Antiproliferative and apoptotic effects of compounds from the flower of Mammea siamensis (Miq.) T. Anders. on human cancer cell lines

Article abstract of DOI:10.1016/j.bmcl.2012.10.127

On the search for anti-cancer compounds from Thai traditional herb medicines, a bioassay-guided fractionation and chemical investigation of the methanol extract of Mammea siamensis flower resulted in the isolation and identification of eight compounds (1-8) including a novel geranylated coumarin, namely mammeanoyl (2), and seven known compounds (1 and 3-8). The structure of new compound 2 was elucidated based on the extensive spectroscopic and chemical methods. Among the isolated compounds, three structurally related coumarins 3, 4, and 5 showed significant antiproliferative activities against human leukemia and stomach cancer cell lines. However, these compounds did not affect the cell viabilities of colon cancer, hepatoma, and normal skin fibroblast cell lines. Further analysis demonstrated that the morphological features of apoptosis including DNA fragmentation and chromatin condensation were observed in human leukemia HL-60 cells treated with compounds 3, 4, and 5. In addition, compound 3 led to caspase-3 activation and cleavage of poly (ADP-ribose) polymerase (PARP), and compound 3-induced DNA fragmentation was inhibited by caspase-specific inhibitors. These results suggest that compound 3, 4, and 5 exert antiproliferative actions through apoptotic cell death in leukemia cells and these compounds may have the potential to be developed into new anti-cancer drug candidates.

Full text of DOI:10.1016/j.bmcl.2012.10.127

Bioorganic & Medicinal Chemistry Letters 23 (2013) 158–162
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Antiproliferative and apoptotic effects of compounds from the flower
of Mammea siamensis (Miq.) T. Anders. on human cancer cell lines
Nguyen Huu Tung a, , Takuhiro Uto a, , Ayana Sakamoto a, Yuka Hayashida a, Yuuki Hidaka a,
Osamu Morinaga a, Sorasak Lhieochaiphant b, Yukihiro Shoyama a,
⇑
a Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Nagasaki International University, 2825-7 Huis Ten Bosch, Sasebo, Nagasaki 859-3298, Japan
b Faculty of Pharmacy, Payap University, Superhighway Chiang Mai-Lampang Road, Muang, Chiang Mai 50000, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
On the search for anti-cancer compounds from Thai traditional herb medicines, a bioassay-guided
fractionation and chemical investigation of the methanol extract of Mammea siamensis flower resulted
in the isolation and identification of eight compounds (1–8) including a novel geranylated coumarin,
namely mammeanoyl (2), and seven known compounds (1 and 3–8). The structure of new compound
2 was elucidated based on the extensive spectroscopic and chemical methods. Among the isolated
compounds, three structurally related coumarins3, 4, and 5 showed significant antiproliferative activities
against human leukemia and stomach cancer cell lines. However, these compounds did not affect the cell
viabilities of colon cancer, hepatoma, and normal skin fibroblast cell lines. Further analysis demonstrated
that the morphological features of apoptosis including DNA fragmentation and chromatin condensation
were observed in human leukemia HL-60 cells treated with compounds 3,4, and 5. In addition, compound
3 led to caspase-3 activation and cleavage of poly (ADP-ribose) polymerase (PARP), and compound
3-induced DNA fragmentation was inhibited by caspase-specific inhibitors. These results suggest that
compound 3, 4, and 5 exert antiproliferative actions through apoptotic cell death in leukemia cells and
these compounds may have the potential to be developed into new anti-cancer drug candidates.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 2 October 2012
Revised 26 October 2012
Accepted 29 October 2012
Available online 7 November 2012
Keywords:
Mammea siamensis
Coumarin
Antiproliferation
Apoptosis
Leukemia cells
Mammea siamensis (Miq.) T. Anders., commonly known as Sarapi
in Thailand, is an evergreen tree belonging to the family of Calo-
phyllaceae, and distributed throughout Thailand, Myanmar, Laos,
Cambodia, and Vietnam. Its flowers have traditionally been used
as a heart tonic, fever-lowering, and enhancement of appetite in
Thailand.1,2 Previous phytochemical studies on the flower of M.
siamensis have led to the isolation of several unique coumarins,3–5
some of which have potential pharmacological and therapeutic
properties.6–8
Apoptosis is a highly regulated programmed cell death process
by which cells undergo inducible non-necrotic cellular suicide,
thus, it plays an important role in anti-carcinogenesis.9 Apoptosis
is characterized by distinct morphological changes such as cell
shrinkage, chromatin condensation, plasma membrane blebbing,
and oligonucleosomal DNA fragmentation.10 The strategy to
selectively induce apoptosis in cancer cells is important for cancer
chemoprevention and chemotherapy, and various compounds that
are used in cancer chemotherapy have apoptotic activity.11
In our research on anti-cancer phytotherapy, we previously re-
ported the potent anti-cancer activity of alkannin derivatives from
Alkanna tinctoria12 and crocin from saffron (Crocus sativus).13,14 As
part of the ongoing study, our current preliminary screening of Thai
medicinal plants found promising antiproliferative effects of a
methanol extract from the M. siamensis flowers on several human
cancer cell lines. In order to isolate compounds showing antiprolif-
erative activity, we performed a bioassay-guided fractionation of
methanolic extract of M. siamensis flower. The air-dried flower of
M. siamensis was extracted with MeOH at 40 °C under sonication.
After removal of solvent, the obtained residue was suspended in
water and successively partitioned with hexane, CH2Cl2, EtOAc,
and n-BuOH to obtain individual fractions. To identify the bioactive
compounds responsible for the antiproliferative activity, each
fraction was examined for the cell proliferation of cancer cell lines
by using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium
bromide (MTT) assay. The activity was concentrated in hexane
and CH2Cl2 fractions, which inhibited the cell proliferation of hu-
man leukemia HL-60 and stomach cancer cells KATO III (Supple-
mentary Fig. 1). Based on the similarity of TLC profile, the hexane
and the CH2Cl2 fractions were combined together, and then
subjected repeatedly to column chromatography over silica gel
and reverse-phase (RP) C18 to afford a new coumarin, named as
mammeanoyl (2), and seven known compounds (Supporting infor-
mation) including mammea B/AC cyclo D (1),3 kayeassamin A (3),8
surangin C (4),6 theraphin B (5),7 siamenol D (6),15 isovitexin (7),16
⇑
Corresponding author. Tel.: +81 956 20 5653; fax: +81 956 20 5622.
E-mail address: shoyama@niu.ac.jp (Y. Shoyama).
These authors contributed equally to this work.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.127

N. H. Tung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 158–162
159
and amentoflavone (8),17 respectively (Fig. 1). The structures of the
known compounds were identified by spectroscopic data and com-
parison with those reported in the literature. To our knowledge,
compounds 7 and 8 were isolated for the first time from Mammea
species.
1.22–1.29 revealed a long straight-chain and saturated acyl group
(RCO–). The 13C NMR spectrum of 2 showed nine signals of the cou-
marin nucleus including a a-substituted a,b-unsaturated c-lactone
group [d 159.5 (C-2), 98.9 (C-3), and 161.8 (C-4)] and an aromatic
ring fully substituted [d 103.1 (C-4a), 159.5 (C-5), 108.3 (C-6),
163.0 (C-7), 105.6 (C-8), and 151.7 (C-8a)]. Further analyses of
the 13C NMR data supported the occurrence of a 1-hydroxyperoxyl
propyl [d 89.9 (C-9), 23.3 (C-10), and 8.6 (C-11)], a geranyl [d 21.8
(C-12), 120.5 (C-13), 136.4 (C-14), 39.7 (C-15), 26.6 (C-16), 124.2
(C-17), 131.4 (C-18), 17.7 (C-19), 16.3 (C-20), and 25.7 (C-21)],
and a 2-methyl-1-oxo-butyl groups [d 208.6 (C-22), 46.0 (C-23),
27.0 (C-24), 11.8 (C-25), and 16.1 (C-26)]. In addition, the remain-
ing resonances including a signal at d 172.1 (C-10), overlapped sig-
nals at d 29–32, and a methyl carbon at d 14.1 (C-160) constituted a
fatty acid moiety, to which either of the phenolic groups at C-5 and
C-7 could undergo esterification. The structure of 2 was found to
have one hydroxyl group since the corresponding acetylated deriv-
ative shown only one methyl singlet at d 2.23 (Supplementary
data). Moreover, the phenolic proton, which had formed a strong
hydrogen bond between the phenolic group at C-7 and the car-
bonyl carbon at C-22 in 3–6 was not observed in 2. This evidence
suggested that the placement of the fatty acid at C-7.4–8,15 To con-
firm the fatty acid moiety, 2 was hydrolyzed in alkaline methanolic
solution resulting in methyl palmitate (Supplementary data). The
structure of 2, especially its linkage sites, was assigned by COSY,
HMQC, and HMBC spectra, respectively. The COSY experiment on
Mammeanoyl (2)18 was obtained as yellow syrup with negative
optical rotation. The molecular formula of 2 was determined as
C
43H66O8 by HR-MS measurement. Its IR spectrum showed charac-
teristic absorptions of hydroxyl (mmax 3416 cmꢀ1) and carbonyl
mmax 1718 cmꢀ1). The UV spectrum exhibited absorption maxima
(
at 223 and 336 nm, similar to those of 5,7-dioxygenated couma-
rins.4–8,15 It was proposed to have a hydroperoxyl group due to
the positive response to N,N-dimethyl-p-phenylenediammonium
dichloride reagent.19–22 The NMR data of 2 (Table 1) disclosed that
2 consisted of a coumarin nucleus and fatty acid moieties in a
molecule. The 1H NMR spectrum of 2 showed two olefinic protons
[d 5.28 (t, J = 6.0 Hz, H-13) and 5.06 (t, J = 6.0 Hz, H-17)], a down-
field-shifted hydroperoxyl-bearing proton [d 5.63 (t, J = 7.2 Hz,
H-9)], a typical singlet signal at d 5.88 (H-3), and six methyl groups
including two triplets at
d 1.08 (J = 7.2 Hz, H-11) and 1.00
(J = 7.2 Hz, H-25), an overlapped doublet at d 1.26 (H-26), and three
vinyl singlets [d 1.76 (H-20), 1.64 (H-21), and 1.57 (H-19)], which
were attributed to the coumarin moiety having a similar substi-
tuted pattern with surangin C,5,6 respectively. Besides, the proton
signals at d 2.35 (2H, t, J = 7.2 Hz, H-20) and 0.88 (3H, t, J = 6.8 Hz,
H-160) and, especially, a cluster of overlapped resonances at d
11
HOO
OH
5
19
18
20
14
9
HO
OH
OH
O
O
16
12
4
6
21
4a
8a
O
7
2
1′
O
O
O
O
8
16′
11
O
HO
O
O
2′
22
O
25
O
26
1
3
2
HO
HO
OH
HO
OH
HO
O
HO
O
O
HO
O
O
HO
O
O
O
O
O
5
4
6
OH
OH
OH
O
HO
O
HO
O
O
OH
O
O
HO
HO
HO
OH
OH
O
OH
OH
7
8
Figure 1. Structures of compounds 1–8.

160
N. H. Tung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 158–162
Table 1
NMR data for mammeanoyl (2)
Position
13C (CDCl3, 100 MHz)
1H (CDCl3, 400 MHz)
5.88, 1H, s
2
3
159.5
98.9
4
4a
5
6
7
8
8a
9
161.8
103.1
159.5
108.3
163.0
105.6
151.7
89.9
5.63, 1H, t (7.2)
2.07, 1H, m
10
23.3
1.97, 1H, m
11
12
13
14
15
16
17
18
19
20
21
22
23
24
8.6
21.8
120.5
136.4
39.7
1.08, 3H, t (7.2)
3.31, 2H, d (6.4)
5.28, 1H, t (6.0)
2.00, 2H, m
2.06, 2H, m
5.06, 1H, t (6.0)
26.6
124.2
131.4
17.7
16.3
25.7
208.6
46.0
27.0
1.57, 3H, s
1.76, 3H, s
1.64, 3H, s
Figure 3. Effects of compounds 1–8 on morphological change of HL-60. (A) Effect of
compound 1–8 on DNA fragmentation. Cells were treated with 12.5 of
compounds 1–8 for 24 h, and DNA fragmentation was analyzed by agarose gel
electrophoresis. M is 100 bp DNA marker. (B) Effect of compound 3, 4, and 5 on
l
M
3.82, 1H, m
1.91, 1H, m
1.48, 1H, m
1.00, 3H, t (7.2)
1.26, overlapped
chromatin condensation. Cells were treated with 12.5 lM of compounds 3, 4, and 5
25
26
11.8
16.1
for 24 h and stained with Hoechst 33258. Nuclear morphology was observed under
a fluorescent microscopy (magnification ꢁ400). Data shown are representative of
three independent experiments with similar results.
Fatty acid moiety
10
172.1
33.7
24.7
29.0–32.0
22.7
14.1
20
2.35, 2H, t (7.2)
1.62, 2H, m
1.22–1.29, overlapped
1.29, 2H, m
30
40–140
150
160
2 indicated the presence of partial structures depicted in bold line
in Figure 2. In the HMBC spectrum, the long-range correlations
were observed between following protons and carbons: H-3/C-
2,4,4a,9; H-9/C-3,4a,10,11; H-10/C-4,9,11; H-12/C-5,6,7,14, H-13/
C-6, H-23/C-8,25, respectively. On the basis of above evidences,
mammeanoyl (2) was structurally characterized as in Figure 1.
In this study, we investigated whether compounds 1–8 had anti-
proliferative activities against various cancer cell lines on the basis
of the fact that the nonpolar fractions (hexane and CH2Cl2) purified
from the methanolic extract of M. siamensis flowers had the strong
antiproliferative activity in our screening test. First, we examined
the effect of compounds 1–8 on proliferation of seven human
cancer cell lines, namely HL-60 (promyelocytic leukemia), U937
(promonocytic leukemia), THP-1 (promyelocytic leukemia), Jurkat
(acute T cell leukemia), KATO III (stomach cancer), HCT-15 (colon
cancer), and HepG2 (hepatoma), and two human normal skin fibro-
blast cell lines, NB1RGB and HF-19. Cells were treated with com-
0.88, 3H, t (6.8)
Assignments were established by HMQC, DQF-COSY, and HMBC spectra. J values (in
Hz) are given in parentheses.
HOO
OH
O
O
O
O
11
O
Figure 2. Selected H–H COSY (bold lines) and HMBC (arrows) correlations of 2.
pounds 1–8 at concentrations ranging from 3.125 to 50
l
M for
Table 2
Antiproliferative effects (IC50) of compounds (1–8) measured by MTT assay using seven human cancer cell lines and two normal skin fibroblast cell lines
Cell type
Leukemia
Cell line
IC50 (l
M)a
1
2
3
4
5
6
7
8
HL-60
U937
THP-1
Jurkat
KATO III
HCT-15
HepG2
NB1RGB
HF-19
37.19
47.56
NA
NA
NA
NA
NA
NA
NA
NAb
NA
NA
NA
NA
NA
NA
NA
NA
11.86
19.95
16.69
19.79
11.95
NA
NA
NA
NA
13.29
27.61
21.54
23.05
10.64
NA
13.65
18.80
9.23
29.85
24.05
NA
NA
NA
NA
29.16
33.35
40.59
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Stomach cancer
Colon cancer
Hepatoma
NA
NA
NA
Normal skin fibroblast
a
IC50 value of each compound was defined as concentration (lM) causing 50% inhibition of cell viability of the control culture.
NA: IC50 >50 lM.
b

N. H. Tung et al. / Bioorg. Med. Chem. Lett. 23 (2013) 158–162
161
Figure 4. Involvement of caspase cascade in compound 3-induced apoptosis. (A) Effect of compound 3 on DNA fragmentation. (B) Effect of compound 3 on the caspase-3
activation and PARP cleavage. Cells were treated with 12.5 M compound 3 for the indicated times. Cells were lysed, and caspase-3, PARP, and b-actin protein levels were
determined by Western blot analysis. b-actin was used as a loading control. (C) The effect of caspase inhibitors on compound 3-induced DNA fragmentation. After
pretreatment with 50 M caspase inhibitors for 1 h, cells were treated with 12.5 M compound 3 for 24 h. DNA fragmentation was analyzed by agarose gel electrophoresis.
l
l
l
Data shown are representative of three independent experiments with similar results.
24 h, and cell proliferation was determined by MTT assay. As shown
in Table 2, among eight tested compounds, compounds 3, 4, and 5
were found to have strongest antiproliferative activities against all
tested leukemia cells and KATO III. However, these compounds
had no effect on the proliferation of other cancer cells and normal
skin fibroblasts. Compounds 1 and 6 also showed antiproliferative
activities in some leukemia cells, but their antiproliferative poten-
cies were weaker than those of compounds 3, 4, and 5. On the other
hand, compounds 2, 7, and 8 had no influence on cell viabilities of all
tested cell lines. Taken together, these results suggest that com-
pounds 3, 4, and 5 are potent antiproliferative compounds against
leukemia cells and stomach cancer cells. In addition, the struc-
ture–activity relationship of coumarins 1–6 indicated that the 7-hy-
droxyl and free 6-prenyl/geranyl groups are important for their
antiproliferative activities. Ngo et al. have investigated the cytotoxic
effect of several coumarines isolated from M. siamensis on four can-
cer cell lines, such as DLD-1 (colon cancer), MCF-7 (breast cancer),
HeLa (cervical cancer), and NCI-H460 (lung cancer).6 Their results
suggest that the number and position of free hydroxyl groups are
important for antiproliferative effect, which agree with our results.
To examine whether antiproliferative activity by compounds 3,
4, and 5 against leukemia cells is related to apoptosis induction,
we analyzed the characteristics of apoptosis including DNA frag-
mentation and nuclear morphological changes using HL-60 cells.
activation and PARP cleavage in a time-dependent manner (Fig. 4B).
To confirm the involvement of caspases in compound 3-induced
apoptosis, the cells were treated with compound 3 in the absence
or presence of caspase inhibitors and then DNA fragmentation
was analyzed. As shown in Figure 4C, DNA fragmentation induced
by compound 3 was weaken by the pretreatment with z-VAD-
FMK (a broad caspase inhibitor) and z-DEVD-FMK (a caspase-3
inhibitor), suggesting that compound 3-induced apoptosis involves
a caspase-dependent pathway in HL-60 cells.
Morikawa et al. recently isolated several coumarins having sim-
ilar structures from the M. siamensis flowers and confirmed the
anti-inflammatory activity.5 Since the relation between the anti-
inflammatory and anti-cancer activity is closely related,25,26 our re-
sults will be deeply supported to their pharmacological potency.
In conclusion, one new geranylated coumarin, mammeanoyl (2)
and seven known compounds (1 and 3–8) were isolated from the
flower of M. siamensis. Among the isolated compounds, three struc-
turally related coumarins 3, 4, and 5 strongly suppressed the cell
proliferation of leukemia and stomach cancer cell lines although
unfortunately the new compound (2) had no inhibitory effect
depending on its structure. Furthermore, the active compounds
(3–5) exert antiproliferative effects through apoptosis induction,
suggesting their potential to be developed into new anti-cancer
drug candidates since these compounds had no inhibitory effect
against normal cell lines. Future molecular analyses of the active
compounds are needed to understand the selectivity of antiprolif-
erative activities against leukemia and stomach cancer cell lines.
Cells were treated with compounds at 12.5 lM for 24 h, DNA frag-
mentation was examined by the classical DNA laddering on agarose
gel electrophoresis. As shown inFigure 3A, the treatment with com-
pounds 3, 4, and 5 clearly induced DNA fragmentation, whereas the
other compounds did not. Next, the nuclear morphology was ob-
served by Hoechst 33258 staining. As shown in Figure 3B, the con-
trol cells demonstrated normal nuclear morphology, but the cells
treated with compounds 3, 4, and 5 induced chromatin condensa-
tions. These results indicate that compounds 3, 4, and 5 exerted
antiproliferative effect through induction of apoptotic cell death.
Activation of caspase-3 plays a central role in the execution
phase of apoptosis.23 After caspase-3 activation, poly (ADP-ribose)
polymerase (PARP), one of specific substrates for caspase-3, are
cleaved which is a hallmark of apoptosis.24 The compound 3, 4,
and 5 have a similar structure and exhibited the same degree of
antiproliferative potencies against leukemia cells. In order to inves-
tigate the detailed mechanism of apoptosis induction, we further
investigated the effect of compound 3 on the caspase-3 activation
Acknowledgments
The research was partly supported by ‘Science and Technology
Research Partnership for Sustainable Development (SATREPS)’ of
Japan Science and Technology Agency (JST) and the Japan Interna-
tional Cooperation Agency (JICA).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.10.
127.
References and notes
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