Design, synthesis and vasodilative activity of tanshinone IIA derivatives

Article abstract of DOI:10.1016/j.bmcl.2012.05.014

A new series of tanshinone IIA (DIIA) derivatives were synthesized through the reaction of brominated tanshinone IIA (1-Br DIIA) and aromatic acids in the presence of K₂CO₃. Twenty compounds were synthesized, and all of them were novel. Vasodilative activities for synthesized compounds were valuated in vitro on the contractile response of vascular thoracic aorta smooth muscle from Wistar rats. The results showed that most compounds exhibited a concentration-dependent inhibition on the contractile response of norepinephrine. Four prepared compounds, 4, 5, 8 and 13 revealed relatively remarkable vasodilative activity.

Full text of DOI:10.1016/j.bmcl.2012.05.014

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5141–5143
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and vasodilative activity of tanshinone IIA derivatives
Yue-Feng Bi a,b, Zhen-Ji Wang a, Ruo-Fei Guan a, Yu-Ting Ye a, Yuan-Yuan Chen a, Yan-Bing Zhang a,b
,
Hong-Min Liu a,b, ,
⇑
a School of Pharmaceutical Science, Zhengzhou University, Ke Xue Da Dao 100, Zhengzhou 450001, PR China
b New Drug Research & Development Center, Zhengzhou University, Zhengzhou 450001, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of tanshinone IIA (DIIA) derivatives were synthesized through the reaction of brominated
tanshinone IIA (1-Br DIIA) and aromatic acids in the presence of K2CO3. Twenty compounds were synthe-
sized, and all of them were novel. Vasodilative activities for synthesized compounds were valuated
in vitro on the contractile response of vascular thoracic aorta smooth muscle from Wistar rats. The results
showed that most compounds exhibited a concentration-dependent inhibition on the contractile
response of norepinephrine. Four prepared compounds, 4, 5, 8 and 13 revealed relatively remarkable
vasodilative activity.
Received 8 April 2012
Revised 23 April 2012
Accepted 7 May 2012
Available online 16 June 2012
Keywords:
Tanshinone IIA
Synthesis
Ó 2012 Elsevier Ltd. All rights reserved.
Vasodilative activity
Danshen, the root of Salvia miltiorrhiza, is one of the commonly
used traditional Chinese medicines which has a definite effect on
cardiovascular and cerebrovascular diseases.1–4 It has been re-
ported that the relaxation by danshen in rat aorta ring is endothe-
lium dependent and is possibly mediated by the nitric oxide-
guanylyl cyclase pathway.5–7 DIIA (Fig. 1) is one of the major li-
pid-soluble components extracted from danshen which shows
the significant effects in cardiovascular system, antiarrhythmic
activity, vasodilation and cardi protection, etc.8,9 But there were
few reports about the vasodilative activity of vascular thoracic aor-
ta smooth muscle of DIIA derivatives.
To improve the polarity and activity of DIIA, a series of re-
searches were carried out in our laboratory. In our previous work,
DIIA derivatives were synthesized through the reaction of DIIA
with aromatic aldehyde in the presence of p-TsOH, their vasodila-
tive activities were investigated in vitro and the results showed the
synthetic products exhibited good activities.10 In this study, DIIA
derivatives were synthesized by the reactions of 1-Br DIIA with
some aromatic acids for the first time. Twenty compounds were
synthesized, and all of them were novel. Their vasodilative activi-
ties were investigated on thoracic aorta rings of rats in vitro. The
results showed that most compounds exhibited a concentration-
dependent inhibition on the contractile response of norepineph-
rine. Four prepared compounds, 4, 5, 8 and 13 revealed relatively
remarkable vasodilative activity.
1-Br DIIA was synthesized by the free radical reaction of DIIA
and NBS in the presence of BPO (Scheme 1).11,12 In the 1H NMR
spectra,13 the shift of two hydrogen protons in the C1 of the cyclo-
olefin of DIIA at dH 3.18 were disappeared in comparison to that of
one hydrogen proton appeared at dH 6.89. In the 13C NMR spectra,
the shift of C1 in DIIA at d 37.91 was upfield in comparison to that
of 1-Br DIIA at d 48.12. It was concluded that one hydrogen proton
was replaced by one bromine in the reaction.
O
O
1
O
DⅡꢀA
Figure 1. Structures of tanshinone IIA (DIIA).
O
O
O
O
Br
O
O
1-Br DⅡA
DⅡꢀA
⇑
Corresponding author. Tel./fax: +86 371 67781739.
E-mail address: liuhm@zzu.edu.cn (H.-M. Liu).
Scheme 1. Reagents and condition: 1 equiv NBS, BPO, anhydrous CCl4, 76–78 °C,
Supported by the National Nature Science Foundation of China.
reflux, 2.5 h.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.014

5142
Y.-F. Bi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5141–5143
Table 1
O
O
The relaxant effects of norepinephrine (10À6 mol/L) induced contraction in rat
O
O
thoracic aorta (X SEM) (n, the number of cases used)
Ar
Br
%Inhibition of norepinephrine contraction in rat thoracic aorta
O
O
Compound
1 Â 10À4
M
n
Compound 1 Â 10À4
M
n
1
2
3
4
5
6
7
8
9
À9.41 2.96
3
6
4
4
4
3
5
3
5
3
3
5
11
12
13
14
15
16
17
18
19
20
À17.83 8.81
12.80 4.45
29.38 7.41
20.22 1.13
À0.37 1.78
À4.92 2.80
À1.67 2.74
1.92 1.97
3
5
4
3
5
3
4
4
4
3
7.58 3.37
À0.25 3.08
23.48 10.04
22.40 4.74
19.05 3.36
9.39 1.30
21.77 1.24
À3.59 0.14
Brominated tanshinone Ⅱ A
P1-P20
Scheme 2. Reagents and condition: 1 equiv K2CO3, aromatic acid, anhydrous DMF,
45–50 °C, 2–3 h.
À2.78 3.92
Those DIIA derivatives were synthesized through the reaction
of 1-Br DIIA and aromatic acids in the presence of K2CO3 (Scheme
2).14,15 Vasodilative activities for synthesized compounds were val-
uated in vitro on the contractile response of vascular thoracic aorta
smooth muscle from male Wistar rats pre-contracted with norepi-
nephrine bitartrate (1 Â 10À6 M) according to the known standard
procedure.16,17 The results were presented in terms of percentage
of the maximal control norepinephrine-induced responses. Most
10 À3.30 1.37
À13.30 3.76
DIIA
1.86 2.75
3.86 1.43
The raw material of 4
The raw
material of
5
The raw
material of
13
5.75 4.30
3.67 2.86
5
5
The raw material of 8
7.78 1.72
5
P1-P20
Compound
Compound
Ar
Ar
120
100
80
60
40
20
0
Compound 4
COO
CH2COO
1
2
3
11
COO
CH2COO
OCH3
OCH3
12
13
0
0.1
0.2
0.4
)
0.5
0.6
Concentr0a.t3ion (mM
CH2COO
COO
Compound 5
120
100
80
60
40
20
0
OCH3
OCH3
COO
CH2COO
4
14
OCH3
OCH3
COO
CH2COO
OH
0
0.1
0.2
0.3
0.4
0.5
0.6
OH
Concentration (mM)
5
6
15
16
CH2COO
Compound 8
COO
120
100
80
60
40
20
0
OH
OH
CH2COO
COO
7
17
0
0.1
0.2
0.3
0.4
0.5
0.6
OH
OH
Concentration (mM)
CH2COO
COO
F
F
8
9
18
19
Compound 13
120
100
80
60
40
20
0
CH2COO
COO
COO
F
F
F
CH2COO
0
0.1
0.2
0.3
0.4
0.5
0.6
Concentration (mM)
10
20
F
Figure 2. Influence of synthesized compounds on contracture induced by norepinephrine bitartrate (NE) in thoracic aortic rings of rats.

Y.-F. Bi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 5141–5143
5143
10. Bi, Y. F.; Xu, H. W.; Liu, X. Q.; Zhang, X. J.; Wang, Z. J.; Liu, H. M. Bioorg. Med.
Chem. Lett. 2010, 20, 4892.
11. Qin, J. K.; Bu, X. Z.; Wang, Y. F.; Du, Z. Y.; Wang, X. Y.; Huang, Z. S.; Ma, L.; An, L.
K.; Gu, L. Q. Chin. Chem. Lett. 2005, 16, 1451.
of compounds showed a concentration-dependent inhibition on
the contractile response of norepinephrine (Table 1). Especially 4,
5, 8 and 13, exhibited better activity (Fig. 2),18 and compared to
their raw materials, the relaxant effects of bioactive products (4,
5, 8 and 13) were improved in varying degrees (Table 1).
The structure–activity relationship showed that the benzoic
acids substituted derivatives presented better pharmacological
vasodilative properties than that of phenylacetic acids substituted
derivatives. Most methoxy-substituing derivatives presented good
pharmacological vasodilative properties, suggesting that, methoxy
has a distinct role to improve the vasodilative activity. In addition,
the electron donating group substituted derivatives presented bet-
ter vasodilative activity than the electron attracting group substi-
tuted derivatives.
In summary, a series of DIIA derivatives have been synthesized
for the first time and the vasodilative activities in vitro of them
were valuated on the contractile response of vascular thoracic aor-
ta smooth muscle from Wistar rats. The results revealed that the
polarity of products contrasted with DIIA was increase and some
synthetic products exhibited good activity. The preliminary struc-
ture–activity relationship showed that it is valuable to develop po-
tent vasodilatve activity of tanshinone IIA derivatives.
12. Reagents and condition: 1 equiv NBS, BPO, anhydrous CCl4, 76–78 °C, reflux,
2.5 h.
13. All newly synthesized compounds have adequate spectral data, for example,
compound 4, IR (KBr, cmÀ1): 3420, 2959, 2932, 2867, 1719, 1678, 1606, 1587,
1537, 1510, 1255, 1164, 1098. 1H NMR (400 MHz, CDCl3, TMS): d 7.90 (d, 2H,
J = 8.8 Hz, H-22, 26), 7.23 (s, 1H, H-15), 6.83 (d, 2H, J = 8.8 Hz, H-23, 25), 6.71(d,
1H, J = 2.7 Hz, H-1), 3.81 (s, 3H, H-27), 2.30–2.37 (m, 1H, H-2a), 2.22 (s, 3H, H-
17), 1.96–2.04 (m, 2H, H-2b,3a), 1.56–1.59 (m, 1H, H-3b), 1.44 (s, 3H, H-18),
1.31 (s, 3H, H-19). 13C NMR (400 MHz, CDCl3, TMS): d 182.40 (C-11), 174.86 (C-
12), 165.24 (C-20), 163.09 (C-24), 161.05 (C-14), 150.83 (C-5), 141.55 (C-15),
138.09 (C-10), 134.10 (C-6), 131.68 (C-22, 26), 128.39 (C-8), 127.01 (C-9),
123.18 (C-21), 122.98 (C-7), 121.36 (C-13), 120.27 (C-16), 113.41 (C-23, 25),
67.25 (C-1), 55.37 (C-27), 34.88 (C-4), 32.37 (C-3), 31.78 (C-18), 31.11 (C-19),
24.80 (C-2), 8.75 (C-17). MS ([M+Na]+): 467.1470.
14. Chakraborti, A. K.; Chankeshwara, S. V. J. Org. Chem. 2009, 74, 1367.
15. Reagents and condition: 1 equiv K2CO3, aromatic acid, anhydrous DMF, 45–
50 °C, 2–3 h.
16. Silva, A. G.; Zapata-Sudo, G.; Kummerle, A. E.; Fraga, C. A. M.; Barreirob, E. J.;
Sudo, R. T. Bioorg. Med. Chem. 2005, 13, 3431.
17. Raimundo, J. M.; Sudo, R. T.; Pontes, L. B.; Antunes, F.; Trachez, M. M.; Zapata-
Sudo, G. Eur. J. Pharmacol. 2006, 530, 117.
18. Screening of vasodilative activity synthesized compounds was carried out on
the thoracic aortic rings of male Wistar rats (200–300 g), which were stunned
and dislocated in the cervical. Then thoracic aortas were immediately
dislodged from Wistar rats and placed in a Krebs–Henseleit solution which
was composed of (in mM): NaCl, 118.0; KCl, 4.7; NaHCO3, 25.0; CaCl2, 2.5;
NaH2PO4, 1.2; MgSO4, 1.2; EDTA, 0.016; glucose, 12 and was saturated in a gas
of 95% O2/5% CO2 at 4 °C. After surface tissues were removed, the aortas were
cut in 2–3 mm ring and fastened in 10 ml organ baths, which maintained at
37 °C in a gas of 95% O2/5% CO2. The preparations were allowed to balance for
2 h under 1.5 g basal tension and the Krebs–Henseleit solution in the organ
baths was changed every 20 min. The integrality of aorta’s endothelium was
checked before synthesized compounds were added to the organ baths. If the
percentage of relaxation of pre-contracted aorta by norepinephrine bitartrate
(1 Â 10À6 M) by acetylcholine (1 Â 10À5 M) was greater than 80%, endothelium
was deemed to be intact. Removal of functional endothelium which was
confirmed by the lack of relaxation (<10%) in the presence of acetylcholine. The
tested compounds were dissolved in dimethylsulfoxide (DMSO) as stock
solution (50 mg/mL). Contrast tests were performed in the presence of DMSO
alone, at the same concentrations as those used with the synthesized
compounds, in order to check contractile response of aorta rings was not
affected. All the results were performed as mean the standard error of the
mean (SEM). Dose–response curves were used to exhibit different effects of
compounds. Differences between different concentrations were considered
statistically significant when paired Student’s t-test was under the condition of
P <0.05.
Acknowledgment
We gratefully acknowledge support from the National Nature
Science Foundation of China.
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