layer was then washed with brine
(100 ml), dried over Na2SO4, filtered and concentrated. The
crude material was purified by column chromatography
(25% ethyl acetate in petroleum ether) to yield 11 (81 mg,
6-(4-(Benzyloxy)phenyl)-9-hydroxy-2,2-diphenyl-8H-[1,3]
dioxolo[4,5-g]chromen-8-one (8)
To a stirring solution of 7 (200 mg, 0.44 mmol) in DMF
(10 ml) was added K2CO3 (107 mg, 0.78 mmol, 1.75 equiv)
and benzyl bromide (0.078 ml, 0.66 mmol, 1.5 equiv). After
stirring at 0 °C for 2 h, the reaction mixture was allowed to
warm to room temperature and the stirring was maintained
for 12 h. Then the reaction mixture was partitioned between
100 ml ethyl acetate and 100 ml water, and the organic layer
was washed with brine (100 ml), dried over Na2SO4, filtered
and concentrated. The crude material was purified by column
chromatography (33% ethyl acetate in petroleum ether) to
yield the tribenzylether 8 (221 mg, 93% yield) as a yellow
solid. 1H NMR (300 MHz, DMSO-d6) ꢁ 13.10 (s, 1H, 5-OH),
10.40 (s, 1H, 4ꢂ-OH), 8.04 (d, 2H, J = 8.7 Hz, 2ꢂ,6ꢂ-H), 7.55-
7.61(m, 4H, -Ph), 7.32-7.48 (m, 11H, -Ph), 7.22 (d, 2H, J =
8.7 Hz, 3ꢂ,5ꢂ-H), 7.08 (s, 1H, 8-H), 6.95 (s, 1H, 3-H), 5.22 (s,
2H, -OCH2); ESI-MS: m/z 541 [M+H]+.
1
94% yield) as a yellow solid. H NMR (300 MHz, DMSO-
d6) ꢁ 12.69 (s, 1H, 5-OH), 7.94 (d, 2H, J = 8.6 Hz, 2ꢂ,6ꢂ-H),
7.44-7.54 (m, 4H, -Ph), 7.32-7.42 (m, 6H, -Ph), 7.00 (s, 1H,
8-H), 6.94 (d, 2H, J = 8.6 Hz, 3ꢂ,5ꢂ-H), 6.62 (s, 1H, 3-H),
5.28 (s, 2H, -OCH2), 4.95 (s, 2H, -OCH2), 4.00 (s, 3H, -
OCH3); ESI-MS: m/z 481 [M+H]+.
5,7-Dihydroxy-2-(4-hydroxyphenyl)-6-methoxy-4H-chro-
men-4-one (3)
To a solution of 11 (100 mg, 0.21 mmol) dissolved in
ethanol (10 ml) and THF (10 ml) was added 10% Pd/C (2
mg) with vigorous stirring. The reaction vessel was then

An Efficient and First Synthesis of 6-O-methyl-scutellarein
Letters in Organic Chemistry, 2013, Vol. 10, No. 10 737
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CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
This work was supported by National Natural Science
Foundation of China (No. 81001382, 81274058, 21302225),
the Program for New Century Excellent Talents by the Min-
istry of Education (NCET-12-0741), 333 High-level Talents
Training Project Funded by Jiangsu Province, Program by
the Fundamental Research Funds for the Central Universities
(JKQ2011001), National Key Technology R&D Program
(2008BAI51B01), Project Funded by the Priority Academic
Program Development of Jiangsu Higher Education Institu-
tions (ysxk-2010), and Construction Project for Jiangsu En-
gineering Center of Innovative Drug from Blood-
conditioning TCM Formulae.
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