Synthesis of novel danshensu alkamine derivatives as potential anti-myocardial ischemia agents

Article abstract of DOI:10.14233/ajchem.2014.16676

Ten novel danshensu alkamine derivatives were synthesized and the preliminary biological activity of these complexes were investigated. The bioassay results indicated that some of derivatives exhibit significant activities on protecting hypoxic H₉

Full text of DOI:10.14233/ajchem.2014.16676

Asian Journal of Chemistry; Vol. 26, No. 23 (2014), 7907-7910
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16676
Synthesis of Novel Danshensu Alkamine Derivatives as Potential Anti-Myocardial Ischemia Agents
1
2
2
2
2
1
1,*
JING-JING SHU , CHUAN ZHANG , TING-FANG WANG , HAO ZOU , LEI JIN , WEI-YING GU and LI-CHAO ZHANG
1Department of pharmacy, Shanghai Seventh People's Hospital, Shanghai 200137, P.R. China
2New Drug Research Center, College of Pharmacy, Second Military Medical University, Guohe Road 325, Shanghai 200433, P.R. China
*Corresponding author: Tel: +86 21 68660665; E-mail: changhaiskin@163.com; sjx220@gmail.com
Received: 12 November 2013;
Accepted: 25 February 2014;
Published online: 15 November 2014;
AJC-16261
Ten novel danshensu alkamine derivatives were synthesized and the preliminary biological activity of these complexes were investigated.
The bioassay results indicated that some of derivatives exhibit significant activities on protecting hypoxic H9C2 cardiomyocytes.
Keywords: Anti-myocardial ischemia activities, Danshensu alkamine derivatives, Synthesis.
However, it has been shown that danshensu has low oral
bioavailability11 and is instability. Therefore, it is necessary
for developing new generation drug suit for clinic from mole-
cular modification of danshensu.
INTRODUCTION
The compounds isolated from Salvia miltiorrhiza root, a
widly used traditional Chinese medicine, have recently
attracted considerable attention owing to their prominent
biological activity. Danshensu is one of the major effective
component of aqueous extracts and has significant pharma-
cological activities such as relaxant coronary arteries1,2, inhibit
platelet aggregation and decrease the levels of blood viscosity3,
improve microcirculation4, protect myocardial ischemia
reperfusion injury5,6. In addition, danshensu inhibit myocardium
cell apoptosis7, protect the endothelial cells against homocys-
teinemia8, radical scavengers and antioxidants9. Previously, we
reported that sodium DSS showed biphasic effects on vessel
tension, low dosage of sodium danshensu produced small
contraction, high dosage produced significant vasodilation10.
Structure-activity relationship studies indicated that
phenyllactic acid in the molecule of danshensu might be
the active site12,13. Present domestic and international
research of danshensu derivatives are most about danshensu
esters while few are about danshensu alkamines. Many
nature products with physiological activity contain alka-
mine structure which is the critical area in many molecules
of medicine14. On the basis of this, we retain structure of
phenyllactic acid and synthetize danshensu alkamine
derivatives (Fig.1) in order to find novel compounds more
stability and better activity.
O
O
HO
HO
C-R
HO
HO
COOH
OH
OH
Danshensu alkamine derivatives 5a-j
Danshensu
CH3
OH
N
OH
OH
N
N
N
H
OH
R=
N
H
H
OH
CH3
5a
5b
5c
5e
5d
CH3
OH
O
OH
N
N
H
OH
CH3
OH
NH
N
H
OH
H
N
OH
5h
OH
5g
5j
5i
5f
OH
Fig.1. Structures of danshensu and danshensu alkamine derivatives 5a-j

7908 Shu et al.
Asian J. Chem.
the reaction, the solution was cooled, than the methanol were
evaporated in vacuo. The residue was purified by flash column
chromatography with a mixture of pet. ether:EtOAc (2:1 to
1:4) as eluent to provide 3-[3,4-bis(benzyloxy)phenyl]-2-
hydroxy-R-propionamide (4a-j).
EXPERIMENTAL
Melting point were conducted on aYamato MP-21 melting
point apparatus and uncorrected. 1H and 13C NMR spectra were
recorded in CDCl3 unless otherwise indicated with a Bruker
AC-300P spectrometer or a BrukerAvance II 600 spectrometer,
using TMS as internal standard. ESI mass spectra were per-
formed on anAPI-3000 LC-MS spectrometer.All compounds
were routinely checked by thin-layer chromatography (TLC)
and 1H NMR. Components were visualized by UV light (254
nm).
3-[3,4-Bis(benzyloxy)phenyl]-2-hydroxy-N-(2-
hydroxyethyl)propanamide (4a): White solid, yeld 92.1 %,
1
m.p.120-121 °C; H NMR (300 MHz, CDCl3): δ 7.46-7.27
(m, 10H, Ar-H), 6.90-6.73 (m, 3H, 2'-H, 5'-H, 6'-H), 5.16 (s,
2H, -OCH2Ph), 5.15 (s, 2H, -OCH2Ph), 4.24-4.21 (m, 1H, 2-
H), 3.66-3.62 (m, 2H, -CH2OH), 3.40-3.34 (m, 2H, -NHCH2-),
3.14 (dd, 1H, J = 13.8, 4.2, 3-H), 2.87 (dd, 1H, J = 16.8, 8.1,
3-H); MS(ESI) m/z calc. for C25H27NO5 421.49, found [M-H]+
420.13.
Synthesis of compounds: All the danshensu derivatives
were synthesized according to the route as shown in Scheme-I.
O
O
O
BnO
COCH3
HO
CONa
HO
COCH3
II
I
3-[3,4-Bis(benzyloxy)phenyl]-2-hydroxy-N-(3-hydroxy-
propyl)propanamide (4b): White solid, yeld 87.32 %,
1
m.p.124-125 °C; H NMR (300 MHz, CDCl3): δ 7.47-7.28
OH
OH
OH
BnO
HO
HO
3
2
1
O
O
HO
C-R
OH
BnO
C-R
IV
III
(m, 10H, Ar-H), 6.93-6.88 (m, 2H, 2'-H, 5'-H), 6.78-6.75 (m,
1H, 6'-H), 5.16 (s, 4H, -OCH2Ph), 4.27-4.24 (m, 1H, 2-H),
3.59-3.55 (m, 2H, NHCH2), 3.41-3.38 (m, 2H, CH2OH), 3.16
(dd, 1H, J = 13.5, 4.2, 3-H), 3.16 (dd, 1H, J = 14.1, 8.1, 3-H),
1.64-1.69 (m, 2H, NHCH2CH2); MS(ESI) m/z calc. for
C26H29NO5 435.51, found [M-H]+ 434.50
OH
HO
BnO
4
5
Scheme-I: Synthetic route for compounds 5a-j
Methyl 3-(3,4-Dihydroxyphenyl)-2-hydroxypropa-
noate (2): Concentrated sulfuric acid (4.6 g, 0.047 mol) was
added to sodium DSS (1) (10 g, 0.045 mol) in anhydrous
methanol (20 mL) and stirred at refluxed for 7 h. After comp-
letion of the reaction, methanol was concentrated to dryness.
The residue was purified by recrystallization from methanol
and chloroform to give pure products 2 (9.1 g).Yield: 95.4 %;
3-[3,4-Bis(benzyloxy)phenyl]2-hydroxy-N-(2-hydro-
xyethyl)-N-methylpropanamide (4c): White solid, yeld 67.3
1
%, m.p. 117-118 °C; H NMR (300 MHz, CDCl3): δ 7.46-
7.27 (m, 10H, Ar-H), 6.89 (d, 1H, J = 8.7, 5'-H), 6.85 (s, 1H,
2'-H), 6.76 (d, 1H, J = 8.1, 6'-H), 5.15 (s, 2H, -OCH2Ph), 5.14
(s, 2H, -OCH2Ph), 4.50-4.41 (m, 1H, 2-H), 3.77-3.66 (m, 2H,
-CH2OH), 3.59 (s, 3H, -NCH3), 3.43-3.50 (m, 2H, -NCH2-),
3.04-2.81 (m, 2H, 3-H); MS (ESI) m/z calc. for C26H29NO5
435.51, found [M-H]+ 434.23.
1
oil. H NMR (300 MHz, acetone-d6): δ 6.67 (s, 1H, 2'-H),
6.65 (d, 1H, J = 7.8, 5'-H), 6.52 (d, 1H, J = 8.1, 6'-H), 4.14-
4.21 (m, 1H, 2-H ), 3.68 (s, 3H, COOCH3), 2.96 (dd, 1H, J =
14.1, 5.4, 3-H), 2.79 (dd, 1H, J = 13.8, 7.5, 3-H); 13C NMR
(300 MHz, acetone-d6): δ 176.37, 146.51, 145.51, 130.34,
122.31, 118.06, 116.66, 73.83, 52.77, 41.61; MS(ESI) m/z calc.
for C10H12O5 212.20, found [M-H]+ 211.65.
3-[3,4-Bis(benzyloxy)phenyl]-2-hydroxy-N-(2-hydro-
xypropyl)propanamide (4d): White solid, yeld 87.32 %,
1
m.p.123-125 °C; H NMR (300 MHz, CDCl3): δ 7.47-7.29
Methyl 3-[3,4-bis(benzyloxy)phenyl]-2-hydroxypro-
panoate(3): Compound 2 (15 g, 0.071 mol), benzyl bromide
(30 g, 0.175 mol), K2CO3 (20 g, 0.145 mol) and KI (2 g, 0.012
mol) were added in anhydrous acetone (100 mL), stirring at
refluxed for 7 h at 70 °C.After the reaction end and the mixture
cool to room temperature, wash the reaction solution with ice
water (30 mL), than extract with acetic ether (3 × 40 mL). The
combined organic extracts were washed with saturated brine
(40 mL) and dried over anhydrous Na2SO4, than evaporated
in vacuo. After filtration and evaporation, the residue was
purified by flash column chromatography with a mixture of
ligarine/EtOAc (3:1 v/v) as eluent to provide the compound
methyl 3-[3,4-bis(benzyloxy)phenyl]-2-hydroxypropanoate
(3).Yield: 69.3 %, white power, m.p. 92-93 °C. 1H NMR (300
MHz, CDCl3): δ 7.47-7.29 (m, 10H, Ar-H), 6.95 (s, 1H, 2'-H),
6.92 (d, 1H, J = 8.4, 5'-H), 6.70 (d, 1H, J = 7.8, 6'-H), 5.04 (s,
2H, -OCH2Ph), 5.07 (s, 2H, -OCH2Ph), 4.17-4.21 (m, 1H, 2-
H ), 3.56 (s, 3H, COOCH3), 2.91 (dd, 1H, J = 10.5, 4.8, 3-H),
2.74 (dd, 1H, J = 14.4, 8.1, 3-H); MS (ESI) m/z calc. for
C10H12O5 392.44, found [M-H]+ 391.14.
(m, 10H, Ar-H), 6.96 (s, 1H, 2'-H), 6.91 (d, 1H, J = 8.1 5'-H),
6.72 (d, 1H, J = 7.8, 6'-H), 5.07 (s, 4H, -OCH2Ph), 4.73-4.71
(m, 1H, 2-H), 3.63-3.52 (m, 1H, CHOH), 3.23-3.42 (m, 2H,
NHCH2), 2.96 (dd, 1H, J = 14.4, 4.2, 3-H), 2.79 (dd, 1H, J =
13.8, 7.2, 3-H), 1.02-0.92 (m, 3H, CH3); MS(ESI) m/z calc.
for C26H29NO5 435.51, found [M-H]+ 434.50.
N-Benzyl-3-[3,4-bis(benzyloxy)phenyl]-2-hydroxy-N-
(2-hydroxyethyl)propanamide(4e):White solid, yeld 61.1 %,
1
m.p.134-136 °C; H NMR (300 MHz, CDCl3): δ 7.46-7.27
(m, 10H, Ar-H), 7.19 (d, 1H, J = 7.5, 5'-H), 7.08 (s, 1H, 2'-H),
7.07 (d, 1H, J = 6.3, 6'-H), 6.89-6.70 (m, 5H, Ar-H), 5.17
(s, 2H, -OCH2Ph), 5.16 (s, 2H, -OCH2Ph), 5.14 (s, 2H,
-NCH2Ph), 4.55-4.52 (m, 1H, 2-H), 3.68-3.65 (m, 2H,
-CH2OH), 3.60-3.42 (m, 2H, -NCH2), 3.17-2.89 (m, 2H, 3-
H); MS(ESI) m/z calc. for C32H33NO5 511.60, found [M-H]+
510.54.
3-[3,4-Bis(benzyloxy)phenyl)-2-hydroxy-N-(1-hydroxy-
2-dimethylethyl)propanamide (4f):White solid, yeld 52.5 %,
1
m.p.126-128 °C; H NMR (300 MHz, CDCl3): δ 7.49-7.27
(m, 10H, Ar-H), 6.93-6.82 (m, 2H, 2'-H, 5'-H, 6'-H), 5.15 (s,
4H, -OCH2Ph), 4.18-4.14 (m, 1H, 2-H), 3.57-3.84 (m, 2H,
-CH2OH), 3.09 (dd, 1H, J = 13.8, 7.5, 3-H), 2.87 (dd, 1H, J =
14.7, 7.5, 3-H), 1.38 (s, 6H, -N(CH3)2); MS (ESI) m/z calc. for
C27H31NO5 449.54, found [M-H]+ 448.33.
3-[3,4-Bis(benzyloxy)phenyl]-2-hydroxy-R-propiona-
mide (4a-j): Compound 3 (0.4 g) and amino alcohol (1.02
mmol) in methanol (20 mL) react in heating reflux. Progress
of the reaction was monitored by TLC. After completion of

Vol. 26, No. 23 (2014)
Synthesis of Novel Danshensu Alkamine Derivatives as Potential Anti-Myocardial Ischemia Agents 7909
3-[3,4-Bis(benzyloxy)phenyl]-2-hydroxy-N-[2-(2-
hydroxyethoxy)ethyl]propanamide (4g): White solid, yeld
53.6 %, m.p.128-129 °C; 1H NMR (300 MHz, CDCl3): δ 7.46-
7.27 (m, 10H, Ar-H), 6.89 (d, 1H, J = 6.6, 5'-H), 6.86 (s, 1H,
2'-H), 6.76 (d, 1H, J = 8.4,6'-H), 5.14 (s, 2H, -OCH2Ph), 5.13
(s, 2H, -OCH2Ph), 4.23-4.19 (m, 1H, 2-H), 3.68-3.65 (m, 2H,
-CH2O), 3.51-3.48 (m, 2H, NHCH2), 3.45-3.43 (m, 2H, OCH2),
3.41-3.47 (m, 2H, CH2OH), 3.13 (dd, 1H, J = 14.1, 4.2, 3-H),
2.82 (dd, 1H, J = 13.8, 8.4, 3-H); MS (ESI) m/z calc. for
C27H31NO6 465.53, found [M-H]+ 464.19.
3-(3,4-Dihydroxyphenyl)-2-hydroxy-N-(2-hydroxyethyl)-
N-methylpropanamide (5c): Oil, yeld 89.3 %; 1H NMR (300
MHz, Acetone-d6): δ 8.08 (bar, 1H, NH), 6.76-6.69 (m, 2H,
2'-H, 5'-H), 6.59 (dd, 1H, J = 8.1, 1.8, 6'-H), 4.65-4.52 (m,
1H, 2-H), 3.71-3.60 (m, 2H, -CH2OH), 3.52 (s, 3H, -NCH3),
3.37-3.22 (m, 2H, -NCH2-), 2.99 (dd, 1H, J = 14.1, 4.8, 3-H),
2.82 (dd, 1H, J = 13.5, 7.5, 3-H); MS (ESI) m/z calc. for
C12H17NO5 255.11, found [M-H]+ 254.31.
3-(3,4-Dihydroxyphenyl)-2-hydroxy-N-(2-hydroxy-
propyl)propanamide (5d): Oil, yeld 97.58 %; 1H NMR (300
MHz, Acetone-d6): δ 8.02 (bar, 1H, NH), 6.75 (s, 1H, 2'-H),
6.72 (d, 1H, J = 6.9, 5'-H), 6.58 (d, 1H, J = 8.1, 6'-H), 4.20-
4.14 (m, 1H, 2-H), 3.63-3.71 (m, 1H, CHOH), 3.26-3.06 (m,
2H, NHCH2), 2.99 (dd, 1H, J = 13.8, 3.6, 3-H), 2.70 (dd, 1H,
J = 14.4, 4.8, 3-H), 1.25-1.02 (m, 3H, CH3); MS(ESI) m/z
calc. for C12H17NO5 255.26, found [M-H]+ 254.12.
3-[3,4-Bis(benzyloxy)phenyl]-2-hydroxy-N,N-bis(2-
hydroxyethyl)propanamide (4h): White solid, yeld 92.1 %,
1
m.p.130-132 °C; H NMR (300 MHz, CDCl3): δ 7.46-7.27
(m, 10H, Ar-H), 6.87 (d, 1H, J = 8.1, 5'-H), 6.75 (s, 1H, 2'-H),
6.72 (d, 1H, J = 7.5, 6'-H), 5.14 (s, 4H, -OCH2Ph), 4.63-4.61
(m, 1H, 2-H), 3.82-3.77 (m, 4H, -CH2OH), 3.71-3.65 (m, 4H,
-NCH2), 2.97-3.84 (m, 2H, 3-H); MS (ESI) m/z calc. for
C27H31NO6 465.54, found [M-H]+ 464.41.
N-Benzyl-3-(3,4-dihydroxyphenyl)-2-hydroxy-N-(2-
hydroxyethyl)propanamide (5e): Oil, yeld 87.1 %; 1H NMR
(300 MHz, Acetone-d6): δ 7.22-7.13 (m, 5H, Ar-H), 6.83 (d,
1H, J = 1.8, 2'-H), 6.76 (d, 1H, J = 7.8, 5'-H), 6.72 (dd, 1H,
J = 8.1, 1.5, 6'-H), 4.59-4.54 (m, 1H, 2-H), 4.42 (s, 2H,
-NCH2Ph), 3.70-3.63 (m, 2H, -CH2OH), 3.29-3.22 (m, 2H,
-NCH2), 2.95 (dd, 1H, J = 13.8, 8.4, 3-H), 2.77 (dd, 1H, J =
13.8, 7.2, 3-H); MS(ESI) m/z calc. for C18H21NO5 331.36,
found [M-H]+ 330.15.
3-[3,4-Bis(benzyloxy)phenyl]-N-(2,3-dihydroxypropyl)
-2-hydroxypropanamide (4i): White solid, yeld 46.6 %,
1
m.p.133-135 °C; H NMR (300 MHz, CDCl3): δ 7.45-7.27
(m, 10H, Ar-H), 6.88 (d, 1H, J = 6.3 5'-H), 6.84 (s, 1H, 2'-H),
6.74 (d, 1H, J = 8.1, 6'-H), 5.12 (s, 4H, -OCH2Ph), 4.22-4.24
(m, 1H, 2-H), 3.67-3.65 (m, 1H, CHOH), 3.47-3.41 (m, 2H,
CH2OH), 3.39-3.35 (m, 2H, NHCH2), 3.11 (dd, 1H, J = 14.1,
4.5, 3-H), 2.96 (dd, 1H, J = 13.8, 5.7, 3-H); MS(ESI) m/z calc.
for C26H29NO6 451.51, found [M-H]+ 450.63.
3-(3,4-Dihydroxyphenyl)-2-hydroxy-N-(1-hydroxy-2-
dimethylethyl)propanamide (5f): Oil, yeld 92.5 %; 1H NMR
(300 MHz, Acetone-d6): δ 7.86 (bar, 1H, NH), 6.16 (s, 1H, 2'-
H), 6.71(d, 1H, J = 7.8, 5'-H), 6.57(d, 1H, J = 7.8, 6'-H), 4.16-
4.32 (m, 1H, 2-H), 3.51-3.42 (m, 2H, -CH2OH), 2.95 (dd, 1H,
J = 11.1, 4.5, 3-H), 2.70 (dd, 1H, J = 13.8, 7.5, 3-H), 1.23 (s,
6H, -N(CH3)2); MS(ESI) m/z calc. for C13H19NO5 269.13, found
[M-H]+ 268.29.
3-[3,4-Bis(benzyloxy)phenyl]-N-(1,3-dihydroxypropan-
2-yl)-2-hydroxypropanamide (4j): White solid, yeld 87.6 %,
1
m.p.130-132 °C; H NMR (300 MHz, CDCl3): δ 7.42-7.28
(m, 10H, Ar-H), 6.86 (d, 1H, J = 7.2 5'-H), 6.82 (s, 1H, 2'-H),
6.72 (d, 1H, J = 8.1, 6'-H), 5.11 (s, 2H, -OCH2Ph), 5.08 (s,
2H, -OCH2Ph), 4.49-4.52 (m, 1H, 2-H), 4.13-4.20 (m, 1H,
NHCH), 3.45-3.58 (m, 4H, CH2OH), 3.11 (dd, 1H, J = 14.1,
3.9, 3-H), 2.96 (dd, 1H, J = 11.1, 6.5, 3-H); MS (ESI) m/z
calc. for C26H29NO6 451.51, found [M-H]+ 450.37.
3-(3,4-Dihydroxyphenyl)-2-hydroxy-N-(2-(2-hydroxy-
ethoxy)ethyl)propanamide (5g): Oil, yeld 89.16 %; 1H NMR
(300 MHz, Acetone-d6): δ 7.99 (bar, 1H, NH), 6.74 (d, 1H,
J = 1.8, 2'-H), 6.70 (d, 1H, J = 8.1, 5'-H), 6.57 (dd, 1H, J =
8.1, 1.8, 6'-H), 4.17 (dd, 1H, J = 7.8, 3.9, 2-H), 3.64-3.59 (m,
2H, -CH2O), 3.52-3.49 (m, 2H, NHCH2), 3.48-3.43 (m, 2H,
OCH2), 3.41-3.34 (m, 2H, CH2OH), 2.97 (dd, 1H, J = 13.8,
3.9, 3-H), 2.69 (dd, 1H, J = 13.8, 7.8, 3-H); MS(ESI) m/z calc.
for C13H19NO6 285.12, found [M-H]+ 284.32.
3-(3,4-Dihydroxyphenyl)-2-hydroxy-R-propionamide
5a-j: Compound 4 (0.53 mol) and Pd/C (20 mg) in acetic ether
(20 mL) are refluxed while strring for 24 h at room tempe-
rutrue. Then the reaction mixture was filtered, evaporated in
vacuo and dried to give 3-(3,4-dihydroxyphenyl)-2-hydroxy-
R-propionamide (5a-j).
3-(3,4-Dihydroxyphenyl)-2-hydroxy-N-(2-hydroxyethyl)-
1
propanamide (5a): Oil, yeld 96.3 %; H NMR (300 MHz,
3-(3,4-Dihydroxyphenyl)-2-hydroxy-N,N-bis(2-hydro-
xyethyl)propanamide (5h): Oil, yeld 96.32 %; 1H NMR (300
MHz, Acetone-d6): δ 7.96 (bar, 1H, NH), 6.77 (d, 1H, J = 2.1,
2'-H), 6.71 (d, 1H, J = 8.1, 5'-H), 6.72 (dd, 1H, J = 7.8, 1.8, 6'-
H), 4.64 (dd, 1H, J = 6.6, 5.4, 2-H), 3.70-3.62 (m, 4H,
-CH2OH), 3.40-3.34 (m, 4H, -NCH2), 2.89 (dd, 1H, J = 13.8,
5.1, 3-H), 2.70 (dd, 1H, J = 13.8, 7.2, 3-H); MS (ESI) m/z
calc. for C13H19NO6 285.29, found [M-H]+ 284.12.
Acetone-d6): δ 7.96 (bar, 1H, NH), 6.74 (d, 1H, J = 2.1, 2'-H),
6.71 (d, 1H, J = 7.8, 5'-H), 6.62 (dd, 1H, J = 7.8, 2.1, 6'-H),
4.25-4.21 (m, 1H, 2-H), 3.65-3.62 (m, 2H, -CH2OH), 3.37-
3.32 (m, 2H, -NHCH2-), 3.01 (dd, 1H, J = 14.1, 3.9, 3-H),
2.82 (dd, 1H, J = 13.8, 7.5, 3-H); MS(ESI) m/z calc. for
C11H15NO5 241.24, found [M-H]+ 240.42.
3-(3,4-Dihydroxyphenyl)-2-hydroxy-N-(3-hydroxy-
propyl)propanamide (5b): Oil, yeld 95.32 %; 1H NMR (300
MHz, Acetone-d6): δ 7.67 (bar, 1H, NH), 6.77 (d, 1H, J =
1.6, 2'-H), 6.72 (d, 1H, J = 8.1, 5'-H), 6.59 (dd, 1H, J = 8.1,
2.1, 6'-H), 4.32 (dd, 1H, J = 7.2, 5.1, 2-H), 3.54-3.47 (m,
2H, CH2OH), 3.33-3.26 (m, 2H, NHCH2), 3.00 (dd, 1H, J =
13.8, 3.6, 3-H), 2.72 (dd, 1H, J = 13.8, 7.8, 3-H), 1.69-1.60
(m, 2H, CH2); MS (ESI) m/z calc. for C12H17NO5 255.26,
found [M-H]+ 254.51.
3-(3,4-Dihydroxyphenyl)-N-(2,3-dihydroxypropyl)-2-
hydroxypropanamide (5i): Oil, yeld 97.2 %; 1H NMR (300
MHz, Acetone-d6): δ 8.06 (bar, 1H, NH), 6.87 (d, 1H, J = 1.5,
2'-H), 6.82 ((d, 1H, J = 7.8, 5'-H), 6.72 (d, 1H, J = 8.1, 1.8, 6'-
H), 4.23 (dd, 1H, J = 8.7, 4.5, 2-H), 3.57-3.54 (m, 1H, CHOH),
3.43-3.37 (m, 2H, CH2OH), 3.36-3.34 (m, 2H, NHCH2), 2.98
(dd, 1H, J = 14.1, 4.5, 3-H), 2.81 (dd, 1H, J = 13.8, 7.5, 3-H);
MS (ESI) m/z calc. for C12H17NO6 271.11, found [M-H]+
270.34.

7910 Shu et al.
Asian J. Chem.
TABLE-1
RELATIVE CELL VIABILITY OF DANSENSU AND ITS DERIVATIVES 5a-j
Drug
DSS
37.5
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
Relative ratio %
39.35
-14.91
-8.66
39.42
45.17
40.34
32.46
9.66
33.88
32.88
3-(3,4-Dihydroxyphenyl)-N-(1,3-dihydroxypropan-2-
yl)-2-hydroxypropanamide (5j): Oil, yeld 87.6 %; 1H NMR
(300 MHz, Acetone-d6): δ 7.95 (bar, 1H, NH), 6.86 (d, 1H,
J = 7.8 5'-H), 6.82 (s, 1H, 2'-H), 6.72 (d, 1H, J = 8.1, 6'-H),
4.37 (dd, 1H, J = 9.6, 4.5, 2-H), 3.75-3.73 (m, 1H, NCH),
3.45-3.42 (m, 4H, CH2OH), 2.97 (dd, 1H, J = 13.8, 3.9, 3-H),
2.78 (dd, 1H, J = 14.1, 7.5, 3-H); MS (ESI) m/z calc. for
C12H17NO6 271.11, found [M-H]+ 270.25.
activity. Other three compounds 5g, 5i, 5j were less but close
to the DSS. Compound 5e was found to be the most active
anti-myocardial ischemia agent.
ACKNOWLEDGEMENTS
This study was supported by the Science and Technology
Commission of Shanghai Special Purpose for Modernization
Of Traditional Chinese Medicine in 2008 (No. 08DZ1970802),
National Basic Research Program of China (2009CB521907)
and Key Discipline Grant of Shanghai Pudong NewArea Health
System (PWZXK2010-11).
Bioassay of danshensu alkamine derivatives: Rat myo-
cardial cell lines H9C2 obtained from Institutes of Biochemistry
and Cell Biology, CAS, Shanghai, China, was maintained in
DMEM medium supplemented with 10 % (v/v) fetal bovine
serum at 37 °C in 5 % CO2 and 95 % air. The cells disassociated
by 0.25 % trypsin were seeded at a density of 1 × 104 cells/
well in 96-well plates, with a volume of 100 µL in each well.
After a period of 24 h, cells were exposed to different
compounds (DSS, 5a-j) at 10 µmol/L or vehicle alone for 2 h,
respectively and then subjected to hypoxia at 37 °C in 5 %
CO2 and 95 % N2. After 24 h, the cells were collected and
MTT assay was performed as previously described15. The
viability of normal cell is presumed as 100 %. The relative
cell viability rate of the derivatives compare to the model assay
was calculated via the following equation:
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RESULTS AND DISCUSSION
Ten novel danshensu alkamine derivatives were synthe-
sized by DSS with substituted ketones. Reaction mixtures were
maintained strring at room temperature, leading to the desired
compounds in 87.1-97.2 % yelds. All the compounds were
identified and characterized by 1H NMR, 13C NMR, ESI-MS.
Anti-myocardial ischemia activities: The result listed in
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activities than that of DSS., while 5b, 5c, 5h showed less potent
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