Triangeliphthalides A-D: Bioactive phthalide trimers with new skeletons from: Angelica sinensis and their production mechanism

Article abstract of DOI:10.1039/c9cc02681a

Triangeliphthalides A-D (1-4), four novel phthalide trimers with two new linkage styles, were isolated from Angelica sinensis, together with two related phthalide dimers (5-6). Their structures including absolute configurations were determined. The production mechanism of phthalide polymers was proposed, and their bioactivities were also evaluated.

Full text of DOI:10.1039/c9cc02681a

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
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DOI: 10.1039/C9CC02681A
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Triangeliphthalides A-D: Bioactive Phthalide Trimers with New
Skeletons from Angelica sinensis and Their Production Mechanism
Received 00th March 20xx,
Accepted 00th April 20xx
Jian Zou,‡a,b Guo-Dong Chen,‡a Huan Zhao,c Xiao-Xia Wang,a Zai-Jun Zhang,d Yi-Bo Qu,e Rong-Rong
He,a Kwok-Fai So,d Xin-Sheng Yao,a Hao Gao*a
DOI: 10.1039/x0xx00000x
from cycloaddition of two or three units of monomeric
phthalides with different linkage styles, which forms a number
of polycyclic skeletons.5 Natural phthalide polymers are a class
of important active components of Traditional Chinese
Medicines (TCMs) from Apiaceae plants4, such as A. Sinensis
(Angelicae Sinensis Radix), L. chuanxiong (Chuanxiong
Rhizoma), L. sinensis (Ligustici Rhizoma Et Radix), and L.
Triangeliphthalides A–D (1–4), four novel phthalide trimers with
two new linkage styles were isolated from Angelica sinensis,
together with two related phthalide dimers (5–6). Their structures
including absolute configurations were determined. The
production mechanism of phthalide polymers was proposed, and
their bioactivities were also evaluated.
jeholense (Ligustici Rhizoma Et Radix). Levistilide
A
(phthalide dimer) is used in the quality control of L. chuanxiong
(Chuanxiong Rhizoma) in China Pharmacopeia 2015. Until
now, most reported polymeric phthalides are dimeric, including
fourteen linkage styles. Only three trimeric phthalides were
reported, and they all derived from the same monomer unit
(ligustilide).5d, 5e In addition, the production mechanism of these
polymeric phthalides remains unclear.
A. sinensis, a well-known medicinal plant, is mainly
cultivated in the northwestern of China. Its dried root (Dang-
gui) is one of the most important TCMs.6 In our preliminary
research on Dang-gui, two pairs of enantiomeric phthalide
trimers (triligustilides A and B) originating from [2+2]/[2+2]
cycloaddition of ligustilide with the linkage style (2−4′/7−3′,
3′′−8′/4′′−9′) and related phthalide dimers were discovered.5e
Further investigation on this plant led to the isolation of four
Phthalides, known as 3H-isobenzofuran-1-ones, are
characterized by a bicyclic nucleus derived from the fusion of a
γ-lactone with a six-membered ring.1 They mainly distribute in
Apiaceae plants such as Angelica sinensis and Ligusticum
chuanxiong, and in several species of fungi.2 They not only
exhibit a broad spectrum of biological activities (antiasthma,
anticonvulsion, inhibition of platelet aggregation, enhancement
of blood flow volume, etc.), but also act as versatile building
blocks in organic synthesis (particularly in the total synthesis of
functionalized naphthalenes, anthracenes, and naphthacene
natural products).1, 3 Their wide range of functions derive from
their tremendous structural diversity. The reported phthalide
natural products, according to the structural characteristics of
phthalide units, are generally classified into three categories: (ⅰ)
8-unsubstituted phthalides, (ⅱ) 8-substituted phthalides, and (ⅲ)
polymeric phthalides.4 The polymeric phthalides are derived
novel phthalide trimers triangeliphthalides A-D
originating from [2+2]/[2+2] cycloaddition with two new
linkage styles (2−8′/7−9′, 3′−8′′/4′−9′′), (3′−8/4′−9,
8′−8′′/9′−9′′). They are the first cases of phthalide trimers from
different monomer units (Z-ligustilide and Z-
Two related phthalide
) and gelispirolide (
(1–4)
a. Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy
/ Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM
and New Drugs Research, Jinan University, Guangzhou 510632, People’s Republic
of China. E-mail: tghao@jnu.edu.cn.
butylidenephthalide).
dimers
diangeliphthalide A (
5
6
) were also
obtained. All compounds were found to exist in racemic
manners through chiral HPLC analysis. After chiral resolution,
four pairs of new phthalide trimers [(+) triangeliphthalide A
b. Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan
University, Guangzhou 510632, People’s Republic of China.
c. College of Traditional Chinese Medicine, Jinan University, Guangzhou 510632,
People’s Republic of China.
(1a)/(−) triangeliphthalide A (1b), (+) triangeliphthalide B
(2a)/(−) triangeliphthalide B (2b), (−) triangeliphthalide C
(3a)/(+) triangeliphthalide C (3b), and (+) triangeliphthalide D
(4a)/(−) triangeliphthalide D (4b)], and two pairs of new
d. Institute of New Drug Research, College of Pharmacy / Guangzhou Key Laboratory
of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan
University, Guangzhou 510632, People’s Republic of China.
e. GMH Institute of Central Nervous System Regeneration, Guangdong Medical ke y
Laboratory of Brain Function and Diseases, Jinan University, Guangzhou 510632,
People’s Republic of China.
phthalide dimers [(−) diangeliphthalide
A
(5a)/(+)
diangeliphthalide 5b), and (−) gelispirolide (6a)/(+)
A
(
†Electronic Supplementary Information (ESI) available: [The NMR data assignments
of 1−6, structural characterizations of 1−6, general experimental procedures, plant
material, extraction and isolation, chiral separations of 1–6, X-ray crystallographic
anallysis of 1, conformational analysis and quantum chemical 13C NMR calculation
of 1, quantum chemical ECD calculations of 1′−6′, antiinflammatory assay of 1−5,
antiplatelet aggregation assay of 1−5, antimicrobial assay of 1−5, the related
operation of LC-HR-ESI(+)MS analysis, computational details, and the 1D and 2D
NMR spectra of 1−6]. See DOI: 10.1039/x0xx00000x
gelispirolide (6b)] were obtained. Herein, we describe the
isolation, planar structure elucidation, chiral resolution,
stereochemistry determination of all compounds (
bioassays (including anti-inflammatory, anti-platelet
aggregation and antimicrobial activities) of new compounds
). Moreover, the production mechanism of phthalide
1−6), and
(1−5
‡ Both authors contributed equally.
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polymers is proposed by LC-HR-ESI(+)MS analysis, TDDFT
and DFT calculation.
Triangeliphthalide B (
2
) was isolated as a yeVlileowwArtoicilel.OTnlhinee
molecular formula of
2
was establishDeOdI: 1a0s.10C393/6CH94C0CO0626(811A7
degrees of unsaturation) from its HR-ESI-MS (m/z 569.2900
[M + H]+, calcd. for [C36H41O6]+: 569.2903). The NMR data of
2
are very similar to those of
1. Detailed analyses of the 1D and
2D NMR data established the same planar structure as that of
1.
The assignments of all proton and carbon resonances are
provided in Table S2. The geometry of the double bond of Δ8
in
2 was assigned as Z configuration by the NOESY correlation
between H-9 and Ha-6. In the 4,5-dihydro-1H,3H-3a,7a-
ethanoisobenzofuran system, the relative configurations of C-2
and C-7 should be fixed as 2R*, 7R*. Furthermore, the NOESY
correlations between Hb-6 and Hb-10′, and between Hb-6′ and
H-9′ indicated that the relative configurations of C-2, C-7, C-8′,
and C-9′ should be fixed as 2R*, 7R*, 8′S*, and 9′R*,
respectively. The NOESY correlations between H-4′ and Ha-
10′′/Hb-10′′, between Hb-5′ and H-9′′, and between Ha-6′/H-9′′
and H-6′′ indicated that the relative configurations of C-3′, C-4′,
C-8′′ and C-9′′ should be fixed as 3′R*, 4′S*, 8′′S*, and 9′′S*,
respectively. The NOESY correlation between Ha-10′ and H-6′′
establish the whole relative configuration of
8′S*, 9′R*,3′R*, 4′S*, 8′′S*, 9′′S*. By the same structure
elucidation procedures as compound , the planar structures of
triangeliphthalides C-D ( ) were established (Figure 1), and
the relative configurations of were determined as 8R*, 9R*,
2 as 2R*, 7R*,
2
3–4
3–4
3′S*, 4′R*, 8′R*, 9′S*, 8′′R*, 9′′S* and 8R*, 9R*, 3′S*, 4′R*,
8′R*, 9′S*, 8′′R*, 9′′S*, respectively. The assignments of all
proton and carbon resonances are provided in Table S3 and
Table S4
.
Figure 1 Chemical structures of 1–6.
Triangeliphthalide A (
1) was isolated as colorless crystals.
The molecular formula of
1 was established as C36H40O6 (17
degrees of unsaturation) from its HR-ESI-MS (m/z 569.2910
[M + H]+, calcd. for [C36H41O6]+: 569.2903). Based on the
molecular formula information, the degree of unsaturation, and
the analyses of 1H–1H COSY and HMBC data, the planar
structure was established as shown in Figure 2
assignments of all proton and carbon resonances are provided
in Table S1. The geometry of the double bond of Δ8 in
was
assigned as Z configuration by the NOESY correlation between
H-9 and Ha-6. In the 4,5-dihydro-1H,3H-3a,7a-
. The
Figure 2. Key 1H–1H COSY and HMBC correlations of 1.
1
ethanoisobenzofuran system, the relative configurations of C-2
and C-7 should be fixed as 2R*, 7R*. Furthermore, the NOESY
correlations between Hb-6 and Ha-10′/Hb-10′, and between H-
6′ and H-9′ indicated that the relative configurations of C-2, C-
7, C-8′, and C-9′ should be fixed as 2R*, 7R*, 8′S*, and 9′R*,
respectively. The NOESY correlations between H-3′ and H-
6′′/H-9′′, between Ha-5′ and Ha-10′′/Hb-10′′, and between H-6′′
and H-9′′ indicated that the relative configurations of C-3′, C-4′,
C-8′′ and C-9′′ should be fixed as 3′R*, 4′S*, 8′′R*, and 9′′R*,
respectively. Thus, there were two possible relative
200
180
160
140
120
100
80
200
180
160
140
120
100
80
y = 0.9968x + 0.2492
R² = 0.9968
y = 0.9973x + 0.217
R² = 0.9973
60
60
40
40
20
20
0
0
configurations for
1, including (2R*, 7R*, 8′S*, 9′R*, 3′R*,
0
50
100
150
200
0
50
100
150
200
4′S*, 8′′R*, 9′′R*)-1-A and (2R*, 7R*, 8′S*, 9′R*, 3′S*, 4′R*,
8′′S*, 9′′S*)-1-B. In order to establish the whole relative
1-A
DP4+ 100%
1-B
0%
8
6
4
2
0
configuration of 1
, the theoretical calculations of 13C NMR data
of the two possible isomers 1-A and 1-B were predicted by
using the GIAO method with the Gaussian 09 software at the
B3LYP/6-31G+(d, p) level. Comparison between the
experimental and the calculated 13C NMR data allowed the
-2
-4
-6
-8
determination of the whole relative configuration of
1 to be
2R*, 7R*, 8′S*, 9′R*, 3′R*, 4′S*, 8′′R*, 9′′R* with a DP4+
(2R*, 7R*, 8'S*, 9'R*, 3'R*, 4'S*, 8''R*, 9''R*)-1-A (2R*, 7R*, 8'S*, 9'R*, 3'S*, 4'R*, 8''S*, 9''S*)-1-B
probability of approximately 100% (Figure 3).7 The relative
Figure 3. The 13C NMR calculation results of two plausible
stereoisomers at B3LYP/6-31G+(d, p) level. (a) Linear
configuration of
1 was confirmed by the single-crystal X-ray
diffraction experiment (Figure 4).
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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correlation plots of calculated vs experimental 13C NMR
chemical shift values for 1-A/1-B of 1. (b) Relative errors
between the calculated 13C NMR chemical shifts of 1-A/1-B and
the recorded 13C NMR data of 1, and DP4+ Probability analysis.
R330). No compounds possessed antiplatelet aggregation and
antimicrobial activities (Table S14 and TDaObIl:e10S.11053V9ie/Cw9ACrtCicl0e2O6n8li1nAe
).
Polymeric phthalides have attracted great attention from
natural products researchers not only for their intriguing
Diangeliphthalide A (
5
) was isolated as a yellow oil. The biological activities but also for their fascinating chemical
molecular formula of
5
was established as C24H26O4 (11 structures.5 Their structure complexity mainly depends on the
degrees of unsaturation) from its HR-ESI-MS (m/z 379.1904 cycloaddition of two or three monomeric phthalides with
[M + H]+, calcd. for [C24H27O4]+: 379.1909). Detailed analyses different linkage styles. In the present research, four phthalide
of the 1D and 2D NMR data (Table S5) established the planar trimers triangeliphthalides A–D (
structure of , and the relative configuration of was possessed two unprecedented linkage styles ((2−8′/7−9′,
determined as 8R*, 9S*, 8′R*, 9′S*. Another related known 3′−8′′/4′−9′′) and (3′−8/4′−9, 8′−8′′/9′−9′′)) with complex
phthalide dimer (compound ) was identified as gelispirolide by polycyclic skeletons. They are the first cases of phthalide
comparison of the NMR data with literature values (Table S6).8 trimers from different monomeric units (Z-ligustilide and Z-
1–4) were obtained, which
5
5
6
Detailed analyses of the 1D and 2D NMR data of
the above deduction.
6
confirmed butylidenephthalide). In addition, two related phthalide dimers,
a new compound diangeliphthalide A ( ) and a known
phthalide dimer gelispirolide ( ), were also isolated. This is the
first time that the optically pure compounds (6a 6b) have been
5
6
/
obtained from racemate, and their absolute configurations are
reported.
60
40
20
60
40
20
60
40
20
#
#
#
**
*
**
**
***
***
***
***
***
*** ***
*** *** ***
0
LPS
0
LPS
0
+
+
5
+
+
+
+
+
5
+
+
+
+
+
5
+
+
+
-
-
+
-
-
-
+
-
-
-
+
-
LPS
3 (M)
4 (M)
Hydrocortisone
10 20 40
10 20 40
10 20 40
2.5
2.5
2.5
(M)
4000
3000
2000
1000
6000
4000
2000
6000
Figure 4. X-ray crystallographic analyses of 1.
#
4000
2000
#
#
The specific optical rotations of
indicating that might be mixtures of enantiomers. This
deduction was confirmed by the observations of in the
chiral HPLC analyses (Figure S1). Based on these chiral HPLC
analyses, these six pairs of enantiomers [(+) 1a / (–) 1b, (+) 2a
1–6 were close to zero,
*** *** ***
***
***
1–6
0
0
LPS
0
LPS
1–6
-
-
-
+
-
+
+
+
+
+
+
-
+
+
5
+
+
+
+
+
5
+
+
+
-
+
-
LPS
3 (M)
-
5
10 20 40
4 (M)
10 20 40Hydrocortisone
-
10 20 40
2.5
2.5
2.5
(M)
/
(–) 2b, (–) 3a / (+) 3b, (+) 4a / (–) 4b, (–) 5a / (+) 5b and (–) 6a Figure 5. Effects of compounds 3–4 and positive control
/ (+) 6b] were obtained (Figure S1). The quantum chemical (hydrocortisone) on the inhibition of IL-6 (a) and TNF-α
calculations of the electronic circular dichroic (ECD) spectra (b). The data represent the mean ± SD of three experiments.
were used to determine the absolute configurations of 1a and *p < 0.1, **p < 0.01, ***p < 0.001 compared with the LPS
group; #p < 0.001 compared with the control group
The plausible modes of formation of 1−6 are proposed as
shown in Scheme 1. Three biosynthetically related phthalide
1b. Since the flexible side chains far away from the chiral
carbons in
the simplified structures of (2R, 7R, 8′S, 9′R, 3′R, 4′S, 8′′R,
9′′R)-1' and (2S, 7S, 8′R, 9′S, 3′S, 4′R, 8′′S, 9′′S)-1' Figure S6
1
had an insignificant effect on the ECD spectrum,9
dimers with three types of linkages (type A, 8–8′ / 9–9′,
(
)
diangeliphthalide A (5); type B, 3–8′ / 4–9′, gelispirolide (6);
were used for the ECD calculations. The predicted ECD curves
of (2R, 7R, 8′S, 9′R, 3′R, 4′S, 8′′R, 9′′R)-1' and (2S, 7S, 8′R, 9′S,
3′S, 4′R, 8′′S, 9′′S)-1′ were almost identical to the experimental
ones of 1a and 1b, respectively. Therefore, the absolute
configurations of 1a and 1b were established as (2R, 7R, 8′S,
9′R, 3′R, 4′S, 8′′R, 9′′R)-1a and (2S, 7S, 8′R, 9′S, 3′S, 4′R, 8′′S,
9′′S)-1b, respectively (Figure S6). The absolute configurations
type C, 2–8′ / 7–9′, tokiaerialide10) derive from two molecules
of monomer phthalides (Z-ligustilide or Z-butylidenephthalide)
through [2+2] cycloaddition. Whereas four novel phthalide
trimers with two new types of linkages (type B+C, 2−8′/7−9′,
3′−8′′/4′−9′′, triangeliphthalides A−B
(
1−
2); type A+B,
3′−8/4′−9, 8′−8′′/9′−9′′, triangeliphthalides C−D
(3−4
))
originate from three molecules of monomer phthalides (Z-
ligustilide or Z-butylidenephthalide) through [2+2]/[2+2]
cycloaddition.
of (2a/2b–6a/6b) were established by the same procedures as
those of 1a/1b, respectively (Electronic Supplementary
Information).
According to classic effects of Dang-Gui and the
established bioassay models in our group, bioassays (including
anti-inflammatory, antiplatelet aggregation and antimicrobial
activity) of all new phthalides (
In the anti-inflammatory assay in LPS-stimulated
RAW264.7 macrophages, compounds exhibited the anti-
inflammatory effects against the production of the pro-
inflammatory cytokines (IL-6) (Figure 5). Compounds and
showed cytotoxic effect on RAW264.7 cells (Electronic
1−5) were carried out.
3−4
1–2
5
Supplementary Information).
Furthermore, compounds
1
−
5
were evaluated for
Scheme 1. The plausible formation modes of compounds
1−6.
inhibition in vitro against platelet aggregation in rat plasma
induced with arachidonic acid (AA), and they were also
evaluated for antimicrobial assays against two bacteria
(Staphylococcus aureus 209P, Escherichia coli ATCC0111),
and two fungi (Canidia albicans FIM709, Aspergillus niger
In order to reveal the production mechanism of these
complex phthalide polymers, we took compounds
6 and 1 as
examples. A LC-HR-ESI(+)MS analysis of the extract of fresh
Dang-gui was carried out, and this extract was obtained through
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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cooling extraction with 95% EtOH/H2O in the dark place. The kinamycins through non-enzymatic deacylation of acyl
View Article Online
LC-HR-ESI(+)MS analysis indicated that the ion peaks (m/z kinamycins.11a Artemisians A–D are antiproliferative
DOI: 10.1039/C9CC02681A
379.1896/C24H27O4 at tR = 31.5 min, and m/z 569.2912/ compounds from Artemisia argyi (a famous TCMs), which
C36H41O6 at tR = 43.9 min) and their MS2 spectra in the extract derive from
a
rare 1,10-4,5-diseco-guaianolide and
a
were consistent with the retention times, the ion peaks (m/z guaianolide diene through non-enzymatic [4
+
2]
379.1898/C24H27O4, and m/z 569.2886/C36H41O6), and the MS2 cycloaddition.11b Diasteltoxins A–C are a class of antitumor
spectra in the chromatograms of
6
and
1, which proved that
6
compounds from
a
sponge-derived fungus Emericella
and
1 are produced in this plant (Electronic Supplementary variecolor, which derive from two units of asteltoxin through
Information). Then, the TDDFT calculations of the excited non-enzymatic [2 + 2] cycloaddition.11c These spontaneously
energy, corresponding wavelength, and excited contribution of generated polymers not only possess complex skeletons but
Z-ligustilide, Z-butylidenephthalide, 6, and 1 were carried out. also exhibit significant bioactivities. The reveal of these novel
It is notable that major monomeric phthalide Z-ligustilide phthalide trimers presented the interesting cases of bioactive
showed the lowest excited energy (3.5703 eV) and the longest spontaneously generated polymers, and can also contribute to
excitation wavelength (λexcitation = 347.26 nm), which indicated the understanding of the chemistry and biology of the important
that Z-ligustilide is the most likely species to be excited (Table traditional medicine Dang-gui.
S16). Furthermore, the DFT result showed that it is feasible for
Z-ligustilide to undergo TS-6 and TS-1 to deliver the [2+2] National Natural Science Foundation of China (3171101305),
cycloaddition products and with the energy barriers of 6.1 Chang Jiang Scholars Program (Hao Gao, 2017) from the
This work was financially supported by grants from the
6
1
and 10.8 Kcal/mol respectively (Figure 6). The calculated Ministry of Education of China, Guangdong Special Support
results showed that phthalide polymers could be spontaneously Program (2016TX03R280), Guangdong Province Universities
generated, but it is not clear whether some enzymes were also and Colleges Pearl River Scholar Funded Scheme (Hao Gao,
involved in the formation of polymers.
2014), Local Innovative and Research Teams Project of
Guangdong Pearl River Talents Program (2017BT01Y036),
and K. C. Wong Education Foundation (Hao Gao, 2016). We
are thanks to the high-performance computing platform of Jinan
University. We are grateful to Zhong-Chao Zhang at the Peking
University for the TDDFT and DFT calculation.
Notes and references
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M. J. Xiong, Z. H. Li, Curr. Org. Chem. 2007, 11, 833.
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Lu, Z. J. Wang, Phytochem. Analysis, 2006, 17, 398; c) S. X.
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893.
5
6
Figure 6. Calculated energies profiles for photo-induced
[2+2] cycloaddition reactions of 6 and 1 via TS-6 (T) (a))
and TS-1 (T) (b)). Free energies are given in kcal/mol.
7
8
9
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Phthalide monomers and polymers are important active
natural constituents of TCMs.4 They are not only used in the
quality control for TCMs such as Z-ligustilide (Angelicae
Sinensis Radix) and levistilide A (Chuanxiong Rhizoma), but
also used as important sources of new drugs such as n-
butylphthalide (a drug for the treatment of ischemic stroke). It
is known that phthalide monomers originate from polyketide
biosynthetic pathway2, and our research revealed that phthalide
polymers could be spontaneously generated through TDDFT
and DFT calculations. For natural products, most of them are
actually enzyme-catalyzed, and some important active
compounds are spontaneously generated such as lomaiviticin A,
artemisians A–D, diasteltoxins A–C and so on.11 Among them,
lomaiviticin A is an antitumor drug and currently under pre-
clinical evaluation, which originates from two molecules of
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Y.G. Zhu, X.D. Jiang, C.Y. Fang, Q.B. Zhang, C.S. Yuan,
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9CC02681A
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Angelica sinensis
Triangeliphthalide A (1)
Four bioactive phthalide trimers with new skeletons were isolated from Angelica sinensis, and their
production mechanism was proposed.