Synthesis and anti-tumor evaluation of novel C-37 modified derivatives of gambogic acid

Article abstract of DOI:10.1002/cjoc.201100693

Gambogic acid (GA, 1), the most prominent representative of Garcinia natural products, has been reported to be a promising anti-tumor agent. In order to further explore the structure-activity relationship of GA and discover novel GA derivatives as anti-tumor agents, 17 novel C-37 modified derivatives of GA were synthesized and evaluated for their in vitro anti-tumor activities against A549, HCT-116, BGC-823, HepG2 and MCF-7 cancer cell lines. Among them, 11 compounds were found to be more potent than GA against some cancer cell lines. Notably, compound 8 was almost 5-10 folds more active than GA against A549 and BGC-823 cell lines with the IC₅₀ values of 0.12 μmol·L ^-1 and 0.57 μmol·L^-1, respectively. Chemical modification at C-37 position of GA by introducing of hydrophilic amines could lead to increased activity and improved drug-like properties. These findings will enhance our understanding of the structure-activity relationship (SAR) of GA and lead to the discovery of novel GA derivatives as potential anti-tumor agents.

Full text of DOI:10.1002/cjoc.201100693

FULL PAPER
DOI: 10.1002/cjoc.201100693
Synthesis and Anti-tumor Evaluation of Novel C-37 Modified
Derivatives of Gambogic Acid
Li, Xianga,b(李想)
Zhang, Xiaojina,b(张晓进)
Gao, Yuana,c(高原)
Sun, Haopeng*,a,b(孙昊鹏)
Wang, Jinxina,b(王进欣)
Zhang, Leia,b(张磊)
Guo, Qinglonga,c(郭青龙)
You, Qidong*,a,b,c(尤启冬)
a State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, Jiangsu 210009, China
b Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University,
Nanjing, Jiangsu 21009, China
c Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University,
Nanjing 210009, China
Gambogic acid (GA, 1), the most prominent representative of Garcinia natural products, has been reported to be
a promising anti-tumor agent. In order to further explore the structure-activity relationship of GA and discover
novel GA derivatives as anti-tumor agents, 17 novel C-37 modified derivatives of GA were synthesized and evalu-
ated for their in vitro anti-tumor activities against A549, HCT-116, BGC-823, HepG2 and MCF-7 cancer cell lines.
Among them, 11 compounds were found to be more potent than GA against some cancer cell lines. Notably, com-
pound 8 was almost 5—10 folds more active than GA against A549 and BGC-823 cell lines with the IC50 values of
－
0.12 μmol•L－ and 0.57 μmol•L , respectively. Chemical modification at C-37 position of GA by introducing of
hydrophilic amines could lead to increased activity and improved drug-like properties. These findings will enhance
our understanding of the structure-activity relationship (SAR) of GA and lead to the discovery of novel GA deriva-
tives as potential anti-tumor agents.
1
1
Keywords gambogic acid, C-37 modified derivatives, anti-tumor activity, structure-activity relationship (SAR)
Introduction
family proteins,[9] inhibit VEGFR2 activation,[14,15] in-
duce proteasome-mediated degradation of mutant
p53,[16] interact with the transferrin receptor TfR1,[17]
elevate the phosphorylation of JNK and p38[18] as well
as inhibit Hsp90 activity.[19] Very recent studies demon-
strated that GA inhibited tumor cell adhesion by sup-
pressing integrin β1 abundance and the membrane lipid
rafts-associated integrin signaling pathway.[20]
Gamboge resin that is secreted from the Garcinia
genus of tropical plants has been used as a traditional
medicine for centuries in Southeast Asia.[1,2] Gambogic
acid (GA, CAS No. 2752-65-0, Figure 1), the most
prominent ingredient of gamboge, has been identified as
a potent anti-tumor agent that inhibited cancer cell pro-
liferation both in vitro and in vivo. In addition, GA dis-
plays minimal toxicity to normal cells and has an ap-
propriate therapeutic window for clinical applica-
tions.[3-7] Practically, GA has finished phase II clinical
trials in cancer patients in China.
Biological investigations showed that the anti-tumor
mechanism of GA was complex and still debatable. Re-
search groups wordwide have reported multiple
anti-tumor mechanisms of GA involving apoptotic in-
duction, cell cycle arrest, cell metastasis inhibition and
anti-angiogenesis. [8-10] It was documented that GA was
capable to inhibit NF-κB activation,[11] suppress telom-
erase activity,[12] inhibit CDK7-mediated phosphoryla-
tion of CDC2/p34,[13] regulate the expressions of bcl-2
HOO3C0
29
27
O
OH
O
26
9
4
10
6
12
7
5
3
8
C
O
19
20
A
B
O 11
D
21
14
18
16
2
O
24
22
23
25
1
31
36
37
38
32
33
35
40
39
34
Figure 1 Chemical structure of GA.
In the past decade, medicinal chemists have put their
*
E-mail: youqidong@gmail.com; Tel.: 0086-025-83271351; Fax: 0086-025-83271351 or sunhaopeng@163.com; Tel.: 0086-025-83271216; Fax:
0086-025-83271216
Received December 12, 2011; accepted January 12, 2012; published online May 7, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201100693 or from the author.
Chin. J. Chem. 2012, 30, 1083—1091
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Li et al.
FULL PAPER
efforts to explore the essential pharmacophoric motif and
structure-activity relationship (SAR) of GA[21] and to dis-
cover novel derivatives of GA as potential anti-tumor
agents. The SAR studies suggested that modifications of
the C-30 carboxyl group, C-6 hydroxyl group, C-8 ketone
group and two prenyl groups are well tolerated, whereas
the C-9＝C-10 double bond is extremely important for the
anti-tumor activity.[22-27] As the framework of GA is very
complicated and contains a number of sensitive functional
groups, the presented GA derivatives were mainly re-
stricted to the modifications at the C-30 and C-6 sites by
simple etherification, acylation and esterification proce-
dures. Inspired by the therapeutic potential of GA, we
ought to develop a chemical strategy that would allow
synthetic access to novel GA derivatives that are modified
at other sites such as the prenyl group to improve solubil-
ity and activity. Previously, we have reported the chemical
studies on oxidation of GA and found that the C-37/38
double bond could be selectively converted into epoxy
moiety using peroxide agent with little effect on other
functional groups.[26] Herein we present a further devel-
opment of this strategy to the synthesis of C-37 modified
derivative of GA and their anti-tumor evaluation.
tion data, the carbon signal of aldehyde group (δC-37
＝
200.8) correlated with two methylene hydrogens (δH-36
＝2.50—2.53 and δH-20＝1.97—2.07). In addition, the
methylene hydrogen attached to C-36 was found to cor-
relate with the quaternary carbon signal (δC-2＝79.3).
These data could certify the oxidation occurred at the
C-37/38 double bond rather than C-32/33 position.
The synthetic routes of the target compounds 1—17
are summarized in Scheme 2. Further oxidation of
compound 20 using Jones reagent at 25 ℃ for 0.5 h
provided compound 1 in 73% yield. Compounds 2—4
were obtained by the condensation of compound 1 with
the corresponding alcohol at 25 ℃ in the presence of
DMAP and EDCI. In a similar manner, compounds 5—
13 were synthesized using the corresponding amines. It
is worth noting that the reaction temperature should be
controlled at 0 ℃ in the case of the aliphatic secondary
amines. Otherwise higher reaction temperature could
lead to the by-products that formed through Michael
addition between the aliphatic amines and the C-9＝
C-10 double bond of α,β-unsaturated ketone moiety of 1.
Nevertheless, when the amino acids were subjected to
the reaction condition with the aim to obtain the target
compounds 14—17, no reaction was observed using
EDCI as the condensing agent. Then we attempted to
use N-hydroxy succinimide to activate the carbonyl
group as in compound 21. Subsequently, compound 21
reacted with corresponding amino acid in presence of
triethylamine using DMSO as solvent and successfully
afforded compounds 14—17.
Results and Discussion
Chemistry
The crude GA was isolated in overall yield of ap-
proximately 5% from commercially available gamboges
resin. It could be purified by converting the crude ex-
tract into the pyridine salt followed by recrystalliza-
tion.[28] Based on the synthetic method reported by our
laboratory,[26] GA was firstly treated with methyl iodide
in acetone in the presence of K2CO3 to give the methyl
ester 18, followed by oxidation reaction using m-CPBA
to regioselectively provide the C-37/38 epoxide inter-
mediate 19 with a combined yield of 34% (Scheme 1).
Initial efforts to convert compound 19 to 20 were using
Pb(OAc)4/TFA or Na2Cr2O7/HClO4 oxidation system
but failed. Then we treated compound 19 with HIO4 as
an oxidation agent, it successfully gave rise to aldehyde
20 in 48% yield under a mild reaction condition. The
structure of compound 20 was further confirmed by
two-dimensional correlation NMR spectra. The 1H
NMR, 13C NMR and HMBC data of 20 were assigned
and listed in Table 1. According to the HMBC correla-
Anti-proliferation and SAR studies
The in vitro anti-proliferative activities of the syn-
thesized 17 novel C-37 modified derivatives of GA
were assessed by the tetrazolium-based MTT assay
using human lung adenocarcinoma A549 cell line, hu-
man colon carcinoma HCT-116 cell line, human gastric
carcinoma BGC-823 cell line, human hepatocellular
carcinoma HepG2 cell line and human breast carcinoma
MCF-7 cell line. Cancer cells were allowed to prolifer-
ate in presence of the respective compounds for 24 h,
and then cell viability was evaluated through measure-
ments of mitochondrial dehydrogenase activity. The
results are summarized in Table 2. In five tested cell
lines, the IC50 value of the parent compound GA ranged
－
1
from 1.1 to 2.9 μmol•L .
Scheme 1 Synthesis of the aldehyde intermediate 20
30
29
MeOOC
OMe O
MeOOC
MeOOC
O
O
27
OMe O
O
OMe O
26
4
10
6
12
7
5
9
c
a
3
8
19
20
b
O11
GA
O
O
21
O
O
14
16 O
2
O
18
O
O
24
22
1
31
36
37
25
32
O
O
35
34
20
19
18
Reagents and conditions: (a) MeI, K2CO3, acetone, 25 ℃, 24 h; (b) m-CPBA, CH2Cl2, 25 ℃, 6 h; (c) HIO4•H2O, THF, 25 ℃, 1 h
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Chin. J. Chem. 2012, 30, 1083—1091

Synthesis and Anti-tumor Evaluation of Novel C-37 Mmodified Derivatives
Table 1 1H NMR, 13C NMR and HMBC data of 20
Atom
No.
HMBC
(C→H)
HMBC
(C→H)
1H
13C
Atom No.
1H
13C
2
79.3
3, 4, 20,36
22
23
24
25
26
27
28
29
30
2.50—2.53 (m, 1H)
48.5
83.2
28.3
29.4
28.8
135.8
127.0
20.3
166.8
24, 25
3
5.49 (d, J＝10.2 Hz 1H)
6.71 (d, J＝10.2 Hz, 1H)
125.6
117.1
108.9
157.6
107.1
174.1
133.5
135.1
4
1.49 (s, 3H)
5
1.75 (s, 3H)
6
2.97 (d, 2H)
7
5.95—5.98 (m, 1H)
26, 29
27
8
10
9
1.69 (s, 3H)
10
7.45 (d, J＝6.9 Hz)
3.46—3.47 (m, 1H)
26
10
3.22—3.24 (m, 1H),
3.34—3.37 (m, 1H)
5.05—5.07 (m, 1H)
11
46.2
31
21.6
12
13
14
16
17
18
19
20
203.4
83.1
10, 21, 26
25, 26
32
121.3
131.4
17.6
31, 34, 35
33
90.5
10, 26
34
1.69 (s, 3H)
155.0
112.1
159.3
27.5
35
1.65 (s, 3H)
24.9
36
2.50—2.53 (m, 2H)
9.13 (s, 3H)
38.4
37
200.8
61.7
20, 36
1.29 (s, 3 H)
OMe
COOMe
3.82 (s, 3H)
1.97—2.07 (m, 2H)
33.5
36
3.43 (s, 3H)
50.5
1.36—1.40 (m, 1H),
2.30 (dd, J＝13.3, 4.5 Hz, 1H)
21
25.1
24, 25
Scheme 2 Synthesis of the target compounds 1—17
8
N
N
O
O
2
3
MeOOC
MeOOC
9
N
O
OMe O
O
OMe O
H
10
11
12
13
N
4
O
d
e
O
R =
O
20
H
O
O
N
OCH3
Cl
O
N
N
N
5
6
O
O
HO
R
H
N
O
O
1
H
7
2
13
N
f
NO2
MeOOC
MeOOC
O
OMe O
O
O
OMe O
S
14
16
17
H
g
O
R =
O
O
SH
15
O
O
O
N
H
O
HOOC
N
O
O
14 17
R
O
21
Reagents and conditions: (d) Jone's reagent, acetone, 25 ℃, 0.5 h; (e) alcohols or amines, DMAP, EDCI, 0—25 ℃, 1—8 h; (f) N-hydroxy-
succinmide, DCC, DMAP, EtOH, 25 ℃, 3 h; (g) amino acid, NEt3, DMSO, 25 ℃, 8 h
－
1
Generally, all the derivatives were found to be less ac-
tive than GA against HepG2 whereas exhibited compara-
ble inhibitory activities for other four cell lines. Among
the synthesized 17 derivatives, 11 compounds displayed
more potent activities than GA against several cancer cell
lines. In A549 cell line, compound 8 exhibited the highest
potency with an IC50 value of 0.12 μmol•L , which was
10 fold more potent than GA. Compounds 5 and 6 were
also found to have 2—3 fold increases in activity. In
HCT-116 cell line, seven compounds (1, 3, 5, 8, 11, 13
and 14) were more active than GA while five compounds
(2, 4, 9, 10 and 12) possessed similar activities.
Chin. J. Chem. 2012, 30, 1083—1091
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Li et al.
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Table 2 Anti-proliferative activity of the target compounds 1—17
－
IC50±SD a/(μmol•L )
1
Compound
A549
HCT-116
BGC-823
HepG2
MCF-7
1
5.45±0.34
6.37±0.47
1.26±0.11
2.10±0.17
0.61±0.053
0.46±0.034
1.27±0.047
0.12±0.035
1.42±0.13
2.83±0.18
4.71±0.23
2.56±0.11
6.10±0.25
71.1±4.64
8.76±0.71
43.8±4.33
＞100
2.21±0.10
2.63±0.15
2.20±0.20
2.94±0.21
1.96±0.17
4.65±0.32
4.83±0.24
1.50±0.12
2.80±0.11
2.51±0.23
1.40±0.054
2.43±0.18
2.12±0.13
1.35±0.079
＞100
8.90±0.65
7.85±0.69
2.25±0.15
11.2±0.082
1.49±0.033
3.93±0.05
2.84±0.18
0.57±0.014
0.93±0.041
7.28±0.15
1.29±0.10
19.3±1.16
7.75±0.42
79.1±6.30
10.4±1.09
＞100
3.15±0.20
4.50±0.38
4.42±0.29
4.67±0.43
5.55±0.13
7.73±0.51
10.5±1.13
3.10±0.091
9.78±0.56
5.12±0.40
8.53±1.02
4.57±0.32
7.54±0.51
3.10±0.095
＞100
6.11±0.52
5.04±0.37
6.77±0.14
5.05±0.18
2.82±0.071
1.52±0.055
10.7±0.95
0.98±0.025
22.3±1.44
12.0±0.87
5.60±0.54
12.2±1.08
3.80±0.20
62.3±5.10
＞100
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
13.5±1.12
＞100
65.5±3.77
35.1±3.68
2.94±0.058
＞100
83.2±5.76
2.61±0.11
＞100
GA
a
1.10±0.021
2.82±0.23
2.79±0.080
The IC50 values were determined from eight different concentrations of compounds at two-fold dilutions, and were the means of two
separate experiments.
In BGC-823 cell line, compound 8 displayed the best
weak potency against the A549, BGC-823 and MCF-7,
whereas in HCT-116 and HepG2 cells, it possessed
comparable anti-tumor activity as GA with an IC50 of
1.3 and 3.1 μmol•L , respectively. This illustrated that
the introduction of glycine group to C-37 site could in-
crease the selectivity against HCT-116 and HepG2 cells.
These findings could enhance our understanding of the
SAR at C-37 site of GA and lead to the development of
novel GA derivatives with improved anti-tumor activity
and drug-like properties.
－
1
potency with an IC50 value of 0.57 μmol•L , which was
almost 5 fold more potent than GA. Meanwhile, three
compounds (5, 9 and 11) were found to have about 2—3
fold increases in activity. In the case of HepG2 cell lines,
only three compounds (1, 8 and 14) were found to be
comparable to GA while two compounds (6 and 8) were
2—3 fold more active than GA in MCF-7 cells.
－
1
Comparing 1 with GA, the removal of hydrophobic
prenyl tail and introduction of hydrophilic carboxyl
group slightly reduced the anti-tumor activity. Further
introduction of hydrophobic motifs such as methyl, iso-
prenyl and tert-butyl groups as compounds 2—4 had
little effect on improving the potency. Inspiringly, com-
pounds 5—9 substituted by aliphatic amines showed
obviously increased activities. Meanwhile, the aliphatic
amines also could improve the solubility and drug-like
properties of the derivatives. Notably, compound 8 con-
taining methylpiperazine substituent was the most ex-
cellent derivative with the IC50 values ranging from 0.12
Conclusions
In conclusion, 17 novel C-37 modified derivatives of
GA were synthesized by a regioselective chemical
modification strategy. The synthesized 17 compounds
were further evaluated for their in vitro anti-tumor ac-
tivities against five human cancer cell lines (A549,
HCT-116, BGC-823, HepG2 and MCF-7) determined
by an MTT assay. Among the synthesized 17 deriva-
tives, 11 compounds displayed more potent activities
than GA against several cancer cell lines. Compound 8
was the most excellent derivative with the IC50 values
ranging from 0.12 to 3.10 μmol•L－1 against the five cell
lines. Especially, compound 8 was almost 5—10 folds
more active than GA against A549 and BGC-823 cell
lines. Introduction of hydrophilic aliphatic amines to
C-37 position of GA was preferred to improve the
anti-tumor activity and solubility. In addition, the hy-
drophobic moiety such as alkyl and phenylamine groups
to 3.10 μmol•L－ against the five cell lines. Comparing
1
the activities between compounds 5—9 and compounds
10—13, it was found that the latter compounds were
less potent in general. This suggested that phenylamine
groups were not a good moiety for improving the activ-
ity at the C-37 site. In addition, although compounds 15
—17 with the flexible amino acid side chains ought to
have greatly improved solubility, they were found to be
less active or even mostly inactive against all the five
cell lines. Compound 14 with glycine also displayed
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Chin. J. Chem. 2012, 30, 1083—1091

Synthesis and Anti-tumor Evaluation of Novel C-37 Mmodified Derivatives
had little effect on increasing the potency, whereas in-
troducing the amino acid moiety to the C-37 position of
GA could generally result in decreased activity. This
work could enhance our understanding of the SAR of
gambogic acid and lead to the discovery of novel GA
derivatives as potential anticancer agents.
135.2 (C-10), 135.8 (C-27), 154.7 (C-16), 157.9 (C-6),
159.3 (C-18), 166.8 (C-30), 174.3 (C-8), 203.4 (C-12);
IR (KBr) ν: 2969, 1731, 1708, 1621, 1586, 1460, 1379,
－
＋
1
878 cm ; ESI-MS m/z: 673 (M＋H) . HRMS calcd for
C40H48O9 (M＋H) 673.3377, found 673.3384.
2-Deisohexyl-2-(4-(3-oxopropyl))-6-methoxy-
gambogic acid methyl ester (20) To a solution of 19
(100 mg, 0.15 mmol) in tetrahydrofuran (10 mL) was
added periodic acid (40 mg, 0.17 mmol) at 0 ℃. The
mixture was stirred at 25 ℃ for 1 h. Then water (10
mL) and ethyl acetate (20 mL) were added. The ethyl
acetate layer was partitioned, washed with brine (10
mL×3), dried over magnesium sulfate and concentrated.
The residue was purified by chromatography on a sil-
ica-gel column eluted with PE-EtOAc (V∶V＝2∶1) to
Experimental
Chemistry
All reagents were purchased from commercial
sources and were used without further purification
unless otherwise noted. Melting points were determined
by a Melt-temp II apparatus and were reported without
any correction. IR spectra were recorded on a Nicolet
1
1
afford 20 (30 mg, 48%) as a yellow oil. H NMR
Impact 410 spectrometer using KBr film. The H NMR
(CDCl3, 300 MHz) δ: 1.29 (s, 3H, C19-H), 1.36—1.40
(m, 1H, C21b-H), 1.49 (s, 3H, C24-H), 1.65 (s, 3H, C35-H),
1.69 (s, 6H, C29-H, C34-H), 1.75 (s, 3H, C25-H), 1.97—
2.07 (m, 2H, C20-H), 2.30 (dd, J＝13.3, 4.5 Hz, 1H,
spectra were collected on Bruker AV-300 MHz instru-
ments using deuterated solvents with tetramethylsilane
(TMS) as internal standard. EI-MS was recorded on
Shimadzu GCMS-2010 apparatus. High resolution mass
spectra (HRMS) were recorded on a Water Q-Tof micro.
Each of the target compounds were purified by silica gel
(60 Å, 70—230 mesh) column chromatography. Con-
centration and evaporation of the solvent after reaction
or extraction were carried out on a rotary evaporator
(Büchi Rotavapor) operated at reduced pressure.
C
21a-H), 2.50—2.53 (m, 3H, C22-H, C36-H), 2.97 (d, J＝
6.8 Hz, 2H, C26-H), 3.22—3.24 (m, 1H, C31b-H), 3.34—
3.37 (m, 1H, C31a-H), 3.43 (s, 3H, COOCH3), 3.46—
3.47 (m, 1H, C11-H), 3.82 (s, 3H, C6-OCH3), 5.05—5.07
(m, 1H, C32-H), 5.49 (d, J＝10.2 Hz, 1H, C3-H), 5.95—
5.98 (m, 1H, C27-H), 6.71 (d, J＝10.2 Hz, 1H, C4-H),
7.45 (d, J＝6.9 Hz, 1H, C10-H), 9.73 (s, 1H, CHO); 13C
NMR (CDCl3, 75 MHz) δ: 17.6 (C-34), 20.3 (C-29),
21.6 (C-31), 24.9 (C-35), 25.1 (C-21), 27.5 (C-19), 28.3
(C-24), 28.8 (C-26), 29.4 (C-25), 33.5 (C-20), 38.4
(C-36), 46.2 (C-11), 48.5 (C-22), 50.5 (30-COOCH3),
61.7 (6-OCH3), 79.3 (C-2), 83.1 (C-13), 83.2 (C-23),
90.5 (C-14), 107.1 (C-7), 108.9 (C-5), 112.1 (C-17),
117.1 (C-4), 121.3 (C-32), 125.6 (C-3), 127.0 (C-28),
131.4 (C-33), 133.5 (C-9), 135.1 (C-10), 135.8 (C-27),
155.0 (C-16), 157.6 (C-6), 159.3 (C-18), 166.8 (C-30),
174.1 (C-8), 200.8 (C-37), 203.4 (C-12); IR (KBr) ν:
2971, 1736, 1718, 1710, 1673, 1464, 1383, 1166, 1020
(37,38)-Epoxy-6-methoxy-gambogic acid methyl
ester (19) To a solution of GA-methyl ester 18 (328
mg, 0.50 mmol) in dry dichloromethane (20 mL) was
added m-CPBA (104 mg, 0.60 mmol) at 0 ℃. The
mixture was stirred at 25 ℃ for 6 h. The reaction mix-
ture was extracted with EtOAc and then the organic
layer was washed with aqueous saturated Na2CO3 and
brine, then dried over magnesium sulfate and concen-
trated. The residue was purified by chromatography on a
silica-gel column eluted with PE-EtOAc (V∶V＝4∶1)
to afford 19 (120 mg, 36%) as a yellow solid. m.p. 72—
1
75 ℃; H NMR (CDCl3, 300 MHz) δ: 1.28 (s, 3H,
－
＋
1
C19-H), 1.42—1.44 (m, 1H, C21b-H), 1.47 (s, 3H, C24-H),
1.58 (s, 3H, C40-H), 1.60 (s, 3H, C39-H), 1.63 (s, 3H,
C35-H), 1.66 (s, 3H, C34-H), 1.69 (s, 3H, C29-H), 1.76 (s,
3H, C25-H), 1.83—1.85 (m, 4H, C20-H, C36-H), 2.30—
2.32 (m, 1H, C21a-H), 2.51 (d, J＝7.4 Hz, 1H, C22-H),
2.67—2.69 (m, 1H, C37-H), 2.98 (d, J＝7.0 Hz, 2H,
C26-H), 3.14—3.16 (m, 1H, C31b-H), 3.29—3.31 (m, 1H,
cm ; ESI-MS m/z: 631 (M＋H) . HRMS calcd for
C37H42O9 (M＋H)＋ 631.2907, found 631.2914.
2-Deisohexyl-2-(4-(2-carboxyethyl))-6-methoxy-
gambogic acid methyl ester (1) To a solution of 21
(20 mg, 0.032 mmol) in acetone (5 mL) were added the
Jone’s reagent (2.5 mol/L, 0.015 mL, 0.038 mmol) at 0
℃. The mixture was stirred at 0 ℃ for 0.5 h. Then
aqueous NaHCO3 (10 mL) and ethyl acetate (20 mL)
was added. The ethyl acetate layer was partitioned,
washed with brine (10 mL×3), dried over magnesium
sulfate and concentrated. The residue was purified by
chromatography on a silica-gel column eluted with
PE-EtOAc (V∶V＝1∶1) to afford 1 (15 mg, 73%) as a
C
31a-H), 3.40 — 3.43 (m, 1H, C11-H), 3.45 (s, 3H,
COOCH3), 3.84 (s, 3H, C6-OCH3), 5.06—5.08 (m, 1H,
C32-H), 5.54 (d, J＝10.2 Hz, 1H, C3-H), 5.95—5.98 (m,
1H, C27-H), 6.67 (d, J＝10.2 Hz, 1H, C4-H), 7.45 (d,
J＝6.8 Hz, 1H, C10-H); 13C NMR (CDCl3, 75 MHz) δ:
17.6 (C-40), 18.1 (C-34), 20.3 (C-29), 21.6 (C-31), 24.4
(C-36), 25.1 (C-21), 25.6 (C-35), 25.7 (C-39), 27.3
(C-19), 28.3 (C-24), 28.9 (C-26), 29.4 (C-25), 37.5
(C-20), 40.4 (C-38), 46.3 (C-11), 48.5 (C-37), 48.8
(C-22), 50.4 (30-COOCH3), 61.6 (6-OCH3), 79.6 (C-2),
83.1 (C-13), 83.2 (C-23), 90.51 (C-14), 106.9 (C-7),
109.1 (C-5), 112.2 (C-17), 116.6 (C-4), 121.2 (C-32),
126.1 (C-3), 127.0 (C-28), 131.4 (C-33), 133.5 (C-9),
1
yellow oil. H NMR (CDCl3, 300 MHz) δ: 1.29 (s, 3H,
C19-H), 1.36—1.39 (m, 1H, C21b-H), 1.41 (s, 3H, C24-H),
1.48 (s, 3H, C34-H), 1.62 (s, 3H, C35-H), 1.69 (s, 3H,
C29-H), 1.76 (s, 3H, C25-H), 1.89—1.99 (m, 2H, C20-H),
2.10—2.12 (m, 1H, C21a-H), 2.20—2.25 (m, 2H, C36-H),
2.45 (d, J＝9.0 Hz, 1H, C22-H), 2.88—2.90 (m, 2H,
C26-H), 3.24—3.26 (m, 1H, C31b-H), 3.29—3.31 (m, 1H,
Chin. J. Chem. 2012, 30, 1083—1091
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1087

Li et al.
FULL PAPER
C31a-H), 3.34 — 3.36 (m, 1H, C11-H), 3.42 (s, 3H,
COOCH3), 3.83 (s, 3H, C6-OCH3), 4.99—5.01 (m, 1H,
C32-H), 5.42 (d, J＝10.2 Hz, 1H, C3-H), 5.88—5.90 (m,
1H, C27-H), 6.59 (d, J＝10.2 Hz, 1H, C4-H), 7.36 (d,
J＝6.9 Hz, 1H, C10-H); IR (KBr) ν: 3330, 3050, 2930,
2856, 1775, 1706, 1655, 1586, 1522, 1438, 1380, 1335,
1226, 1128, 1097, 1026, 740 cm ; ESI-MS m/z: 647
(M ＋ H) ＋ . HRMS calcd for C37H42O10 (M ＋ H)
647.2851, found 647.2841.
689.3316.
2-Deisohexyl-2-(4-(3-(tert-butoxy)-3-oxopropyl))-
6-methoxy-gambogic acid methyl ester (4) Yield
37%, yellow oil; 1H NMR (CDCl3, 300 MHz) δ: 1.20 (s,
9H, OC(CH3)3), 1.29 (s, 3H, C19-H), 1.33—1.35 (m, 1H,
C
21b-H), 1.36 (s, 3H, C24-H), 1.40 (s, 3H, C34-H), 1.50 (s,
－
1
3H, C35-H), 1.63 (s, 3H, C29-H), 1.70 (s, 3H, C25-H),
1.79—1.85 (m, 2H, C20-H), 1.89—1.91 (m, 2H, C36-H),
2.09—2.11 (m, 1H, C21a-H), 2.45 (d, J＝9.0 Hz, 1H,
C22-H), 2.86—2.89 (m, 2H, C26-H), 3.13—3.14 (m, 1H,
C
31b-H), 3.15—3.18 (m, 1H, C31a-H), 3.30—3.32 (m, 1H,
General procedure for the preparation of com-
pounds 2—4
C11-H), 3.33 (s, 3H, COOCH3), 3.74 (s, 3H, C6-OCH3),
4.98—5.00 (m, 1H, C32-H), 5.43 (d, J＝10.2 Hz, 1H,
C3-H), 5.87—5.89 (m, 1H, C27-H), 6.61 (d, J＝10.2 Hz,
1H, C4-H), 7.37 (d, J＝6.9 Hz, 1H, C10-H); IR (KBr) ν:
3385, 2945, 1778, 1714, 1639, 1583, 1454, 1260, 1124,
To a solution of 1 (40 mg, 0.062 mmol) in corre-
sponding alcohol (5 mL) was added DMAP (9 mg, 0.74
mmol) and EDCI (14 mg, 0.074 mmol). The mixture
was stirred at 25 ℃ for 8 h. Then aqueous saturated
NH4Cl (10 mL) and ethyl acetate (20 mL) were added.
The ethyl acetate layer was partitioned, washed with
brine (10 mL×3), dried over magnesium sulfate and
concentrated. The residue was purified by chromatog-
raphy on a silica-gel column eluted with PE-EtOAc
(V∶V＝4∶1) to afford compounds 2—4, respectively.
2-Deisohexyl-2-(4-(3-ethoxy-3-oxopropyl))-6-
methoxy-gambogic acid methyl ester (2) Yield 48%,
－
＋
1
1108, 1034, 750 cm ; ESI-MS m/z: 703 (M＋H) .
HRMS calcd for C41H50O10 (M＋H) 703.3477, found
703.3464.
General procedure for the preparation of com-
pounds 5—13
To a solution of 1 (40 mg, 0.062 mmol) in tetrahy-
drofuran (5 mL) was added DMAP (9 mg, 0.74 mmol)
and EDCI (14 mg, 0.074 mmol). The mixture was
stirred for 0.5 h and then the corresponding amine
(0.062 mmol) was added. After being stirred for 8 h,
aqueous saturated NH4Cl (10 mL) and ethyl acetate (20
mL) were added. The ethyl acetate layer was partitioned,
washed with brine (10 mL×3), dried over magnesium
sulfate and concentrated. The residue was purified by
chromatography on a silica-gel column eluted with
PE-EtOAc (V∶V＝2∶1) to afford compounds 5—13,
respectively.
1
yellow oil; H NMR (CDCl3, 300 MHz) δ: 1.26—1.29
(m, 6H, C19-H, OCH2CH3), 1.37—1.39 (m, 1H, C21b-H),
1.41 (s, 3H, C24-H), 1.48 (s, 3H, C34-H), 1.62 (s, 3H,
C35-H), 1.69 (s, 3H, C29-H), 1.76 (s, 3H, C25-H), 1.99—
2.06 (m, 2H, C20-H), 2.08—2.09 (m, 2H, C36-H), 2.17—
2.19 (m, 1H, C21a-H), 2.49 (d, J＝9.0 Hz, 1H, C22-H),
2.96—2.98 (m, 2H, C26-H), 3.21—3.23 (m, 1H, C31b-H),
3.31—3.33 (m, 1H, C31a-H), 3.38—3.40 (m, 1H, C11-H),
3.43 (s, 3H, COOCH3), 3.58—3.60 (m, 2H, OCH2CH3),
3.81 (s, 3H, C6-OCH3), 5.04—5.07 (m, 1H, C32-H), 5.50
(d, J＝10.2 Hz, 1H, C3-H), 5.94—5.96 (m, 1H, C27-H),
6.69 (d, J＝9.9 Hz, 1H, C4-H), 7.44 (d, J＝6.9 Hz, 1H,
C10-H); IR (KBr) ν: 3384, 2962, 1713, 1649, 1587, 1428,
2-Deisohexyl-2-(4-(3-morpholino-3-oxopropyl))-6-
methoxy-gambogic acid methyl ester (5) Yield 27%,
1
yellow oil; H NMR (CDCl3, 300 MHz) δ: 1.29 (s, 3H,
—
C19-H), 1.37 1.39 (m, 1H, C21b-H), 1.40 (s, 3H, C24-H),
－
1
1380, 1144, 1108, 1034, 750 cm ; ESI-MS m/z: 675
(M ＋ H) ＋ . HRMS calcd for C39H46O10 (M ＋ H)
675.3164, found 675.3160.
1.48 (s, 3H, C34-H), 1.64 (s, 3H, C35-H), 1.69 (s, 3H,
—
C29-H), 1.74 (s, 3H, C25-H), 1.79 1.84 (m, 2H, C20-H),
2.03 2.09 (m, 2H, C36-H), 2.16 2.18 (m, 1H, C21a-H),
—
—
2-Deisohexyl-2-(4-(3-isoprpoxy-3-oxopropyl))-6-
methoxy-gambogic acid methyl ester (3) Yield 42%,
2.27 2.38 (m, 4H, morpholino), 2.51 (d, J 9.3 Hz,
—
＝
—
—
1H, C22-H), 2.97 2.99 (m, 2H, C26-H), 3.20 3.22 (m,
1
—
—
yellow oil; H NMR (CDCl3, 300 MHz) δ: 1.21—1.22
1H, C31b-H), 3.24 3.25 (m, 1H, C31a-H), 3.37 3.39 (m,
(m, 6H, OCH(CH3)2), 1.29 (s, 3H, C19-H), 1.37—1.39
(m, 1H, C21b-H), 1.41 (s, 3H, C24-H), 1.48 (s, 3H, C34-H),
1.61 (s, 3H, C35-H), 1.70 (s, 3H, C29-H), 1.76 (s, 3H,
C25-H), 1.99—2.06 (m, 2H, C20-H), 2.07—2.09 (m, 2H,
C36-H), 2.17—2.19 (m, 1H, C21a-H), 2.52 (d, J＝9.3 Hz,
1H, C22-H), 2.96—2.98 (m, 2H, C26-H), 3.24—3.26 (m,
1H, C31b-H), 3.29—3.31 (m, 1H, C31a-H), 3.39—3.41 (m,
1H, C11-H), 3.43 (s, 3H, COOCH3), 3.58—3.60 (m, 1H,
OCH(CH3)2), 3.81 (s, 3H, C6-OCH3), 5.05—5.07 (m,
1H, C32-H), 5.50 (d, J＝10.2 Hz, 1H, C3-H), 5.94—5.96
(m, 1H, C27-H), 6.69 (d, J＝10.2 Hz, 1H, C4-H), 7.44 (d,
J＝6.9 Hz, 1H, C10-H); IR (KBr) ν: 3385, 2926, 1771,
1711, 1629, 1585, 1453, 1424, 1380, 1260, 1226, 1122,
1H, C11-H), 3.43 (s, 3H, COOCH ), 3.46 23.63 (m, 4H,
—
—
3
morpholino), 3.82 (s, 3H, C6-OCH ), 5.03 5.05 (m, 1H,
3
C32-H), 5.52 (d, J 10.2 Hz, 1H, C3-H), 5.97 5.99 (m,
＝
—
1H, C27-H), 6.70 (d, J 9.9 Hz, 1H, C4-H), 7.44 (d, J
＝
＝
6.9 Hz, 1H, C10-H); IR (KBr) ν: 3403, 2961, 2925, 2858,
1773, 1715, 1646, 1586, 1453, 1430, 1378, 1228, 1194,
＋
－1
1121, 1031, 734 cm ; ESI-MS m/z: 716 (M H)＋.
HRMS calcd for C41H49NO10 (M H) 716.3429, found
716.3409.
2-Deisohexyl-2-(4-(3-oxo-3-(piperidin-1-yl)propyl))-
6-methoxy-gambogic acid methyl ester (6) Yield
＋
1
22%, yellow oil; H NMR (CDCl , 300 MHz) δ: 1.24
—
3
1.27 (m, 2H, piperidinyl), 1.29 (s, 3H, C19-H), 1.37 1.38
—
－
＋
1
—
1108, 1034, 750 cm ; ESI-MS m/z: 689 (M＋H) .
(m, 1H, C21b-H), 1.39 (s, 3H, C24-H), 1.41 1.44 (m, 4H,
HRMS calcd for C40H48O10 (M＋H) 689.3326, found
1088
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1083—1091

Synthesis and Anti-tumor Evaluation of Novel C-37 Mmodified Derivatives
piperidinyl), 1.60 (s, 3H, C34-H), 1.64 (s, 3H, C35-H), 1.69
—
3H, C25-H), 1.96 1.99 (m, 2H, C20-H), 2.08 2.11 (m,
— —
(s, 3H, C29-H), 1.74 (s, 3H, C25-H), 1.98 2.01 (m, 2H,
2H, C36-H), 2.17 2.19 (m, 1H, C21a-H), 2.31 2.38 (m,
— —
＝
C20-H), 2.07 2.10 (m, 2H, C36-H), 2.15 2.17 (m, 1H,
4H, diethylamino), 2.51 (d, J 9.3 Hz, 1H, C22-H), 2.97
—
—
—
C
21a-H), 2.31 2.35 (m, 4H, piperidinyl), 2.51 (d, J 9.3
2.99 (m, 2H, C26-H), 3.19 3.21 (m, 1H, C31b-H),
＝
—
—
Hz, 1H, C22-H), 2.96 2.98 (m, 2H, C26-H), 3.19 3.21
3.30 3.31 (m, 1H, C31a-H), 3.37 3.39 (m, 1H, C11-H),
— —
—
—
—
—
(m, 1H, C31b-H), 3.28 3.29 (m, 1H, C31a-H), 3.35 3.37
3.43 (s, 3H, COOCH ), 3.81 (s, 3H, C6-OCH ), 5.04
—
3 3
(m, 1H, C11-H), 3.39 (s, 3H, COOCH3), 3.82 (s, 3H,
5.06 (m, 1H, C32-H), 5.54 (d, J 10.2 Hz, 1H, C3-H),
＝
C6-OCH ), 5.04 5.06 (m, 1H, C32-H), 5.54 (d, J 10.2
5.97 5.99 (m, 1H, C27-H), 6.68 (d, J 9.9 Hz, 1H,
＝
—
＝
—
＝
3
Hz, 1H, C3-H), 5.97 5.99 (m, 1H, C27-H), 6.69 (d, J
＝
C4-H), 7.44 (d, J 6.9 Hz, 1H, C10-H); IR (KBr) ν: 3405,
—
＝
9.9 Hz, 1H, C4-H), 7.44 (d, J 6.9 Hz, 1H, C10-H); IR
2974, 2931, 1774, 1714, 1633, 1587, 1459, 1432, 1380,
－1
(KBr) ν: 3384, 2931, 2859, 1772, 1716, 1632, 1587, 1452,
1318, 1224, 1196, 1129, 1096, 1030, 735 cm ; ESI-MS
－1
1431, 1379, 1225, 1192, 1130, 1024, 739 cm ; ESI-MS
m/z: 702 (M H)＋. HRMS calcd for C H NO (M H)
＋
＋
41 51
9
m/z: 714 (M H)＋. HRMS calcd for C H NO (M H)
702.3637, found 702.3610.
＋
＋
42 51
9
714.3637, found 714.3620.
2-Deisohexyl-2-(4-(3-((4-4-methylphenylamino)-3-
oxopropyl))-6-methoxy-gambogic acid methyl ester
(10) Yield 33%, white oil; 1H NMR (CDCl3, 300 MHz) δ:
1.26 (s, 3H, 4-methylphenylamino), 1.29 (s, 3H, C19-H),
1.39—1.41 (m, 1H, C21b-H), 1.43 (s, 3H, C24-H), 1.51 (s,
3H, C34-H), 1.66 (s, 3H, C35-H), 1.68 (s, 3H, C29-H), 1.78
(s, 3H, C25-H), 1.94—1.97 (m, 2H, C20-H), 2.08—2.10
(m, 2H, C36-H), 2.17—2.19 (m, 1H, C21a-H), 2.48 (d, J＝
9.3 Hz, 1H, C22-H), 2.96—2.98 (m, 2H, C26-H), 3.25—
3.27 (m, 1H, C31b-H), 3.32—3.34 (m, 1H, C31a-H), 3.37—
3.39 (m, 1H, C11-H), 3.43 (s, 3H, COOCH3), 3.81 (s, 3H,
C6-OCH3), 5.08—5.10 (m, 1H, C32-H), 5.53 (d, J＝10.2
Hz, 1H, C3-H), 5.94—5.96 (m, 1H, C27-H), 6.70 (d, J＝
10.2 Hz, 1H, C4-H), 6.96 (s, 1H, NH), 7.09 (d, J＝8.4 Hz,
2H, 4-methylphenylamino), 7.30 (d, J＝8.1 Hz, 2H,
4-methylphenylamino), 7.44 (d, J＝6.9 Hz, 1H, C10-H);
IR (KBr) ν: 3385, 2926, 1771, 1711, 1629, 1585, 1453,
2-Deisohexyl-2-(4-(3-oxo-3-(pyrrolidin-1-yl)propyl))-
6-methoxy-gambogic acid methyl ester (7) Yield
21%, yellow oil; 1H NMR (CDCl3, 300 MHz) δ: 1.29 (s,
3H, C19-H), 1.38 1.40 (m, 1H, C21b-H), 1.43 (s, 3H,
—
C24-H), 1.48 (s, 3H, C34-H), 1.64 (s, 3H, C35-H), 1.69 (s,
—
3H, C29-H), 1.75 (s, 3H, C25-H), 1.82 1.86 (m, 4H,
pyrrolidinyl), 2.00 2.03 (m, 2H, C20-H), 2.09 2.12
—
—
—
(m, 2H, C36-H), 2.17 2.19 (m, 1H, C21a-H), 2.29 2.33
—
(m, 4H, pyrrolidinyl), 2.51 (d, J 9.3 Hz, 1H, C22-H),
＝
—
—
2.97 2.99 (m, 2H, C26-H), 3.23 3.25 (m, 1H, C31b-H),
—
—
3.27 3.29 (m, 1H, C31a-H), 3.40 3.42 (m, 1H, C11-H),
3.43 (s, 3H, COOCH ), 3.81 (s, 3H, C6-OCH ), 5.07
—
3
3
5.09 (m, 1H, C32-H), 5.54 (d, J 10.2 Hz, 1H, C3-H),
＝
5.96 5.98 (m, 1H, C27-H), 6.68 (d, J 9.9 Hz, 1H,
＝
—
＝
C4-H), 7.44 (d, J 6.9 Hz, 1H, C10-H); IR (KBr) ν: 3404,
2967, 2936, 2880, 1773, 1715, 1630, 1587, 1451, 1433,
－
1
－1
1382, 1338, 1229, 1195, 1125, 1027, 735 cm ; ESI-MS
1424, 1380, 1260, 1226, 1122, 1108, 1034, 750 cm ;
ESI-MS m/z: 736 (M ＋ H) ＋ . HRMS calcd for
C44H49NO9 (M＋H) 736.3486, found 736.3477.
m/z: 700 (M H)＋. HRMS calcd for C H NO (M H)
＋
＋
41 49
9
700.3486, found 700.3476.
2-Deisohexyl-2-(4-(3-(4-methylpiperazin-1-yl)-
3-oxopropyl))-6-methoxy-gambogic acid methyl ester
(8) Yield 23%, yellow oil; 1H NMR (CDCl3, 300 MHz)
2-Deisohexyl-2-(4-(3-((4-methylphenylamino)-3-
oxopropyl))-6-methoxy-gambogic acid methyl ester
(11) Yield 34%, white oil; 1H NMR (CDCl3, 300 MHz) δ:
1.29 (s, 3H, C19-H), 1.36—1.38 (m, 1H, C21b-H), 1.40 (s,
3H, C24-H), 1.51 (s, 3H, C34-H), 1.62 (s, 3H, C35-H), 1.68
(s, 3H, C29-H), 1.78 (s, 3H, C25-H), 1.94—1.97 (m, 2H,
C20-H), 2.08—2.10 (m, 2H, C36-H), 2.15—2.18 (m, 1H,
C21a-H), 2.49 (d, J＝9.0 Hz, 1H, C22-H), 2.96—2.98 (m,
2H, C26-H), 3.25—3.27 (m, 1H, C31b-H), 3.31—3.33 (m,
1H, C31a-H), 3.39—3.41 (m, 1H, C11-H), 3.43 (s, 3H,
COOCH3), 3.77 (s, 3H, 4-methoxyphenylamino), 3.81 (s,
3H, C6-OCH3), 5.08—5.10 (m, 1H, C32-H), 5.54 (d, J＝9.9
Hz, 1H, C3-H), 5.94—5.96 (m, 1H, C27-H), 6.71 (d, J＝
10.2 Hz, 1H, C4-H), 6.82 (d, J＝8.7 Hz, 2H, 4-meth-
oxyphenylamino), 6.92 (s, 1H, NH), 7.32 (d, J＝8.7 Hz,
2H, 4-methoxyphenylamino), 7.44 (d, J＝6.9 Hz, 1H,
C10-H); IR (KBr) ν: 3371, 2965, 2929, 1775, 1714, 1655,
1587, 1461, 1427, 1382, 1293, 1226, 1196, 1127, 1098,
δ: 1.29 (s, 3H, C19-H), 1.37 1.38 (m, 1H, C21b-H), 1.39
—
(s, 3H, C24-H), 1.52 (s, 3H, C34-H), 1.64 (s, 3H, C35-H),
—
1.69 (s, 3H, C29-H), 1.74 (s, 3H, C25-H), 1.95 1.98 (m,
2H, C20-H), 2.04 2.07 (m, 2H, C36-H), 2.16 2.18 (m,
—
—
1H, C21a-H), 2.32 (s, 3H, NCH ), 2.35 2.41 (m, 8H,
＝
—
3
4-methylpiperazinyl), 2.52 (d, J 9.3 Hz, 1H, C22-H),
2.96 2.98 (m, 2H, C26-H), 3.19 3.21 (m, 1H, C31b-H),
—
—
—
—
3.26 3.28 (m, 1H, C31a-H), 3.38 3.40 (m, 1H, C11-H),
3.43 (s, 3H, COOCH ), 3.83 (s, 3H, C6-OCH ), 5.04
—
3
3
5.06 (m, 1H, C32-H), 5.52 (d, J 10.2 Hz, 1H, C3-H),
＝
5.96 5.98 (m, 1H, C27-H), 6.69 (d, J 9.9 Hz, 1H,
＝
—
＝
C4-H), 7.44 (d, J 6.9 Hz, 1H, C10-H); IR (KBr) ν: 3404,
3049, 2970, 2927, 2856, 2796, 1774, 1712, 1651, 1586,
1459, 1433, 1379, 1322, 1291, 1227, 1198, 1136, 1029,
＋
－1
733 cm ; ESI-MS m/z: 729 (M H)＋. HRMS calcd for
－
1
＋
1024, 732 cm ; ESI-MS m/z: 752 (M＋H) . HRMS calcd
for C44H49NO10 (M＋H)＋ 752.3429, found 752.3424.
2-Deisohexyl-2-(4-(3-((4-chloroxyphenylamino)-3-
oxopropyl))-6-methoxy-gambogic acid methyl ester
C H N O (M H) 729.3746, found 729.3730.
＋
42 52
2
9
2-Deisohexyl-2-(4-(3-(diethylamino)-3-oxopropyl))-
6-methoxy-gambogic acid methyl ester (9) Yield
1
25%, white oil; H NMR (CDCl , 300 MHz) δ: 1.08
—
—
3
1.11 (m, 6H, diethylamino), 1.29 (s, 3H, C19-H), 1.38
1
(12) Yield 43%, yellow oil; H NMR (CDCl3, 300
1.40 (m, 1H, C21b-H), 1.43 (s, 3H, C24-H), 1.48 (s, 3H,
C34-H), 1.64 (s, 3H, C35-H), 1.69 (s, 3H, C29-H), 1.74 (s,
MHz) δ: 1.28 (s, 3H, C19-H), 1.38—1.39 (m, 1H,
C21b-H), 1.40 (s, 3H, C24-H), 1.51 (s, 3H, C34-H), 1.65 (s,
Chin. J. Chem. 2012, 30, 1083—1091
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1089

Li et al.
FULL PAPER
3H, C35-H), 1.68 (s, 3H, C29-H), 1.77 (s, 3H, C25-H),
1.96—1.99 (m, 2H, C20-H), 2.08—2.10 (m, 2H, C36-H),
2.16—2.18 (m, 1H, C21a-H), 2.46 (d, J＝9.3 Hz, 1H,
C22-H), 2.95—2.97 (m, 2H, C26-H), 3.19—3.21 (m, 1H,
C31b-H), 3.25—3.27 (m, 1H, C31a-H), 3.41—3.43 (m, 1H,
C11-H), 3.42 (s, 3H, COOCH3), 3.81 (s, 3H, C6-OCH3),
5.08—5.10 (m, 1H, C32-H), 5.52 (d, J＝10.2 Hz, 1H,
C3-H), 5.93—5.95 (m, 1H, C27-H), 6.72 (d, J＝10.5 Hz,
1H, C4-H), 7.04 (s, 1H, NH), 7.22 (d, J＝8.7 Hz, 2H,
4-chlorophenylamino), 7.36 (d, J ＝ 8.7 Hz, 2H,
4-chlorophenylamino), 7.44 (d, J＝6.9 Hz, 1H, C10-H);
IR (KBr) ν: 3371, 2965, 2929, 1775, 1714, 1655, 1587,
1461, 1427, 1382, 1293, 1226, 1196, 1127, 1098, 1024,
2-Deisohexyl-2-(4-(3-((carboxymethyl)amino)-3-
oxopropyl))-6-methoxy-gambogic acid methyl ester
(14) Yield 32%, yellow oil; H NMR (CDCl3, 300
1
MHz) δ: 1.27 (s, 3H, C19-H), 1.30 (s, 3H, C24-H), 1.38—
1.40 (m, 1H, C21b-H), 1.47 (s, 3H, C34-H), 1.66 (s, 3H,
C35-H), 1.70 (s, 3H, C29-H), 1.76 (s, 3H, C25-H), 1.94—
1.97 (m, 2H, C20-H), 2.05—2.07 (m, 2H, C36-H), 2.28—
2.30 (m, 1H, C21a-H), 2.55 (d, J＝9.3 Hz, 1H, C22-H),
2.96 — 2.98 (m, 2H, C26-H), 3.07 — 3.10 (m, 2H,
NHCH2COOH), 3.14—3.16 (m, 1H, C31b-H), 3.27—
3.29 (m, 1H, C31a-H), 3.42 (s, 3H, COOCH3), 3.59—
3.61 (m, 1H, C11-H), 3.83 (s, 3H, C6-OCH3), 5.09—5.11
(m, 1H, C32-H), 5.53 (d, J＝10.2 Hz, 1H, C3-H), 5.93 (s,
1H, NH), 5.93—5.95 (m, 1H, C27-H), 6.67 (d, J＝10.2
Hz, 1H, C4-H), 7.44 (d, J＝6.9 Hz, 1H, C10-H); IR (KBr)
ν: 3386, 2927, 2858, 1774, 1711, 1649, 1590, 1455,
－
＋
1
732 cm ; ESI-MS m/z: 756 (M＋H) . HRMS calcd for
C43H46NClO9 (M＋H) 756.2934, found 756.2924.
2-Deisohexyl-2-(4-(3-((3-nitrophenylamino)-3-oxo-
propyl))-6-methoxy-gambogic acid methyl ester (13)
－
1
1422, 1302, 1229, 1188, 1132, 1028, 734 cm ; ESI-MS
m/z: 704 (M＋H)＋. HRMS calcd for C39H45NO11 (M＋
H) 704.3065, found 704.3060.
1
Yield 36%; yellow oil; H NMR (CDCl3, 300 MHz) δ:
1.28 (s, 3H, C19-H), 1.39—1.41 (m, 1H, C21b-H), 1.43 (s,
3H, C24-H), 1.52 (s, 3H, C34-H), 1.64 (s, 3H, C35-H),
1.69 (s, 3H, C29-H), 1.78 (s, 3H, C25-H), 1.99—2.00 (m,
2H, C20-H), 2.09—2.11 (m, 2H, C36-H), 2.16—2.18 (m,
1H, C21a-H), 2.48 (d, J＝9.3 Hz, 1H, C22-H), 2.95—2.97
(m, 2H, C26-H), 3.24—3.26 (m, 1H, C31b-H), 3.31—3.33
(m, 1H, C31a-H), 3.42—3.44 (m, 1H, C11-H), 3.43 (s, 3H,
COOCH3), 3.79 (s, 3H, C6-OCH3), 5.08—5.10 (m, 1H,
C32-H), 5.53 (d, J＝10.2 Hz, 1H, C3-H), 5.95—5.97 (m,
1H, C27-H), 6.71 (d, J＝10.2 Hz, 1H, C4-H), 7.44 (d,
J＝6.9 Hz, 1H, C10-H), 7.45—7.46 (m, 2H, 3-nitro-
phenylamino), 7.91 (d, J＝8.1 Hz, 2H, 3-nitrophenyl-
amino), 8.17 (s, 1H, NH); IR (KBr) ν: 3371, 2965, 2929,
1775, 1714, 1655, 1587, 1461, 1427, 1382, 1293, 1226,
2-Deisohexyl-2-(4-(3-((1-carboxy-2-methylpropyl)-
amino)-3-oxopropyl))-6-methoxy-gambogic
acid
1
methyl ester (15) Yield 32%, yellow oil; H NMR
(CDCl3, 300 MHz) δ: 0.84—0.88 (m, 7H, CH(CH3)2), 1.26
(s, 3H, C19-H), 1.28 (s, 3H, C24-H), 1.37—1.39 (m, 1H,
C
21b-H), 1.45 (s, 3H, C34-H), 1.66 (s, 3H, C35-H), 1.75 (s,
3H, C29-H), 1.79 (s, 3H, C25-H), 1.89—1.92 (m, 2H,
C20-H), 1.99—2.01 (m, 2H, C36-H), 2.17—2.19 (m, 1H,
C21a-H), 2.53 (d, J＝9.0 Hz, 1H, C22-H), 2.95—2.97 (m,
2H, C26-H), 3.19—3.21 (m, 1H, C31b-H), 3.27—3.29 (m,
1H, C31a-H), 3.42 (s, 3H, COOCH3), 3.58—3.60 (m, 1H,
C11-H), 3.78 (s, 3H, C6-OCH3), 4.11—4.13 (m, 1H,
NHCHCOOH), 5.10—5.12 (m, 1H, C32-H), 5.52 (d, J＝
10.2 Hz, 1H, C3-H), 5.95—5.97 (m, 1H, C27-H), 6.34 (s,
1H, NH), 6.66 (d, J＝10.2 Hz, 1H, C4-H), 7.42 (d, J＝6.6
Hz, 1H, C10-H); IR (KBr) ν: 3371, 2965, 2929, 1775, 1714,
1655, 1587, 1461, 1427, 1382, 1293, 1226, 1196, 1127,
－
1
1196, 1127, 1098, 1024, 732 cm ; ESI-MS m/z: 767
(M ＋H)＋ . HRMS calcd for C43H46N2O11 (M ＋H)
767.3174, found 767.3173.
－
1
＋
1098, 1024, 732 cm ; ESI-MS m/z: 746 (M＋H) . HRMS
calcd for C42H51NO11 (M＋H) 746.3535, found 746.3533.
2-Deisohexyl-2-(4-(3-((1-carboxy-3-(methylthio)-
propyl)amino)-3-oxopropyl))-6-methoxy-gambogic
General procedure for the preparation of com-
pounds 14—17
To a solution of 1 (80 mg, 0.12 mmol) in ethanol (5
mL) was added DMAP (18 mg, 0.15 mmol) and N,N'-
dicyclohexylcarbodiimide (30 mg, 0.15 mmol). The
mixture was stirred for 0.5 h and then N-hydroxy-
succinimide (18 mg, 0.16 mmol) was added. After being
stirred at 25 ℃ for 3 h, aqueous saturated NH4Cl (10
mL) and ethyl acetate (20 mL) were added. The ethyl
acetate layer was partitioned, washed with brine (10 mL
×3), dried over magnesium sulfate and concentrated.
The residue was dissolved in dimethyl sulfoxide (2 mL)
and then the corresponding amino acid (0.54 mmol) and
triethylamine (0.4 mL) were added to the solution. After
being stirred at 25 ℃ for 8 h, aqueous NH4Cl (10 mL)
and ethyl acetate (20 mL) were added. The ethyl acetate
layer was partitioned, washed with brine (10 mL×3),
dried over magnesium sulfate and concentrated. The
residue was purified by chromatography on a silica-gel
column eluted with EtOAc-MeOH (V∶V＝16∶1) to
afford compounds 14—17, respectively.
1
acid methyl ester (16) Yield 24%, yellow oil; H
NMR (CDCl3, 300 MHz) δ: 1.26 (s, 3H, C19-H), 1.28 (s,
3H, C24-H), 1.37—1.39 (m, 1H, C21b-H), 1.45 (s, 3H,
C34-H), 1.65 (s, 3H, C35-H), 1.75 (s, 3H, C29-H), 1.79 (s,
3H, C25-H), 1.89—1.91 (m, 2H, C20-H), 1.94—2.00 (m,
7H, CH2CH2SCH3), 2.02—2.03 (m, 2H, C36-H), 2.17—
2.19 (m, 1H, C21a-H), 2.55 (d, J＝9.0 Hz, 1H, C22-H),
2.94—2.96 (m, 2H, C26-H), 3.19—3.21 (m, 1H, C31b-H),
3.27—3.29 (m, 1H, C31a-H), 3.42 (s, 3H, COOCH3),
3.58—3.60 (m, 1H, C11-H), 3.78 (s, 3H, C6-OCH3), 4.20
—4.22 (m, 1H, NHCHCOOH), 5.10—5.12 (m, 1H,
C32-H), 5.54 (d, J＝9.9 Hz, 1H, C3-H), 5.96—5.98 (m,
1H, C27-H), 6.65 (d, J＝10.2 Hz, 1H, C4-H), 6.88 (s, 1H,
NH), 7.42 (d, J＝6.9 Hz, 1H, C10-H); IR (KBr) ν: 3384,
2969, 2935, 2799, 2744, 2670, 2529, 2489, 1710, 1659,
1588, 1457, 1424, 1350, 1229, 1172, 1135, 1031, 751
－
＋
1
cm ; ESI-MS m/z: 778 (M＋H) . HRMS calcd for
C42H51NSO11 (M＋H) 778.3256, found 778.3238.
1090
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1083—1091

Synthesis and Anti-tumor Evaluation of Novel C-37 Mmodified Derivatives
2-Deisohexyl-2-(4-(3-((1-carboxy-2-mercaptoethyl)-
amino)-3-oxopropyl))-6-methoxy-gambogic acid
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(CDCl3, 300 MHz) δ: 1.26 (s, 3H, C19-H), 1.28 (s, 3H,
C24-H), 1.37—1.39 (m, 1H, C21b-H), 1.45 (s, 3H, C34-H),
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C36-H), 2.17—2.19 (m, 1H, C21a-H), 2.55 (d, J＝9.0 Hz,
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(m, 1H, C31a-H), 3.42 (s, 3H, COOCH3), 3.58—3.60 (m,
1H, C11-H), 3.78 (s, 3H, C6-OCH3), 4.20—4.22 (m, 1H,
NHCHCOOH), 5.10—5.12 (m, 1H, C32-H), 5.54 (d, J＝
9.9 Hz, 1H, C3-H), 5.96—5.98 (m, 1H, C27-H), 6.65 (d,
J＝10.2 Hz, 1H, C4-H), 6.88 (s, 1H, NH), 7.42 (d, J＝
6.9 Hz, 1H, C10-H); IR (KBr) ν: 3384, 2970, 2933, 2799,
2744, 2674, 2529, 2489, 1717, 1654, 1587, 1457, 1424,
－
1
1360, 1229, 1178, 1135, 1038, 755 cm . ESI-MS m/z:
750 (M＋H)＋. HRMS calcd for C40H47NSO11 (M＋H)
750.2943, found 750.2940.
Anti-proliferation activity
Cancer cell lines involved in this study were ob-
tained from Cell Bank of Shanghai, Institute of Bio-
chemistry and Cell Biology, Chinese Academy of Sci-
ences. Cells were cultured in 90% RPMI 1640 medium
(GIBCO, Invitrogen Corporation, NY) supplemented
with 10% fetal bovine serum (Sijiqing, Zhejiang, China),
100 μg/mL benzyl penicillin and 100 mg/mL strepto-
mycin in a humidified environment with 5% CO2 at 37
℃. Samples containing ＞95% gambogic acid isolated
from Gamboge resin according to the protocols reported
previously was used in the experiments. All the tested
compounds were dissolved in DMSO to a concentration
of 0.01 mol•L－1 and stored at －4 ℃.
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in a parallel manner for each concentration of target
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±SE. Control cells were given only culture media. Af-
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570 nm. Survival ratio (%) was calculated using the
following equation: survival ratio＝(Atreatment/Acontrol)×
100%. IC50 was taken as the concentration that caused
50% inhibition of cell viabilities and calculated by the
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Acknowledgement
This work was supported by the National Natural
Science Foundation of China (Nos. 90713038,
21072231, 30873157) and National Major Science and
Technology Project of China (Innovation and Develop-
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(Cheng, F.)
Chin. J. Chem. 2012, 30, 1083—1091
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1091