Studies on chemical-structure modification and structure-activity relationship of gambogic acid derivatives at carbon(34)

Article abstract of DOI:10.1002/cbdv.201200081

Gambogic acid (GA), a natural product, was identified as a promising antitumor agent. To further explore the structure-activity relationship of GA and discover novel GA derivatives as antitumor agents, 19 novel GA derivatives modified at C(34) were synthesized and evaluated against A549, BGC-823, U251, HepG2, and MB-231 cancer cell lines by cellular assays. Among them, 15 compounds were found to be more potent than GA against some cancer cell lines. Notably, compound 3 possessed potent inhibitory activities against five cell lines with IC₅₀ values ranging between 0.24 and 1.09μM. Compounds 9 and 18 were seven to eightfold more active than GA against A549 cell line. Chemical modification at C(34) of GA by introducing of hydrophilic aliphatic amines resulted in increased activity and improved drug-like properties. These findings will enhance our understanding of the SAR of GA and can lead to the discovery of novel GA derivatives as potential antitumor agents.

Full text of DOI:10.1002/cbdv.201200081

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Studies on Chemical-Structure Modification and StructureꢀActivity
Relationship of Gambogic Acid Derivatives at Carbon(34)
by Xiao-Jin Zhanga), Xiang Lia), Ying-Rui Yanga), Hao-Peng Sun*b), Yuan Gaoc), Lei Zhangb),
Jin-Xin Wangb), Qing-Long Guoc), and Qi-Dong You*a)c)
a) State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009,
P. R. China (phone/fax: þ86-25-83271351; e-mail: youqidong@gmail.com)
b) Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China
(phone/fax: þ86-25-83271216; e-mail: sunhaopeng@163.com)
c) Key Laboratory of Carcinogenesis and Intervention of Jiangsu Province, China Pharmaceutical
University, Nanjing 210009, P. R. China
Gambogic acid (GA), a natural product, was identified as a promising antitumor agent. To further
explore the structureꢀactivity relationship of GA and discover novel GA derivatives as antitumor agents,
19 novel GA derivatives modified at C(34) were synthesized and evaluated against A549, BGC-823,
U251, HepG2, and MB-231 cancer cell lines by cellular assays. Among them, 15 compounds were found
to be more potent than GA against some cancer cell lines. Notably, compound 3 possessed potent
inhibitory activities against five cell lines with IC50 values ranging between 0.24 and 1.09 mm. Compounds
9 and 18 were seven to eightfold more active than GA against A549 cell line. Chemical modification at
C(34) of GA by introducing of hydrophilic aliphatic amines resulted in increased activity and improved
drug-like properties. These findings will enhance our understanding of the SAR of GA and can lead to
the discovery of novel GA derivatives as potential antitumor agents.
Introduction. – Gambogic acid (GA) is the major active ingredient of gamboges, a
brownish to orange resin exuded by Garcinia hanburyi tree used as a folk medicine for
centuries in Southeast Asia [1][2]. The structure of gambogic acid (Fig. 1) was
determined by analysis of its NMR [3] and single-crystal X-ray diffraction data [4], and
was confirmed recently by circular dichroism (CD) spectrometry [5]. It contains a
unique 4-oxatricyclo[4.3.1.0]decan-2-one ring system, which is found in the natural
products isolated from plants in the genus Garcinia [6]. Preclinical studies have
Fig. 1. Chemical structures of gambogic acid (GA)
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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demonstrated that GA possesses potent cytotoxicity against a broad spectrum of
human cancers, such as hepatoma, gastric carcinoma, brain glioma, lung cancer, breast
carcinoma [7–10]. In addition, GA displays minimal toxicity to normal cells and has an
appropriate therapeutic window for clinical applications [11][12]. Practically, GA has
been subjected to a phase-I clinical trial as anticancer agent in China, with a dose
regimen developed for subsequent phase-II testing [13].
The significant antitumor activity of GA has attracted worldwide increasing
interest. Biological investigations revealed that the antitumor mechanism of GA is
complex and still debatable, and further research is required to clarify its mode of
action. Multiple mechanisms have been proposed including apoptotic induction, cell
cycle arrest, cell-metastasis inhibition and anti-angiogenesis [6]. It was reported that
GA could suppress nuclear factor-kB (NF-kB) activation [14], inhibit the activity of
human telomerase reverse transcriptase (hTERT) [15] and cyclin-dependent kinase 7
(CDK7)-mediated phosphorylation of CDC2/p34 [16], regulate the expressions of bcl-
2 family proteins [17], suppress vascular endothelial growth factor receptor 2
(VEGFR2) activation [18][19], induce proteasome-mediated degradation of mutant
p53 [20], interact with the transferrin receptor TfR1 [21], elevate the phosphorylation
of c-Jun N-terminal kinases (JNK) [22] as well as inhibit heat shock protein 90 (Hsp90)
activity [23]. Very recent studies demonstrated that GA inhibited tumor cell adhesion
by suppressing integrin b1 abundance and the membrane lipid rafts-associated integrin
signaling pathway [24]. All studies mentioned above indicate that GA is a potent
antitumor agent, and the antitumor efficacy of GA arises through multiple mechanisms
that involve diverse molecular targets.
As GA is considered a potential multi-target antitumor agent, the aim now is to
create more GA derivatives to study its structureꢀactivity relationship (SAR) and for
further exploration of the biological mechanism. Preliminary SAR studies suggested
that modifications at the C(30)OOH, HOꢀC(6), C(8)¼O, and two prenyl groups are
well-tolerated, whereas the C(9)¼C(10) bond seems to play an important role for the
cytotoxicity [8][25–27]. As the framework of GA is very complicated with a number of
sensitive functional groups, the presented GA derivatives were mainly restricted to
modifications at C(30) and C(6) by simple etherification, acylation, and esterification
procedures [8][28–29]. 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 groups to improve solubility and
activity. Very recently, we have reported the synthesis and SAR studies of a series of
gambogic acid derivatives modified at C(39) of the prenyl group on A ring [30]. Here,
we further present a selectively chemical-modification strategy to synthesize novel GA
derivatives modified at C(34) of the prenyl group on ring B (Fig. 2). A series of C(34)-
modified GA derivatives have been synthesized and evaluated for their anti-
proliferation effects using five human cancer cell lines. The SARs of the in vitro
antitumor effects of these compounds is also discussed.
Results and Discussion. – Chemistry. The crude GA was isolated in overall yield of
ca. 5% from commercially available gamboge resin. It was purified by converting the
crude extract to the pyridine salt, followed by recrystallization [3]. The synthesis of
derivatives 1–19 are outlined in the Scheme. Based on the synthetic method we

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Fig. 2. Chemical structures of compounds 1–19
Scheme. Synthesis of GA Derivatives 1–19
t
a) SeO2, BuOOH, CH2Cl2, r.t., 5 h. b) 1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDCI), 4-
(dimethylamino)pyridine (DMAP), MeOH, r.t., 8 h. c) TsCl, DMAP, CH2Cl2, 08, 8 h. d) MeI, K2CO3,
acetone. e) Corresponding amines or alcohols, K2CO3, KI, acetone, microwave irradiation (MWI),
200 W, 60–808, 5–10 min.
reported in [26], GA was first treated with the oxidative agent SeO2 and t-BuOOH in
CH2Cl2 at room temperature to selectively oxidize the Me(34) group to allylic alcohol
moiety. This reaction provided 20 as a major product in 21% yield with a 72% recovery
of reactant by controlling the amount of SeO2 and the reaction time. The structure of
compound 20 was determined by its HMBC spectrum. As shown in Fig. 3, the H-atom
signal of CH2(34) was shifted to the low field (d(H) 3.96), due to the newly introduced
OH group, and coupled with that of C(32) (d(C) 123.7). The observed selectivity can
be rationalized by a H-bond formed between the C(30)OOH group and the O-atom of

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CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
Fig. 3. HMBC Spectrum of compound 20
the oxidative reagent SeO2. Thus, the oxidation is prone to occurring at the prenyl
group on ring B that is more close to SeO2 in space. Methylation of the C(30)OOH
group of 20 by using EDCI and DMAP in MeOH at room temperature provided 21 in
90% yield. Then, 21 was treated with TsCl and DMAP in CH2Cl2 at 08 to afford the Cl-
substituted product 22 in 88% yield. Reaction of 22 with MeI in the presence of K2CO3
in acetone at room temperature furnished 19 in 95% yield.
With 19 in hand, the stage was set to introduce various substituents at C(34).
Initially, reaction of 19 with aliphatic amines was carried out in the presence of K2CO3
and KI in acetone at 08 for 6 h. However, it provided the desired C(34)-substituted
derivatives in very low yields, but gave a significant proportion of C(10)-substituted by-
products, which were probably formed through Michael addition reaction between the
a,b-unsaturated ketone in 19 and relatively high nucleophilic aliphatic amines. Even
when the temperature was further decreased to ꢀ208, no reaction occurred. In the case
of aromatic amines and alcohols, the reaction did not proceed even carried out at a
higher temperature (608) due to their low activities.
On account of the advantages of microwave irradiation (MWI) in accelerating
organic reactions, improving conversions, and providing clean products, we tested this
conversion under MWI with the same reaction system. First, the reaction between 19
and morpholine was selected as a test reaction to optimize the reaction conditions
under MWI. When the reaction was carried out under MWI (100 W, 608) in 5 min,
compound 1 was obtained in 5% yield. The yield slightly increased to 10% with 89%
recovery of 19 when prolonging the reaction time to 15 min. Although the yields were

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relatively low, no C(10)-substituted by-product was observed. Next, the power of MWI
was raised from 100 to 200 W. In this case (200 W, 608, 5 min), the yield rapidly
increased to 75% with a 24% recovery of 19. Further increasing the reaction
temperature to 808 or prolonging reaction time to 10 min at 200 W resulted in
decreased yields and led to the formation of by-product. Thus, the optimal MWI
conditions were 200 W, 608, and 5 min for aliphatic amines, and compounds 1–10 were
obtained in 66–80% yields. Similarly, the optimal MWI conditions were determined as
200 W, 808, and 5 min for aromatic amines, and compounds 11–15 were obtained in
yields between 74 and 79%. Furthermore, the optimal MWI conditions for alcohols
were 200 W, 1008, and 10 min, and compounds 16–18 were obtained in 72–76% yields.
StructureꢀActivity Relashionship. The in vitro antiproliferative activities of these 19
novel C(34)-modified derivatives of GA were assessed by MTT (¼ 3-(4,5-dimethylth-
iazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay using human lung cancer
A549, human gastric carcinoma BGC-823, human brain glioma U251, human
hepatocellular carcinoma HepG2, and human breast carcinoma MB-231 cell lines.
The results are compiled in the Table. In five tested cell lines, the IC50 values of the
parent compound GA ranged from 0.14 to 2.31 mm.
Table. Cytotoxicity Data of GA and Its Derivatives
Compound
IC50 ꢁSD [mm]
A549
BGC-823
U251
HepG2
MB-231
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
GA
3.54ꢁ0.13
0.69ꢁ0.022
0.74ꢁ0.047
1.52ꢁ0.11
3.54ꢁ0.26
0.93ꢁ0.080
2.41ꢁ0.19
1.13ꢁ0.077
0.29ꢁ0.010
2.06ꢁ0.18
1.52ꢁ0.092
1.13ꢁ0.065
1.82ꢁ0.12
1.13ꢁ0.10
2.80ꢁ0.13
1.82ꢁ0.089
2.06ꢁ0.17
0.34ꢁ0.012
0.93ꢁ0.033
2.31ꢁ0.13
1.71ꢁ0.089
2.74ꢁ0.18
0.67ꢁ0.018
2.74ꢁ0.20
1.71ꢁ0.13
2.28ꢁ0.17
6.85ꢁ0.41
1.54ꢁ0.10
1.37ꢁ0.092
4.57ꢁ0.22
6.85ꢁ0.35
1.52ꢁ0.040
2.74ꢁ0.21
0.49ꢁ0.021
2.74ꢁ0.17
2.28ꢁ0.15
1.96ꢁ0.093
2.04ꢁ0.11
1.14ꢁ0.049
1.37ꢁ0.050
1.32ꢁ0.11
1.66ꢁ0.12
1.02ꢁ0.032
1.21ꢁ0.075
0.54ꢁ0.035
2.02ꢁ0.13
2.74ꢁ0.21
1.87ꢁ0.11
1.93ꢁ0.15
9.50ꢁ0.78
1.90ꢁ0.13
2.07ꢁ0.11
2.35ꢁ0.19
2.11ꢁ0.20
2.16ꢁ0.13
1.28ꢁ0.095
1.36ꢁ0.10
0.30ꢁ0.022
0.66ꢁ0.029
0.19ꢁ0.020
1.34ꢁ0.10
5.31ꢁ0.24
2.62ꢁ0.19
1.09ꢁ0.076
1.20ꢁ0.10
1.56ꢁ0.11
0.89ꢁ0.062
2.40ꢁ0.14
5.25ꢁ0.24
0.40ꢁ0.036
3.73ꢁ0.18
4.25ꢁ0.22
1.34ꢁ0.10
2.28ꢁ0.16
1.88ꢁ0.12
4.13ꢁ0.27
1.15ꢁ0.10
1.02ꢁ0.088
0.22ꢁ0.012
0.87ꢁ0.024
0.24ꢁ0.020
0.84ꢁ0.061
0.24ꢁ0.012
0.77ꢁ0.033
0.29ꢁ0.017
0.67ꢁ0.025
0.46ꢁ0.030
0.29ꢁ0.019
0.36ꢁ0.023
1.13ꢁ0.056
0.31ꢁ0.020
0.29ꢁ0.017
2.40ꢁ0.13
0.41ꢁ0.036
0.89ꢁ0.035
0.26ꢁ0.011
0.26ꢁ0.012
0.14ꢁ0.011
0.53ꢁ0.027
0.24ꢁ0.021
As a result of cytotoxicity screening, our newly synthesized compounds 1–19
exerted significant in vitro inhibitory effects on some cell growth. The selectivity of
most derivatives for A549 cells was highly increased, while all the derivatives were
identified as possessing lower effects against U251 compared with other four cell lines.
Against A549 cell line, among the 19 derivatives, 15 displayed more potent activities

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than GA. Compound 9 exhibited the highest potency with an IC50 value of 0.29 mm,
which was eightfold more potent than GA. Compound 18 was also found to be
sevenfold more active. Meanwhile, compounds 2 and 3 were ca. two- to threefold more
potent than GA. In BGC-823 cell line, three compounds, 3, 14, and 19, showed 1.2–2.8-
fold more cytotoxicity than GA, while five compounds, 1, 5, 8, 9, and 12, possessed
comparable activities. Compounds 7 and 11 were the least active with fivefold
decreased potency as compared to GA. Against HepG2 cell line, compound 18
displayed the best antitumor activity with an IC50 value of 0.14 mm and was 1.7-fold
more active than GA, whereas the rest was found to possess less potency. Against
MB231 cell line, only compounds 9 and 18 were of comparable potency as GAwith IC50
values of 0.40 and 0.22 mm, respectively. In the case of U251 cell line, all of the
derivatives had lower anti-proliferative effects than GA.
In general, compounds 3 and 18 exhibited potent cytotoxicities against all the five
cancer cell lines with IC50 values ranging from 0.24 to 1.09 mm, and from 0.14 to 2.04 mm,
respectively. Comparing 19 with GA, the replacement of Me group with Cl led to
sustained antitumor activity. Further introduction of RO groups such as EtO and iPrO
groups slightly reduced the activity as observed with compounds 16 and 17.
t
Interestingly, compound 18 with a more hydrophobic and sterically bulky Bu moiety
showed obviously increased activities. Meanwhile, introduction of aromatic amino
moieties at C(34) as in compounds 10–15 had little effect on the potency. Moreover,
most of the compounds containing aliphatic amino substituents at C(34) possessed
cytotoxicities comparable to that of GA. Especially, compound 3 with 4-methylpiper-
azin-1-yl moiety displayed low mm inhibition against A549, BGC-823, and HepG2 cells
with IC50 values of 0.74, 0.67, and 0.24 mm, respectively. Introduction of other aliphatic
amino moieties such as piperidin-1-yl, Et2N, and Bu2N selectively increased the activity
against HepG2 cells and led to three- to tenfold increase. Notably, the H2O solubility of
these compounds could be greatly improved due to the introduction of the hydrophilic
aliphatic amines. These findings could enhance our understanding of the SAR with
respect to the modifications at C(34) of GA and lead to the development of novel GA
derivatives with improved antitumor activities and drug-like properties.
Conclusions. – Although these experiments were preliminary, the results of SAR
study suggested that promising antitumor agents could be obtained by the conversion
of Me(34). 19 Novel C(34)-modified derivatives of GA were synthesized based on a
regioselective chemical modification strategy. All of these derivatives were evaluated
for their in vitro antitumor activities against five human cancer cell lines (A549, BGC-
823, U251, HepG2, and MB-231) by a MTT assy. Among the 19 derivatives, 15
displayed more potent activities than GA against several cancer cell lines. Compound 3
with a hydrophilic 4-methylpiperazin-1-yl group at C(34) possessed potent inhibitory
activities against the five cell lines with IC50 values ranging between 0.24 and 1.09 mm.
Especially, compounds 9 and 18 were seven to eightfold more active than GA against
A549 cell line. Introduction of hydrophilic aliphatic amino moieties at C(34) of GAwas
preferred to improve the antitumor activity and solubility. Meanwhile, the aromatic
amino groups had little effect on increasing the potency. In addition, introducing the
RO moiety such as tBuO group at C(34) of GA could increase the activity, whereas the
i
cytotoxicities were decreased in the case of EtO and PrO groups. This work could

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
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enhance our understanding of the SARs of gambogic acid and lead to the discovery of
novel GA derivatives as potential antitumor agents.
This work was supported by the Project Program of State Key Laboratory of Natural Medicines, the
National Natural Science Foundation of China (Nos. 90713038, 21072231, and 30873157), and the
National Major Science and Technology Project of China (Innovation and Development of New Drugs.
Nos. 2008ZX09401-001 and 2009ZX09501-003).
Experimental Part
General. All reagents and solvents were obtained from commercial suppliers. The reagents were
used as received. Solvents were routinely distilled prior to use. Each of the target compounds were
purified by flash column chromatography (FC) on silica gel 60 (SiO2; 200–300 mesh; Qingdao Marine
Chemical Factory). IR Spectra: Nicolet Impact 410 spectrometer (4000–400 cmꢀ1) in KBr; ˜n in cmꢀ1
.
1H-, 13C-, and 2D-NMR spectra: Bruker AV-300 instrument in CDCl3; d in ppm rel. to Me4Si as internal
standard, J in Hz. ESI-MS: Agilent 1100 LC/MSD (70 eV) spectrometers; in m/z. HR-ESI-MS: Waters
Q-Tofmicro; in m/z.
Gambogic Acid (GA). GA was isolated and purified from gamboges resin as described in [3].
34-Hydroxygambogic Acid (¼(2Z)-4-[(1R,3aS,5S,11R,14aS)-3a,4,5,7-Tetrahydro-8-hydroxy-13-
[(2E)-4-hydroxy-3-methylbut-2-en-1-yl]-3,3,11-trimethyl-11-(4-methylpent-3-en-1-yl)-7,15-dioxo-3H,
11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl]-2-methylbut-2-enoic Acid; 20). GA (628 mg,
1 mmol) was dissolved in CH2Cl2 (2 ml) and added dropwise to a clear soln. of SeO2 (6.0 mg, 0.05 mmol)
and t-BuOOH (75%, 270 mg, 3 mmol) in CH2Cl2 (10 ml) at r.t. After stirring at r.t. for 5 h, the mixture
was diluted with Et2O (10 ml). The mixture was then sequentially washed with aq. 10% KOH, H2O, and
brine. The org. layer was separated, dried (Na2SO4), filtered, and concentrated. The residue was purified
by FC (AcOEt/petroleum ether (PE) 1:1) to afford 20 (130 mg, 21%). Yellow oil. IR: 3457, 3420, 2970,
2923, 1736, 1689, 1623, 1592, 1454, 1436, 1400, 1381, 1330, 1176, 1138, 1047. 1H-NMR (300 MHz, CDCl3):
12.79 (s, HOꢀC(10)); 7.54 (d, J¼6.5, HꢀC(10)); 6.59 (d, J ¼10.0, HꢀC(4)); 5.93–5.75 (m, HꢀC(27));
5.43 (d, J¼10.0, HꢀC(3)); 5.40–5.38 (m, HꢀC(37)); 5.06–5.03 (m, HꢀC(32)); 3.96 (d, J¼5.5, CH2(34));
3.52–3.48 (m, HꢀC(11)); 3.33–3.29 (m, 1 H, CH2(31)); 3.15–3.12 (m, 1 H, CH2(31)); 2.93 (dd, J¼4.4,
4.3, CH2(26)); 2.50 (d, J¼9.3, HꢀC(22)); 2.31 (dd, J¼4.5, 4.4, 1 H, CH2(21)); 2.04–2.02 (m, CH2(36));
1.78 (s, Me(25)); 1.72 (s, Me(29)); 1.70–1.68 (m, CH2(20)); 1.66 (s, Me(39)); 1.55 (s, Me(40)); 1.48 (s,
Me(35)); 1.41 (s, Me(24)); 1.39–1.35 (m, 1 H, CH2(21)); 1.25 (s, Me(19)). 13C-NMR (75 MHz, CDCl3):
203.0 (C(12)); 178.8 (C(8)); 170.3 (C(30)); 161.2 (C(18)); 157.6 (C(16)); 157.4 (C(6)); 136.5 (C(27));
135.1 (C(10)); 134.2 (C(33)); 133.3 (C(9)); 131.8 (C(38)); 128.5 (C(28)); 124.6 (C(3)); 123.8 (C(37));
123.7 (C(32)); 115.8 (C(4)); 106.9 (C(17)); 102.8 (C(5)); 100.4 (C(7)); 90.7 (C(14)); 83.8 (C(23)); 83.6
(C(13)); 81.2(C(2)); 68.3 (C(34)); 49.0 (C(22)); 46.9 (C(11)); 41.7 (C(20)); 30.0 (C(25)); 29.7 (C(26));
28.8 (C(24)); 27.1 (C(19)); 25.5 (C(39)); 25.3 (C(35)); 22.6 (C(36)); 21.2 (C(31)); 20.9 (C(21)); 20.8
(C(29)); 17.51 (C(40)). ESI-MS: 667 ([MþNa]þ ), 683 ([MþK]þ ). HR-MS: 667.2888 ([MþNa]þ
,
C38H44NaOþ9 ; calc. 667.2883).
34-Hydroxygambogic Acid Methyl Ester (¼ Methyl (2Z)-4-[(1R,3aS,5S,11R,14aS)-3a,4,5,7-Tetrahy-
dro-8-hydroxy-13-[(2E)-4-hydroxy-3-methylbut-2-en-1-yl]-3,3,11-trimethyl-11-(4-methylpent-3-en-1-yl)-
7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl]-2-methylbut-2-enoate; 21). To a
stirred soln. of 20 (100 mg, 0.16 mmol) in MeOH (5 ml) at r.t. were added DMAP (23 mg, 0.19 mmol)
and EDCI (36 mg, 0.19 mmol). The resulting mixture was stirred for 8 h at r.t., and then the reaction was
quenched with brine. The mixture was extracted with AcOEt (3ꢂ5 ml). The combined org. layer was
dried (Na2SO4), filtered, and concentrated. The residue was purified by FC (AcOEt/PE 1:4) to afford 21
(94 mg, 90%). Yellow oil. IR: 3467, 3420, 2968, 2924, 1736, 1690, 1622, 1592, 1453, 1434, 1382, 1329, 1138,
1047. 1H-NMR (300 MHz, CDCl3): 12.85 (s, HOꢀC(6)); 7.53 (d, J¼6.9, HꢀC(10)); 6.69 (d, J¼10.2,
HꢀC(4)); 5.96–5.78 (m, HꢀC(27)); 5.46 (d, J¼10.2, HꢀC(3)); 5.29–5.26 (m, HꢀC(32)); 5.07–5.04 (m,
HꢀC(37)); 3.98–3.95 (m, CH2(34)); 3.87 (s, COOMe); 3.43–3.39 (m, HꢀC(11)); 3.30–3.28 (m, 1 H,
CH2(31)); 3.20–3.17 (m, 1 H, CH2(31)); 2.97–2.95 (m, CH2(26)); 2.53 (d, J¼9.3, HꢀC(22)); 2.33–2.30
(m, 1 H, CH2(21)); 2.06–2.04 (m, CH2(36)); 1.82 (s, Me(25)); 1.74 (s, Me(29)); 1.71–1.69 (m, CH2(20));

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CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
1.65 (s, Me(39)); 1.61 (s, Me(35)); 1.47 (s, Me(40)); 1.45 (s, Me(24)); 1.38–1.34 (m, 1 H, CH2(21)); 1.29 (s,
Me(19)). ESI-MS: 659 ([MþH]þ ).
34-Chlorogambogic Acid Methyl Ester (¼ Methyl (2Z)-4-[(1R,3aS,5S,11R,14aS)-13-[(2E)-4-
Chloro-3-methylbut-2-en-1-yl]-3a,4,5,7-tetrahydro-8-hydroxy-3,3,11-trimethyl-11-(4-methylpent-3-en-1-
yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl]-2-methylbut-2-enoate; 22). To
a stirred soln. of 21 (320 mg, 0.51 mmol) in CH2Cl2 (15 ml) at 08 were added TsCl (117 mg, 0.61 mmol)
and DMAP (125 mg, 1.68 mmol). The resulting mixture was stirred for 8 h at 08, and then the mixture was
diluted with CH2Cl2 (20 ml). The mixture was then sequentially washed with aq. 17% HCl, H2O, and
brine. The org. layer was separated, dried (Na2SO4), filtered, and concentrated. The residue was purified
by FC (AcOEt/PE 1:4) to afford 22 (285 mg, 88%). Yellow oil. IR: 3455, 3415, 2966, 2925, 1736, 1710,
1655, 1607, 1585, 1463, 1429, 1384, 1223, 1144, 1046. 1H-NMR (300 MHz, CDCl3): 12.86 (s, OH); 7.55 (d,
J¼6.9, HꢀC(10)); 6.70 (d, J¼10.2, HꢀC(4)); 5.93–5.77 (m, HꢀC(27)); 5.46 (d, J¼10.2, HꢀC(3)); 5.41–
5.39 (m, HꢀC(32)); 5.07–5.05 (m, HꢀC(37)); 4.00–3.96 (m, CH2(34)); 3.87 (s, COOMe); 3.43–3.40 (m,
HꢀC(11)); 3.32–3.29 (m, 1 H, CH2(31)); 3.19–3.17 (m, 1 H, CH2(31)); 3.01–2.98 (m, CH2(26)); 2.55–
2.53 (m, HꢀC(22)); 2.31–2.30 (m, 1 H, CH2(21)); 2.07–2.03 (m, CH2(36)); 1.82 (s, Me(25)); 1.74 (s,
Me(29)); 1.70–1.68 (m, CH2(20)); 1.67 (s, Me(39)); 1.62 (s, Me(35)); 1.45 (s, Me(40)); 1.43 (s, Me(24));
1.37–1.34 (m, 1 H of CH2(21)); 1.29 (s, Me(19)). ESI-MS: 667 ([MþH]þ ).
34-Chloro-6-methoxygambogic Acid Methyl Ester (¼ Methyl (2Z)-4-[(1R,3aS,5S,11R,14aS)-13-
[(2E)-4-Chloro-3-methylbut-2-en-1-yl]-3a,4,5,7-tetrahydro-8-methoxy-3,3,11-trimethyl-11-(4-methylpent-
3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl]-2-methylbut-2-enoate;
19). To a stirred mixture of 22 (200 mg, 0.31 mmol) and anh. K2CO3 (600 mg, 0.43 mmol) in acetone
(10 ml) at 08 was added dropwise MeI (0.4 ml, 0.64 mmol). The resulting mixture was stirred for 24 h at
r.t., and then the mixture was filtered and concentrated. The residue was purified by FC (AcOEt/PE 1:4)
to afford 19 (197 mg, 95%). Yellow oil. IR: 3442, 3050, 2966, 2925, 1734, 1709, 1655, 1607, 1586, 1463,
1
1427, 1384, 1225, 1143, 1046. H-NMR (300 MHz, CDCl3): 7.54 (d, J¼6.9, HꢀC(10)); 6.68 (d, J¼10.2,
HꢀC(4)); 5.92–5.80 (m, HꢀC(27)); 5.48 (d, J¼10.2, HꢀC(3)); 5.28–5.25 (m, HꢀC(32)); 5.06–5.04 (m,
HꢀC(37)); 3.99–3.94 (m, CH2(34)); 3.87 (s, COOMe); 3.43 (s, MeO); 3.42–3.39 (m, HꢀC(11)); 3.31–
3.29 (m, 1 H, CH2(31)); 3.21–3.18 (m, 1 H, CH2(31)); 3.00–2.97 (m, CH2(26)); 2.51 (d, J¼9.3,
HꢀC(22)); 2.33–2.29 (m, 1 H, CH2(21)); 2.09–2.07 (m, CH2(36)); 1.80 (s, Me(25)); 1.76 (s, Me(29));
1.71–1.69 (m, CH2(20)); 1.68 (s, Me(39)); 1.64 (s, Me(35)); 1.47 (s, Me(40)); 1.43 (s, Me(24)); 1.37–1.35
(m, 1 H, CH2(21)); 1.28 (s, Me(19)). ESI-MS: 691 ([MþH]þ ).
General Procedure for the Preparation of 1–18. A sealed glass tube (10 ml) containing a suspension
of 19 (20 mg, 0.029 mmol), K2CO3 (4 mg, 0.029 mmol), KI (5 mg, 0.030 mmol), and corresponding amine
or alcohol (0.035 mmol) in acetone (2 ml) was introduced into the cavity of CEM microwave reactor and
irradiated at 200 W for 5–10 min at 60–808 (5 min at 608 for 1–10, 5 min at 808 for 11–15, and 10 min at
1008 for 16–18). After cooling to r.t. by an air flow, the tube was removed from the totor, and then the
reaction was quenched with brine. The mixture was extracted with AcOEt (3ꢂ5 ml). The combined org.
layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by FC (AcOEt/PE 1:4 to
1:1) to afford the target compounds 1–18 as yellow oils in 66–80% yields.
6-Methoxy-34-(morpholin-4-yl)gambogic Acid Methyl Ester (¼ Methyl (2Z)-4-[(1R,3aS,5S,11R,
14aS)-3a,4,5,7-Tetrahydro-8-methoxy-3,3,11-trimethyl-13-[(2E)-3-methyl-4-(morpholin-4-yl)but-2-en-1-
yl]-11-(4-methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl]-
2-methylbut-2-enoate; 1). Yield: 75%. IR: 3409, 3053, 2962, 2925, 2857, 1717, 1648, 1586, 1454, 1431, 1377,
1
1228, 1193, 1122, 1032, 733. H-NMR (300 MHz, CDCl3): 7.42 (d, J¼6.9, HꢀC(10)); 6.67 (d, J¼10.2,
HꢀC(4)); 5.96–5.85 (m, HꢀC(27)); 5.53 (d, J¼10.2, HꢀC(3)); 5.28–5.25 (m, HꢀC(32)); 5.11–5.08 (m,
HꢀC(37)); 3.87 (s, COOMe); 3.73–3.66 (m, 4 H, morpholine), 3.43 (s, MeO); 3.38–3.36 (m, HꢀC(11));
3.26–3.23 (m, 1 H, CH2(31)); 2.99–2.97 (m, 1 H, CH2(31)); 2.88–2.83 (m, CH2(26)); 2.51 (d, J¼9.3,
HꢀC(22)); 2.32–2.29 (m, 1 H, CH2(21)); 2.28–2.23 (m, 4 H, morpholine); 2.11–2.09 (m, CH2(36));
1.88–1.84 (m, CH2(34)); 1.79 (s, Me(25)); 1.75 (s, Me(29)); 1.71–1.67 (m, CH2(20)); 1.64 (s, Me(39));
1.60 (s, Me(35)); 1.45 (s, Me(40)); 1.39 (s, Me(24)); 1.36–1.33 (m, 1 H, CH2(21)); 1.29 (s, Me(19)). ESI-
MS: 742 ([MþH]þ ). HR-MS: 742.3932 ([MþH]þ , C44H56NO9þ ; calc. 742.3955).
6-Methoxy-34-(piperidin-1-yl)gambogic Acid Methyl Ester (¼ Methyl (2Z)-4-{(1R,3aS,5S,11R,
14aS)-3a,4,5,7-Tetrahydro-8-methoxy-3,3,11-trimethyl-11-(4-methylpent-3-en-1-yl)-13-[(2E)-3-methyl-4-

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
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(piperidin-1-yl)but-2-en-1-yl]-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl}-2-
methylbut-2-enoate; 2). Yield: 80%. IR: 2933, 2858, 1773, 1715, 1642, 1586, 1433, 1377, 1327, 1225, 1129,
1021, 738. 1H-NMR (300 MHz, CDCl3): 7.43 (d, J¼6.6, HꢀC(10)); 6.67 (d, J¼9.9, HꢀC(4)); 5.95–5.86
(m, HꢀC(27)); 5.54 (d, J¼10.2, HꢀC(3)); 5.26–5.22 (m, HꢀC(32)); 5.11–5.07 (m, HꢀC(37)); 3.82 (s,
COOMe); 3.43 (s, MeO); 3.40–3.37 (m, HꢀC(11)); 3.28–3.24 (m, 1 H, CH2(31)); 2.98–2.96 (m, 1 H,
CH2(31)); 2.80–2.76 (m, CH2(26)); 2.51 (d, J¼9.6, HꢀC(22)); 2.32–2.29 (m, 1 H, CH2(21)); 2.30–2.26
(m, 4 H, piperidine); 2.09–2.07 (m, CH2(36)); 1.81–1.78 (m, CH2(34)); 1.75 (s, Me(25)); 1.69 (s,
Me(29)); 1.68–1.66 (m, CH2(20)); 1.65 (s, Me(39)); 1.59 (s, Me(35)); 1.45 (s, Me(40)); 1.39 (s, Me(24));
1.38–1.33 (m, 1 H, CH2(21)); 1.29 (s, Me(19)); 1.28–1.21 (m, 6 H, piperidine). ESI-MS: 740 ([MþH]þ ).
HR-MS: 7740.4138 ([MþH]þ , C45H58NO8þ ; calc. 740.4157).
6-Methoxy-34-(4-methylpiperazin-1-yl)gambogic Acid Methyl Ester (¼ Methyl (2Z)-4-
[(1R,3aS,5S,11R,14aS)-3a,4,5,7-Tetrahydro-8-methoxy-3,3,11-trimethyl-13-[(2E)-3-methyl-4-(4-methyl-
piperazin-1-yl)but-2-en-1-yl]-11-(4-methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-
g]pyrano[3,2-b]xanthen-1-yl]-2-methylbut-2-enoate; 3). Yield: 74%. IR: 3403, 2930, 2859, 2796, 1774,
1713, 1646, 1586, 1453, 1431, 1377, 1286, 1227, 1132, 1034, 738. 1H-NMR (300 MHz, CDCl3): 7.43 (d, J¼
6.9, HꢀC(10)); 6.67 (d, J¼10.2, HꢀC(4)); 5.97–5.86 (m, HꢀC(27)); 5.53 (d, J¼10.2, HꢀC(3)); 5.27–5.23
(m, HꢀC(32)); 5.10–5.06 (m, HꢀC(37)); 3.81 (s, COOMe); 3.43 (s, MeO); 3.42–3.38 (m, HꢀC(11));
3.27–3.24 (m, 1 H, CH2(31)); 2.99–2.96 (m, 1 H, CH2(31)); 2.92–2.89 (m, CH2(26)); 2.51–2.49 (m,
HꢀC(22)); 2.45–2.42 (m, 8 H, piperazine); 2.37 (s, MeN); 2.33–2.30 (m, 1 H, CH2(21)); 2.10–2.06 (m,
CH2(36)); 1.81–1.78 (m, CH2(34)); 1.75 (s, Me(25)); 1.70 (s, Me(29)); 1.69–1.67 (m, CH2(20)); 1.64 (s,
Me(39)); 1.57 (s, Me(35)); 1.46 (s, Me(40)); 1.40 (s, Me(24)); 1.38–1.36 (m, 1 H, CH2(21)); 1.34 (s,
Me(19)). ESI-MS: 755 ([MþH]þ ). HR-MS: 755.4252 ([MþH]þ , C45H59N2Oþ8 ; calc. 755.4266).
6-Methoxy-34-(pyrrolidin-1-yl)gambogic Acid Methyl Ester (¼ Methyl (2Z)-4-{(1R,3aS,5S,11R,
14aS)-3a,4,5,7-Tetrahydro-8-methoxy-3,3,11-trimethyl-11-(4-methylpent-3-en-1-yl)-13-[(2E)-3-methyl-4-
(pyrrolidin-1-yl)but-2-en-1-yl]-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl}-2-
methylbut-2-enoate; 4). Yield: 71%. IR: 3404, 3052, 2965, 2932, 1773, 1715, 1630, 1587, 1451, 1434, 1378,
1332, 1297, 1229, 1193, 1129, 1027, 728. 1H-NMR (300 MHz, CDCl3): 7.43 (d, J¼6.9, HꢀC(10)); 6.68 (d,
J¼10.2, HꢀC(4)); 5.95–5.86 (m, HꢀC(27)); 5.55 (d, J¼10.2, HꢀC(3)); 5.35–5.32 (m, HꢀC(32)); 5.10–
5.08 (m, HꢀC(37)); 3.82 (s, COOMe); 3.40 (s, MeO); 3.39–3.38 (m, HꢀC(11)); 3.26–3.24 (m, 1 H,
CH2(31)); 2.98–2.96 (m, 1 H, CH2(31)); 2.82–2.79 (m, CH2(26)); 2.63–2.56 (m, 4 H, pyrrolidine); 2.52–
2.50 (m, HꢀC(22)); 2.32–2.30 (m, 1 H, CH2(21)); 2.09–2.07 (m, CH2(36)); 1.81–1.78 (m, CH2(34)); 1.75
(s, Me(25)); 1.70 (s, Me(29)); 1.69–1.67 (m, CH2(20)); 1.64 (s, Me(39)); 1.57 (s, Me(35)); 1.46 (s,
Me(40)); 1.40 (s, Me(24)); 1.37–1.35 (m, 1 H, CH2(21)); 1.34 (s, Me(19)); 1.23–1.16 (m, 4 H,
pyrrolidine). ESI-MS: 726 ([MþH]þ ). HR-MS: 726.3977 ([MþH]þ , C44H56NOþ8 ; calc. 726.4006).
34-(Ethylamino)-6-methoxygambogic Acid Methyl Ester (¼ Methyl (2Z)-4-{(1R,3aS,5S,11R,14aS)-
13-[(2E)-4-(Ethylamino)-3-methylbut-2-en-1-yl]-3a,4,5,7-tetrahydro-8-methoxy-3,3,11-trimethyl-11-(4-
methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl}-2-methyl-
but-2-enoate; 5). Yield: 73%. IR: 3368, 2933, 2392, 1772, 1716, 1655, 1586, 1452, 1423, 1380, 1328, 1299,
1228, 1127, 760. 1H-NMR (300 MHz, CDCl3): 7.42 (d, J¼6.9, HꢀC(10)); 6.67 (d, J¼10.2, HꢀC(4)); 5.95–
5.87 (m, HꢀC(27)); 5.54 (d, J¼10.2, HꢀC(3)); 5.25–5.22 (m, HꢀC(32)); 5.10–5.08 (m, HꢀC(37)); 3.82
(s, COOMe); 3.43 (s, MeO); 3.41–3.37 (m, HꢀC(11)); 3.26–3.24 (m, 1 H, CH2(31)); 2.99–2.96 (m, 1 H,
CH2(31)); 2.79–2.77 (m, CH2(26)); 2.51 (d, J¼9.6, HꢀC(22)); 2.32–2.29 (m, 1 H, CH2(21)); 2.28–2.23
(m, MeCH2NH); 2.09–2.06 (m, CH2(36)); 1.80–1.78 (m, CH2(34)); 1.75 (s, Me(25)); 1.69 (s, Me(29));
1.68–1.66 (m, CH2(20)); 1.65 (s, Me(39)); 1.59 (s, Me(35)); 1.45 (s, Me(40)); 1.39 (s, Me(24)); 1.37–1.34
(m, 1 H, CH2(21)); 1.29 (s, Me(19)); 1.07–1.02 (m, MeCH2NH). ESI-MS: 714 ([MþH]þ ). HR-MS:
714.3977 ([MþH]þ , C43H56NOþ8 ; calc. 714.4006).
34-(Diethylamino)-6-methoxygambogic Acid Methyl Ester (¼ Methyl (2Z)-4-{(1R,3aS,5S,11R,
14aS)-13-[(2E)-4-(Diethylamino)-3-methylbut-2-en-1-yl]-3a,4,5,7-tetrahydro-8-methoxy-3,3,11-trimeth-
yl-11-(4-methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl}-2-
methylbut-2-enoate; 6). Yield: 76%. IR: 3405, 2965, 2933, 1775, 1715, 1652, 1587, 1453, 1424, 1379, 1326,
1127, 1027, 738. 1H-NMR (300 MHz, CDCl3): 7.43 (d, J¼6.6, HꢀC(10)); 6.67 (d, J¼10.2, HꢀC(4)); 5.95–
5.86 (m, HꢀC(27)); 5.54 (d, J¼10.2, HꢀC(3)); 5.29–5.26 (m, HꢀC(32)); 5.10–5.07 (m, HꢀC(37)); 3.82
(s, COOMe); 3.46 (s, MeO); 3.39–3.36 (m, HꢀC(11)); 3.27–3.25 (m, 1 H, CH2(31)); 2.98–2.96 (m, 1 H,

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CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
CH2(31)); 2.91–2.88 (m, CH2(26)); 2.52 (d, J¼9.6, HꢀC(22)); 2.51–2.45 (m, (MeCH2)2N); 2.30–2.28
(m, 1 H, CH2(21)); 2.10–2.07 (m, CH2(36)); 1.83–1.81 (m, CH2(34)); 1.78 (s, Me(25)); 1.71 (s, Me(29));
1.69–1.67 (m, CH2(20)); 1.64 (s, Me(39)); 1.60 (s, Me(35)); 1.47 (s, Me(40)); 1.40 (s, Me(24)); 1.36–1.33
(m, 1 H, CH2(21)); 1.29 (s, Me(19)); 1.05–1.02 (m, (MeCH2)2N). ESI-MS: 728 ([MþH]þ ). HR-MS:
728.4127 ([MþH]þ , C44H58NOþ8 ; calc. 728.4157).
34-(Diisopropylamino)-6-methoxygambogic Acid Methyl Ester (¼ Methyl (2Z)-4-[(1R,3aS,5S,11R,
14aS)-13-{(2E)-4-[Bis(1-methylethyl)amino]-3-methylbut-2-en-1-yl}-3a,4,5,7-tetrahydro-8-methoxy-
3,3,11-trimethyl-11-(4-methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-
b]xanthen-1-yl]-2-methylbut-2-enoate; 7). Yield: 78%. IR: 3403, 3342, 2930, 2393, 1770, 1716, 1650, 1587,
1450, 1418, 1382, 1265, 1229, 1201, 1060, 1035, 753. 1H-NMR (300 MHz, CDCl3): 7.43 (d, J¼6.9,
HꢀC(10)); 6.67 (d, J¼10.2, HꢀC(4)); 5.96–5.87 (m, HꢀC(27)); 5.54 (d, J¼10.2, HꢀC(3)); 5.27–5.25 (m,
HꢀC(32)); 5.14–5.11 (m, HꢀC(37)); 3.82 (s, COOMe); 3.43 (s, MeO); 3.40–3.38 (m, HꢀC(11)); 3.29–
3.26 (m, 1 H, CH2(31)); 2.99–2.96 (m, 1 H, CH2(31)); 2.93–2.91 (m, (Me2CH)2N); 2.90–2.88 (m,
CH2(26)); 2.52 (d, J¼9.3, HꢀC(22)); 2.32–2.28 (m, 1 H, CH2(21)); 2.12–2.10 (m, CH2(36)); 1.85–1.82
(m, CH2(34)); 1.76 (s, Me(25)); 1.70 (s, Me(29)); 1.69–1.67 (m, CH2(20)); 1.65 (s, Me(39)); 1.62 (s,
Me(35)); 1.45 (s, Me(40)); 1.38 (s, Me(24)); 1.36–1.34 (m, 1 H, CH2(21)); 1.26 (s, Me(19)); 0.97–0.92 (m,
(Me2CH)2N). ESI-MS: 756 ([MþH]þ ). HR-MS: 56.4443 ([MþH]þ , C46H62NOþ8 ; calc. 756.4475).
34-(Dipropylamino)-6-methoxygambogic Acid Methyl Ester (¼ Methyl (2Z)-4-{(1R,3aS,5S,11R,
14aS)-13-[(2E)-4-(Dipropylamino)-3-methylbut-2-en-1-yl]-3a,4,5,7-tetrahydro-8-methoxy-3,3,11-tri-
methyl-11-(4-methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-
yl}-2-methylbut-2-enoate; 8). Yield: 74%. IR: 3369, 2960, 2931, 1774, 1716, 1652, 1586, 1455, 1427, 1379,
1331, 1263, 1228, 1124, 1026, 753. 1H-NMR (300 MHz, CDCl3): 7.43 (d, J¼6.9, HꢀC(10)); 6.67 (d, J¼9.9,
HꢀC(4)); 5.96–5.87 (m, HꢀC(27)); 5.54 (d, J¼10.2, HꢀC(3)); 5.25–5.23 (m, HꢀC(32)); 5.11–5.08 (m,
HꢀC(37)); 3.82 (s, COOMe); 3.43 (s, MeO); 3.39–3.37 (m, HꢀC(11)); 3.28–3.25 (m, 1 H, CH2(31));
3.00–2.97 (m, 1 H, CH2(31)); 2.85–2.82 (m, CH2(26)); 2.51 (d, J¼9.0, HꢀC(22)); 2.32–2.30 (m, 1 H,
CH2(21)); 2.29–2.25 (m, (MeCH2CH2)2N); 2.09–2.05 (m, CH2(36)); 1.82–1.78 (m, CH2(34)); 1.75 (s,
Me(25)); 1.70 (s, Me(29)); 1.68–1.66 (m, CH2(20)); 1.65 (s, Me(39)); 1.61 (s, Me(35)); 1.45 (s, Me(40));
1.44–1.41 (m, (MeCH2CH2)2N); 1.39 (s, Me(24)); 1.36–1.34 (m, 1 H, CH2(21)); 1.29 (s, Me(19)); 0.87–
0.82 (m, (MeCH2CH2)2N). ESI-MS: 756 ([MþH]þ ). HR-MS: 56.4443 ([MþH]þ , C46H62NOþ8 ; calc.
756.4475).
34-(Dibutylamino)-6-methoxygambogic Acid Methyl Ester (¼ Methyl (2Z)-4-{(1R,3aS,5S,11R,
14aS)-13-[(2E)-4-(Dibutylamino)-3-methylbut-2-en-1-yl]-3a,4,5,7-tetrahydro-8-methoxy-3,3,11-trimeth-
yl-11-(4-methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl}-2-
methylbut-2-enoate; 9). Yield: 66%. IR: 3403, 2926, 2860, 2390, 1772, 1716, 1653, 1587, 1456, 1423, 1380,
1080, 1026, 792, 727. 1H-NMR (300 MHz, CDCl3): 7.43 (d, J¼6.9, HꢀC(10)); 6.68 (d, J¼10.2, HꢀC(4));
5.96–5.86 (m, HꢀC(27)); 5.54 (d, J¼10.2, HꢀC(3)); 5.25–5.22 (m, HꢀC(32)); 5.10–5.08 (m, HꢀC(37));
3.82 (s, COOMe); 3.43 (s, MeO); 3.38 (m, HꢀC(11)); 3.27 (m, 1 H, CH2(31)); 3.01–2.98 (m, 1 H,
CH2(31)); 2.88–2.86 (m, CH2(26)); 2.52 (d, J¼9.0, HꢀC(22)); 2.31–2.29 (m, 1 H, CH2(21)); 2.28–2.23
(m, (MeCH2CH2CH2)2N); 2.12–2.10 (m, CH2(36)); 1.86–1.84 (m, CH2(34)); 1.82 (s, Me(25)); 1.79 (s,
Me(29)); 1.77–1.75 (m, CH2(20)); 1.69 (s, Me(39)); 1.59 (s, Me(35)); 1.50–1.47 (m, (MeCH2CH2
CH2)2N); 1.45 (s, Me(40)); 1.38 (s, Me(24)); 1.35–1.33 (m, 1 H, CH2(21)); 1.29 (s, Me(19)); 1.25–1.20
(m, (MeCH2CH2CH2)2N); 0.92–0.87 (m, (MeCH2CH2CH2)2N). ESI-MS: 784 ([MþH]þ ). HR-MS:
784.4753 ([MþH]þ , C48H66NOþ8 ; calc. 784.4783).
6-Methoxy-34-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}gambogic Acid Methyl Ester (¼ Meth-
yl (2Z)-4-{(1R,3aS,5S,11R,14aS)-3a,4,5,7-Tetrahydro-8-methoxy-3,3,11-trimethyl-11-(4-methylpent-3-en-
1-yl)-13-[(2E)-3-methyl-4-{4-[4-(trifluoromethoxy)phenyl]piperazin-1-yl}but-2-en-1-yl]-7,15-dioxo-
3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl}-2-methylbut-2-enoate; 10). Yield: 69%. IR:
1
3403, 2962, 2684, 1773, 1716, 1657, 1588, 1515, 1452, 1418, 1383, 1263, 1058, 1028, 802, 753. H-NMR
(300 MHz, CDCl3): 7.36 (d, J¼6.9, HꢀC(10)); 7.04 (d, J¼8.4, 2 H, F3COꢀC6H4N); 6.83 (d, J¼8.7, 2 H,
F3COꢀC6H4N); 6.61 (d, J¼10.2, HꢀC(4)); 5.89–5.68 (m, HꢀC(27)); 5.47 (d, J¼10.2, HꢀC(3)); 5.27–
5.24 (m, HꢀC(32)); 5.04–5.02 (m, HꢀC(37)); 3.75 (s, COOMe); 3.40–5.38 (m, HꢀC(11)); 3.36 (s, MeO);
3.32–3.29 (m, 1 H, CH2(31)); 3.17–3.12 (m, N(CH2CH2)2N); 2.92–2.90 (m, 1 H, CH2(31)); 2.85–2.83
(m, CH2(26)); 2.43–2.40 (m, HꢀC(22)); 2.22–2.19 (m, 1 H, CH2(21)); 2.09–2.07 (m, CH2(36)); 1.77–

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2305
1.74 (m, CH2(34)); 1.69 (s, Me(25)); 1.62 (s, Me(29)); 1.59–1.57 (m, CH2(20)); 1.52 (s, Me(39)); 1.39 (s,
Me(35)); 1.31 (s, Me(24)); 1.29–1.26 (m, 1 H, CH2(21)); 1.21 (s, Me(40)); 1.19 (s, Me(19)). ESI-MS: 901
([MþH]þ ). HR-MS: 901.4223 ([MþH]þ , C51H60F3N2Oþ9 ; calc. 901.4245).
6-Methoxy-34-[(3-nitrophenyl)amino]gambogic Acid Methyl Ester (¼ Methyl (2Z)-4-
[(1R,3aS,5S,11R,14aS)-3a,4,5,7-Tetrahydro-8-methoxy-3,3,11-trimethyl-13-{(2E)-3-methyl-4-[(3-nitro-
phenyl)amino]but-2-en-1-yl}-11-(4-methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-
g]pyrano[3,2-b]xanthen-1-yl]-2-methylbut-2-enoate; 11). Yield: 74%. IR: 3404, 2933, 1717, 1656, 1585,
1
1455, 1427, 1379, 1266, 1227, 1129, 1036, 878, 753. H-NMR (300 MHz, CDCl3): 7.51–7.48 (m, 1 H, 3-
NO2ꢀC6H4NH); 7.43 (d, J¼6.9, HꢀC(10)); 7.36–7.34 (m, 1 H, 3-NO2ꢀC6H4NH); 7.26–7.24 (m, 1 H, 3-
NO2ꢀC6H4NH); 6.82–6.78 (m, 1 H, 3-NO2ꢀC6H4NH); 6.66 (d, J¼10.2, HꢀC(4)); 5.97–5.86 (m,
HꢀC(27)); 5.52 (d, J¼10.2, HꢀC(3)); 5.39–5.36 (m, HꢀC(32)); 5.08–5.06 (m, HꢀC(37)); 3.81 (s,
COOMe); 3.65 (s, CH2(26)); 3.43 (s, MeO); 3.39–3.36 (m, HꢀC(11)); 3.26–3.23 (m, 1 H, CH2(31));
2.98–2.96 (m, 1 H, CH2(31)); 2.49 (d, J¼9.3, HꢀC(22)); 2.31–2.28 (m, 1 H, CH2(21)); 2.11–2.09 (m,
CH2(36)); 1.81–1.78 (m, CH2(34)); 1.73 (s, Me(25)); 1.68 (s, Me(29)); 1.63–1.61 (m, CH2(20)); 1.60 (s,
Me(39)); 1.58 (s, Me(35)); 1.47 (s, Me(40)); 1.39 (s, Me(24)); 1.36–1.33 (m, 1 H, CH2(21)); 1.28 (s,
Me(19)). ESI-MS: 793 ([MþH]þ ). HR-MS: 793.3673 ([MþH]þ , C46H53N2O1þ0 ; calc. 793.3695).
6-Methoxy-34-(thiazol-5-ylamino)gambogic Acid Methyl Ester (¼ Methyl (2Z)-4-{(1R,3aS,5S,11R,
14aS)-3a,4,5,7-Tetrahydro-8-methoxy-3,3,11-trimethyl-11-(4-methylpent-3-en-1-yl)-13-[(2E)-3-methyl-4-
(thiazol-5-ylamino)but-2-en-1-yl]-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-
yl}-2-methylbut-2-enoate; 12). Yield: 74%. IR: 3385, 2926, 1771, 1711, 1629, 1585, 1453, 1424, 1380, 1260,
1226, 1122, 1108, 1034, 750. 1H-NMR (300 MHz, CDCl3): 7.43 (d, J¼6.9, HꢀC(10)); 6.68 (d, J¼9.9,
HꢀC(4)); 6.68 (m, 2 H, thiazole); 5.99–5.88 (m, HꢀC(27)); 5.53 (d, J¼10.2, HꢀC(3)); 5.08–5.05 (m,
HꢀC(32)); 4.81–4.78 (m, HꢀC(37)); 3.81 (s, COOMe); 3.43 (s, MeO); 3.39–3.37 (m, HꢀC(11)); 3.24–
3.21 (m, 1 H, CH2(31)); 2.99–2.96 (m, 1 H, CH2(31)); 2.91 (s, CH2(26)); 2.55 (d, J¼9.3, HꢀC(22)); 2.31–
2.28 (m, 1 H, CH2(21)); 2.11–2.08 (m, CH2(36)); 1.83–1.81 (m, CH2(34)); 1.75 (s, Me(25)); 1.69 (s,
Me(29)); 1.66–1.64 (m, CH2(20)); 1.63 (s, Me(39)); 1.57 (s, Me(35)); 1.46 (s, Me(40)); 1.40 (s, Me(24));
1.37–1.34 (m, 1 H, CH2(21)); 1.29 (s, Me(19)). ESI-MS: 755 ([MþH]þ ). HR-MS: 755.3336 ([MþH]þ
,
C43H51N2O8Sþ ; calc. 755.3361).
6-Methoxy-34-[(4-methylphenyl)amino]gambogic Acid Methyl Ester (¼ Methyl (2Z)-4-
[(1R,3aS,5S,11R,14aS)-3a,4,5,7-Tetrahydro-8-methoxy-3,3,11-trimethyl-13-{(2E)-3-methyl-4-[(4-methyl-
phenyl)amino]but-2-en-1-yl}-11-(4-methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-
g]pyrano[3,2-b]xanthen-1-yl]-2-methylbut-2-enoate; 13). Yield: 75%. IR: 3396, 2965, 2927, 2861, 1774,
1712, 1655, 1586, 1519, 1453, 1427, 1378, 1307, 1228, 1191, 1128, 1023, 736. 1H-NMR (300 MHz, CDCl3):
7.43 (d, J¼6.9, HꢀC(10)); 6.96 (d, J¼8.4, 2 H, 4-MeꢀC6H4NH); 6.66 (d, J¼10.2, HꢀC(4)); 6.50 (d, J¼
8.4, 2 H, 4-MeꢀC6H4NH); 5.95–5.85 (m, HꢀC(27)); 5.52 (d, J¼10.2, HꢀC(3)); 5.35–5.32 (m, HꢀC(32));
5.09–5.07 (m, HꢀC(37)); 3.81 (s, COOMe); 3.74 (s, 4-MeꢀC6H4NH); 3.56 (s, CH2(26)); 3.43 (s, MeO);
3.39–3.36 (m, HꢀC(11)); 3.27–2.25 (m, 1 H, CH2(31)); 2.98–2.96 (m, 1 H, CH2(31)); 2.48 (d, J¼9.3,
HꢀC(22)); 2.30–2.28 (m, 1 H, CH2(21)); 2.12–2.08 (m, CH2(36)); 1.82–1.79 (m, CH2(34)); 1.74 (s,
Me(25)); 1.68 (s, Me(29)); 1.65–1.63 (m, CH2(20)); 1.62 (s, Me(39)); 1.60 (s, Me(35)); 1.44 (s, Me(40));
1.39 (s, Me(24)); 1.35–1.33 (m, 1 H, CH2(21)); 1.28 (s, Me(19)). ESI-MS: 762 ([MþH]þ ). HR-MS:
62.3979 ([MþH]þ , C47H56NOþ8 ; calc. 762.4006).
6-Methoxy-34-[(4-methoxyphenyl)amino]gambogic Acid Methyl Ester (¼ Methyl (2Z)-4-
[(1R,3aS,5S,11R,14aS)-3a,4,5,7-Tetrahydro-8-methoxy-13-{(2E)-4-[(4-methoxyphenyl)amino]-3-methyl-
but-2-en-1-yl}-3,3,11-trimethyl-11-(4-methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-
g]pyrano[3,2-b]xanthen-1-yl]-2-methylbut-2-enoate; 14). Yield: 79%. IR: 3367, 2930, 2864, 2655, 2526,
1
2383, 2238, 2101, 1710, 1659, 1586, 1513, 1452, 1426, 1380, 1241, 1131, 1032, 752. H-NMR (300 MHz,
CDCl3): 7.43 (d, J¼6.9, HꢀC(10)); 6.74 (d, J¼8.7, 2 H, 4-MeOꢀC6H4NH); 6.66 (d, J¼9.9, HꢀC(4)); 6.57
(d, J¼8.7, 2 H, 4-MeOꢀC6H4NH); 5.95–5.83 (m, HꢀC(27)); 5.52 (d, J¼10.2, HꢀC(3)); 5.35–5.32 (m,
HꢀC(32)); 5.08–5.06 (m, HꢀC(37)); 3.81 (s, COOMe); 3.74 (s, 4-MeOꢀC6H4NH); 3.49 (s, CH2(26));
3.43 (s, MeO); 3.38–3.35 (m, HꢀC(11)); 3.26–2.23 (m, 1 H, CH2(31)); 2.98–2.96 (m, 1 H, CH2(31)); 2.48
(d, J¼9.3, HꢀC(22)); 2.31–2.28 (m, 1 H, CH2(21)); 2.11–2.08 (m, CH2(36)); 1.82–1.80 (m, CH2(34));
1.78 (s, Me(25)); 1.74 (s, Me(29)); 1.69–1.66 (m, CH2(20)); 1.63 (s, Me(39)); 1.60 (s, Me(35)); 1.44 (s,

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CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
Me(40)); 1.39 (s, Me(24)); 1.36–1.34 (m, 1 H, CH2(21)); 1.28 (s, Me(19)). ESI-MS: 777 ([MþH]þ ). HR-
MS: 778.3912 ([MþH]þ , C47H56NO9þ ; calc. 778.3955).
34-[(4-Chlorophenyl)amino]-6-methoxygambogic Acid Methyl Ester (¼ Methyl (2Z)-4-
[(1R,3aS,5S,11R,14aS)-13-{(2E)-4-[(4-Chlorophenyl)amino]-3-methylbut-2-en-1-yl}-3a,4,5,7-tetrahy-
dro-8-methoxy-3,3,11-trimethyl-11-(4-methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-
g]pyrano[3,2-b]xanthen-1-yl]-2-methylbut-2-enoate; 15). Yield: 75%. IR: 3403, 2933, 1772, 1710, 1658,
1587, 1454, 1424, 1381, 1312, 1260, 1225, 1190, 1130, 1028, 751. 1H-NMR (300 MHz, CDCl3): 7.43 (d, J¼
6.9, HꢀC(10)); 7.08 (d, J¼8.7, 2 H, 4-ClꢀC6H4NH); 6.66 (d, J¼9.9, HꢀC(4)); 6.50 (d, J¼8.7, 2 H, 4-
ClꢀC6H4NH); 5.96–5.85 (m, HꢀC(27)); 5.51 (d, J¼9.9, HꢀC(3)); 5.33–5.30 (m, HꢀC(32)); 5.13–5.11
(m, HꢀC(37)); 3.81 (s, COOMe); 3.50 (s, CH2(26)); 3.43 (s, MeO); 3.39–3.36 (m, HꢀC(11)); 3.26–3.22
(m, 1 H, CH2(31)); 2.98–2.95 (m, 1 H, CH2(31)); 2.47 (d, J¼9.3, HꢀC(22)); 2.31–2.28 (m, 1 H,
CH2(21)); 2.11–2.09 (m, CH2(36)); 1.81–1.78 (m, CH2(34)); 1.73 (s, Me(25)); 1.72 (s, Me(29)); 1.69–1.66
(m, CH2(20)); 1.63 (s, Me(39)); 1.58 (s, Me(35)); 1.48 (s, Me(40)); 1.39 (s, Me(24)); 1.36–1.34 (m, 1 H,
CH2(21)); 1.28 (s, Me(19)). ESI-MS: 782 ([MþH]þ ). HR-MS: 782.3427 ([MþH]þ , C46H53ClNOþ8 ; calc.
782.3454).
34-Ethoxy-6-methoxygambogic Acid Methyl Ester (¼ Methyl (2Z)-4-[(1R,3aS,5S,11R,14aS)-13-
[(2E)-4-Ethoxy-3-methylbut-2-en-1-yl]-3a,4,5,7-tetrahydro-8-methoxy-3,3,11-trimethyl-11-(4-methylpent-
3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl]-2-methylbut-2-enoate;
16). Yield: 74%. IR: 3405, 2932, 2393, 1717, 1653, 1586, 1451, 1424, 1381, 1074, 1029, 768. 1H-NMR
(300 MHz, CDCl3): 7.43 (d, J¼6.9, HꢀC(10)); 6.68 (d, J¼10.2, HꢀC(4)); 5.95–5.84 (m, HꢀC(27)); 5.54
(d, J¼10.2, HꢀC(3)); 5.33–5.30 (m, HꢀC(32)); 5.10–5.08 (m, HꢀC(37)); 3.82 (s, COOMe); 3.44 (s,
MeO); 3.43–3.41 (m, MeCH2O); 3.41–3.39 (m, CH2(34)); 3.38–3.36 (m, HꢀC(11)); 3.29–3.27 (m, 1 H,
CH2(31)); 3.26–3.24 (m, 1 H, CH2(31)); 2.97 (s, CH2(26)); 2.51 (d, J¼9.6, HꢀC(22)); 2.30–2.28 (m, 1 H,
CH2(21)); 2.11–2.08 (m, CH2(36)); 1.75 (s, Me(25)); 1.69 (s, Me(29)); 1.66–1.64 (m, CH2(20)); 1.63 (s,
Me(39)); 1.57 (s, Me(35)); 1.46 (s, Me(40)); 1.40 (s, Me(24)); 1.37–1.35 (m, 1 H, CH2(21)); 1.29 (s,
Me(19)); 1.22–1.19 (m, MeCH2O). ESI-MS: 701 ([MþH]þ ). HR-MS: 701.3669 ([MþH]þ , C42H53O9þ ;
calc. 701.3690).
34-Isopropoxy-6-methoxygambogic Acid Methyl Ester (¼ Methyl (2Z)-4-{(1R,3aS,5S,11R,14aS)-
3a,4,5,7-Tetrahydro-8-methoxy-3,3,11-trimethyl-13-{(2E)-3-methyl-4-[(1-methylethyl)oxy]but-2-en-1-yl}-
11-(4-methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl}-2-
methylbut-2-enoate; 17). Yield: 72%. IR: 3404, 2931, 2392, 2220, 2084, 1725, 1650, 1590, 1383, 1266, 1060,
1
1028, 754. H-NMR (300 MHz, CDCl3): 7.46 (d, J¼6.9, HꢀC(10)); 6.27–6.24 (m, HꢀC(4)); 6.08–5.99
(m, HꢀC(27)); 5.11–5.08 (m, HꢀC(3)); 4.89–4.87 (m, HꢀC(32), HꢀC(37)); 3.82 (s, COOMe); 3.47–
3.45 (m, CH2(34)); 3.44 (s, MeO); 3.43–3.41 (m, Me2CHO); 3.39–3.37 (m, HꢀC(11)); 3.28–3.26 (m,
1 H, CH2(31)); 3.25–3.22 (m, 1 H, CH2(31)); 2.97 (s, CH2(26)); 2.51 (d, J¼9.6, HꢀC(22)); 2.30–2.28 (m,
1 H, CH2(21)); 2.11–2.08 (m, CH2(36)); 1.75 (s, Me(25)); 1.69 (s, Me(29)); 1.66–1.64 (m, CH2(20)); 1.63
(s, Me(39)); 1.57 (s, Me(35)); 1.46 (s, Me(40)); 1.40 (s, Me(24)); 1.38–1.35 (m, 1 H, CH2(21)); 1.29 (s,
Me(19)); 1.23–1.20 (m, Me2CHO). ESI-MS: 715 ([MþH]þ ). HR-MS: 715.3826 ([MþH]þ , C43H54O9þ ;
calc. 715.3846).
34-(tert-Butoxy)-6-methoxygambogic Acid Methyl Ester (¼ Methyl (2Z)-4-[(1R,3aS,5S,11R,14aS)-
13-[(2E)-4-(tert-Butoxy)-3-methylbut-2-en-1-yl]-3a,4,5,7-tetrahydro-8-methoxy-3,3,11-trimethyl-11-(4-
methylpent-3-en-1-yl)-7,15-dioxo-3H,11H-1,5-methanofuro[3,4-g]pyrano[3,2-b]xanthen-1-yl]-2-methyl-
but-2-enoate; 18). Yield: 76%. IR: 3419, 3056, 2962, 2932, 2862, 1721, 1656, 1586, 1455, 1426, 1377, 1319,
1
1265, 1226, 1137, 738. H-NMR (300 MHz, CDCl3): 7.47–7.45 (m, HꢀC(10)); 6.28–6.25 (m, HꢀC(4));
6.07–5.99 (m, HꢀC(27)); 5.12–5.09 (m, HꢀC(3)); 4.91–4.89 (m, HꢀC(32), HꢀC(37)); 3.82 (s,
COOMe); 3.42 (s, MeO); 3.41–3.39 (m, CH2(34)); 3.38–3.35 (m, HꢀC(11)); 3.29–3.27 (m, 1 H,
CH2(31)); 3.26–3.24 (m, 1 H, CH2(31)); 2.97 (s, CH2(26)); 2.51 (d, J¼9.6, HꢀC(22)); 2.30–2.28 (m, 1 H,
CH2(21)); 2.11–2.09 (m, CH2(36)); 1.75 (s, Me(25)); 1.69 (s, Me(29)); 1.66–1.64 (m, CH2(20)); 1.63 (s,
Me(39)); 1.57 (s, Me(35)); 1.46 (s, Me(40)); 1.40 (s, Me(24)); 1.37–1.34 (m, 1 H, CH2(21)); 1.29 (s,
Me(19)); 1.21 (s, tBu). ESI-MS: 729 ([MþH]þ ). HR-MS: 729.3986 ([MþH]þ , C44H57Oþ9 ; calc.
729.4003).
Antiproliferation Activity. Cancer cell lines used in this study were obtained from the Cell Bank of
Shanghai, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences. Cells were cultured in

CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)
2307
90% RPMI 1640 Medium (GIBCO, Invitrogen Corporation, USA) supplemented with 10% fetal bovine
serum (Sijiqing, Zhejiang, China), 100 mg/ml benzyl penicillin, and 100 mg/ml streptomycin in a
humidified environment with 5% CO2 at 378. Samples containing>95% GA 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 0.01m and stored at ꢀ48.
Cell viabilities were measured by a colorimetric assay using MTT (Sigma, Ltd.) as described in [31].
Experiments carried out in triplicate in a parallel manner for each concentration of target compounds
used, and the results were presented as meanꢁSE. Control cells were given only culture media. After
incubation for 48 h, absorbance (A) was measured at 570 nm. Survival ratio (%) was calculated using the
following equation: survival ratio [%]¼(Atreatment/Acontrol)ꢂ100%. The IC50 value was taken as the
concentration that caused 50% inhibition of cell viabilities and calculated by the SAS statistical software.
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