Design, synthesis and structure-activity relationships of mangostin analogs as cytotoxic agents

Article abstract of DOI:10.1039/C8RA08409B

In order to better understand the structure-activity relationship of mangostin, a series of xanthone derivatives based on α-mangostin were designed and synthesized. All the compounds were evaluated for their cytotoxicity against a panel of five human canc

Full text of DOI:10.1039/C8RA08409B

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Design, synthesis and structure–activity
relationships of mangostin analogs as cytotoxic
Cite this: RSC Adv., 2018, 8, 41377
agents†
c
Xiao-Qian Chi,ab Cheng-Ting Zi,
Hong-Mei Li,a Liu Yang,a Yong-Feng Lv,ab
Jin-Yu Li,ab Bo Hou,ab Fu-Cai Ren,ab Jiang-Miao Hu
and Jun Zhoua
a
*
In order to better understand the structure–activity relationship of mangostin, a series of xanthone
derivatives based on a-mangostin were designed and synthesized. All the compounds were evaluated for
their cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7 and
SW480) using MTT assays. Most of them showed cytotoxicity and most of all, compounds 1a and 2h
showed the highest cytotoxic potency by HL-60 cancer cell lines with IC50 values of 5.96 mM and 6.90
mM respectively; compound 3e showed the highest cytotoxic potency against SMMC-7221 cancer cell
line with IC50 values of 3.98 mM; compounds 2e and 2m showed lower cytotoxicity but higher selectivity
than a-mangostin against HL-60 and SMMC-7221 cancer cell lines respectively. Structure–activity
relationship analysis indicates that the maintenance of the isopentene group at C-8 is essential for the
cytotoxic activity.
Received 10th October 2018
Accepted 26th November 2018
DOI: 10.1039/c8ra08409b
rsc.li/rsc-advances
clinically approved drugs based on a-mangostin because of
its high hydrophobicity, low selectivity24 and low
bioavailability.25,26
1. Introduction
a-Mangostin (1) (Fig. 1) is a kind of bioactive xanthone
derivative, which can be isolated from the pericarps of the
mangosteen fruit (Garcinia mangostana L.).1,2 This compound
has shown increasing promise due to an abundance of
therapeutic functions, including anti-tumor,3 anti-oxidant,4
anti-inammatory,5,6 anti-bacterial,7–10 and inhibition of fatty
acid synthase,11,12 neuraminidase,13 a-glycosidase14 and
cholinesterase.15 The broad spectrum of mangostin against
cancer cell lines has attracted considerable awareness;
pharmacological16–19 and medicinal chemistry20 research of
a-mangostin has been widely performed. Pharmacological
studies have revealed that mangostin possesses potent anti-
tumor activity both in vitro and in vivo. a-Mangostin has been
found in the past few decades to exhibit anticancer proper-
ties on various cancer models in vivo. a-Mangostin can also
be used in combination with other chemotherapeutic agents
to increase therapeutic efficacy or reduce side effects.21–23
Despite its promising therapeutic values, there are no
To overcome these drawbacks, related a-mangostin deriva-
tives have been synthesized through various modications of
the phenolic hydroxyl groups (C-1, C-3 and C-6 positions)10,27
and substitution reactions (C-4 and C-5 positions).28,29 Chemical
isolation of oxidative cyclized isopentene groups (C-2 and C-8
positions) has been reported,30 and however, the modica-
tions of the isopentene groups are limited. Thus, chemical
modications of the isopentene groups of mangostin were done
herein to get more derivatives.
In this manuscript, a series of a-mangostin derivatives were
synthesized and then all compounds were evaluated for cyto-
toxic activities against ve human cancer cell lines, including
HL-60 (leukemia), SMMC-7721 (hepatoma cells), A-549 (lung
cancer), MCF-7 (breast cancer) and SW480 (colon cancer). To
study the selectivity of tumor cells and normal cells, their
growth inhibitory effect was evaluated against human normal
pulmonary epithelial cells (BEAS-2B).
aState Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan
Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese
Academy of Sciences, Kunming 650201, People'
hujiangmiao@mail.kib.ac.cn
s Republic of China. E-mail:
bUniversity of Chinese Academy of Sciences, Beijing 100049, People's Republic of China
cCollege of Science, Yunnan Agricultural University, Kunming 650201, People's
Republic of China
† Electronic supplementary information (ESI) available: Abbreviation for the
manuscript, NMR and MS spectrum of synthesized compounds. See DOI:
10.1039/c8ra08409b
Fig. 1 The structure of a-mangostin.
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2. Results and discussion
2.1 Chemical synthesis
The synthesized compounds (1a–1l, 2a–2u, 3a–3e) can be
divided into three groups according to the variety of functional
groups: the isopentene groups (C-2 and C-8 positions), the
phenolic hydroxyl groups (C-1, C-3 and C-6 positions) and the
vacant sites of benzene ring (C-4 and C-5 positions).
2.1.1 The modication of phenolic hydroxyl groups (C-1, C-
3 and C-6 positions). There are three free phenolic hydroxyl
groups (C-1, C-3 and C-6 positions) in a-mangostin, which are
suitable for chemical modications. It is noteworthy that the
hydroxyl group at the C-1 position is less reactive because an
intermolecular hydrogen bond may form between the hydroxyl
group (C-1) and the carbonyl group (C-8), thus harsher condi-
tions are required for C-1 alkylation. Therefore we could control
the condition of O-alkylation reaction so that it occurred only at
C-3 and C-6 positions by using mild reaction conditions.
Treatment of a-mangostin with BrBn in the presence of
K2CO3/acetone gave compound 1a; acetylation of a-mangostin
with Ac2O in the addition of DMAP furnished a mixture of
compounds 1b and 1c, which were separated by silica gel
chromatography; the methylation compounds 1d and 1e were
prepared by reaction of a-mangostin with (CH3)2SO4 in the
presence of K2CO3, followed again by chromatographic sepa-
ration; alkylation of a-mangostin to the desired compounds 1f
and 1g was accomplished by reactions with BrCH2CHCH2 and
Scheme 2 Reagents and conditions: OsO4, NMO, acetone-H2O (1 : 1),
rt, 12–78%.
the reaction with various bromo-carboxylic acid esters and NaH
(Scheme 1). Unfortunately, they showed complete absence of
cytotoxicity.
In general, the alkylation of phenolic hydroxyl groups of
mangostin can mainly cause the loss of cytotoxicity, so we
focused on the structural modications of isopentyl groups of
mangostin.
2.1.2 The modication of isopentene group (C-2 and C-8
positions). Compounds 2a–2u were designed to test whether
the modication of isopentene groups could enhance the
cytotoxicity activity and improve their selectivity between
normal and tumour cells. The synthetic methodologies used to
synthesize the derivatives 2a–2u are outlined in Schemes 2–7.
Firstly, a-mangostin derivatives based on the oxidation of
isopentene group (at C-2 and C-8 positions) were synthesized. a-
Mangostin was treated with OsO4 and NMO in mixed solvent
(acetone : H2O ¼ 1 : 1) to afford compounds 2a–2c, using
a similar method as reported in the literature,33 with yields of
10%, 12% and 78% respectively. These products containing
functional groups of O-diol act as key intermediates for the
further synthesis of mangostin derivatives.
ꢀ
K2CO3 in acetone at 65 C, followed by partial catalytic hydro-
genation to afford 78% and 75% yields respectively. For the
prenylation compound 1h, a-mangostin was reacted with
BrCH2CHC(CH3)2 at 65 ꢀC for 12 h resulting in yields of 15%.31
To speak of, we also designed a series of a-mangostin
derivatives by attaching different lengths (1–4) of carbon chains
carboxylic ester groups to the free hydroxyl groups (at C-1, C-3
and C-6 positions) according to the references.32 Therefore
compounds 1i–1l were synthesized in good yields (25–60%) by
Compounds 2a and 2b have many identical partial structure
similarities: one O-diol hydroxyl group and one isopentene
group; the structural differences were substitution positions at
C-2 or C-8 positions. As shown in Scheme 3, the isopentene
group of compounds 2a and 2b was reduced to isopentyl group
under H2, Pd/C to afford compounds 2d and 2e in high yields
from 78% to 98%. Compounds 2r and 2t were separately
Scheme 1 Reagents and conditions: BrBn, K2CO3, acetone, reflux,
80% for 1a; Ac2O, DMAP, DCM, cool temperature to room tempera-
ture, 80% for 1b and 1c; (CH3)2SO4, K2CO3, acetone, reflux, 80% for 1d
and 1e; BrCH2CHCH2, K2CO3, acetone, reflux, 78% for 1f; Pd/C, H2,
MeOH, rt, 75% for 1g; BrCH2CHC(CH3)2, K2CO3, acetone, reflux, 15%
for 1h; BrCH2CO2CH3, NaH, acetone, reflux, 60% for 1i; BrCH2CO2-
CH2CH3, NaH, acetone, reflux, 60% for 1j; BrCH2CH2CH2CO2CH3,
NaH, acetone, reflux, 25% for 1k; BrCH2CH2CH2CO2CH2CH3, NaH,
acetone, reflux, 25% for 1l.
Scheme 3 Reagents and conditions: H2, Pd/C, MeOH, rt, 78–98%.
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2.1.3 The substitution reaction at C-4 and C-5 (C-4 and C-5
positions). In addition to a scaffold leading to diverse func-
tionalities, the biology effects of halogens is worth studying.
Considering the vacant sites of C-4 and C-5 positions of man-
gostin, the chloride and bromide substitution compounds 3a–
3e were generated accompanied by a small amount of N-chlor-
osuccinimide (NCS) and N-bromobutanimide (NBS) respec-
tively. The halogenated a-mangostin derivatives were
synthesized as shown in Scheme 7.
In conclusion, we had synthesized three series of mangostin
derivatives. All reactions were described in the experimental
section. All synthesized target compounds were puried by
column chromatography (silica gel, 200–300 mesh, petroleum
ether/ethyl acetate, 1 : 1 / 20 : 1) and their structures were
Scheme 4 Reagents and conditions: NaIO4, THF–H2O (2 : 1), rt, 40–
60%.
1
elucidated by H NMR, 13C NMR, electrospray ionization mass
spectrometry (ESI-MS) and high-resolution mass spectrometry
(HR-ESIMS).
2.2 Evaluation of biological activity
The cytotoxicity of these derivatives was evaluated in vitro
against ve human cancer cell lines (HL-60, SMMC-7721, A-549,
MCF-7 and SW480). Cisplatin (DDP) and Adriamycin (ADM)
were taken as control drugs and their IC50 data were present in
Tables 1, 2 and 3. The inhibitory of the tested compounds on
cell viability was measured by the MTT colorimetric methods. A
few of them showed higher potency than the parent compound
and most of them displayed moderate cytotoxicity against all
ve cancer cell lines. In order to test the cytotoxicity of these
derivatives with promising anticancer activity on normal cells,
their growth inhibitory effect was evaluated against human
normal pulmonary epithelial cells (BEAS-2B).
Overall, these synthesized compounds show a broad range of
growth inhibitory effect against all ve cancer cell lines tested.
In general, the HL-60 cell line was most sensitive to these
compounds. Noteworthy, compound 2h possesses remarkable
anti-proliferation activity against all the tested cancer cell lines.
Compound 2e, which solely possesses notable anti-proliferation
activity against HL-60 cancer cells (IC50 ¼ 18.65 ꢁ 0.23 mM) is
non-cytotoxic to BEAS-2B cell line. Moreover, several
compounds (2a, 2f, 2k, 2n and 2r) with pretty anti-proliferation
activity against all the tested cancer cell lines are observed to be
less toxic to BEAS-2B cells compared with a-mangostin. The
results suggest that these compounds are more sensitive to
certain tested cancer cells than normal cells in vitro and hence
possess good selectivity.
These data have allowed us to carry out a structure and
activity relationship (SAR) study on the inuence of the modi-
cations of the isopentene group and halogen atoms in the
cholinesterase inhibitory activities. The main conclusions can
be summarized as follows:
(1) With respect to the SAR, the effects of the substitution
reactions at phenolic hydroxyl groups were examined. Di-
substitution at both C-3 and C-6 hydroxyl groups (1a–1l) cau-
ses totally decrease in the cytotoxicity of mangostin against the
ve tested cancer cell lines; while the acetylation form of
mangostin (1b and 1c) can remain the cytotoxic activity,
Scheme 5 Reagents and conditions: NaH, CH3I, DMF, rt, 60%.
prepared from a-mangostin (1) and g-mangostin (2s) under the
same conditions as for preparation of compounds 2d and 2e
(Scheme 7). Compound 2d was prepared in 80% from 2a by
catalytic hydrogenation, which served as starting material for
the synthesis of oxidation product analogous. As shown in
Scheme 4, compounds 2a, 2c and 2d, having the vicinal diol
groups, were oxidized by NaIO4 in mixed solvent (THF : H2O ¼
2 : 1) to afford compounds 2f, 2g and 2h with good yields (40–
60%) according to the relative reference.34
With compounds 2a and 2d in hands, in order to increase
their lipotropic properties, different contents of various alkyl-
ation products were obtained (Scheme 5). Methylation of
compounds 2a and 2d with CH3I–NaH yielded the total meth-
ylation products 2i and 2j.
In order to discuss the structure–activity relationship (SAR)
more entirely, then we turned to synthesize the cyclization
series of xanthone derivatives 2k–2p (Scheme 6) according to
the relevant references.35,36 Initially, the cyclization of a-man-
gostin with DDQ afforded compound 2k with a yield of 40%; a-
mangostin was oxidized with m-CPBA in the presence of
NaHCO3 to yield compounds 2l and 2m followed again by
chromatographic separation in 4% to 49% yields; compound 2n
was obtained through an addition reaction in which a-man-
gostin was reacted with HCOOH with yield of 25%; the treat-
ment of a-mangostin with p-TsOH produced compounds 2o, 2p
and 2q, which were separated by silica gel chromatography with
a relatively low yield of 12–23%; compound 2u was prepared by
the cyclization of 2,4-dihydroxybenzoic acid and phloroglucin
ꢀ
under the condition of Eaton's reagents at 60 C.
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Scheme 6 Reagents and conditions: (a) DDQ, toluene, reflux, 41%; (b) m-CPBA, NaHCO3, CH2Cl2, rt, 4–49%; (c) HCOOH, acetone, rt, 25%; (d) p-
TsOH, toluene–CH2Cl2 (2 : 1), rt, 12–23%.
compound 1a possessed the most potent cytotoxicity against
HL-60 cancer cell line with IC50 value of 5.96 ꢁ 0.16 mM. In
summary, the numbers of phenolic hydroxyl groups have
certain effects on maintaining cytotoxicity.
(2) The oxidation of the isopentene group at C-8 causes
drastically decreases in the cytotoxicity of mangostin against all
the tested cancer cell lines. Compounds 2b, 2c, 2g, 2l and 2m
displayed weak activity, all having IC50 > 40 mM, indicating that
the isopentene group at C-8 was necessary for the cytotoxicity
and the hydroxyl group at C-8 can cause totally loss of the
cytotoxicity. However, one interesting exception is observed:
compound 2e possesses notable anti-proliferation activity
against HL-60 cancer cells with IC50 value of 18.65 ꢁ 0.23 mM.
(3) Several structure features and their effects need to be
pointed out. Oxidation of the isopentene group at C-2
(compounds 2a, 2d, 2f, 2k, 2m and 2n) generally resulted in
slightly decreased activity or comparative activity with one
exception. Compound 2h exhibited greater activity against HL-
60 and SMMC-7221 cell lines with IC50 values of 6.90 ꢁ 0.55
mM and 6.92 ꢁ 0.55 mM respectively. These data indicate the
number and position of hydroxyl group at C-2 have limited
Scheme 7 Reagents and conditions: (a) H2, Pd/C, MeOH, rt, 95%; (b)
NCS/NBS, DCM or THF, rt, 12–60%; (c) Eaton's reagents, 60 ꢀC, 60%.
potency on the cytotoxicity and selectivity.
(4) By comparing compounds 1 and 2r, 2a and 2d, 2b and 2e,
2f and 2h, 2s and 2t, it is obvious to nd that the reduction of
Table 1 In vitro cytotoxic activity (IC50, mM) of mangostin derivatives
IC50 ꢁ SD (mM)
Compounds
HL-60
SMMC-7721
A-549
MCF-7
SW480
BEAS-2B
1
1a
1b
DDP
ADM
15.04 ꢁ 0.33
5.96 ꢁ 0.16
11.92 ꢁ 0.48
3.19 ꢁ 0.18
0.14 ꢁ 0.00
10.30 ꢁ 0.48
11.64 ꢁ 0.61
13.56 ꢁ 0.32
18.03 ꢁ 0.49
0.90 ꢁ 0.03
13.82 ꢁ 0.61
10.27 ꢁ 0.42
11.60 ꢁ 0.24
13.75 ꢁ 0.74
0.30 ꢁ 0.01
10.81 ꢁ 1.12
12.95 ꢁ 0.44
16.65 ꢁ 1.32
28.42 ꢁ 3.71
0.90 ꢁ 0.02
14.45 ꢁ 0.85
15.85 ꢁ 0.46
16.17 ꢁ 0.13
14.77 ꢁ 2.15
0.11 ꢁ 0.01
15.81 ꢁ 1.02
NT
NT
>40
>40
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Table 2 In vitro cytotoxic activity (IC50, mM) of mangostin derivatives
IC50 ꢁ SD (mM)
Compounds
HL-60
SMMC-7721
A-549
MCF-7
SW480
BEAS-2B
1
15.04 ꢁ 0.33
18.22 ꢁ 0.48
>40
10.30 ꢁ 0.48
23.42 ꢁ 1.29
>40
13.82 ꢁ 0.61
19.82 ꢁ 1.42
>40
10.81 ꢁ 1.12
23.65 ꢁ 0.64
>40
14.45 ꢁ 0.85
>40
>40
15.81 ꢁ 1.02
2a
2b
2c
18.31 ꢁ 0.51
NT
NT
>40
>40
>40
>40
>40
2d
2e
2f
2g
2h
2i
21.59 ꢁ 2.41
18.65 ꢁ 0.23
14.96 ꢁ 0.80
>40
26.87 ꢁ 3.75
35.96 ꢁ 0.99
>40
>40
>40
>40
>40
>40
>40
>40
11.93 ꢁ 0.28
>40
18.03 ꢁ 1.49
>40
19.75 ꢁ 0.26
18.24 ꢁ 0.79
27.20 ꢁ 2.42
>40
>40
NT
6.90 ꢁ 0.55
6.92 ꢁ 0.55
11.77 ꢁ 0.13
17.97 ꢁ 0.23
>40
15.86 ꢁ 0.2
>40
17.56 ꢁ 0.60
>40
>40
>40
NT
2j
>40
>40
>40
>40
>40
NT
2k
2l
13.72 ꢁ 0.50
11.52 ꢁ 0.17
11.47 ꢁ 0.33
16.80 ꢁ 1.04
17.35 ꢁ 1.15
18.60 ꢁ 0.70
>40
>40
>40
>40
>40
NT
2m
2n
2o
2p
2q
2r
2s
2t
2u
DDP
ADM
>40
53.75 ꢁ 0.26
26.31 ꢁ 1.04
>40
>40
NT
15.68 ꢁ 0.34
6.57 ꢁ 0.14
6.51 ꢁ 0.49
>40
>40
>40
>40
NT
14.40 ꢁ 0.05
16.96 ꢁ 0.77
24.62 ꢁ 0.47
22.69 ꢁ 2.35
29.34 ꢁ 1.02
>40
>40
>40
>40
NT
>40
NT
11.13 ꢁ 0.15
7.39 ꢁ 0.33
13.72 ꢁ 0.06
>40
>40
NT
14.93 ꢁ 0.15
10.07 ꢁ 0.59
15.56 ꢁ 0.17
>40
>40
NT
8.29 ꢁ 0.59
5.33 ꢁ 0.43
12.32 ꢁ 0.12
>40
>40
NT
14.46 ꢁ 0.15
8.40 ꢁ 0.67
11.59 ꢁ 0.52
>40
NT
NT
14.35 ꢁ 0.41
7.43 ꢁ 0.65
6.48 ꢁ 0.08
NT
>40
>40
3.19 ꢁ 0.18
18.03 ꢁ 0.49
13.75 ꢁ 0.74
28.42 ꢁ 3.71
14.77 ꢁ 2.15
0.14 ꢁ 0.00
0.90 ꢁ 0.03
0.30 ꢁ 0.01
0.90 ꢁ 0.02
0.11 ꢁ 0.01
the isopentene group to isopentyl group has no signicant cytotoxicity, for example, compound 3e is up to three times
effect on the decrease or increase of cytotoxicity. more cytotoxic than the parent compound with IC50 value of
(5) The totally methylation of compounds 2a and 2d cause 3.98 ꢁ 0.63 mM for SMMC-7721 cell lines.
the disappearance of cytotoxicity of compound 2i and 2j.
However, the cytotoxicity of compounds 2c and 2g with 5–7
3. Experimental
hydroxyl groups also completely disappeared. Compound 2s (g-
3.1 Materials and methods
mangostin) is more active than compound 1 (a-mangostin)
indicating the importance of the presence of hydroxyl group at
the C-7 position, whereby substituting it with methoxy group
reduced the cytotoxicity. To summarize, a certain number of
hydroxyl groups contribute to the maintenance of cytotoxic
activity. The number and location of hydroxyl functional groups
have different effects on cytotoxicity.
(6) A closer look at the data reveals that the effect of halo-
genation on the selective potency of these compounds is quite
subtle. Some of the halogenated products showed better
All reagents were purchased from Sigma-Aldrich or Aladdin or
Innochem Co. Ltd. and were of commercial quality. They were
used as received without further purication. Solvents were
dried by standard methods prior to use. The other reagents were
of analytical grade. Air and moisture sensitive reactions were
performed under nitrogen atmosphere. All synthesized target
compounds were puried by column chromatography (silica
gel, petroleum ether/ethyl acetate, 1 : 1 ꢂ 20 : 1) and their
structures were elucidated by H NMR, 13C NMR, electrospray
1
Table 3 In vitro cytotoxic activity (IC50, mM) of mangostin derivatives
IC50 ꢁ SD (mM)
Compounds
HL-60
SMMC-7721
A-549
MCF-7
SW480
BEAS-2B
1
3a
3b
3c
3d
3e
DDP
ADM
15.04 ꢁ 0.33
>40
>40
16.91 ꢁ 0.19
14.55 ꢁ 0.40
14.87 ꢁ 0.33
3.19 ꢁ 0.18
0.14 ꢁ 0.00
10.30 ꢁ 0.48
34.67 ꢁ 2.22
24.11 ꢁ 0.16
8.07 ꢁ 0.76
10.76 ꢁ 1.02
3.98 ꢁ 0.63
18.03 ꢁ 0.49
0.90 ꢁ 0.03
13.82 ꢁ 0.61
>40
>40
14.30 ꢁ 0.85
16.18 ꢁ 0.13
12.02 ꢁ 0.19
13.75 ꢁ 0.74
0.30 ꢁ 0.01
10.81 ꢁ 1.12
>40
14.45 ꢁ 0.85
>40
>40
36.63 ꢁ 0.74
17.30 ꢁ 0.49
21.29 ꢁ 0.44
14.77 ꢁ 2.15
0.11 ꢁ 0.01
15.81 ꢁ 1.02
>40
>40
21.83 ꢁ 0.14
16.05 ꢁ 0.47
20.74 ꢁ 0.18
>40
22.18 ꢁ 0.20
16.01 ꢁ 0.66
21.92 ꢁ 0.50
19.66 ꢁ 0.62
28.42 ꢁ 3.71
0.90 ꢁ 0.02
>40
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ionization mass spectrometry (ESI-MS) and high-resolution 22), 20.9 (C-24), 18.2, 17.9 (C-14, C-19); positive ESIMS m/z 517
mass spectrometry (HR-ESIMS). Mass spectra were performed [M + Na]+.
on an API QSTAR time-of-ight spectrometer (MDS Sciqaszex,
1,3,6-Tri-O-acetyl-a-mangostin (1c). Yield 80%, 1H NMR
Concord, Ontario, Canada) and LCMS-IT-TOF (Shimadzu, (CDCl3, 500 MHz) d 7.13 (s, 1H, H-5), 7.09 (s, 1H, H-4), 5.17 (br t,
Kyoto, Japan) spectrometer. NMR spectra were recorded on H, J ¼ 7.0 Hz, H-12), 5.03 (br t, H, J ¼ 7.0 Hz, H-17), 4.06 (d, 2H,
Bruker AM-400 and DRX-500 instruments with TMS as the H-16), 3.75 (s, 3H, 7-OCH3), 3.27 (d, 2H, H-11), 2.46, 2.37, 2.33
internal standard (Bruker, Bremerhaven, Germany). The (each s, each 3H, COCH3), 1.82, 1.75, 1.67, 1.42 (each s, each 3H,
chemical shis were given in d (ppm) with reference to the H-14, H-15, H-19, H-20); 13C NMR (CDCl3, 125 MHz) d 176.1 (C-
solvent signal. 1H NMR data were reported in the order of 9), 169.3 (C-21), 168.2 (C-22), 168.1 (C-23), 154.5 (C-3), 153.2 (C-
chemical shi, multiplicity (s, singlet; d, doublet; t, triplet; m, 1), 153.1 (C-10a), 148.8 (C-4a), 148.5 (C-7), 146.7 (C-6), 139.0 (C-
multiple resonances), number of protons, and coupling 8), 132.5, 131.8 (C-13, C-18), 123.6, 122.9 (C-12, C-17), 120.9 (C-
constant (J) in hertz (Hz). Column chromatography was per- 8a), 118.9 (C-2), 113.6 (C-9a), 110.3 (C-5), 109.0 (C-4), 61.6
formed on silica gel (200–300 and 300–400 mesh, Qingdao (OCH3), 26.2 (C-16), 25.8, 25.6 (C-15, C-20), 23.5 (C-11), 21.2,
Marine Chemical Inc., Qingdao, China) with the indicated 21.0, 20.9 (C-21, C-23, C-25), 18.2, 17.9 (C-14, C-19); positive
solvents. The fractions were monitored by TLC and the spots ESIMS m/z 537 [M + H]+.
were visualized by UV light and sprayed with 10% H2SO4 in
EtOH, followed by heating.
3,6-Di-O-methyl-a-mangostin (1d). Yield 80%, 1H NMR (CDCl3,
500 MHz) d 6.73 (s, 1H, H-5), 6.32 (s, 1H, H-4), 5.24 (br t, 2H, J ¼
7.3 Hz, H-12, H-17), 4.13 (d, 2H, J ¼ 6.6 Hz, H-16), 3.95, 3.90
(each s, each 3H, 3-OCH3, 6-OCH3), 3.79 (s, 3H, 7-OCH3), 3.35 (d,
2H, J ¼ 7.1 Hz, H-11), 1.82, 1.80 (each s, each 3H, H-14, H-19),
1.68 (s, 6H, H-15, H-20); 13C NMR (CDCl3, 125 MHz) d 182.0
3.2 Synthetic procedures and crystallography
3.2.1 General procedure for synthesis of compound 1a–1l. (C-9), 163.4 (C-3), 159.8 (C-1), 158.0 (C-10a), 155.4 (C-4a), 155.2
Potassium carbonate and corresponding brominated (C-7), 144.0 (C-6), 137.3 (C-8), 131.8, 131.7 (C-13, C-18), 123.2,
compounds were added to a solution of a-mangostin (41 mg, 0.1 122.3 (C-12, C-17), 112.1 (C-8a), 111.5 (C-2), 104.0 (C-9a), 98.2 (C-
mmol) in acetone. The reaction mixture was heated at reux for 5), 88.7 (C-4), 61.0 (7-OCH3), 56.0, 55.8 (3-OCH3, 6-OCH3), 26.2
24 h. The reaction was cooled to room temperature and the (C-16), 25.9 (C-15, C-20), 21.4 (C-11), 18.2, 17.8 (C-14, C-19);
solvent was removed under reduced pressure. The residue was positive ESIMS m/z 439 [M + H]+.
diluted with ethyl acetate and then washed with saturated
1,3,6-Tri-O-methyl-a-mangostin (1e). Yield 80%, 1H NMR
NaHCO3 (aq) and brine. The organic phase was dried over (CDCl3, 500 MHz) d 6.74 (s, 1H, H-5), 6.61 (s, 1H, H-4), 5.35 (br t,
anhydrous Na2SO4 and concentrated in vacuo. The crude H, J ¼ 6.5 Hz, H-12), 5.21 (br t, H, J ¼ 7.0 Hz, H-17), 4.17 (d, 2H, J
product was puried by column chromatography on silica gel to ¼ 6.7 Hz, H-16), 3.98, 3.94, 3.89, 3.82 (each s, each 3H, 1-OCH3,
afford intermediated 1a to 1l.
3-OCH3, 6-OCH3, 7-OCH3), 3.42 (d, 2H, J ¼ 7.0 Hz, H-11), 1.82,
3,6-Di-O-benzyl-a-mangostin (1a). Yield 80%, 1H NMR (CDCl3, 1.80 (each s, each 3H, H-15, H-20), 1.68 (s, 6H, H-14, H-19); 13
C
500 MHz) d 13.51 (s, 1H, 1-OH), 7.48–7.34 (m, 10H, Ar-H), 6.75 NMR (CDCl3, 125 MHz) d 176.3 (C-9), 162.1 (C-3), 158.6 (C-1),
(s, 1H, H-5), 6.34 (s, 1H, H-4), 5.28 (br t, 2H, J ¼ 7.0 Hz, H-12, H- 157.0 (C-10a), 156.6 (C-4a), 154.3 (C-6), 143.9 (C-7), 137.4 (C-8),
17), 5.18, 5.15 (each s, each 2H, H-21, H-28), 4.15 (d, 2H, J ¼ 131.5, 131.3 (C-13, C-18), 123.8, 122.8 (C-12, C-17), 120.5 (C-2),
6.5 Hz, H-16), 3.83 (s, 3H, 7-OCH3), 3.41 (d, 2H, J ¼ 7.0 Hz, H- 114.7 (C-9a), 110.9 (C-8a), 97.8 (C-5), 94.2 (C-4), 62.0 (1-OCH3),
11), 1.86–1.59 (s, each 3H, H-14, H-15, H-19, H-20); 13C NMR 60.9 (7-OCH3), 55.9, 55.9 (3-OCH3, 6-OCH3), 29.7 (C-16), 26.0,
(CDCl3, 125 MHz) d 182.0 (C-9), 162.4 (C-3), 159.9 (C-1), 157.0 (C- 25.9 (C-15, C-20), 22.4 (C-11), 18.2, 17.9 (C-14, C-19); positive
6), 155.2 (C-10a), 155.0 (C-4a), 144.2 (C-7), 137.4 (C-8), 136.3, ESIMS m/z 453 [M + H]+.
135.7 (C-22, C-29), 131.8, 131.6 (C-13, C-18), 128.8, 128.6, 128.4,
3,6-Bis(allyloxy)-1-hydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-
1
128.1, 127.4, 127.2 (C-23, C-24, C-25, C-26, C-27, C-30, C-31, C- yl)-9H-xanthen-9-one (1f). Yield 78%, H NMR (CDCl3, 500 MHz)
32, C-33, C-34), 123.3, 122.4 (C-12, C-17), 112.3 (C-8a), 111.8 d 13.49 (s, 1H, 1-OH), 6.69 (s, 1H, H-5), 6.27 (s, 1H, H-4), 6.08 (m,
(C-2), 104.1 (C-9a), 99.4 (C-5), 89.8 (C-4), 70.7, 70.2 (C-21, C-28), 2H, –CH], H-22, H-25), 5.47, 5.34 (m, each 2H, ]CH2, H-23, H-
61.0 (OCH3), 26.2 (C-16), 26.0, 25.9 (C-15, C-20), 21.6 (C-11), 26), 5.25 (br t, 2H, J ¼ 6.0 Hz, H-12, H-17), 4.66, 4.60 (each d, each
18.2, 17.8 (C-14, C-19); positive ESIMS m/z 591 [M + H]+.
2H, J ¼ 5.0 Hz, –OCH2, H-21, H-24), 4.13 (d, 2H, J ¼ 7.0 Hz, H-16),
1
3,6-Di-O-acetyl-a-mangostin (1b). Yield 82%, H NMR (CDCl3, 3.81 (s, 3H, 7-OCH3), 3.38 (d, 2H, J ¼ 7.0 Hz, H-11), 1.85, 1.79
500 MHz) d 13.42 (s, 1H, 1-OH), 7.13 (s, 1H, H-5), 6.64 (s, 1H, H- (each s, each 3H, H-15, H-20), 1.68 (s, 6H, H-14, H-19); 13C NMR
4), 5.17 (br t, 2H, J ¼ 7.0 Hz, H-12, H-17), 4.13 (d, 2H, J ¼ 6.0 Hz, (CDCl3, 125 MHz) d 182.0 (C-9), 162.2 (C-3), 159.9 (C-1), 156.9 (C-
H-16), 3.77 (s, 3H, 7-OCH3), 3.32 (d, 2H, J ¼ 7.0 Hz, H-11), 2.39, 4a), 155.2 (C-10a), 155.0 (C-6), 144.1 (C-7), 137.4 (C-8), 132.5, 132.0
2.34 (each s, each 3H, COCH3), 1.83, 1.78 (each s, each 3H, H-15, (C-22, C-25), 131.8, 131.6 (C-13, C-18), 123.3, 122.3 (C-12, C-17),
H-20), 1.68 (s, 6H, H-14, H-19); 13C NMR (CDCl3, 125 MHz) 118.5, 111.7 (C-23, C-26), 112.1 (C-8a), 111.7 (C-2), 104.0 (C-9a),
d 182.9 (C-9), 168.5 (C-23), 168.1 (C-21), 161.0 (C-1), 154.9 (C-3), 99.2 (C-5), 89.6 (C-4), 69.4, 69.1 (C-21, C-24), 60.9 (7-OCH3), 26.2
154.1 (C-4a), 153.7 (C-10a), 149.4 (C-7), 146.7 (C-6), 139.2 (C-8), (C-16), 26.0, 25.9 (C-15, C-20), 21.5 (C-11), 18.2, 17.9 (C-14, C-19);
132.4, 132.3 (C-13, C-18), 122.6, 121.3 (C-12, C-17), 116.9 (C- positive ESIMS m/z 491 [M + H]+.
8a), 116.2 (C-2), 110.6 (C-5), 107.1 (C-9a), 100.3 (C-4), 61.7
1-Hydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-yl)-3,6-dipro-
(OCH3), 26.5 (C-16), 25.9, 25.7 (C-15, C-20), 22.3 (C-11), 21.0 (C- poxy-9H-xanthen-9-one (1g). Yield 75%, 1H NMR (CDCl3, 500
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MHz) d 13.50 (s, 1H, 1-OH), 6.69 (s, 1H, H-5), 6.27 (s, 1H, H-4), 17.7 (C-14, C-19), 14.1 (C-24, C-28); positive ESIMS m/z 605 [M +
5.25 (br t, 2H, J ¼ 7.0 Hz, H-12, H-17), 4.13 (d, 2H, J ¼ 6.5 Hz, H- Na]+.
16), 4.03, 3.98 (each t, each 2H, J ¼ 6.5 Hz, H-21, H-24), 3.81 (s,
Dimethyl-4,40-((1-hydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-
3H, 7-OCH3), 3.36 (d, 2H, J ¼ 7.0 Hz, H-11), 1.93–1.06 (m, 10H, 1-yl)-9-oxo-9H-xanthene-3,6-diyl)bis(oxy))dibutanoate (1k). Yield
–CH2, –CH3); 13C NMR (CDCl3, 125 MHz) d 182.0 (C-9), 162.8 (C- 25%, H NMR (DMSO-d6, 500 MHz) d 13.44 (s, 1H, 1-OH), 6.87
1
3), 159.8 (C-1), 157.5 (C-4a), 155.3 (C-10a), 155.1 (C-6), 144.0 (C- (s, 1H, H-5), 6.38 (s, 1H, H-4), 5.10 (br t, 2H, J ¼ 7.0 Hz, H-12, H-
7), 137.1 (C-8), 131.7, 131.3 (C-13, C-18), 123.3, 122.5 (C-12, C- 17), 4.10, 4.05 (each t, each 2H, H-21, H-26), 3.93 (d, 2H, J ¼
17), 111.8 (C-2), 111.4 (C-8a), 103.8 (C-9a), 98.7 (C-5), 89.2 (C- 6.5 Hz, H-16), 3.67 (s, 3H, 7-OCH3), 3.61, 3.60 (each s, each 3H,
4), 70.3, 70.0 (C-21, C-24), 60.8 (7-OCH3), 26.2 (C-16), 26.0, H-25, H-30), 3.14 (d, 2H, J ¼ 7.0 Hz, H-11), 2.50 (m, 4H, H-23, H-
25.9 (C-15, C-20), 22.5, 22.3 (C-22, C-25), 21.4 (C-11), 18.2, 17.8 28), 2.02 (m, 4H, H-22, H-27), 1.74, 1.68, 1.60, 1.59 (each s, each
(C-14, C-19), 10.7, 10.6 (C-23, C-26); positive ESIMS m/z 517 [M + 3H, H-14, H-15, H-19, H-20); 13C NMR (DMSO-d6, 125 MHz)
Na]+.
d 181.3 (C-9), 172.9, 172.9 (C-24, C-29), 162.3 (C-3), 158.8 (C-1),
3,6-Di-O-3,3-dimethylallyl-a-mangostin (1h). Yield 15%, 1H 157.2 (C-4a), 154.7 (C-10a), 154.6 (C-6), 143.6 (C-7), 135.7 (C-8),
NMR (DMSO-d6, 500 MHz) d 13.50 (s, 1H, 1-OH), 7.03 (d, 1H, J ¼ 130.5 (C-13, C-18), 123.4, 122.3 (C-12, C-17), 110.7 (C-8a),
4.2 Hz, H-5), 6.55 (s, 1H, J ¼ 4.3 Hz, H-4), 5.49, 5.46 (each t, each 110.4 (C-2), 102.8 (C-9a), 99.3 (C-5), 89.7 (C-4), 67.8, 67.3 (C-21,
1H, J ¼ 6.6 Hz, H-22, H-27), 5.13 (br t, 2H, H-12, H-17), 4.71, 4.64 C-26), 60.3 (7-OCH3), 51.4 (C-25, C-30), 29.9, 29.8 (C-23, C-28),
(each d, each 2H, J ¼ 6.5 Hz, H-21, H-26), 3.99 (d, 2H, J ¼ 6.0 Hz, 25.5 (C-16), 25.4, 24.0, 23.9 (C-15, C-20, C-22, C-27), 20.9 (C-
H-16), 3.68 (s, 3H, 7-OCH3), 3.19 (d, 2H, J ¼ 7.0 Hz, H-11), 1.77, 11), 17.9, 17.5 (C-14, C-19); positive ESIMS m/z 633 [M + Na]+.
1.75, 1.75, 1.72, 1.69, 1.60, 1.59 (s, each 3H, H-14, H-15, H-19, H-
Diethyl-4,40-((1-hydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-
20, H-24, H-25, H-29, H-30); 13C NMR (DMSO-d6, 125 MHz) yl)-9-oxo-9H-xanthene-3,6-diyl)bis(oxy))dibutanoate (1l). Yield
1
d 181.5 (C-9), 162.5 (C-3), 158.8 (C-1), 157.3 (C-4a), 154.8 (C-10a), 25%, H NMR (CDCl3, 500 MHz) d 13.49 (s, 1H, 1-OH), 6.72 (s,
154.6 (C-6), 143.9 (C-7), 138.7, 138.2 (C-23, C-28), 135.7 (C-8), 1H, H-5), 6.29 (s, 1H, H-4), 5.23 (br t, 2H, J ¼ 7.0 Hz, H-12, H-17),
130.7, 130.5 (C-13, C-18), 123.5 (C-12, C-17), 122.1 (C-22, C-27), 4.15 (m, 8H, H-21, H-25, H-27, H-31), 4.09 (t, 2H, J ¼ 6.0 Hz, H-
119.1 (C-8a), 118.8 (C-2), 102.8 (C-9a), 99.8 (C-5), 90.3 (C-4), 16), 3.79 (s, 3H, 7-OCH3), 3.35 (d, 2H, J ¼ 7.1 Hz, H-11), 2.56 (dt,
65.7, 65.4 (C-21, C-26), 60.3 (7-OCH3), 25.6 (C-16), 25.5 (C-15, 4H, J ¼ 7.2, 12.5 Hz, H-23, H-29), 2.20 (m, 4H, H-22, H-28), 1.85,
C-20, C-25, C-30), 21.0 (C-11), 18.2, 18.1, 18.0, 17.6 (C-14, C-19, 1.79 (each s, each 3H, H-15, H-20), 1.68 (s, 6H, H-14, H-19), 1.27
C-24, C-29); positive ESIMS m/z 547 [M + H]+.
Dimethyl-2,20-((1-hydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-
(t, 6H, H-26, H-32); 13C NMR (CDCl3, 125 MHz) d 182.0 (C-9),
173.1, 172.9 (C-24, C-30), 162.5 (C-3), 159.9 (C-1), 157.2 (C-4a),
1-yl)-9-oxo-9H-xanthene-3,6-diyl)bis(oxy))diacetate (1i). Yield 155.3 (C-10a), 155.1 (C-6), 144.0 (C-7), 137.3(C-8), 131.8, 131.5
1
60%, H NMR (DMSO-d6, 500 MHz) d 13.47 (s, 1H, 1-OH), 7.03 (C-13, C-18), 123.2, 122.5 (C-12, C-17), 112.1 (C-8a), 111.5 (C-2),
(s, 1H, H-5), 6.50 (s, 1H, H-4), 5.17 (m, 2H, H-12, H-17), 5.07, 104.0 (C-9a), 98.8 (C-5), 89.3 (C-4), 67.6, 67.2 (C-21, C-27), 60.9,
4.98 (each s, each 2H, H-21, H-24), 4.01 (d, 2H, J ¼ 6.3 Hz, H-16), 60.6 (C-25, C-31), 60.5 (7-OCH3), 30.6 (C-23, C-29), 26.2 (C-16),
3.76, 3.73, 3.72 (each s, each 3H, 23-OCH3, 26-OCH3, 7-OCH3), 25.9, 25.8, 24.4, 24.3 (C-15, C-20, C-22, C-28), 21.4 (C-11), 18.2,
3.27 (d, 2H, J ¼ 7.1 Hz, H-11), 1.77, 1.72, 1.61, 1.60 (each s, each 17.8 (C-14, C-19), 14.2 (C-26, C-32); positive ESIMS m/z 661 [M +
3H, H-14, H-15, H-19, H-20); 13C NMR (DMSO-d6, 125 MHz) Na]+.
d 181.6 (C-9), 168.6, 168.5 (C-22, C-25), 161.5 (C-3), 159.0 (C-1),
3.2.2 General procedure for synthesis of compound 2a–2c.
156.4 (C-4a), 154.5 (C-10a), 154.4 (C-6), 143.7 (C-7), 136.2 (C-8), A 1% (w/v) osmium tetroxide solution (100 ml) in t-BuOH was
130.9, 130.7 (C-13, C-18), 123.3, 121.9 (C-12, C-17), 111.4 (C- added to a mixture of a-mangostin (1) (41 mg, 0.1 mmol), NMO
8a), 111.0 (C-2), 103.3 (C-9a), 99.9 (C-5), 90.2 (C-4), 65.2, 65.1 (17.6 mg, 0.15 mmol), acetone (1 mL) and water (1 mL), and the
(C-21, C-24), 60.4 (7-OCH3), 52.1, 52.0 (C-23, C-26), 25.6 (C-16), whole was stirred at room temperature for 24 h. Sodium sulte
25.6, 25.5 (C-15, C-20), 21.0 (C-11), 18.0, 17.7 (C-14, C-19); was added to the resulting mixture and stirring was continued
negative ESIMS m/z 553 [M ꢃ H]ꢃ.
for a further 30 min. The mixture was diluted with water,
extracted with ethyl acetate (3 ꢄ 20 mL). The combined organic
Diethyl-2,20-((1-hydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-
yl)-9-oxo-9H-xanthene-3,6-diyl)bis(oxy))diacetate (1j). Yield 60%, layers were dried over sodium sulfate and concentrated in vacuo
1H NMR (DMSO-d6, 500 MHz) d 13.49 (s, 1H, 1-OH), 7.04 (s, 1H, to give a yellow solid. The residue was puried on column
H-5), 6.51 (s, 1H, H-4), 5.20, 5.15 (each t, each 1H, J ¼ 7.0 Hz, H- chromatograph using petroleum ether/ethyl acetate (1 : 1) to
12, H-17), 5.06, 4.97 (each s, each 2H, H-21, H-25), 4.19 (m, 4H, afford 2a (4.4 mg, 10%), 2b (5 mg, 12%) and 2c (37 mg, 78%).
H-23, H-27), 4.02 (d, 2H, J ¼ 7.0 Hz, H-16), 3.76 (s, 3H, 7-OCH3),
1,3,6-Trihydroxy-2-(2,3-dihydroxy-3-methylbutyl)-7-methoxy-8-
1
3.28 (d, 2H, J ¼ 7.0 Hz, H-11), 1.77, 1.72, 1.61, 1.60 (each s, each (3-methyl-2-butenyl)xanthone (2a). Yield 10%, H NMR (CD3OD,
3H, H-14, H-15, H-19, H-20), 1.22 (m, 6H, H-24, H-28); 13C NMR 500 MHz) d 6.70 (s, 1H, H-5), 6.27 (s, 1H, H-4), 5.21 (br t, 1H, J ¼
(DMSO-d6, 125 MHz) d 181.6 (C-9), 168.1, 168.0 (C-22, C-26), 6.5 Hz, H-200), 4.07 (d, 2H, J ¼ 6.5 Hz, H-100), 3.75 (s, 3H, 7-OCH3),
161.5 (C-3), 159.0 (C-1), 156.5 (C-4a), 154.6 (C-10a), 154.5 (C-6), 3.61 (dd, 1H, J ¼ 2.5, 10.0 Hz, H-20), 3.04 (dd, 1H, J ¼ 2.5,
143.8 (C-7), 136.2 (C-8), 130.9, 130.8 (C-13, C-18), 123.3, 121.9 14.0 Hz, H-10), 2.68 (dd, 1H, J ¼ 10.0, 14.0 Hz, H-10), 1.82, 1.66
(C-12, C-17), 111.4 (C-8a), 111.0 (C-2), 103.3 (C-9a), 99.9 (C-5), (each s, each 3H, H-400, H-500), 1.26 (s, 6H, H-40, H-50); 13C NMR
90.3 (C-4), 65.3, 65.2 (C-21, C-25), 61.0, 60.9 (C-23, C-27), 60.4 (CD3OD, 125 MHz) d 183.2 (C-9), 164.4 (C-3), 162.1 (C-1), 158.1
(7-OCH3), 25.6 (C-16), 25.6, 25.5 (C-15, C-20), 21.0 (C-11), 18.0, (C-6), 156.8 (C-4a), 156.6 (C-10a), 144.9 (C-7), 138.5 (C-8), 131.9
(C-30), 125.1 (C-200), 112.2 (C-8a), 109.8 (C-2), 103.8 (C-9a), 102.8
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(C-5), 93.9 (C-20), 80.0 (C-4), 74.0 (C-30), 61.3 (OCH3), 27.1 (C-10), 164.2 (C-1), 161.5 (C-3), 158.0 (C-4a), 156.6 (C-10a), 156.1 (C-6),
26.0 (C-100), 25.8, 25.6, 25.2, 18.3; negative ESIMS m/z 443 [M ꢃ 145.7 (C-7), 136.3 (C-8), 112.8 (C-8a), 112.8 (C-2), 103.6 (C-9a),
H]ꢃ.
103.2 (C-5), 93.3 (C-4), 80.8 (C-20), 74.3 (C-30), 60.9 (OCH3),
39.1 (C-200), 29.6 (C-10), 29.5 (C-300), 25.9, 25.3, 23.1, 21.2 (C-100);
1,3,6-Trihydroxy-2-(3-methyl-2-butenyl)-7-methoxy-8-(2,3-
dihydroxy-3-methylbutyl)xanthone (2b). Yield 12%, 1H NMR negative ESIMS m/z 445 [M ꢃ H]ꢃ; HRESIMS m/z 445.1867 [M ꢃ
(CD3OD, 500 MHz) d 6.77 (s, 1H, H-5), 6.28 (s, 1H, H-4), 5.22 (m, H]ꢃ (calcd for C24H29O8, 445.1868).
1H, H-20), 3.84 (s, 3H, 7-OCH3), 3.66 (dd, 1H, J ¼ 2.8, 10.2 Hz, H-
Tetrahydro-a-mangostin (2r). Yield 95%, 1H NMR (CD3OD, 500
200), 3.54 (dd, 2H, J ¼ 2.8, 12.3 Hz, H-100), 3.33 (m, 2H, H-10), 1.77, MHz) d 6.60 (s, 1H, H-5), 6.17 (s, 1H, H-4), 3.77 (s, 3H, 7-OCH3),
1.65 (each s, each 3H, H-400, H-500), 1.34, 1.33 (each s, each 3H, H- 3.24 (m, 2H, H-100), 2.57 (m, 2H, H-10), 1.70 (m, 1H, J ¼ 6.6,
40, H-50); 13C NMR (CD3OD, 125 MHz) d 184.0 (C-9), 164.2 (C-3), 13.1 Hz, H-30), 1.56 (m, 1H, J ¼ 6.6, 13.1 Hz, H-300), 1.39 (m, 4H,
161.5 (C-1), 158.3 (C-4a), 156.7 (C-10a), 156.4 (C-6), 145.9 (C-7), H-20, H-200), 0.99, 0.97, 0.95, 0.94 (each s, each 3H, H-40, H-50, H-
136.5 (C-8), 131.8 (C-30), 123.7 (C-20), 112.9 (C-8a), 111.8 (C-2), 400, H-500); 13C NMR (CD3OD, 125 MHz) d 183.1 (C-9), 163.6 (C-1),
103.7 (C-9a), 103.2 (C-5), 93.3 (C-4), 80.7 (C-200), 74.3 (C-300), 161.7 (C-3), 157.6 (C-4a), 156.7 (C-6), 156.0 (C-10a), 144.5 (C-7),
60.9 (OCH3), 29.6 (C-100), 26.0, 25.8, 25.4, 22.2 (C-10), 17.9; 140.4 (C-8), 112.5 (C-8a), 112.2 (C-2), 103.7 (C-9a), 102.5 (C-5),
negative ESIMS m/z 443 [M ꢃ H]ꢃ.
93.0 (C-4), 61.5 (7-OCH3), 41.5 (C-20), 39.1 (C-200), 30.1 (C-30),
29.5 (C-300), 26.2 (C-100), 23.1 (C-40, C-5ꢃ0), 23.0 (C-400, C-500), 21.2 (C-
1,3,6-Trihydroxy-7-methoxy-2,8-bis(2,3-dihydroxy-3-methyl-
1
butyl)-9H-xanthen-9-one (2c). Yield 78%, H NMR (CD3OD, 500 10); negative ESIMS m/z 413 [M ꢃ H] .
MHz) d 6.74 (s, 1H, H-5), 6.29 (s, 1H, H-4), 3.85 (s, 3H, 7-OCH3),
3.2.4 General procedure for synthesis of compound 2f–2h.
3.65 (m, 1H, H-200), 3.61 (m, 1H, H-20), 3.56 (m, 2H, H-100), 3.02 A solution of 2a, 2c or 2d (0.1 mmol) in mixed reagent (2 mL,
(dd, 1H, J ¼ 2.4, 14.0 Hz, H-10), 2.68 (dd, 1H, J ¼ 10.2, 14.0 Hz, H- THF : H2O ¼ 2 : 1) was added NaIO4 (26 mg, 0.12 mmol) at cool
10), 1.33, 1.32, 1.26, 1.25 (each s, each 3H, H-40, H-50, H-400, H-500); temperature. Aer the addition was completed, the reaction
13C NMR (CD3OD, 125 MHz) d 183.9 (C-9), 164.9 (C-3), 161.9 (C- solution was allowed to warm to room temperature. Aer stir-
1), 158.3 (C-4a), 156.7 (C-10a), 156.7 (C-6), 145.9 (C-7), 136.5 (C- ring for 4 h, the reaction mixture was diluted with water,
8), 112.8 (C-8a), 110.0 (C-2), 103.7 (C-9a), 103.3 (C-5), 94.0 (C-4), extracted with ethyl acetate (3 ꢄ 10 mL). The organic phase
80.6 (C-200), 79.8 (C-20), 74.3 (C-300), 74.0 (C-30), 61.0 (OCH3), 29.6 solvent was washed with brine, dried over anhydrous sodium
(C-100), 25.9, 25.8 (C-10), 25.6, 25.4, 25.2; negative ESIMS m/z 477 sulfate, and then concentrated in vacuo to give a yellow solid.
[M ꢃ H]ꢃ; HRESIMS m/z 477.1766 [M ꢃ H]ꢃ (calcd for The crude product was puried on column chromatograph
C
24H29O10, 477.1766).
3.2.3 General procedure for synthesis of compound 2d, 2e or 2h.
and 2r. A solution of 1, 2a or 2b (44 mg, 0.1 mmol) and 10% Pd/ 1,3,6-Trihydroxy-7-methoxy-8-(3-methylbut-2-en-1-yl)-2H-furo
using petroleum ether/ethyl acetate (2 : 1 ꢂ 4 : 1) to afford 2f, 2g
1
C (5 mg) in CH3OH (2 mL) was placed under an atmosphere of [3,2-b]xanthen-5(3H)-one (2f). Yield 60%, H NMR (CD3OD, 500
hydrogen. Aer stirring for 24 h, the reaction mixture was MHz) d 6.64 (s, 1H, H-5), 6.21 (s, 1H, H-4), 5.19 (m, 1H, H-200),
ltered through lter paper and concentrated under reduced 4.83 (t, 1H, J ¼ 5.7 Hz, H-20), 4.02 (t, 2H, J ¼ 6.2 Hz, H-100), 3.74 (s,
pressure. The crude product was puried on column chro- 3H, 7-OCH3), 2.91 (m, 2H, H-10), 1.81, 1.66 (each s, each 3H, H-
matograph using petroleum ether/ethyl acetate (1 : 1 ꢂ 2 : 1) to 400, H-500); 13C NMR (CD3OD, 125 MHz) d 183.1 (C-9), 164.2 (C-3),
afford 2d, 2e or 2r respectively.
1,3,6-Trihydroxy-2-(2,3-dihydroxy-3-methylbutyl)-7-methoxy-8-
162.4 (C-1), 158.0 (C-6), 156.7 (C-4, C-10a), 144.8 (C-7), 138.5 (C-
8), 131.8 (C-300), 125.1 (C-200), 112.1 (C-8a), 107.0 (C-2), 103.7 (C-
isopentyl-9H-xanthen-9-one (2d). Yield 78%, 1H NMR (CD3OD, 9a), 102.8 (C-5), 99.0 (C-20), 93.5 (C-4), 61.3 (OCH3), 30.9 (C-10),
500 MHz) d 6.62 (s, 1H, H-5), 6.21 (s, 1H, H-4), 3.78 (s, 3H, 7- 27.1 (C-100), 26.0, 18.3; negative ESIMS m/z 383 [M ꢃ H]ꢃ;
OCH3), 3.60 (dd, 1H, J ¼ 2.4, 10.1 Hz, H-20), 3.26 (m, 2H, H-100), HRESIMS m/z 383.1134 [M ꢃ H]ꢃ (calcd for C21H19O7,
3.01 (dd, 1H, J ¼ 2.4, 14.1 Hz, H-10), 2.65 (dd, 1H, J ¼ 10.1, 383.1136).
14.1 Hz, H-10), 1.71 (m, 1H, H-300), 1.41 (m, 2H, H-200), 1.26 (s, 6H,
1,3,6-Trihydroxy-7-methoxy-8-(2,3-dihydroxy-3-methylbutyl)-
H-400, H-500), 1.00, 0.98 (each s, each 3H, H-40, H-50); 13C NMR 2H-furo[3,2-b]xanthen-5(3H)-one (2g). Yield 50%, 1H NMR
(CD3OD, 125 MHz) d 183.1 (C-9), 164.2 (C-1), 162.1 (C-3), 157.8 (CD3OD, 500 MHz) d 6.67 (s, 1H, H-5), 6.21 (s, 1H, H-4), 4.83 (t,
(C-4a), 156.7 (C-10a), 156.5 (C-6), 144.6 (C-7), 140.4 (C-8), 112.1 1H, J ¼ 5.7 Hz, H-20), 3.84 (s, 3H, 7-OCH3), 3.63 (m, 1H, H-200),
(C-8a), 109.6 (C-2), 103.8 (C-9a), 102.6 (C-5), 93.9 (C-4), 80.0 (C- 3.48 (m, 2H, H-100), 2.91 (dd, 2H, J ¼ 5.7, 14.4 Hz, H-10), 1.32, 1.31
200), 74.0 (C-300), 61.5 (OCH3), 41.4 (C-20), 30.1 (C-30), 26.3 (C-100), (each s, each 3H, H-400, H-500); 13C NMR (CD3OD, 125 MHz)
25.8 (C-10), 25.7, 25.1, 23.0; negative ESIMS m/z 445 [M ꢃ H]ꢃ; d 183.8 (C-9), 164.7 (C-3), 162.3 (C-1), 158.2 (C-6), 156.7 (C-4a),
HRESIMS m/z 445.1870 [M ꢃ H]ꢃ (calcd for C24H29O8, 156.6 (C-10a), 145.9 (C-7), 136.4 (C-8), 112.7 (C-8a), 107.3 (C-2),
445.1868).
103.6 (C-9a), 103.3 (C-5), 98.9 (C-20), 93.7 (C-4), 80.6 (C-200),
74.3 (C-300), 60.9 (OCH3), 30.9 (C-10), 29.6 (C-100), 25.9, 25.4;
1,3,6-Trihydroxy-2-isopentyl-7-methoxy-8-(2,3-dihydroxy-3-
methylbutyl)-9H-xanthen-9-one (2e). Yield 78%, 1H NMR negative ESIMS m/z 417 [M ꢃ H]ꢃ; HRESIMS m/z 417.1187 [M ꢃ
(CD3OD, 500 MHz) d 6.66 (d, 1H, J ¼ 1.8 Hz, H-5), 6.18 (d, 1H, J ¼ H]ꢃ (calcd for C21H21O9, 417.1191).
1.6 Hz, H-4), 3.84 (s, 3H, 7-OCH3), 3.63 (dd, 1H, J ¼ 2.7, 10.5 Hz,
1,3,6-Trihydroxy-7-methoxy-8-isopentyl-2H-furo[3,2-b]
H-200), 3.48 (m, 2H, H-100), 2.56 (m, 2H, H-10), 1.55 (m, 1H, H-30), xanthone-5(3H)-one (2h). Yield 60%, 1H NMR (CD3OD, 500 MHz)
1.37 (m, 2H, H-20), 1.32 (s, 6H, H-400, H-500), 0.95, 0.93 (each s, d 6.65 (s, 1H, H-5), 6.23 (s, 1H, H-4), 4.84 (t, 1H, J ¼ 5.7 Hz, H-20),
each 3H, H-40, H-50); 13C NMR (CD3OD, 125 MHz) d 183.8 (C-9), 3.79 (s, 3H, 7-OCH3), 3.29 (m, 2H, H-100), 2.94 (m, 2H, H-10), 1.72
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(m, 1H, H-300), 1.42 (m, 2H, H-200), 1.00, 0.99 (each s, each 3H, H-
400, H-500); 13C NMR (CD3OD, 125 MHz) d 183.1 (C-9), 164.2 (C-3),
162.5 (C-1), 157.9 (C-6), 156.7 (C-4a), 156.7 (C-10a), 144.7 (C-7),
140.4 (C-8), 112.1 (C-8a), 107.0 (C-2), 103.8 (C-9a), 102.6 (C-5),
99.0 (C-20), 93.5 (C-4), 61.3 (OCH3), 41.5 (C-200), 30.9 (C-10), 30.1
(C-300), 26.2 (C-100), 23.0; negative ESIMS m/z 385 [M ꢃ H]ꢃ;
HRESIMS m/z 385.1295 [M ꢃ H]ꢃ (calcd for C21H21O7,
385.1293).
3.2.5 General procedure for synthesis of compound 2i–2j. A
solution of 2a or 2d (0.1 mmol) and NaH (80 mg, 2 mM) in DMF
(2 mL) was placed under an atmosphere of nitrogen, aer stir-
ring for 30 min, the reaction mixture was added CH3I (0.2 mL, 3
mM). Aer stirring for 4 h, the reaction mixture was diluted with
water, extracted with ethyl acetate (3 ꢄ 10 mL). The organic
phase solvent was washed with brine, dried over anhydrous
sodium sulfate, and then concentrated in vacuo to give a yellow
solid. The crude product was puried on column chromato-
graph using petroleum ether/ethyl acetate (9 : 1) to afford 2i or
2j.
2-(2,3-Dimethoxy-3-methylbutyl)-1,3,6,7-tetramethoxy-8-(3-
methylbut-2-en-1-yl)-9H-xanthen-9-one (2i). Yield 60%, 1H NMR
(DMSO-d6, 500 MHz) d 6.98 (s, 1H, H-5), 6.82 (s, 1H, H-4), 5.15
(br t, 1H, J ¼ 7.0 Hz, H-17), 3.99 (dd, 2H, J ¼ 6.6, 15.6 Hz, H-16),
3.92, 3.77, 3.68 (each s, each 3H, 1-OCH3, 3-OCH3, 6-OCH3, 7-
OCH3), 3.39 (dd, 1H, J ¼ 3.0, 10.0 Hz, H-11), 3.15 (s, 3H, 12-
OCH3), 2.93 (s, 3H, 13-OCH3), 2.85 (dd, 1H, J ¼ 10.0, 13.4 Hz, H-
12), 2.66 (dd, 1H, J ¼ 3.0, 13.4 Hz, H-11), 1.76, 1.58, 1.15, 1.11
(each s, each 3H, C-14, C-15, C-19, C-20); 13C NMR (DMSO-d6,
125 MHz) d 175.2 (C-9), 162.5 (C-3), 158.5 (C-1), 157.0 (C-10a),
156.2 (C-4a), 153.7 (C-6), 143.6 (C-7), 135.6 (C-8), 130.3 (C-18),
123.9 (C-17), 118.4 (C-2), 113.7 (C-8a), 110.0 (C-9a), 98.5 (C-5),
94.5 (C-12), 84.6 (C-4), 77.2 (C-13), 61.3 (1-OCH3), 60.4 (7-
OCH3), 60.1 (12-OCH3), 56.3 (3-OCH3, 6-OCH3), 48.9 (13-OCH3),
25.6, 25.3 (C-16), 23.8 (C-11), 22.1, 20.6, 18.0; positive ESIMS m/z
537 [M + Na]+; HRESIMS m/z 537.2472 [M + Na]+ (calcd for
9-Hydroxycalabaxanthone (2k). Yield 40%, H NMR (CD3OD,
500 MHz) d 6.66 (s, 1H, H-5), 6.62 (d, 1H, J ¼ 10.0 Hz, H-10), 6.13
(s, 1H, H-4), 5.61 (d, 1H, J ¼ 10.0 Hz, H-20), 5.20 (br t, 1H, J ¼
6.5 Hz, H-200), 4.03 (d, 2H, J ¼ 6.5 Hz, H-100), 3.75 (s, 3H, 7-OCH3),
1.81, 1.66, 1.43 (each s, each 3H, H-40, H-50, H-400, H-500); 13C
NMR (CD3OD, 125 MHz) d 183.2 (C-9), 161.0 (C-1), 158.9 (C-3),
158.2 (C-4a), 157.5 (C-10a), 156.7 (C-6), 145.0 (C-7), 138.5 (C-8),
131.9 (C-300), 128.3 (C-20), 125.0 (C-200), 116.4 (C-10), 112.1 (C-
8a), 105.3 (C-2), 104.4 (C-9a), 102.9 (C-5), 94.9 (C-4), 79.0 (C-
30), 61.3 (OCH3), 28.6, 27.1 (C-100), 26.0, 18.3; negative ESIMS m/z
407 [M ꢃ H]ꢃ.
A solution of mangostin (0.1 mmol) in DCM (2 mL) was
placed under an atmosphere of nitrogen, a m-CPBA solution in
DCM (2 mL) was then added drop wise over 10 min. The reac-
tion mixture was stirred at 0 ꢀC for 12 h, washed with 10%
sodium hydrogen sulte solution (10 mL), saturated hydrogen
carbonate solution (10 mL), saturated sodium chloride (10 mL)
and dried with anhydrous sodium sulfate. The reaction mixture
was concentrated in vacuo to give a yellow solid and the crude
product was puried on column chromatograph using petro-
leum ether/ethyl acetate (9 : 1) to afford 2l and 2m respectively.
1-((3,3-Dimethyloxiran-2-yl)methyl)-3,6,8-trihydroxy-2-methoxy-
7-(3-methylbut-2-en-1-yl)-9H-xanthen-9-one (2l). Yield 4%, 1H
NMR (DMSO-d6, 600 MHz) d 13.82 (s, 1H, 1-OH), 6.79 (s, 1H, H-
5), 6.30 (s, 1H, H-4), 5.28 (d, 1H, J ¼ 4.8 Hz, H-200), 5.15 (t, 1H, J ¼
6.6 Hz, H-20), 4.02 (t, 2H, J ¼ 6.0 Hz, H-100), 3.71 (d, H, J ¼ 6.3 Hz,
H-10), 3.70 (s, 3H, 7-OCH3), 2.79 (dd, H, J ¼ 16.8 Hz, H-10), 1.77,
1.62, 1.30, 1.24 (each s, each 3H, H-40, H-50, H-400, H-500); 13C
NMR (DMSO-d6, 150 MHz) d 181.4 (C-9), 161.2 (C-3), 159.6 (C-1),
157.3 (C-4a), 154.9 (C-10a), 154.2 (C-6), 143.4 (C-7), 136.5 (C-8),
130.5 (C-30), 123.6 (C-20), 109.8 (C-8a), 102.8 (C-2), 102.1 (C-
10a), 101.8 (C-5), 93.4 (C-4), 79.0 (C-200), 66.9 (C-300), 60.2
(OCH3), 25.8 (C-100), 25.6 (C-50), 25.3, 25.0, 21.2 (C-10, C-400, C-500),
18.1(C-40); negative ESIMS m/z 425 [M ꢃ H]ꢃ; HRESIMS m/z
425.1600 [M ꢃ H]ꢃ (calcd for C24H25O7, 425.1600).
1
C
29H38NaO8, 537.2464).
Mangostanin (2m). Yield 49%, H NMR (DMSO-d6, 500 MHz)
2-(2,3-Dimethoxy-3-methylbutyl)-8-isopentyl-1,3,6,7-tetrame-
d 13.63 (s, 1H, 1-OH), 6.78 (s, 1H, H-5), 6.37 (s, 1H, H-4), 5.15 (br t,
1H, J ¼ 6.5 Hz, H-200), 4.73 (m, 1H, H-20), 3.99 (d, 2H, J ¼ 6.6 Hz, H-
100), 3.69 (s, 3H, 7-OCH3), 3.03 (d, 2H, J ¼ 8.6 Hz, H-10), 1.75, 1.61,
1.14, 1.12 (each s, each 3H, H-40, H-50, H-400, H-500); 13C NMR
(DMSO-d6, 125 MHz) d 181.5 (C-9), 166.6 (C-1), 157.2 (C-6), 157.1 (C-
10a), 156.4 (C-4a), 154.7 (C-3), 143.6 (C-7), 136.3 (C-8), 130.4 (C-300),
123.6 (C-200), 109.8 (C-8a), 107.8 (C-2), 102.9 (C-9a), 101.7 (C-5), 91.6
(C-20), 88.0 (C-4), 70.0 (C-30), 60.2 (OCH3), 26.0 (C-10), 25.8, 25.7,
25.6 (C-100), 25.0, 18.0; negative ESIMS m/z 425 [M ꢃ H]ꢃ.
thoxy-9H-xanthen-9-one (2j). Yield 60%, 1H NMR (DMSO-d6, 500
MHz) d 6.93 (s, 1H, H-5), 6.78 (s, 1H, H-4), 3.92, 3.91, 3.76, 3.70
(each s, each 3H, 1-OCH3, 3-OCH3, 6-OCH3, 7-OCH3), 3.37 (dd,
1H, J ¼ 3.0, 10.0 Hz, H-12), 3.24 (m, 2H, H-16), 3.14, 2.92 (each s,
each 3H, 12-OCH3, 13-OCH3), 2.84 (m, 1H, H-11), 2.64 (dd, 1H, J
¼ 3.0, 13.0 Hz, H-11), 1.14, 1.10, 0.95, 0.94 (each s, each 3H, C-
14, C-15, C-19, C-20); 13C NMR (DMSO-d6, 125 MHz) d 175.1 (C-
9), 162.4 (C-3), 158.6 (C-1), 156.8 (C-4a), 156.2 (C-10a), 153.7 (C-
6), 143.4 (C-7), 137.5 (C-8), 118.3 (C-2), 113.7 (C-8a), 110.0 (C-9a),
98.3 (C-12), 94.4 (C-5), 84.6 (C-13), 77.2 (C-4), 61.2, 60.6, 60.1,
56.3, 56.2 (1-OCH3, 3-OCH3, 6-OCH3, 12-OCH3, 13-OCH3), 48.9
(C-17), 28.3 (C-18), 24.2 (C-16), 23.7 (C-11), 22.5, 22.5, 22.1, 20.6;
positive ESIMS m/z 539 [M + Na]+; HRESIMS m/z 539.2625 [M +
Na]+ (calcd for C29H40NaO8, 539.2621).
1,3,6-Trihydroxy-2-(3-hydroxy-3-methylbutyl)-7-methoxy-8-(3-
1
methylbut-2-en-1-yl)-9H-xanthen-9-one (2n). Yield 25%, H NMR
(CD3OD, 500 MHz) d 6.70 (s, 1H, H-5), 6.24 (s, 1H, H-4), 5.22 (t,
1H, J ¼ 6.5 Hz, H-200), 3.82 (s, 3H, 7-OCH3), 3.34–3.40 (m, 4H, H-
10, H-100), 1.77 (s, 3H, H-40), 1.73 (m, 2H, H-20), 1.65 (s, 3H, H-500),
1.33 (s, 6H, H-40, H-50); 13C NMR (CD3OD, 125 MHz) d 183.2 (C-
9), 163.7 (C-3), 161.6 (C-1), 160.0 (C-6), 156.8 (C-10a), 156.2 (C-
4a), 144.7 (C-7), 139.9 (C-8), 131.7 (C-300), 123.8 (C-200), 112.2
(C-8a), 111.5 (C-2), 103.8 (C-9a), 102.7 (C-5), 93.1 (C-4), 71.9 (C-
30), 61.5 (OCH3), 45.6 (C-20), 29.0, 26.0, 23.6 (C-100), 22.2 (C-10),
17.9; negative ESIMS m/z 427 [M ꢃ H]ꢃ.
A solution of mangostin (0.1 mmol) and DDQ (27 mg, 0.12
mM) in toluene (2 mL) was placed in a ask with round bottom
(10 mL), aer slowly heating up to 120 ꢀC. Aer stirring for 4 h,
the reaction mixture was concentrated in vacuo to give a yellow
solid. The crude product was puried on column chromato-
graph using petroleum ether/ethyl acetate (9 : 1) to afford 2k.
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3-Isomangostin hydrate (2o). Yield 23%, 1H NMR (CD3OD, 500
MHz) d 6.65 (s, 1H, H-5), 6.12 (s, 1H, H-4), 3.82 (s, 3H, 7-OCH3),
3.36 (m, 2H, H-100), 2.65 (m, 2H, H-10), 1.83 (t, 2H, J ¼ 6.8 Hz, H-
20), 1.72 (m, 2H, H-200), 1.34, 1.32 (s, 12H, H-40, H-50, H-400, H-500);
13C NMR (CD3OD, 125 MHz) d 183.2 (C-9), 161.9 (C-1), 161.6 (C-
3), 158.8 (C-4a), 157.0 (C-10a), 156.0 (C-6), 144.9 (C-7), 139.7 (C-
8), 111.8 (C-8a), 104.7 (C-2), 103.6 (C-9a), 102.9 (C-5), 94.8 (C-4),
77.1 (C-30), 71.9 (C-300), 61.5 (OCH3), 45.5 (C-200), 32.8 (C-20), 29.0,
27.0, 23.6 (C-100), 17.0 (C-10); negative ESIMS m/z 427 [M ꢃ H]ꢃ.
1-Isomangostin hydrate (2p). Yield 12%, 1H NMR (CD3OD, 500
MHz) d 6.66 (s, 1H, H-5), 6.29 (s, 1H, H-4), 3.80 (s, 3H, 7-OCH3),
3.37 (m, 2H, H-100), 2.66 (m, 2H, H-10), 1.82 (t, 2H, J ¼ 6.9 Hz, H-
20), 1.75 (m, 2H, H-200), 1.40 (s, 6H, H-40, H-400), 1.32 (s, 6H, H-50,
H-500); 13C NMR (CD3OD, 125 MHz) d 179.0 (C-9), 161.9 (C-1),
161.6 (C-2), 158.2 (C-4a), 157.1 (C-10a), 155.8 (C-6), 144.8 (C-7),
139.5 (C-8), 114.7 (C-8a), 107.6 (C-9a), 106.2 (C-2), 102.2 (C-5),
93.9 (C-4), 76.7 (C-30), 71.9 (C-300), 61.4 (OCH3), 45.5 (C-200),
32.6 (C-20), 30.8, 29.2, 26.8 (C-100), 24.0, 23.2, 18.1 (C-10); negative
ESIMS m/z 427 [M ꢃ H]ꢃ.
159.4 (C-10a), 128.3 (C-8), 114.7 (C-8a), 114.2 (C-7), 103.1 (C-
9a, C-2), 99.0 (C-5), 95.0 (C-4); negative ESIMS m/z 243 [M ꢃ H]ꢃ.
3.2.6 General procedure for synthesis of compound 3a–3e.
A solution of 1 or 2r (0.1 mmol) and NBS or NCS (40 mg, 0.22
mM) in DCM or THF (2 mL) was placed under an atmosphere of
nitrogen. Aer stirring for 24 h, the reaction mixture was
diluted with saturated sodium thiosulfate solution, extracted
with dichloromethane (3 ꢄ 10 mL). The organic phase solvent
was washed with brine, dried over anhydrous sodium sulfate,
and then concentrated in vacuo to give a yellow solid. The crude
product was puried on column chromatograph using petro-
leum ether/ethyl acetate (9 : 1) to afford 3a–3e.
1
4-Chloro-a-mangostin (3a). Yield 30%, H NMR (CD3OD, 500
MHz) d 6.77 (s, 1H, H-5), 5.21 (br t, 2H, H-20, H-200), 4.05 (d, 2H, J
¼ 6.5 Hz, H-100), 3.76 (s, 3H, 7-OCH3), 3.34 (m, 2H, H-10), 1.82,
1.78, 1.66, 1.65 (each s, each 3H, H-40, H-50, H-400, H-500); 13C
NMR (CD3OD, 125 MHz) d 182.7 (C-9), 160.5 (C-1), 159.6 (C-3),
158.8 (C-10a), 156.5 (C-6), 151.2 (C-4a), 145.4 (C-7), 138.5 (C-8),
132.1, 131.9 (C-30, C-300), 125.0, 123.5 (C-20, C-200), 112.8 (C-8a),
111.6 (C-2), 103.8 (C-9a), 103.0 (C-5), 98.5 (C-4), 61.3 (7-OCH3),
27.1 (C-100), 26.0, 26.0 (C-40, C-400), 22.9 (C-10), 18.3, 18.0 (C-10, C-
100); negative ESIMS m/z 443 [M ꢃ H]ꢃ.
1
1-Isomangostin (2q). Yield 20%, H NMR (CD3OD, 500 MHz)
d 6.61 (s, 1H, H-5), 6.05 (s, 1H, H-4), 5.21 (br t, H, J ¼ 6.5 Hz, H-
200), 4.02 (d, 2H, J ¼ 6.5 Hz, H-100), 3.75 (s, 3H, 7-OCH3), 2.62 (t,
2H, J ¼ 6.8 Hz, H-10), 1.81 (m, 2H, H-20), 1.81, 1.67, 1.33 (each s,
each 3H, H-40, H-50, H-400, H-500); 13C NMR (CD3OD, 125 MHz)
d 183.1 (C-9), 161.8 (C-3), 161.5 (C-1), 158.3 (C-4a), 156.8 (C-10a),
155.9 (C-6), 144.8 (C-7), 138.4 (C-8), 131.6 (C-300), 125.2 (C-200),
111.9 (C-8a), 104.6 (C-9a), 103.5 (C-2), 102.9 (C-5), 94.8 (C-4),
77.0 (C-30), 61.3 (7-OCH3), 32.8 (C-20), 27.1, 27.0 (C-40, C-400),
26.0 (C-200), 18.3 (C-50, C-500), 17.0 (C-100); negative ESIMS m/z 409
[M ꢃ H]ꢃ.
4-Bromo-a-mangostin (3b). Yield 12%, 1H NMR (CDCl3, 500
MHz) d 13.69 (s, 1H, 1-OH), 6.97 (s, 1H, H-5), 5.25 (br t, 2H, H-20,
H-200), 4.08 (d, 2H, J ¼ 6.5 Hz, H-100), 3.82 (s, 3H, 7-OCH3), 3.46
(m, 2H, H-10), 1.83, 1.82, 1.71, 1.69 (each s, each 3H, H-40, H-50,
H-400, H-500); 13C NMR (CDCl3, 125 MHz) d 181.8 (C-9), 160.0 (C-
1), 156.8 (C-3), 155.5 (C-10a), 155.0 (C-6), 150.7 (C-4a), 143.0 (C-
7), 137.2 (C-8), 133.4, 132.4 (C-30, C-300), 122.9, 121.4 (C-20, C-200),
111.9 (C-8a), 110.6 (C-2), 104.3 (C-9a), 101.9 (C-5), 86.4 (C-4),
62.1 (7-OCH3), 26.6 (C-100), 25.9, 25.8 (C-40, C-400), 22.3 (C-10),
18.3, 17.9 (C-10, C-100); negative ESIMS m/z 488 [M ꢃ H]ꢃ.
4,5-Dibromo-a-mangostin (3c). Yield 50%, 1H NMR (CD3OD,
500 MHz) d 5.20 (br t, 2H, H-20, H-200), 4.03 (d, 2H, J ¼ 6.5 Hz, H-
100), 3.75 (s, 3H, 7-OCH3), 3.36 (d, 2H, J ¼ 7.0 Hz, H-10), 1.82, 1.79,
1.66, 1.66 (each s, each 3H, H-40, H-50, H-400, H-500); 13C NMR
(CD3OD, 125 MHz) d 182.6 (C-9), 160.4 (C-1), 160.1 (C-3), 156.1
(C-10a), 153.4 (C-6), 152.1 (C-4a), 145.2 (C-7), 137.3 (C-8), 132.5,
132.4 (C-30, C-300), 124.5, 123.1 (C-20, C-200), 113.2 (C-8a), 112.4 (C-
2), 104.5 (C-9a), 97.6 (C-5), 87.8 (C-4), 62.0 (7-OCH3), 27.1 (C-100),
26.0, 26.0 (C-40, C-400), 23.1 (C-10), 18.4, 18.0 (C-10, C-100); negative
ESIMS m/z 567 [M ꢃ H]ꢃ; HRESIMS m/z 564.9863 [M ꢃ H]ꢃ
(calcd for C24H23Br2O6, 564.9867).
g-Mangostin (2s). 1H NMR (CD3OD, 500 MHz) d 6.66 (s, 1H, H-
5), 6.22 (s, 1H, H-4), 5.25 (br t, 2H, J ¼ 6.5 Hz, H-20, H-200), 4.11 (d,
2H, J ¼ 6.7 Hz, H-100), 3.34 (m, 2H, H-10), 1.83, 1.78 (each s, each
3H, H-40, H-400), 1.65 (s, 6H, H-50, H-500); 13C NMR (CD3OD, 125
MHz) d 183.6 (C-9), 163.4 (C-3), 161.5 (C-1), 156.3 (C-4a), 154.0
(C-10a), 153.2 (C-6), 142.0 (C-7), 131.7, 131.6 (C-30, C-300), 129.5
(C-8), 124.8, 124.0 (C-20, C-200), 112.2 (C-8a), 111.1 (C-2), 103.9 (C-
9a), 100.9 (C-5), 92.9 (C-4), 26.6 (C-100), 26.1, 26.0 (C-40, C-400),
22.2 (C-10), 18.3, 17.9 (C-50, C-500); negative ESIMS m/z 395 [M ꢃ
H]ꢃ.
Tetrahydro-g-mangostin (2t). Yield 96%, 1H NMR (CD3OD, 500
MHz) d 6.64 (s, 1H, H-5), 6.21 (s, 1H, H-4), 3.35 (m, 2H, H-100),
2.60 (m, 2H, H-10), 1.70, 1.57 (dt, each 1H, J ¼ 6.6, 13.2 Hz, H-30,
H-300), 1.42 (m, 4H, H-20, H-200), 1.00, 0.99, 0.95, 0.94 (each s,
each 3H, H-40, H-50, H-400, H-500); 13C NMR (CD3OD, 125 MHz)
d 183.6 (C-9), 163.4 (C-1), 161.7 (C-3), 156.1 (C-4a), 154.1 (C-10a),
153.0 (C-6), 141.8 (C-7), 131.6 (C-8), 112.3 (C-8a), 112.2 (C-2),
103.9 (C-9a), 100.8 (C-5), 92.9 (C-4), 40.4, 39.2 (C-20, C-200), 30.0
(C-30), 29.5 (C-300), 25.8 (C-100), 23.1 (C-40, C-50, C-400, C-500), 21.2
(C-10); negative ESIMS m/z 399 [M ꢃ H]ꢃ.
4-Bromo-tetrahydro-a-mangostin (3d). Yield 12%, 1H NMR
(DMSO-d6, 500 MHz) d 13.86 (s, 1H, 1-OH), 6.79 (s, 1H, H-5), 3.74
(s, 3H, 7-OCH3), 3.20 (m, 2H, H-100), 2.61 (m, 2H, H-10), 1.65 (dt,
H, J ¼ 6.5, 13.0 Hz, H-300), 1.53 (dt, H, J ¼ 6.5, 13.0 Hz, H-30), 1.33
(dt, 4H, J ¼ 16.5, 7.0 Hz, H-20, H-200), 0.95, 0.93, 0.91, 0.89 (each s,
each 3H, H-40, H-50, H-400, H-500); 13C NMR (DMSO-d6, 125 MHz)
d 181.2 (C-9), 159.0 (C-1), 158.5 (C-3), 157.2 (C-10a), 154.5 (C-6),
150.2 (C-4a), 143.6 (C-7), 138.5 (C-8), 112.4 (C-8a), 109.6 (C-2),
102.9 (C-9a), 101.6 (C-5), 86.7 (C-4), 60.4 (7-OCH3), 39.0, 37.5
(C-20, C-200), 28.3, 27.7 (C-30, C-300), 24.6 (C-100), 22.5, 22.4 (C-40, C-
400, C-50, C-500), 20.6 (C-10); negative ESIMS m/z 491 [M ꢃ H]ꢃ;
HRESIMS m/z 491.1072 [M ꢃ H]ꢃ (calcd for C24H28BrO6,
491.1069).
1,3,6-Trihydroxy-9H-xanthen-9-one (2u). Yield 60%, 1H NMR
(CD3OD, 500 MHz) d 7.97 (d, 1H, H-8), 6.82 (dd, 1H, J ¼ 2.2,
8.8 Hz, H-7), 6.73 (d, 1H, J ¼ 2.2 Hz, H-2), 6.27 (d, 1H, J ¼ 2.2 Hz,
H-2), 6.13 (d, 1H, J ¼ 2.2 Hz, H-2); 13C NMR (CD3OD, 125 MHz)
d 181.2 (C-9), 166.7 (C-1), 165.7 (C-3), 164.6 (C-7), 159.4 (C-4a),
41386 | RSC Adv., 2018, 8, 41377–41388
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1
4,5-Dibromo-tetrahydro-a-mangostin (3e). Yield 60%, H NMR
(DMSO-d6, 500 MHz) d 13.54 (s, 1H, 1-OH), 3.70 (s, 3H, 7-OCH3),
Conflicts of interest
3.16 (m, 2H, H-100), 2.59 (m, 2H, H-10), 1.63 (dt, H, J ¼ 6.5, There are no conicts to declare.
13.0 Hz, H-300), 1.53 (dt, H, J ¼ 6.5, 13.0 Hz, H-30), 1.32 (m, 4H, H-
20, H-200), 0.93, 0.92, 0.90, 0.89 (each s, each 3H, H-40, H-50, H-400,
Acknowledgements
H-500); 13C NMR (DMSO-d6, 125 MHz) d 182.7 (C-9), 160.7 (C-1),
This work was nancially supported by grants of National Key
Research and Development Program of China
160.6 (C-3), 156.3 (C-10a), 153.4 (C-6), 152.0 (C-4a), 145.4 (C-7),
139.2 (C-8), 114.6 (C-8a), 112.3 (C-2), 104.6 (C-9a), 98.1 (C-5),
88.8 (C-4), 63.3 (7-OCH3), 41.0, 39.3 (C-20, C-200), 30.1, 29.5 (C-
30, C-300), 26.4 (C-100), 24.3, 24.2 (C-40, C-400, C-50, C-500), 22.4 (C-10);
negative ESIMS m/z 571 [M ꢃ H]ꢃ; HRESIMS m/z 569.0170 [M ꢃ
H]ꢃ (calcd for C24H27Br2O6, 569.0174).
(2017YFD0201402), the Yunnan Provincial Science and Tech-
nology Department (2017ZF003-04 and 2015HB093). The
authors thank the staff of analytical group and the staff of
natural drug activity screening centre of the State Key Labora-
tory of Phytochemistry and Plant Resources in West China,
Kunming Institute of Botany, Chinese Academy of Sciences, for
measurements of all spectra and the activity screening of all
compounds.
3.3 Biological assays
The following human cancer cell lines were used: HL-60,
SMMC-7721, A-549, MCF-7 and SW-480. These cells were ob-
tained from ATCC (Manassas, VA, USA). All the cells were
cultured in RPMI-1640 or DMEM medium (Hyclone, Logan, UT,
USA), supplemented with 10% fetal bovine serum at 37 ꢀC in
a humidied atmosphere with 5% CO2. Cell viability was
assessed by conducting colorimetric measurements of the
amount of insoluble formazan formed in living cells based on
the reduction of MTS (Sigma, St. Louis, MO, USA). Briey, 100
mM of adherent cells were seeded into each well of a 96-well cell
culture plate and allowed to adhere for 12 h before drug addi-
tion, while suspended cells were seeded just before drug addi-
tion, both with an initial density of 1 ꢄ 105 cells per mL in 100
mM medium, Each tumour cell line was exposed to the test
compound at various concentrations in triplicate for 48 h, with
cisplatin and paclitaxel (Sigma) as positive controls. Aer the
incubation, MTS (100 mg) was added to each well and the
incubation continued for 4 h at 37 ꢀC. The cells were lysed with
100 mM of 20% SDS–50% DMF aer removal of 100 mM
medium. The optical density of the lysate was measured at
490 nm in a 96-well microtiter plate reader (Bio-Rad 680). The
IC50 value of each compound was calculated by Reed and
Muench's method.
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