ArticlePDF Available

Isolation of Pyranocoumarins from Angelica Gigas

SAGE Publications Inc
Natural Product Communications
Authors:

Abstract

A mixture of diastereomers of the coumarin glycoside 3′-O-â-D- glucopyranosyl-3′,4′-dihydroxanthyletin (1), along with six known pyranocoumarins, columbianoside (4), marmesin (5), 3′-hydroxy-3′, 4′-dihydroxanthyletin (6), decursin (7), decursinol angelate (8), and isoimperatorin (9), were isolated from the roots of Angelica gigas Nakai. The racemic compound 1 was successfully separated by preparative HPLC to obtain a new isomer 3′(S)-O-β-D-glucopyranosyl-3′,4′- dihydroxanthyletin (2), and a known isomer 3′(R)-O-β-D- glucopyranosyl-3′,4′-dihydroxanthyletin (3). The absolute configuration of compounds 2 and 3 was determined by comparison of optical rotation and NMR data of their acid hydrolysis products.
Isolation of Pyranocoumarins from Angelica gigas
V.L. Niranjan Reddya, Atul N. Jadhava, Bharathi Avulaa and Ikhlas A. Khana,b*
aNational Center for Natural Products Research, Research Institute of Pharmaceutical Sciences,
The University of Mississippi, University, MS-38677, USA
bDepartment of Pharmacognosy, School of Pharmacy, The University of Mississippi,
University, MS-38677, USA
ikhan@olemiss.edu
Received: November 5th, 2007; Accepted: March 9th, 2008
A mixture of diastereomers of the coumarin glycoside 3-O-β-D-glucopyranosyl-3,4-dihydroxanthyletin (1), along with six
known pyranocoumarins, columbianoside (4), marmesin (5), 3-hydroxy-3,4-dihydroxanthyletin (6), decursin (7), decursinol
angelate (8), and isoimperatorin (9), were isolated from the roots of Angelica gigas Nakai. The racemic compound 1 was
successfully separated by preparative HPLC to obtain a new isomer 3(S)-O-β-D-glucopyranosyl-3,4-dihydroxanthyletin (2),
and a known isomer 3(R)-O-β-D-glucopyranosyl-3,4-dihydroxanthyletin (3). The absolute configuration of compounds 2 and
3 was determined by comparison of optical rotation and NMR data of their acid hydrolysis products.
Keywords: Angelica gigas, Umbelliferae, coumarins.
The plant Angelica gigas Nakai (Umbelliferae) grows
in Korea on moist soils at altitudes of above 200 m
[1]. The roots, also known as Korean angelica (‘Zam
Dang Gui’), are used in traditional medicine as a
sedative, anodyne, tonic and in the treatment of
anemia [1]. A. gigas has been studied extensively
and reported to contain different classes of
chemical constituents that include coumarins,
triterpenoids, essential oils, and polyacetylenes [2].
Pharmacological evaluations of this plant report
antibacterial and antiamnestic effects, depression of
cardiac contraction, activation of protein kinase C,
and antitumor activity [3-5]. A. gigas is known to be
a rich source of coumarins, some of which have been
found to possess neuroprotective activity and shown
to inhibit acetyl cholinesterase [6,7]. Extract of
A. gigas has also been found to possess
antinociceptive effects in various pain models [8].
Recently, we have reported the bioavailability and
blood-brain barrier transport of these compounds [9].
In the present study, we are reporting the isolation
and structural elucidation of six known
pyranocoumarins 4-9, and separation of the mixture
of diastereomers 1 by preparative HPLC to yield a
new compound 2 and a known compound 3, being
reported for the first time from the plant. In addition,
compound 1 was separated into R and S isomers
(2a and 3a) by acetylation (Scheme-1), followed by
purification using reverse phase (RP-18) column
chromatography.
Compound 1 was isolated from the methanolic
extract of roots of A. gigas. This compound showed a
characteristic 1H NMR spectrum for coumarin
compounds with low intensity signals indicating the
presence of isomers. These were successfully
separated into compounds 2 and 3 by reverse phase
HPLC, as detailed in the experimental section.
Compound 2 was a white solid, [α]D25 21.24 (c 0.37,
pyridine), and showed a quasi-molecular ion peak
[M+H+] at m/z 409.1667 in HR-ESIMS, indicating
the molecular formula to be C20H24O9. Signals at
1711 and 1619 cm-1 in the IR spectrum were assigned
to a carbonyl group and an aromatic system of a
coumarin skeleton, respectively. The aromatic region
of the 1H NMR spectrum of 2 revealed a pair of
doublets at δ 6.31 (1H, d, J = 10.0 Hz) and 7.68
(1H, d, J = 9.6 Hz), which were attributed to the
H-3 and H-4 signals of the α-pyrone ring system. It
also revealed a pair of singlets at δ 7.13 (1H, s) and
NPC Natural Product Communications 2008
Vol. 3
No. 5
785 - 790
786 Natural Product Communications Vol. 3 (5) 2008 Niranjan Reddy et al.
*
Ac
2
O/Py
R
+
O O O
HO
R
15% HCl
MeOH, ref lux
Mp: 194-195ºC
[α]
D
= -26.67 (CH Cl
3
,c,0.195)
Mp: 174-175ºC
[α]
D25
=-15.36(CHCl
3
,c,0.155)
Reported [12], Mp. 176-178ºC; [α]
D25
=-13.9(CHCl
3
,c,0.05)
3'(R)-Hydroxy-3',4'-dihydroxanthyletin (11)
3'-O-β-D-glucopyranosyl-3',4'-dihydroxanthyletin (1)
3a
S
O O O
HO
S
15% HCl
MeOH, ref lux
Mp: 194-195ºC
[α]
D
= +29.77 (CHCl
3
, c, 0.04)
3'(S)-Hydroxy-3',4'-dihydroxanthyletin (10)
2a
Mp: 174-175ºC
[α]
D25
= +12.17 (CH Cl
3
,c,0.06)
Reported [12], Mp. 178ºC; [α]
D22
=+10.8(CHCl
3
,c,0.65)
3' 3'
3'
O O O
O
O
OH
OH
HO
HO
O O O
O
O
OAc
OAc
AcO
AcO
3'
O O O
O
O
OAc
OAc
AcO
AcO
Scheme 1: Acetylation and subsequent hydrolysis of compound 1.
Table 1: 1H (400 MHz) and 13C NMR (100 MHz) data of
coumarins 2 and 3 (pyridine-d5, in δ ppm).
3-(S)-O-β-D-
glucopyranosyl-3, 4-
dihydroxanthyletin (2)
3-(R)-O-β-D-
glucopyranosyl-3, 4-
dihydroxanthyletin (3)
Position
1H 13C 13C 1H
2 - 161.5 161.5 -
3 6.31 (d, 10.0 Hz) 112.2 112.4 6.30 (d, 8.4 Hz)
4 7.68 (d, 9.6 Hz) 144.6 144.6 7.62 (d, 9.6 Hz)
5 7.13 (s) 124.1 124.4 7.05 (s)
6 - 126.1 126.1 -
7 - 164.1 164.2 -
8 6.76 (s) 97.7 97.8 6.76 (s)
9 - 156.2 156.3 -
10 - 113.1 113.2 -
2’ - 78.2 78.2 -
3’ 5.00 (t, 7.6 Hz) 91.2 91.1 5.12 (t, 7.6 Hz)
4’ 3.18 (dd, 16.0,
9.2 Hz)
3.56 (dd, 16.0,
8.0 Hz)
30.0 30.3 3.27 (dd, 16.0,
8.8 Hz)
3.48 (dd, 16.0,
7.6 Hz)
Gem
(CH3)2 1.56 (s)
23.8
22.5 24.2
21.8 1.59 (s)
1.44 (s)
1” 5.14 (overlap)* 99.1 99.2 5.09 (d, 8.0 Hz)
2” 3.98(t, 8.0) 75.4 75.5 3.97(overlap)
3” 3.88.-3.91 78.3 78.6 3.97(overlap)
4” 4.20-4.25 71.8 72.0 4.17-4.22
5” 4.25-4.29 78.8 79.0 4.21-4.24
6” 4.30-4.34
62.8 63.1 4.35 (dd, 12.0,
5.7 Hz)
4.56
(br d,11.2 Hz)
6.76 (1H, s), which corresponded to the signals of H-
5 and H-8 of a benzene ring. Together, this indicated
that 2 was a coumarin substituted at C-6 and C-7.
Furthermore, the 1H NMR spectrum revealed signals
at δ 5.00 (1H, t, J = 7.6 Hz, H-3), δ 3.18 (1H, dd,
J =16.0, 9.2 Hz, Ha-4), and 3.56 (1H, dd, J =16.0,
8.0 Hz, Hb-4), which indicated the presence of a
Table 2: 1H (400 MHz) and 13C NMR (100 MHz) data of
coumarins 2a and 3a (CDCl3, in δ ppm).
3-(S)-(2, 3, 4, 6-tetra-O-acetyl-
β-D-glucopyranosyloxy)-3, 4-
dihydroxanthyletin (2a)
3-(R)-(2, 3, 4, 6-tetra-O-
acetyl-β-D-
glucopyranosyloxy)-3, 4-
dihydroxanthyletin (3a)
Position
1H 13C 13C 1H
2 -- 163.2 163.1 --
3 6.21 (1H, d, 9.5 Hz) 112.3 112.4 6.21 (1H, d, 9.5 Hz)
4 7.60 (1H, d, 9.5 Hz) 143.6 143.7 7.60 (1H, d, 9.5 Hz)
5 7.21 (1H, s) 123.3 123.4 7.25 (1H, s)
6 -- 124.9 125.2 --
7 -- 161.4 161.3 --
8 6.69 (1H, s) 97.7 97.6 6.69 (1H, s)
9 -- 155.7 155.6 --
10 -- 112.7 112.8 --
2’ -- 78.5 78.4 --
3’ 4.76 (1H, t, 8.4 Hz) 89.9 90.1 4.69 (1H, t, 8.0 Hz)
4’ 3.18
(1H, dd, 16.8, 10.0 Hz)
3.24
(1H, dd, 16.8, 8.4 Hz)
29.4 29.6 3.13 (1H, dd, 16.8,
9.6 Hz)
3.32 (1H, dd, 16.8,
8.4 Hz)
Gem
(CH3)2 1.37 (3H, s)
1.28 (3H, s) 24.0
20.9 23.9
22.0 1.32 (3H, s)
1.27 (3H, s)
1” 4.79 (1H, d, 8.0 Hz) 95.6 95.6 4.82 (1H, d, 8.0 Hz)
2” 4.92
(1H, dd, 9.6, 8.0 Hz) 71.3 71.6 4.91 (1H, dd, 9.6,
8.0 Hz)
3” 5.21 (1H, t, 9.6 Hz) 72.8 72.9 5.19 (1H, t, 9.6 Hz)
4” 5.02 (1H, t, 9.6 Hz) 68.8 68.7 5.01 (1H, t, 9.6 Hz)
5” 3.72 (1H, m) 71.7 71.6 3.48 (1H, m)
6” 4.21 (1H, dd, 12.0,
2.4 Hz)
4.14 (1H. dd, 12.4,
6.0 Hz)
62.3 61.8 3.83 (1H. dd, 12.4,
4.4 Hz)
3.54 (1H, dd, 12.0,
2.4 Hz)
2”-OAc 1.83 (3H, s) 20.4
169.1 20.5
169.1 1.99 (3H, s)
3”-OAc 1.99 (3H, s) 20.6
169.4 20.6
169.4 1.99 (3H, s)
4”-OAc 2.04 (3H, s) 20.6
170.2 20.6
170.2 1.99 (3H, s)
6”-OAc 2.06 (3H, s) 20.7
170.3 20.7
170.3 2.05 (3H, s)
CH2-CHOH substituted moiety in the molecule.
Comparison with the chemical shifts [12]
and coupling patterns of the skeleton of smyrinol also
Coumarins from Angelica gigas Natural Product Communications Vol. 3 (5) 2008 787
OO O
S
OO O
R
OO O
HO
OO
HO
O
*
OO
O
O
OOO
O
O
O
OO O
O
45
78
9
2.R=H
2a.R=Ac 3.R=H
3a.R=Ac
6
3' 3'
4'
2'
5
6
789
10
2
3
4
1''
2''
3''
4'' 5''
6''
O
O
OR
OR
RO
RO
O
O
OR
OR
RO
RO
O
OO
O
O
OH
OH
HO
HO
H H
Key HMBC Correlations
Figure 1: Pyranocoumarins from Angelica gigas.
also showed an attached group at C-3. In the HMQC
spectrum (Figure 1), the two proton signals at δ 3.18
and 3.56 correlated with the carbon signal at δ 30.0,
showing a lack of substitution at C-4. These same
signals (δ 3.18, 3.56) also correlated with the carbon
signals at δ 124.1 (C-5) and 126.1 (C-6) in the
HMBC spectrum, confirming the lack of substitution.
The signals at δ 99.1 (C-1′′), 75.4 (C-2′′), 78.3
(C-3′′), 71.8 (C-4′′), 78.9 (C-5′′), and 62.8 (C-6′′) in
the 13C NMR spectrum were due to the presence of a
glucose moiety, as confirmed by hydrolysis and TLC
with a standard. In the HMBC spectrum, the proton
signal at δ 5.14 (C1′′ -H) correlated with the carbon
signal at δ 91.2 (C-3), which indicated that the
glucose moiety is attached to C-3. Thus, compound
2 was elucidated as 3-(S)-O-β-D-glucopyranosyl-
3,4-dihydroxanthyletin. Using optical rotation in
addition to 1D and 2D NMR data, compound 3 was
elucidated as 3-(R)-O-β-D-glucopyranosyl-3,4-
dihydroxanthyletin, earlier reported from
Peucedanum dissolutum with the same sign of optical
rotation [12].
In order to prove this, we re-investigated the obtained
racemic compound 1 by acetylation (Ac2O/Py),
followed by chromatography on a reverse phase
(RP-18) column to obtain 3(S)-(2,3,4,6-tetra-O-
acetyl-β-D-glucopyranosyloxy)-3,4-dihydroxanthy-
letin (2a) [[α]D25 +29.76º (c 0.04, CHCl3)] and 3(R)-
(2, 3, 4, 6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3,
4-dihydroxanthyletin (3a) [[α]D25 -26.66º (c 0.195,
CHCl3)]. The signals in the 1H NMR and 13C NMR
spectra were assigned by HMQC and HMBC
correlations and are listed in the experimental
section. Acid hydrolysis of 2a and 3a gave products
that were identified as 3-(S)-hydroxy-3, 4-
dihydroxanthyletin (10) and 3-(R)-hydroxy-3, 4-
dihydroxanthyletin (11), respectively, by comparison
of spectral data and optical rotations with those
reported in the literature [11-12]. Optical rotation was
used to assign the absolute configuration of C-3 in 2
and 3 as S and R, respectively. Thus, these chemical
structures were elucidated as 3-(S)-O-β-D-
glucopyranosyl-3,4-dihydroxanthyletin (2) and 3-
(R)-O-β-D-glucopyranosyl-3,4-dihydroxanthyletin
(3).
Compound 2 is a new natural product, whereas
compound 3 is being reported for the first time from
A. gigas.
788 Natural Product Communications Vol. 3 (5) 2008 Niranjan Reddy et al.
Experimental
General procedures: Melting points were taken on a
Thomas Hoover Unimelt capillary-melting-point
apparatus, and UV spectra were recorded on a Varian
Cary 50 Bio UV-visible spectrophotometer. Optical
rotations were measured on an Autopol-IV
polarimeter. IR spectra were recorded on a Bruker
Tensor-27 FT-IR spectrometer. NMR spectra
(1H, 13C, COSY, HMQC, and HMBC) were recorded
in CDCl3 or DMSO-d6 on a Bruker DRX 400
spectrometer operating at 400 MHz for 1H and 100
MHz for 13C, running gradients and using residual
solvent peaks as internal references. For compound 2
and 3, the NMR spectra were recorded on a Varian
400 NMR spectrometer in pyridine-d5. The high-
resolution mass spectrum of 2 was acquired on an
Agilent Series 1100 SL spectrometer. Column
chromatography was performed using silica gel
(40 μm, J. T. Baker) and reversed-phase silica gel
(RP-18, 40 μm, J. T. Baker). Preparative HPLC was
performed on a Waters LC Module-I-Plus with a
Synergy Max RP-18, 80 Å column (250 X 10 mm,
4μ).
Plant materials: Roots of A. gigas were obtained
from Korea (Jinbo Kangwondo) and a voucher
specimen (No. 2994 ANGIA) has been deposited at
the NCNPR repository, University of Mississippi,
Mississippi, USA.
Extraction and isolation: The dried powdered roots
(1.0 kg) of A. gigas were extracted with CHCl3 (4 ×
3L) and MeOH (3 × 3L) using an ultrasonic bath.
After the removal of solvent in vacuo, the CHCl3 and
MeOH extracts yielded 117.7 g and 40.2 g,
respectively. The CHCl3 extract was subjected to
silica gel column chromatography using gradient
elution with mixtures of n-hexane-EtOAc-MeOH to
afford seven fractions (Fraction 1-7). Fraction 2 (1.23
g) was subjected to silica gel column chromatography
with n-hexane: EtOAc (97:3) yielding compound 9
(6 mg). Fraction 3 (76.25 g) yielded a mixture of
structural isomers 7 and 8 [9]. Fraction 5 (4.34 g)
was subjected to C18 RP silica gel column
chromatography with n-hexane:EtOAC:acetone
(5:4:1) and yielded compound 5 (3.2 mg) and
crude compound 6 (11.0 mg). The pure compound 6
(3.1 mg) was obtained by silica gel column
chromatography eluting with n-hexane:EtOAc (1:1).
Fraction 6 (1.73 g) was subjected to silica gel column
chromatography eluting with CHCl3:MeOH (9:1) and
yielded compounds 4 (8 mg) and 1 (40 mg). Fraction-
7 (2.3 g) was subjected to Sephadex LH-20 column
chromatography eluting with DCM:MeOH (1:1) to
obtain compound 4 (80 mg).
The MeOH extract (30.1 g) was suspended in
aqueous methanol and partitioned with n-hexane and
CHCl3. After concentrating the aqueous fraction,
24.3 g of crude extract was obtained. A portion of
this (20.4 g) was subjected to C18 RP silica gel
column chromatography using MeOH:H2O (7:3).
This yielded compound 1 (3.2 g), which was further
purified on silica gel column chromatography eluting
with CHCl3:MeOH (9:1) to afford a mixture of
diastereomers (1) (1.8 g). This mixture (25 mg) was
purified by preparative HPLC on a Synergy Max RP-
18, 80 Å column (250 X 10 mm, 4μ), eluting with
H2O-Reagent alcohol-ACN (83:15:2) at 3 mL/min to
obtain compounds 2 (5 mg, tR 48.0 min) and 3 (12
mg, tR 52.0 min).
3(S)-O-β-D-Glucopyranosyl-3, 4-dihydroxanthy-
letin (2)
White solid.
MP: 212-214ºC.
[α]D25: 21.52 (c 0.37, pyridine).
IR
ν
max: 3254, 2875, 1711, 1619, 1565, 1445, 1390,
1260, 1076, 1033, 893, 849 cm-1.
UV λmax: 334 nm.
1H NMR (400 MHz, pyridine-d5): Table 1.
13C NMR: (100 MHz, pyridine-d5): Table 1.
HR ESIMS: m/z: 409.1667 (C20H24O9 calcd.
409.1500 for [M + H]+).
3(R)-O-β-D-Glucopyranosyl-3, 4-dihydroxanthy-
letin (3)
White solid.
MP: 212-214ºC.
[α]D25: -21.24 (c 0.37, pyridine).
IR
ν
max: 2874, 1713, 1621, 1563, 1447, 1390, 1256,
1073, 1028, 849 cm-1.
UV λmax: 334 nm.
1H NMR (400 MHz, pyridine-d5): Table 1.
13C NMR: (100 MHz, pyridine-d5): Table 1.
HR ESIMS: m/z: 409.1658 (C20H24O9 calcd.
409.1500 for [M + H]+).
Acetylation of 3-O-
β
-D-glucopyranosyl-3, 4-
dihydroxanthyletin (1): Compound 1 (200 mg) was
dissolved in pyridine (1 mL) and acetic anhydride (4
mL). The solution was warmed in a hot-water bath
for 1 h and then left overnight in the dark. The crude
Coumarins from Angelica gigas Natural Product Communications Vol. 3 (5) 2008 789
product was washed with water followed by 10%
HCl and then extracted with EtOAc. The EtOAc
layer was concentrated under reduced pressure to
give a crude product, which was purified by C18 RP
silica gel column chromatography using the non-
protic solvent n-hexane: EtOAc (1:1). This gave pure
compounds 3-(S)-(2, 3, 4, 6-tetra-O-acetyl-β-D-
glucopyranosyloxy)-3,4-dihydroxanthyletin (2a, 55
mg) and 3-(R)-(2, 3, 4, 6-tetra-O-acetyl-β-D-
glucopyranosyloxy)-3,4-dihydroxanthyletin (3a, 45
mg).
3-(S)-(2, 3, 4, 6-Tetra-O-acetyl-β-D-glucopyrano-
syloxy)-3,4-dihydroxanthyletin (2a)
White solid.
MP:194-195ºC.
[α]D25: +29.77 (c 0.04, CHCl3).
IR
ν
max: 1743, 1719, 1625, 1564, 1487, 1366, 1257,
1229, 1121, 1088, 1040, 959, 909, 851, 719 cm-1.
UV λmax: 335, 195 nm.
1H NMR (400 MHz, CDCl3): Table 2.
13C NMR: (100 MHz, CDCl3): Table 2.
HR ESIMS: m/z: 577.1901 (C28H32O13 calcd
577.1923 for [M + H]+).
3-(R)-(2, 3, 4, 6-Tetra-O-acetyl-β-D-glucopyrano-
syloxy)-3,4-dihydroxanthyletin (3a)
White solid.
MP: 194-195ºC.
[α]D25: -26.66 (c 0.195, CHCl3).
IR
ν
max: 2922, 1738, 1714, 1628, 1566, 1490, 1446,
1398, 1363, 1259, 1214, 1088, 1178, 1146, 1124,
1092, 1048, 964, 908, 856, 825 cm-1.
UV λmax: 335, 195 nm.
1H NMR (400 MHz, CDCl3): Table 2.
13C NMR: (100 MHz, CDCl3): Table 2.
HR ESIMS: m/z: 577.1889 (C28H32O13 calcd
577.1923 for [M + H]+).
Acid hydrolysis of 3-(S)-(2, 3, 4, 6-tetra-O-acetyl-
β-D-glucopyranosyloxy)-3,4-dihydroxanthyletin
(2a): Compound 2a (15 mg) was dissolved in MeOH
(5 mL), 15% HCl (2 mL) was added, and the reaction
mixture refluxed for 1 h. The solution was
neutralized with 10% NaOH, and extracted with
CHCl3. The CHCl3 layer was dried with Na2SO4 and
concentrated under reduced pressure. The residue
was purified by silica gel column chromatography
with n-hexane:EtOAc (2:3) to give 3(S)-hydroxy-
3,4-dihydroxanthyletin (10, 3.1 mg).
3(S)-Hydroxy-3,4-dihydroxanthyletin (10)
White solid.
MP: 174-175ºC; 178ºC [2].
[α]D25: +12.17 (c 0.06, CHCl3); +10.8 (c 0.65,
CHCl3) [2].
IR
ν
max: 3583, 3493, 3250, 2925, 2854, 2394, 1712,
1632, 1370, 1261, 1117, 952 cm-1.
1H NMR (400 MHz, CDCl3): δ 6.19 (1H, d, J = 9.2
Hz, H-3), 7.57 (1H, d, J = 9.2 Hz, H-4), 7.19 (1H, s,
H-5), 6.72 (1H, s, H-8), 4.71 (1H, t, J = 8.2 Hz, H-3),
3.62 (1H, bs, 3-OH), 3.19 (2H, dd, J = 12.0, 10.0 Hz,
H-4), 1.35 (3H, s, C-2-CH3), 1.23 (3H, s, C-2-CH3).
HR ESIMS: m/z: 247.1002 (C14H14O4 calcd 247.0992
for [M + H]+).
Acid hydrolysis of 3-(R)-(2, 3, 4, 6-tetra-O-acetyl-
β-D-glucopyranosyloxy)-3,4-dihydroxanthyletin
(3a): Compound 3a (10 mg) was dissolved in MeOH
(5 mL), 15% HCl (2 mL) was added, and the reaction
mixture refluxed for 1 h. The solution was
neutralized with 10% NaOH, and extracted with
CHCl3. The CHCl3 layer was dried with Na2SO4 and
concentrated under reduced pressure. The residue
was purified by preparative TLC, developed with
n-hexane:EtOAc (2:3) to give 3(R)-hydroxy-3,4-
dihydroxanthyletin (11, 2.1 mg).
3-(R)-Hydroxy-3, 4-dihydroxanthyletin (11)
White solid.
MP: 174-175ºC; 176-178ºC [2].
[α]D25: -15.36 (c 0.155, CHCl3); -13.9 (c 0.05,
CHCl3) [2].
IR
ν
max: 3488, 2923, 2852, 2392, 2348, 2283, 1709,
1631, 1461, 1400, 1269, 1139, 950, 818 cm-1.
1H NMR (400 MHz, CDCl3): δ 6.21 (1H, d, J = 9.6
Hz, H-3), 7.59 (1H, d, J = 9.6 Hz, H-4), 7.21 (1H, s,
H-5), 6.74 (1H, s, H-8), 4.73 (1H, t, J = 8.4 Hz, H-3),
3.64 ((1H, bs, 3-OH), 3.21 (2H, dd, J = 12.4, 9.2 Hz,
H-4), 1.37 (3H, s, C-2-CH3), 1.23 (3H, s, C-2-CH3).
HR-ESIMS: m/z: 247.0989 (C14H14O4 calcd
247.0992 for [M + H]+).
Acknowledgments - Authors are thankful to Dr
Young-Whan Choi for the plant material and
Christina Coleman for reading the manuscript. This
research was funded in part by “Botanical Dietary
Supplements: Science-Base for Authentication”
funded by the Food and Drug Administration grant
number FD-U-002071-06.
790 Natural Product Communications Vol. 3 (5) 2008 Niranjan Reddy et al.
References
[1] Jung DJ, Porzel A, Huneck S. (1991) Gigasol and other coumarins from Angelica gigas. Phytochemistry, 30, 710-712.
[2] Lee S, Lee YS, Jung SH, Shin KH, Kim BK, Kang SS. (2003) Antitumor activity of decursinol angelate and decursin from
Angelica gigas. Archives of Pharmacal Research, 26, 727-730.
[3] Lee S, Shin DS, Kim JS, Oh KB, Kang SS. (2003) Antibacterial coumarins from Angelica gigas roots. Archives of Pharmacal
Research, 26, 449-452.
[4] Ahn KS, Sim WS, Kim IH. (1996) Decursin: A cytotoxic agent and protein kinase C activator from the root of Angelica gigas.
Planta Medica, 62, 7–9.
[5] Ahn KS, Sim WS, Lee, IK, Seu, YB, Kim IH. (1997) Decursinol angelate, A cytotoxic and protein kinase C activating agent from
the root of Angelica gigas. Planta Medica, 63, 360–361.
[6] Kang SY, Lee KY, Sung SH, Park MJ, Kim YC. (2001) Coumarins isolated from Angelica gigas inhibit acetyl cholinesterase:
structure activity relationship. Journal of Natural Products, 64, 683–685.
[7] Kang YG, Lee JH, Chae HJ, Kim DH, Lee S, Park SY. (2003) HPLC analysis and extraction methods of decursin and decursinol
angelate in Angelica gigas roots. Korean Journal of Pharmacognosy, 34, 201-205.
[8] Choi SS, Han KJ, Lee HK, Han EJ, Suh WH. (2003) Antinociceptive profiles of crude extract from roots of Angelica gigas Nakai
in various pain models. Biological & Pharmaceutical Bulletin, 26, 1283-1288.
[9] Madgula VLM, Avula B, Reddy NVL, Khan IA, Khan SI. (2007) Transport of decursin and decursinol angelate across Caco-2 and
MDR-MDCK cell monolayers: In vitro models for intestinal and blood-brain barrier permeability. Planta Medica, 73, 330-335.
[10] Mchale D, Khopkar PP, Sheridan JB. (1987) Coumarin glycosides from Citrus flavedo. Phytochemistry, 26, 2547-2549.
[11] Abu-Mustsfa EA, Fayez MBE. (1961) Natural coumarins.I. Marmesin and marmesinin, further products from the fruits of Ammi
majus L.. Journal of Organic Chemistry, 26, 161-166.
[12] Masuda T, Takasugi M, Anetai M. (1998) Psoralen and other linear furanocoumarins as phytoalexins in Glehnia littoralis.
Phytochemistry, 47, 13-16.
[13] Nemoto T, Oshima T, Shibasaki M. (2003) Enantioselective total synthesis of (+)-decursin and related natural compounds using
catalytic asymmetric epoxidation of an enone. Tetrahedron, 59, 6889-6897.
[14] Wu XL, Li Y, Kong LY, Min Z. (2004) Two compounds from Peucedanum dissolutum. Journal of Asian Natural Products
Research, 6, 301-305.
... Beside these pyranocoumarins, other compounds included simple coumarins (Fig. 1B) such as umbelliferone (Konoshima et al., 1968;Jung et al., 1991), and scopoletin and furanocoumarins (Fig. 1C), for example, bergapten , xanthotoxin , imperatorin , isoimperatorin (Reddy et al., 2008;Am. J. Chin. ...
... Re-use and distribution is strictly not permitted, except for Open Access articles. Yoo et al., 2008), marmesin (Kim et al., 2006b;Reddy et al., 2008;Yoo et al., 2008) and its glucoside marmesinin , and nodakenetin (Konoshima et al., 1968;Jung et al., 1991) and its glucoside nodakenin (Jung et al., 1991;Yoo et al., 2008). See our earlier review for additional chemical structures and the botanical biosynthetic pathways for DOH core and the more complex pyranocoumarins (Zhang et al., 2012a). ...
Article
Angelica gigas Nakai (AGN) root is a medicinal herbal widely used in traditional medicine in Korea. AGN root ethanolic extract dietary supplements are marketed in the United States for memory health and pain management. We comprehensively reviewed the anticancer, analgesic, pro-memory and other bio-activities of AGN extract and its signature phytochemicals decursin, decursinol angelate, and decursinol a decade ago in 2012 and updated their anticancer activities in 2015. In the last decade, significant progress has been made for understanding the pharmacokinetics (PK) and metabolism of these compounds in animal models and single dose human PK studies have been published by us and others. In addition to increased knowledge of the known bioactivities, new bioactivities with potential novel health benefits have been reported in animal models of cerebral ischemia/stroke, anxiety, sleep disorder, epilepsy, inflammatory bowel disease, sepsis, metabolic disorders, osteoporosis, osteoarthritis, and even male infertility. Herein, we will update PK and metabolism of pyranocoumarins, review in vivo bioactivities from animal models and human studies, and critically appraise the relevant active compounds, the cellular and molecular pharmacodynamic targets, and pertinent mechanisms of action. Knowledge gaps include whether human pyranocoumarin PK metrics are AGN dose dependent and subjected to metabolic ceiling, or metabolic adaptation after repeated use. Critical clinical translation challenges include sourcing of AGN extracts, product consistency and quality control, and AGN dose optimization for different health conditions and disease indications. Future research directions are articulated to fill knowledge gaps and address these challenges.
... Two precursors of decursin, DOH and its enantiomer aegelinol ( Figure 1), were also isolated from the aerial parts of AGN (Reddy et al., 2008). DOH is a direct analog of decursin (C 14 H 14 O 4 ) with MW = 246 Da, where the (CH 3 ) 2 -C=CH-COO-side chain is simplified with a hydroxyl (-OH) group. ...
Article
Full-text available
Many naturally derived compounds are currently used in oncotherapy. Besides official medicine, complementary and alternative medicine practices, including old herbal remedies, are widely used and accepted as additional tools in cancer treatment. Angelica gigas Nakai (AGN), a medicinal herb in Asia, has roots historically used in medicine. This review focuses on key bioactive compounds from AGN roots – decursin, decursinol angelate (DA), and decursinol (DOH). Exploring their source, biosynthesis, and therapeutic mechanisms, the review highlights their role in cancer treatment. Biotechnological strategies for enhanced production and semisynthetic derivatives with anticancer properties are discussed. The study emphasizes the promising pharmacological potential of decursin, DA, and DOH in various therapeutic applications, particularly cancer treatment. The review also underscores innovative approaches to increase production and explores semisynthetic derivatives as a promising avenue for future natural product‐based drug discovery. This concise overview provides valuable insights into the potential of AGN‐derived compounds in the field of natural product‐based therapeutics.
Article
Korean Angelica gigas Nakai (AGN) is a major medicinal herb used in Asian countries such as Korea and China. Traditionally, its dried root has been used to treat anemia, pain, infection and articular rheumatism in Korea, most often through boiling in water to prepare the dosage forms. The pyranocoumarin compound decursin and its isomer decursinol angelate (DA) are the major chemical components in the alcoholic extracts of the root of AGN. The in vitro anti-tumor activities of decursin and/or DA against prostate cancer, lung cancer, breast cancer, colon cancer, bladder cancer, sarcoma, myeloma and leukemia have been increasingly reported in the past decade whereas the in vivo efficacy in mouse models was established only for a few organ sites. Preliminary pharmacokinetics study by us and others in rodent models indicated that decursinol (DOH), which has much less in vitro direct anti-cancer activities by itself, is the major and rapid in vivo hydrolysis metabolite of both decursin and DA. Besides decursin, DA and DOH, other chemical components in AGN such as polysaccharides and polyacetylenes have been reported to exert anti-cancer and anti-inflammation activities as well. We systematically reviewed the published literature on the anti-cancer and other bio-activities effects of AGN extract and decursin, DA and DOH, as well as other chemicals identified from AGN. Although a number of areas are identified that merit further investigation, one critical need is first-in-human studies of the pharmacokinetics of decursin/DA to determine whether humans differ from rodents in absorption and metabolism of these compounds.
Article
This paper is intended as an investigation of the analysis of high-performance liquid chromatography and the method of extraction of decursin and decursinol angelate in Angelica gigas roots. There are three kinds of extraction methods: distilled water, 50% EtOH and 100% EtOH. The condition of HPLC was obtained on a reversed-phase column (Polarity dC18, 4.6 x 250 mm, 5 μm) using a phosphate buffer-acetonitrile-sodium lauryl sulfate as the mobile phase. Under these chromatographic conditions, UV detector was 230 nm, column temperature 30°C and the speed of a current 1.0 ml/min, respectively. The results of extraction with distilled water, 50% EtOH and 100% EtOH in Angelica gigas roots were as follows. The concentrations of decursin and decursinol angelate were 182 and 153 ppm (distilled water), 3,142 and 2,547 ppm (50% EtOH) and 3,341 and 2,778 ppm (100% EtOH). There were high positive correlations between the concentrations of decursin and EtOH (r=0.8928, p<0.01) and decursinol angelate and EtOH (r=0.9009, p<0.01).
Article
Acetylcholinesterase (AChE) inhibitory activity−guided fractionation of Angelica gigas led to isolation and identification of a new coumarin, peucedanone (12), and isolation of 11 known coumarins. Among them, decursinol (1) represented the highest inhibitory activity toward AChE in vitro. The correlation of the inhibitory activities of the coumarins toward AChE with their chemical structures was studied.
Article
The enantioselective total syntheses of (+)-decursin (1) and related natural dihydropyranocoumarins (−)-prantschimgin (3), (+)-decursinol (4), and (+)-marmesin (5) were achieved for the first time using catalytic asymmetric epoxidation of an enone as the key step. Catalytic asymmetric epoxidation of the enone was effectively promoted by the novel multifunctional asymmetric catalyst generated from La(O-i-Pr)3, BINOL, and Ph3AsO in a 1:1:1 ratio to afford epoxide in 94% yield and 96% ee, which was recrystallized to give optically pure epoxide. After conversion to the common key intermediate (−)-peucedanol (7), all natural dihydropyranocoumarins were synthesized through palladium-catalyzed intramolecular C–O coupling reactions. A possible reaction mechanism of the catalytic asymmetric epoxidation of enones is also described based on X-ray analysis, laser desorption/ionization time-of-flight mass spectrometry, kinetic studies, and asymmetric amplification studies.
Article
Inoculation of Glehnia littoralis root slices with Pseudomonas cichorii induced the production of four linear furanocoumarin phytoalexins, psoralen, xanthotoxin, bergapten and demethylsuberosin, of which the former three have been reported as constituents of the crude drug Glehnia root. A time-course study on the respective P. cichorri-inoculated, UV-irradiated and non-irradiated root slices showed greatly increasing concentrations of the furanocoumarins after stress treatment. Psoralen, xanthotoxin and bergapten in the crude drug were considered, at least in part, to be stress metabolites produced during processing.
Article
The following coumarins have been isolated from the aerial parts of Angelica gigas: decursin, a 2:1 mixture of decursinol and its enantiomer aegelinol, a racemic mixture of (+)- and (−)-agasyllin, prenyletin, nodakenetin, nodakenin and gigasol, the first dimethyleneoxy-bis-coumarin.
Article
The isolation of marmesinin and its synthesis are described. Several reactions with marmesin and its derivatives establish that bromination and nitration occur at the six position and the same is suggested to happen with nodakenetin and analogous dihydrofurocoumarins. A correlation has been made between marmesin and products derived from peucedanin.
Article
Two coumarin glycosides of possible taxonomic significance have been isolated from aqueous extracts of bitter orange flavedo and shown to be the new natural products 8-(1-β-D- glucopyranosyloxy-1-methylethyl)-8,9-dihydro-2H-furo-[2,3-h]-1-benzopyran-2-one and 8-(3-β-D-glucopyranosyloxy-2-hydroxy -3-methylbutyl)-7-methoxy-2H-1-benzopyran-2-one. The latter glycoside was also present in aqueous extracts of grapefruit and pummelo flavedo but at lower levels. All the flavedo extracts contained meranzin, meranzin hydrate and isomeranzin.
Article
A cytotoxic compound was purified from the root of Angelica gigas Nakai by silica gel chromatography and preparative HPLC. As a result of the structure analysis by mass, IR, 1H-NMR, and 13C-NMR spectrometry, the effective compound was identified as decursin, a pyranocoumarin characterized originally from Angelica decursiva Fr. et Sav. In vitro cytotoxicity testing showed that decursin displayed toxic activity against various human cancer cell lines, for which the ED50 of decursin was about 5-16 micrograms/ml. On the other hand, decursin displayed relatively low cytotoxicity against normal fibroblasts. Decursin also activated protein kinase C (PKC) in vitro, which indicates that the cytotoxic activity of decursin may be related to the protein kinase C activation.
Article
A cytotoxic compound was purified from the root of Angelica gigas Nakai by normal phase HPLC. As a result of the structure analysis by mass, IR, 1H-NMR, and 13C-NMR spectrometry, the compound was identified as decursinol angelate, a structural isomer of decursin, and characterized originally from Sesei grandivittatum. Decursinol angelate showed in vitro cytotoxicity and protein kinase C activating activities like decursin.
Article
Systematic fractionation of Angelica gigas roots led to the isolation of linear furano(pyrano)coumarins such as bergapten (1), decursinol angelate (2), decursin (3), nodakenetin (4) and nodakenin (5). The antibacterial activities of those compounds against pathogenic bacteria were investigated. Among the compounds tested, decursinol angelate (2) and decursin (3) exhibited significant antibacterial activity against Bacillus subtilis with the minimum inhibitory concentrations (MICs) of 50 and 12.5 microg/mL, respectively.