Synthesis and anti-cancer activity evaluation of novel prenylated and geranylated chalcone natural products and their analogs

Article abstract of DOI:10.1016/j.ejmech.2015.01.007

Four natural chalcones bearing prenyl or geranyl groups, i.e., bavachalcone (1a), xanthoangelol (1b), isobavachalcone (1c), and isoxanthoangelol (1d) were synthesized by using a regio-selective iodination and the Suzuki coupling reaction as key steps. The first total synthesis of isoxanthoangelol (1d) was achieved in 36% overall yield. A series of diprenylated and digeranylated chalcone analogs were also synthesized by alkylation, regio-selective iodination, aldol condensation, Suzuki coupling and [1,3]-sigmatropic rearrangement. The structures of the 11 new derivatives were confirmed by 1H NMR, 13C NMR and HRMS. The anticancer activity of these new chalcone derivatives against human tumor cell line K562 were evaluated by MTT assay in vitro. SAR studies suggested that the 50-prenylation/geranylation of the chalcones significantly enhance their cytotoxic activity. Among them, Bavachalcone (1a) displayed the most potent cytotoxic activity against K562 with IC50 value of 2.7 mM. The morphology changes and annexin-V/PI staining studies suggested that those chalcone derivatives inhibited the proliferation of K562 cells by inducing apoptosis.

Full text of DOI:10.1016/j.ejmech.2015.01.007

European Journal of Medicinal Chemistry 92 (2015) 439e448
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and anti-cancer activity evaluation of novel prenylated and
geranylated chalcone natural products and their analogs
Hao-Meng Wang a, Li Zhang a, Jiang Liu a, Zhao-Liang Yang a, Hong-Ye Zhao a, Yao Yang a,
,
Di Shen a, Kui Lu a, Zhen-Chuan Fan b c, Qing-Wei Yao d, Yong-Min Zhang e,
,
, *
Yu-Ou Teng a *, Yu Peng a
a Key Lab of Industrial Fermentation Microbiology, Tianjin Key Lab of Industrial Microbiology, Sino-French Joint Lab of Food Nutrition/Safety and Medicinal
Chemistry, Tianjin University of Science and Technology, Tianjin 300457, PR China
b Key Laboratory of Food Nutrition and Safety (Tianjin University of Science & Technology), Ministry of Education, Tianjin 300457, PR China
c Obesita & Algaegen LLC, College Station, TX 77845, USA
d Sphinx Scientific Laboratory, 1250 East State Street, Sycamore, IL 60178, USA
e
ꢀ
ꢀ
Universite Pierre et Marie Curie-Paris 6, Institut Parisien de Chimie Moleculaire UMR CNRS 8232, 4 place Jussieu, 75005 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Four natural chalcones bearing prenyl or geranyl groups, i.e., bavachalcone (1a), xanthoangelol (1b),
isobavachalcone (1c), and isoxanthoangelol (1d) were synthesized by using a regio-selective iodination
and the Suzuki coupling reaction as key steps. The first total synthesis of isoxanthoangelol (1d) was
achieved in 36% overall yield. A series of diprenylated and digeranylated chalcone analogs were also
synthesized by alkylation, regio-selective iodination, aldol condensation, Suzuki coupling and [1,3]-
sigmatropic rearrangement. The structures of the 11 new derivatives were confirmed by 1H NMR, 13C
NMR and HRMS. The anticancer activity of these new chalcone derivatives against human tumor cell line
K562 were evaluated by MTT assay in vitro. SAR studies suggested that the 50-prenylation/geranylation of
the chalcones significantly enhance their cytotoxic activity. Among them, Bavachalcone (1a) displayed
Received 1 October 2014
Received in revised form
13 December 2014
Accepted 5 January 2015
Available online 6 January 2015
Keywords:
Prenyled chalcones
Geranylated chalcones
Antitumor agents
K562 cell
the most potent cytotoxic activity against K562 with IC50 value of 2.7 mM. The morphology changes and
annexin-V/PI staining studies suggested that those chalcone derivatives inhibited the proliferation of
K562 cells by inducing apoptosis.
Apoptosis
© 2015 Elsevier Masson SAS. All rights reserved.
1. Introduction
of Angelica keiskei [9], exhibits antibacterial activity against Gram-
Positive pathogenic bacteria [10], antitumor-promoting activity
Chalcones containing prenyl or geranyl groups are an abundant
subclass of flavonoids which are widely found in nature and display
and cytotoxicity against neuroblastoma cells, which induced
apoptotic cell death via the mitochondrial pathway and had no
cytotoxicity against normal cells [11]. The newly discovered com-
pound 1d, 20, 40, 4-trihydroxy- 5-geranyl chalcone, coined here as
isoxanthoangelol, was isolated from the leaves of Artocarpus com-
munis, and reported to possess anticancer activity in SW 872 hu-
man liposarcoma cells (Fig. 1) [12].
Due to their structural uniqueness and potent bioactivity, the
synthesis of prenylated and geranylated chalcone natural products
has attracted much attention in recent years. In 2010, Jung reported
the first total synthesis of 1b with a total yield of 16.8% starting from
4-dihydroxyacetophenone (1) [13]. Sugamoto subsequently
finished the total synthesis of 1a, 1b and 1c with 12.4%, 28.1% and
17.2% overall yield respectively [14]. All of these syntheses used O-
alkylation followed by Claisen rearrangement as the key steps to
a
variety of biological and pharmacological activities. Iso-
bavachalcone (1c), first isolated from Psoralea corylifolia [1],
showed antibacterial, antifungal, anticancer, anti-reverse tran-
scriptase, antitubercular, and antioxidant activities [2e4]. Bava-
chalcone (1a), also isolated from soraleaorylifolia [1,5], was shown
to display a significant inhibitory effect on baculovirus-expressed
BACE-1 in vitro [6] as well as osteoclast differentiation [7]. These
natural chalcones also exhibit extremely high
a-glucosidase
inhibitory activity [8]. Xanthoangelol (1b), isolated from fresh roots
* Corresponding authors.
E-mail addresses: tyo201485@tust.edu.cn (Y.-O. Teng), yupeng@tust.edu.cn
(Y. Peng).
http://dx.doi.org/10.1016/j.ejmech.2015.01.007
0223-5234/© 2015 Elsevier Masson SAS. All rights reserved.

440
H.-M. Wang et al. / European Journal of Medicinal Chemistry 92 (2015) 439e448
Fig. 1. The structures of chalcone natural products and their derivatives.
introduce the prenyl or geranyl groups. However, poor regiose-
lectivity of the rearrangement limited their further use. Recently,
McGlinchey applied iodination and Stille coupling to the synthesis
of isobavachalocone. But the overall efficiency was low due to poor
regiochemical control for the iodination as well as the low yield for
the Stille coupling [15]. The 30, 50-diprenylated chalcone Medi-
cagenin (2a) was isolated from the roots of Crotalaria medicagenia
DC [16] and synthesized later by Narender [17] with a poor regio-
selectivity. However, no work has been reported on the synthesis
and biological activity evaluation of other digeranylated chalcones,
including 2b and analogs 2c and 2d.
Scheme 1. Synthetic route for target compounds 1a, 1d, 37 and 38.
Scheme 2. Iodination of compound 14.
As part of our ongoing program on the synthesis of flavonoid
and chalcone natural products, we have recently reported a
regioselective iodination of flavonoids by NIS under neutral con-
ditions [18], regioselective iodinations of chalcone derivatives using
this protocol and the total synthesis of the aforementioned chal-
cone natural products by Suzuki coupling of the iodinated in-
termediates as the key step [19,20]. In this paper, we would like to
report in details the synthesis and anticancer activity evaluation of
the 30 and/or 50 prenylated/geranylated chalcone natural products
(1aed, 2a) and their derivatives (2bed, 33e40) as well as the likely
molecular mechanism of their cytotoxic activity.
2. Chemistry
As shown in Scheme 1, iodide 3 was readily synthesized from
the bis-MOM intermediate 2 by iodination of 1 with NIS in DMF
[16]. Base promoted condensation of 3 with aldehyde 4 afforded the
iodo precursor 5 which was converted into 6 and 7 by PdCl2(dppf)
catalyzed and microwave-assisted coupling reaction with the cor-
responding boronic acid pinacol esters in good yields. Removal of
the MOM protecting groups finished the first total synthesis of
isoxanthoangelol (1d) in 36% overall yield and the improved
preparation of Bavachalcone (1a) in 35% overall yield respectively.
The corresponding 20, 40, 4-trimethoxy derivatives 37 and 38 were
obtained when 1a and 1d were treated with iodomethane and NaH
in dry DMF in excellent yield.
The synthesis of isobavachalocone (1c) and xanthoganelol (1b)
necessitates a 2-iodo-4-acetylresorcinol derivative such as 15
(Scheme 2). Unfortunately, iodination of the mono-MOM protected
substrate 14 led to the formation of 15 along with a significant
amount of its regioisomer 16. However, utilization of an alternative
iodination system (I2/KIO3) [21] provided a much cleaner access to
the analogous iodide 8 directly from 1 (Scheme 3).
Scheme 3. Synthetic route for target compounds 1b, 1c, 39 and 40.
respectively, from the commercial material 4-acetylresorcinol (1).
Compound 39 and 40 were prepared from 1b and 1c by methyl-
ation with MeI in 88% and 81% yield, respectively.
To synthesize the 30, 50-disubstituted chalcones Medicagenin
(2a) and 2d, we initially planned to employ the Pd-catalyzed
coupling reaction to install the second prenyl/geranyl side-chain.
This route required a 50-iodo-30- prenylated intermediate such as
23 (Scheme 4). Unfortunately, when using a protocol for the
regieoselective iodination developed for the flavonoid substrates
[18], the desired iodination product 23 was not formed. Therefore
we decided to utilize the combination of Pd-catalyzed coupling
reaction (for 50-substitution) and O-alkylation/Claisen rearrange-
ment (for 30-substitution) to prepare the target compounds.
As shown in Scheme 5, compounds 6 and 7 were selectively
deprotected with 1 M HCl at 0 ꢀC to give the compounds 11a and
With compound 8 in hands, the total synthesis of both xan-
thoganelol (1b) and isobavachalocone (1c) was achieved unevent-
fully under similar conditions with an overall yield of 53% and 50%

H.-M. Wang et al. / European Journal of Medicinal Chemistry 92 (2015) 439e448
441
11b; the latter were treated with prenylbromide or geranylbromide
under basic conditions to provide the alkylated products 12aed.
The 1, 30 rearrangement of these ethers were catalyzed by mag-
nesium silicate (Florisil®,100e200 mesh) [22] at 140 ꢀC in dry
toluene to provide the desired compounds 13aed. Removal of the
MOM protection groups was initially attempted with 3 M HCl at
60 ꢀC, but the reaction only gave a low yield of the final target
compounds 2aed. Deprotection of 13aed was finally achieved in
75e81% yield when 6% (v/v) of con. H2SO4 in THF and isopropanol
at room temperature. To the best of our knowledge, this protocol of
MOM deprotection has not been previously reported in the litera-
ture. The trimethoxy compounds 33e36 were prepared by
methylation of 2aed with MeI in the presence of NaH in good
yields.
Scheme 4. Iodination of compound 21.
3. Results and discussion
The in vitro antitumor activities of the newly synthesized prenyl
and geranyl substituted chalcone natural products and their de-
rivatives on human tumor cell K562 were evaluated by MTT assay
with Camptothecin as the positive control.
As can be seen from the data in Table 1, that 50-mono-substi-
tution could significantly improve chalcone's cytotoxicy, as the 50-
prenylated chalcone Bavachalcone (1a) and 50-geranylated chal-
cone Isoxanthoangelol (1d) exhibited the inhibitory potency
against K562 at least 10 (for 1a) and 7 times (for 1d) stronger than
their unsubstituted counterpart isoliquiritigenin itself, which sug-
gested that the relatively large size and the hydrophobic nature of
the substitution group at this position of the molecule could
potentially become a key factor to improve the anticancer activity
of the substituted chalcone derivatives.
Scheme 5. Synthetic route for target compounds 2aed and 33e36.
The 30-geranyl mono-substituted chalcone Xanthoangelol (1b)
also showed good cytotoxic activity (3.98
mM). However, the
Table 1
Antitumor activities of chalcone derivatives in vitro.
No.
Entry
R1
R2
R3
X
Y
IC50
(m
M) K562
IC50(mM) HUV-EC
1
2
3
4
5
6
7
8
1a
1b
1c
1d
2a
2b
2c
2d
33
34
35
36
37
38
39
40
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
Prenyl
H
H
H
2.77 1.07
3.98 0.62
29.49 2.26
4.33 3.59
3.25 0.23
31.65 6.58
8.07 4.98
10.65 5.30
19.33 1.24
17.53 4.88
15.96 4.32
21.62 2.09
3.04 0.38
4.64 1.31
21.91 4.4
9.58 4.74
29.27 6.83
0.13 0.04
39.73 2.32
>100
>100
Geranyl
Prenyl
H
Geranyl
Prenyl
Geranyl
Geranyl
Prenyl
Prenyl
Prenyl
Geranyl
Geranyl
Prenyl
Geranyl
H
30.18 1.28
20.26 1.70
45.70 12.70
35.31 1.41
37.28 1.24
36.33 4.76
33.90 2.56
37.72 3.40
46.46 1.96
45.58 11.79
78.01 1.87
54.76 10.69
37.68 4.67
41.17 1.48
0.20 0.01
Prenyl
Geranyl
Prenyl
Geranyl
Prenyl
Geranyl
Prenyl
Geranyl
H
9
10
11
12
13
14
15
16
17
18
H
Prenyl
Geranyl
H
H
H
Isoliquiritigein
Camptothecin

442
H.-M. Wang et al. / European Journal of Medicinal Chemistry 92 (2015) 439e448
potency of it 30-prenylated counterpart (1c) dropped by 7.5 folds
against K562. Similar trend was noticed when the trimethoxyl 30-
geranylated compound 40 was compared to trimethoxyl 30-pre-
nylated compound 39. This observation suggests that the good
inhibitory activity of 1b does not simply correlate with the hydro-
phobic nature of the geranyl group. The size and spatial orientation
of the extra prenyl moiety (comparing to 1c) may also play a role.
As shown in Table 1, the activity of the 30, 50-diprenylated
did cause 2-7 folds activity drop from their trihydroxy counterparts.
This observation suggested that the methoxy moieties at the 20 and
40 positions maybe too crowded for the 30-substitution and there-
fore the 30-prenyl/geranyl moiety might lose their favorite 3-
dimentional orientation for the good inhibition.
To determine the cytotoxic activity on normal human cells, MTT
assay was used for the evaluation of the cytotoxic potency of the
target compounds against the human umbilical vein endothelial
cell lines HUVEC. As compared to the cytotoxic potency to the K562
cells, all the targets compounds showed higher cell viability rate for
HUVEC cells, which suggested that these compounds possessed low
cytotoxicity to normal human cells HUVEC than to cancer cells
K562 (Table 1).
chalcone 2a (Medicagenin) against K562 (3.25
mM) was 9 time
better than that of its mother chalcone (isoliquiritigenin). However,
when one of the two prenyl groups in compound 2a was replaced
with geranyl moiety, namely for 50-prenyl-30-geranyl chalcones 2d
and 34, 30-prenyl-50-geranyl chalcones 2c and 35 as well as the
30,50-digeranylated chalcone 2b and 36, their potency dropped 2e6
folds from that of 2a.
In this study, the molecular mechanism of the cytotoxic activity
of the chalcone derivatives with an IC50 value less than 5.0 mM was
To examine the impact of the 20, 40, 4-trihydroxy groups on the 30
or/and 50-prenylated/geranylated chalcones' cytotoxic activity
against K562, 8 novel trimethoxy 30 or/and 50 substituted chalcone
derivatives were synthesized from their trihydroxy counterparts.
The test results illustrated that the methoxy group did not enhance
the potency. The trimethoxy 50-prenylated/geranylated compounds
(37 and 38) maintained a good inhibition, indicating that hydrogen
bond donor of the hydroxyl groups in these 50-substituted chal-
cones are not necessary for their activity and their 20, 40, 4 positions
might tolerance certain size of O-linked substitution without
sacrificing their potency. However, in the presence of a 30-prenyl/
geranyl moiety (33e36, 39 and 40), the 20, 40, 4-trimethoxy groups
investigated on K562 cells. It was obvious that treatment with
chalcone derivatives causes K562 cells’ typical apoptotic
morphology change, e.g. cell shrinkage and/or blebbing. As shown
in Fig. 2A, the apoptotic cells were clearly observed in K562 cells
after treatment with the chalcone derivatives for 48 h. Flow cyto-
metic analysis also showed that apoptotic cells appeared in chal-
cone derivatives-treated K562 cells when double labelled with
annexin-V-FITC and PI (Fig. 2B). After treatment with the chal-
cone derivatives, the apoptotic rates (Annexin Vþ/PIꢁ) of K562 cells
were increased to at least 37.5% of the total cells whereas only 5.0%
cells were observed as apoptotic cells in the control. Taken together,
these results suggested that the chalcone derivatives inhibited the
Fig. 2. Chalcone derivatives induced apoptosis in K562 cells. (A) Morphological changes induced by chalcone derivatives (30 mM) treatment for 48 h were observed. (B) Chalcone
derivatives-treated K562 cells were labeled with Annexin-V-FITC and PI and apoptosis was determined using FACS analysis. Data was shown as the mean of three independent
experiments. The cell percentage in each area was indicated.

H.-M. Wang et al. / European Journal of Medicinal Chemistry 92 (2015) 439e448
443
proliferation of K562 cells by inducing apoptosis.
white solid; 1H NMR (400 MHz, CDCl3):
d
2.59 (s, 3H), 3.51 (s, 6H),
5.27 (s, 2H), 5.28 (s, 2H), 6.91 (s, 1H), 8.22 (s, 1H); 13C NMR
4. Conclusions
(100 MHz, DMSO-d6): d 31.7, 56.7, 56.7, 94.7, 94.9, 101.3, 124.1, 141.0,
158.6, 160.0, 196.6; HRMS (ESI) m/z Calcd for C12H15IO5Na [MþNa]þ
In summary, the first total synthesis of isoxanthoangelol (1d)
was accomplished in 5 steps and 36% overall yield. The improved
synthesis of bavachalcone (1a), xanthoangelol (1b) and iso-
bavachalcone (1c) as well as the preparation of a series of novel 30
or/and 50 prenylated/geranylated chalcone derivatives were
accomplished. The anticancer activity of the 16 newly synthesized
chalcone derivatives against human tumor cell line K562 were
evaluated and the test result illustrated that the 50-prenylation/
geranylation of the chalcones could significantly enhance their
cytotoxic activity and the 30-geranyl mono-substituted chalcone
388.9862; found: 388.9859.
5.1.3. (E)-1-(5-iodo-2,4-bis(methoxymethoxy)phenyl)-3-
(4(methoxymethoxy)phenyl)prop-2-en-1-one (5)
To a stirred solution of compound 3 (366.00 mg, 1.00 mmol) and
4-(methoxymethoxy)benzaldehyde (174.41 mg, 1.05 mmol) in
ethanol (5 mL) was slowly added 60% KOH (2 mL) at 0 ꢀC, then the
reaction mixture was warm to room temperature and stirred for
12 h. After completion of reaction, the reaction mixture was
extracted with ethyl acetate (3 ꢂ 20 mL). The organic layers were
combined, washed with saturated sodium chloride solution, dried
over sodium sulfate, filtrated, and concentrated under vacuum to
get a reside which was recrystallized from ethyl acetate to afford
compound 5 (475.00 mg, 92%) as a yellow solid; 1H NMR (CDCl3,
Xanthoangelol (1b) also showed good cytotoxic activity (3.98 mM).
However, the introduce of another prenyl/geranyl groups and/or
the 20, 40, 4-trimethoxy groups did not further improve the activity.
Moreover, the molecular mechanism of the cytotoxic activity of 6
chalcone derivatives were also investigated on K562 cells and the
results suggested that chalcone derivatives inhibited the prolifer-
ation of K562 cells by inducing apoptosis. Further optimization of
the structure to improve the bioavailability and solubility is
ongoing.
400 MHz): d 3.50 (s, 6H), 3.55 (s, 3H), 5.23 (s, 2H), 5.26 (s, 2H), 5.31
(s, 2H), 6.96 (s, 1H), 7.07 (d, J ¼ 8.8 Hz, 2H), 7.31 (d, J ¼ 16 Hz, 1H),
7.55 (d, J ¼ 8.4 Hz, 2H), 7.64 (d, J ¼ 16 Hz, 1H), 8.10 (s, 1H); 13C NMR
(100 MHz, CHCl3)
d 56.2, 56.7, 56.7, 94.2, 95.0, 95.2, 102.2, 116.5,
124.7, 125.9, 128.8, 130.0, 140.7, 143.1, 157.6, 159.1, 159.3, 190.0;
HRMS (ESI) m/z Calcd for C21H23IO7Na [MþNa]þ 537.0386; found:
537.0378.
5. Experimental section
5.1. Chemistry
5.1.4. (E)-1-(2,4-bis(methoxymethoxy)-5-(3-methylbut-2-en-1-yl)
phenyl)-3-(4-(methoxymethoxy)phenyl)prop-2-en-1-one (6)
All chemicals (reagent grade) used were purchased from Sigma-
Aldrich (U.S.A) and Aladdin-Reagent Co., Ltd (China). The solvents
for reaction were distilled over Na (for toluene and THF) or CaH2
(for CH2Cl2) under a nitrogen atmosphere. All reactions were car-
ried out in oven-dried glassware under an inert atmosphere (ni-
trogen or argon). Microwave reaction was carried out in Biotage
Initiator made in Sweden. TLC was run on the silica gel coated
aluminum sheets (Silica Gel 60GF254, E. Merck, Germany). 1H NMR
and 13C NMR were recorded on a Bruker AVANCE instrument
(400 MHz). ESI mass spectra were obtained on an LCQ-Advantayc-
MAX (LAM10188, Finnigan, Co., Ltd, USA). The purity of the final
products was determined by HPLC (LabTech) on a Diamonsil C18
To a stirred solution of compound 5 (514.00 mg, 1.00 mmol) and
3-Methyl-2-butenylboronic acid pinacol ester (235.00 mg,
1.20 mmol) in anhydrous DMF (3 mL) was added PdCl2(dppf)
(36.60 mg, 0.05 mmol, 0.05 equiv), Cesium carbonate (456.00 mg,
1.40 mmol). The mixture was heated at 70 ꢀC by microwave for 2 h.
The reaction mixture was cooled and monitored by TLC. After
completion of the reaction, the reaction mixture was filtrated and
evaporated under vacuum. The residue was purified by silica gel
column chromatography to afford compound 6 (384.00 mg, 84%) as
yellow oil; 1H NMR (CDCl3, 400 MHz):
d
¼ 1.71 (s, 6H), 3.29 (d,
J ¼ 7.6 Hz 2H), 3.48 (d, 9H), 5.21 (d, 4H), 5.25 (s, 3H), 6.90 (s, 1H),
7.04 (d, J ¼ 8.8 Hz, 2H), 7.37 (d, J ¼ 15.6 Hz, 1H), 7.52 (m, 3H), 7.62 (d,
column (4.6 mm ꢂ 250 mm, 5
m
m) with methanol/H2O (90/10 v/v)
J ¼ 15.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d
¼ 17.8, 25.8, 28.1,
at 0.5 mL/min flow rate and 254 nm detector wavelength.
56.2, 56.3, 56.6, 94.2, 94.3, 95.5, 101.7, 116.5, 122.2, 123.7, 124.7,
125.5, 129.2, 129.9, 131.5, 132.6, 142.0, 155.8, 158.5, 158.8, 191.4;
HRMS (ESI) m/z Calcd for C26H32O7Na [MþNa]þ 479.2046; found:
479.2043.
5.1.1. 1-(2,4-bis(methoxymethoxy)phenyl)ethanone (2)
To
a stirred solution of 1-(2,4-dihydroxyphenyl)ethanone
(152.00 mg, 1.00 mmol) and anhydrous NaH (96.00 mg, 4.00 mmol)
in dry Dichloromethane (5.00 mL) was slowly added chloromethyl
methyl ether (483.00 mg, 6.00 mmol) at 0 ꢀC and stirred for 2 h. The
reaction mixture was monitored by TLC. After completion of the
reaction, the reaction mixture was diluted with CH2Cl2 (20 mL). The
organic layer was washed with H2O (3 ꢂ 10 mL), dried over Mg2SO4
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography to afford compound 2
(210.00 mg, 87%) as a white solid; 1H and 13C NMR identical with
literature data [24]; LRMS (ESI) m/z: 263.09 [MþNa]þ.
5.1.5. Bavachalocone (1a)
To a solution of compound 6 (100.00 mg, 0.22 mmol) in MeOH
(2 mL), was added 1N aqueous hydrochloric acid (1 mL) at 0 ꢀC. The
reaction mixture was heated to 50 ꢀC for 6 h. The reaction was
cooled to room temperature and MeOH was removed in vacuo.
Ethyl acetate (10 mL) was then added and the layers were sepa-
rated. The aqueous layer was extracted with Ethyl acetate
(2x10 mL) and the combined organic layers were dried MgSO4
concentrated in vacuo to give a residue which was purified by flash
chromatography on silica gel (eluant:n-hexane/EtOAc ¼ 15:1) to
afford Bavachalocone (1a) (53.00 mg, 75%, Purity: 97%) as a yellow
solid: 1H and 13C NMR identical with literature data [1]; LRMS (ESI)
m/z 325 [MþH]þ
5.1.2. 5-iodo-2,4-bis(methoxymethoxy)phenyl)ethanone (3)
To a solution of compound 2 (0.24 g, 1.00 mmol) in dry DMF
(4 mL), was added NIS (0.27 g, 1.20 mmol), after the addition, the
mixture was stirred at 70 ꢀC for 10 h. The reaction mixture was
diluted with CH2Cl2 (20 mL), and the mixture was poured into
saturated sodium bicarbonate solution (10 mL). The organic layer
was washed with H2O (3 ꢂ 10 mL), dried over Mg2SO4 and
concentrated under reduced pressure. The residue was purified by
column chromatography to afford compound 3 (0.26 g, 70%) as a
5.1.6. (E)-1-(5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-2,4-
bis(methoxymethoxy)phenyl)-3-(4-(methoxymethoxy)phenyl)prop-
2-en-1-one (7)
To a stirred solution of compound 5 (514.00 mg, 1.00 mmol) and
geranylboronic acid pinacol ester (317.00 mg, 1.20 mmol) in

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H.-M. Wang et al. / European Journal of Medicinal Chemistry 92 (2015) 439e448
anhydrous DMF (3 mL) was added PdCl2(dppf) (36.60 mg,
0.05 mmol), Cesium carbonate (456.00 mg, 1.40 mmol). The
mixture was heated at 70 ꢀC by microwave for 2 h. The reaction
mixture was cooled and monitored by TLC. After completion of the
reaction, the reaction mixture was filtrated and evaporated under
vacuum. The residue was purified by silica gel column chroma-
tography to afford compound 7 (431.00 mg, 82%) as yellow oil; 1H
vigorously overnignt. Then the mixture was diluted with water,
extracted with ethyl acetate (3 ꢂ 100 mL), the combine the organic
layers was washed with brine dry over sodium sulfate, filtered and
concentrated under reduced pressure to provide the compound 8
(18.00 g, 98%) as offwhite solid. 1H and 13C NMR identical with
literature data [21]; LRMS (ESI) m/z 277 [MþH]þ
NMR (DMSO-d6,400 MHz):
d
1.53 (s, 3H), 1.60 (s, 3H), 1.68 (s, 3H),
5.1.11. 1-(3-Iodo-2,4-bis(methoxymethoxy)phenyl)ethanone (9)
To a stirred solution of compound 8 (278.00 mg, 1.00 mmol) and
anhydrous NaH (96.00 mg, 4.00 mmol) in dry Dichloromethane
(5 mL) was slowly added chloromethyl methyl ether (483.00 mg,
6.00 mmol) at 0 ꢀC and stirred for 2 h. The reaction mixture was
monitored by TLC. After completion of the reaction, the reaction
mixture was diluted with CH2Cl2 (20 mL), the organic layer was
washed with H2O (3 ꢂ 10 mL), dried over Mg2SO4 and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography to afford compound 9 (330.00 mg, 90%) as
2.04 (m, 4H), 3.25 (d, J ¼ 7.2 Hz, 2H), 3.36 (s, 3H), 3.39 (s, 3H), 3.41
(s, 3H), 5.07 (t, J ¼ 16.8 Hz, 1H), 5.25 (m, 3H), 5.28 (s, 2H), 5.31 (s,
2H), 6.89 (s, 1H), 7.07 (d, J ¼ 8.8 Hz, 2H), 7.41 (d, J ¼ 16 Hz, 1H), 7.51
(d, J ¼ 16 Hz, 1H), 7.67 (d, J ¼ 8.8 Hz, 2H); 13C NMR (100 MHz,
DMSO-d6):d 16.2, 17.7, 25.7, 26.7, 28.0, 39.8, 56.1, 56.3, 56.6, 94.2,
94.3, 95.5, 101.7, 116.5, 122.1, 122.8, 123.7, 124.3, 124.8, 125.5, 129.2,
129.8, 131.4, 131.5, 136.2, 142.1, 155.8, 158.6, 158.8, 191.4; HRMS (ESI)
m/z Calcd for C31H40O7Na [MþNa]þ 547.2672; found: 547.2669.
5.1.7. (E)-1-(5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-2,4-
dihydroxyphenyl)-3-(4hydroxyphenyl)prop-2-en-1-one (1d)
The procedure is the same as the preparation of Bavachalocone
by using compound 7 (100.00 mg, 0.19 mmol) as substrate to give
compound 1d (55.00 mg, 73%, purity: 100%) as a yellow solid. 1H
and 13C NMR identical with literature data [12]; LRMS (ESI) m/z 392
[MþH]þ
colorless oil. 1H NMR (CDCl3, 400 MHz):
d 2.61 (s, 3H), 3.51 (s, 3H),
3.56 (s, 3H), 5.07 (s, 2H), 5.30 (s, 2H), 6.91 (d, J ¼ 8.4 Hz, 1H), 7.58 (d,
J ¼ 8.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
d 30.2, 56.6, 58.6,
87.0, 94.9, 101.2, 110.1, 129.0, 131.0, 157.1, 160.1, 198.6; HRMS (ESI) m/
z Calcd for C12H15I1O5Na [MþNa]þ 388.9862; found: 388.9854.
5.1.12. (E)-1-(3-iodo-2,4-bis(methoxymethoxy)phenyl)-3-(4-
(methoxymethoxy)phenyl)prop-2-en-1-one (10)
5.1.8. (E)-1-(2,4-dimethoxy-5-(3-methylbut-2-en-1-yl)phenyl)-3-
(4-methoxyphenyl)prop-2-en-1-one (37)
The procedure is the same as the preparation of compound 5 by
using compound 9 (100.00 mg, 0.27 mmol) as substrate to give
compound 10(134.00 mg, 95%) as yellow oil. 1H NMR (CDCl3,
Compound 37 A mixture of compound 1a (0.10 g, 1 equiv),
anhydrous NaH (0.05 g, 4 equiv), and CH3I (dropwise addition of
0.15 g, 3.5 equiv) was stirred in DMF (3 mL) at 0 ꢀC and stirred for
2 h. The reaction mixture was monitored by TLC. After completion
of the reaction, the reaction mixture was diluted with CH2Cl2
(20 mL), the organic layer was washed with H2O (3 ꢂ 10 mL), dried
over Mg2SO4 and concentrated under reduced pressure. The res-
idue was purified by silica gel column chromatography to afford
compound 37 (80.00 mg, 71%, purity: 95%) as colorless oil. 1H NMR
400 MHz):
d 3.48 (s, 3H), 3.51 (s, 3H), 3.53 (s, 3H), 5.03 (s, 2H), 5.21
(s, 2H), 5.31 (s, 2H), 6.94 (d, J ¼ 8.4 Hz, 1H), 7.05 (d, J ¼ 8.8 Hz, 2H),
7.24 (d, J ¼ 20.4 Hz, 1H), 7.56 (d, J ¼ 8.8 Hz, 2H), 7.59 (d, J ¼ 8.8 Hz,
1H), 7.65 (d, J ¼ 16 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 56.2, 56.6,
58.8, 86.8, 94.2, 94.9, 101.4, 110.3, 116.5, 124.3, 128.5, 129.2, 130.2,
131.5, 143.7, 157.1, 159.2, 159.8, 190.9; HRMS (ESI) m/z Calcd for
C
21H23I1O7Na [MþNa]þ 537.0386; found: 537.0382.
(CDCl3, 400 MHz):
d
1.70 (s, 3H), 1.72 (s, 3H), 3.29 (d, J ¼ 7.2 Hz 2H),
5.1.13. (E)-1-(2,4-bis(methoxymethoxy)-3-(3-methylbut-2-en-1-yl)
phenyl)-3-(4-(methoxymethoxy)phenyl)prop-2-en-1-one (21)
The procedure is the same as the preparation of compound 6 by
using compound 10 (100.00 mg, 0.19 mmol) as substrate to give
compound 21 (75.00 mg, 84%), as yellow oil. 1H NMR (CDCl3,
3.84 (s, 3H), 3.90 (s, 3H), 3.92 (s, 3H), 5.27 (t, J ¼ 7.2 Hz 1H), 6.45 (s,
1H), 6.91 (d, J ¼ 4.8 Hz, 2H), 7.26 (s, 1H), 7.40 (d, J ¼ 15.6 Hz,1H), 7.54
(d, J ¼ 10.4 Hz, 3H), 7.64 (d, J ¼ 16 Hz,1H); 13C NMR (100 MHz,
DMSO-d6): d 17.8, 25.8, 27.7, 55.4, 55.6, 56.1, 95.0, 114.3, 121.4, 122.3,
122.7, 125.2, 128.3, 129.9, 131.9, 132.6, 141.7, 158.9, 161.2, 161.5,
190.8; HRMS (ESI) m/z Calcd forC23H26O4Na [MþNa]þ 389.1729;
found: 389.1725.
400 MHz): d 1.70 (s, 3H), 1.80 (s, 3H), 3.45 (s, 3H), 3.46 (d, 2H),3.48
(s, 3H), 3.48 (s, 3H), 4.92 (s, 2H), 5.21 (s, 2H), 5.23 (m, 1H), 5.25 (s,
2H), 6.94 (d, J ¼ 8.8 Hz, 1H), 7.05 (d, J ¼ 8.4 Hz, 2H), 7.24 (d,
J ¼ 16.8 Hz, 1H),7.47 (d, J ¼ 8.4 Hz, 1H), 7.55 (d, J ¼ 8.8 Hz, 2H), 7.65
5.1.9. (E)-1-(5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-2,4-
(d, J ¼ 16 Hz,1H); 13C NMR (100 MHz, CDCl3):
d 18.0, 23.4, 25.8, 56.2,
dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one 4 (38)
The procedure is the same as the preparation of compound 37
by using compound 1d (480.00 mg, 0.19 mmol) as substrate to give
compound 38 (400.00 mg, 75%, purity: 98%) as a yellow oil. 1H NMR
57.9, 94.0, 94.1, 101.3, 109.5, 116.5, 122.6, 124.8, 124.9, 128.1, 128.7,
128.8, 130.1, 131.7, 143.2, 155.5, 158.6, 159.1, 192.2; HRMS (ESI) m/z
Calcd for C26H32O7Na [MþNa]þ 479.2046; found: 479.2043;
(CDCl3,400 MHz):
d
1.60 (s, 3H), 1.68 (s, 3H), 1.79 (s, 3H), 2.15 (m,
5.1.14. (E)-1-(3-((E)-3,7-dimethylocta-2,6-dien-1-yl)-2,4-
bis(methoxymethoxy)phenyl)-3-(4-(methoxymethoxy)phenyl)prop-
2-en-1-one (22)
The procedure is the same as the preparation of compound 21
by using compound 10 (100.00 mg, 0.19 mmol) as substrate to give
compound 22 (84.00 mg, 82%), as yellow oil; 1H NMR (DMSO-d6,
4H), 3.35 (d, J ¼ 7.2 Hz, 2H), 3.84 (s, 3H), 3.90 (s, 3H), 3.92 (s, 3H),
5.10 (m, 1H), 5.33 (t, J ¼ 6.8 Hz, 1H), 6.42 (s, 1H), 6.88 (d, J ¼ 8.4 Hz,
2H), 7.43 (d, J ¼ 15.6 Hz,1H), 7.56 (d, J ¼ 8.4 Hz, 2H), 7.63 (s,1H), 7.83
(d, J ¼ 15.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6):
d 16.1, 17.7, 25.7,
26.7, 27.6, 39.8, 55.4, 55.6, 56.2, 95.0,114.3, 121.4, 122.2,122.8,124.3,
125.2, 128.3, 129.9, 131.3, 131.6, 131.9, 136.2, 141.8, 158.9, 161.2, 161.5,
190.8. HRMS (ESI) m/z Calcd for C28H34O4Na [MþNa]þ 457.2355;
found: 457.2368.
400 MHz):
d
1.52 (s, 3H), 1.59 (d, J ¼ 5.6 Hz, 3H), 1.77 (s, 3H), 1.95 (t,
J ¼ 6.8 Hz, 2H), 2.01 (t, J ¼ 7.2 Hz, 2H), 3.34 (s, 2H), 3.36 (s, 3H), 3.38
(s, 3H), 3.39 (s, 3H), 4.86 (s, 2H), 5.03 (t, J ¼ 6.4 Hz, 1H), 5.17 (t,
J ¼ 16 Hz, 1H), 5.25 (s, 2H), 5.31 (s, 2H), 6.98 (d, J ¼ 8.4 Hz, 1H), 7.07
(d, J ¼ 8.8 Hz, 2H), 7.29 (d, J ¼ 16 Hz,1H), 7.46 (d, J ¼ 8.8 Hz,1H), 7.53
(d, J ¼ 15.6 Hz, 1H), 7.70 (d, J ¼ 8.8 Hz, 2H); 13C NMR (100 MHz,
5.1.10. 1-(2,4-Dihydroxy-3-iodophenyl)ethanone (8)
To
a
solution of 2,4-Dihydroxyacetophenone(10.00 g,
65.73 mmol) in ethanol (50 mL) and water (80 mL) was added
iodine(7.51 g, 29.59 mmol) and potassium iodate (2.81 g,
13.13 mmol) at room temperature. The reaction was stirred
DMSO- d6): d 16.5, 18.0, 23.4, 25.9, 26.5, 56.2, 56.2, 57.7, 94.1, 94.1,
101.1, 109.9, 116.9, 122.8, 124.5, 124.6, 124.9, 128.0, 128.6, 128.9,
130.7, 131.2, 135.1, 143.1, 155.3, 158.4, 159.1, 191.3; HRMS (ESI) m/z

H.-M. Wang et al. / European Journal of Medicinal Chemistry 92 (2015) 439e448
445
Calcd for C31H40O7Na [MþNa]þ 547.2672; found: 547.2669.
5.1.21. (E)-1-(2-(((Z)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-4-
(methoxymethoxy)-5-(3-methylbut-2-en-1-yl)phenyl)-3-(4-
(methoxymethoxy)phenyl)prop-2-en-1-one (12d)
5.1.15. Isobavachalcone (1c)
To a stirred solution of Compound 11a (412.00 mg, 1.00 mmol)
and NaH (52.00 mg, 1.30 mmol) in dry DMF (5 mL) was slowly
added Geranylbromide (282.00 mg, 1.30 mmol) at 0 ꢀC and stirred
for 2 h. The reaction mixture was monitored by TLC. After
completion of the reaction, the reaction mixture was diluted with
CH2Cl2 (20 mL). The organic layer was washed with H2O
(3 ꢂ 10 mL), dried over Mg2SO4 and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography to afford compound 12d (500.00 mg, 90%) as a colorless
The procedure is the same as the preparation of Bavachalocone
by using compound 21 (100.00 mg, 0.22 mmol) as substrate to give
compound 1c (53.00 mg, 75%, purity: 98%), as yellow powder. 1H
and 13C NMR identical with literature data [1]; HRMS (ESI) m/z
Calcd for C20H20O4 [MþH]þ 324.1362; found:324.1365.
5.1.16. Xanthoangelol (1b)
The procedure is the same as the preparation of Bavachalocone
by using compound 22 (100.00 mg, 0.19 mmol) as substrate to give
compound 1b (54.00 mg, 72%, purity: 98%), as yellow powder. 1H,
13C NMR and EIMS identical with literature data [9].
oil; 1H NMR (400 MHz, CDCl3)
d 7.62 (s, 2H), 7.58 (s, 1H), 7.52 (d,
J ¼ 8.7 Hz, 2H), 7.02 (d, J ¼ 8.7 Hz, 2H), 6.72 (s,1H), 5.50 (t, J ¼ 6.2 Hz,
1H), 5.31e5.24 (m, 1H), 5.24 (s, 2H), 5.13 (s,2H), 5.05 (m, 1H), 4.62
(d, J ¼ 6.7 Hz, 2H), 3.50 (s, 3H), 3.48 (s, 3H), 3.28 (d, J ¼ 7.3 Hz, 2H),
2.13e2.00 (m, 4H), 1.72 (m, 9H), 1.64 (s, 3H), 1.56 (s, 3H). 13C NMR
5.1.17. (E)-1-(2,4-dimethoxy-5-(3-methylbut-2-en-1-yl)phenyl)-3-
(4-methoxyphenyl)prop-2-en-1-one (39)
(100 MHz, CDCl3)
d 190.5, 159.1, 158.6, 158.2, 141.8, 141.1, 132.4,
The procedure is the same as the preparation of compound 37
by using compound 1c (100.00 mg, 0.19 mmol) as substrate to give
compound 39 (100.00 mg, 88%, purity: 98%), as yellow oil. 1H NMR
132.2,131.9,129.8,129.6,125.9,123.7,123.3,122.7,122.4,119.1,116.4,
99.5, 94.2, 66.0, 56.1, 39.5, 28.1, 26.3, 25.8, 25.6,17.8,17.7,16.8. HRMS
(ESI) m/z Calcd for C34H44O6H [MþH]þ 549.3216; found: 549.3138.
(CDCl3, 400 MHz):
d
1.69 (s, 3H), 1.79 (s, 3H), 3.40 (d, J ¼ 6.8 Hz 2H),
3.70 (s, 3H), 3.84 (s, 3H), 3.88 (s, 3H), 5.19 (t, J ¼ 6.8 Hz 1H), 6.72 (d,
5.1.22. (E)-1-(5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-2-(((E)-3,7-
dimethylocta-2,6-dien-1-yl)oxy)-4-(methoxymethoxy)phenyl)-3-
(4-(methoxymethoxy)phenyl)prop-2-en-1-one (12b)
J ¼ 8.4 Hz 1H), 6.91 (d, J ¼ 8.4 Hz, 2H), 7.41 (d, J ¼ 16 Hz, 1H), 7.58
(m,3H), 7.69 (d, J ¼ 15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 17.9,
22.8, 25.8, 55.4, 55.8, 63.1, 106.3, 114.4, 122.7, 123.9, 24.1, 126.3,
127.9, 129.6, 130.2, 131.6, 143.1, 158.9, 161.4, 161.4, 191.7; HRMS(ESI)
m/z Calcd for C23H26O4Na [MþNa]þ 389.1729; found: 389.1726;
To a stirred solution of compound 11b (480.00 mg, 1.00 mmol)
and NaH (52.00 mg, 1.30 mmol) in dry DMF (5 mL) was slowly
added Geranylbromide (282.00 mg, 1.30 mmol) at 0 ꢀC and stirred
for 2 h. The reaction mixture was monitored by TLC. After
completion of the reaction, the reaction mixture was diluted with
CH2Cl2 (20 mL). The organic layer was washed with H2O
(3 ꢂ 10 mL), dried over Mg2SO4 and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography to afford compound 12b (550.00 mg, 89%) as a colorless
5.1.18. (E)-1-(5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-2,4-
dimethoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (40)
The procedure is the same as the preparation of compound 39
by using compound 1b (100.00 mg, 0.19 mmol) as substrate to give
compound 40 (90.00 mg, 81%, purity: 95%), as yellow oil. 1H
oil; 1H NMR (400 MHz, CDCl3)
d
7.63 (d, J ¼ 3.3 Hz, 2H), 7.58 (d,
NMR(CDCl3, 400 MHz):
d 1.60 (s, 3H), 1.68 (s, 3H), 1.79 (s, 3H), 2.15
J ¼ 1.7 Hz, 2H), 7.53 (dd, J ¼ 9.0, 5.3 Hz, 1H), 7.06e6.95 (m, 2H), 6.73
(s, 1H), 5.51 (d, J ¼ 6.6 Hz, 1H), 5.29 (t, J ¼ 7.2 Hz, 1H), 5.25 (s, 2H),
5.20 (s, 2H), 5.07 (m, 2H), 4.62 (d, J ¼ 6.6 Hz, 2H), 3.49 (s, 3H), 3.48
(s, 3H),3.30 (d, J ¼ 7.2 Hz, 2H), 2.18e1.91 (m, 8H), 1.72 (m, 6H), 1.66
(m, 4H), 3.41 (d, J ¼ 6.8 Hz, 2H), 3.69 (s, 3H),3.84 (s, 3H), 3.88 (s, 3H),
5.18 (m, 2H), 6.72 (d, J ¼ 8.4 Hz, 1H), 6.91 (d, J ¼ 8.8 Hz, 2H), 7.41 (d,
J ¼ 15.6 Hz, 1H), 7.58 (m, 3H), 7.69 (d, J ¼ 16 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6):d 16.1, 17.7, 25.7, 26.7, 27.6, 39.8, 55.4, 55.6,
(m, 6H),1.60e1.52 (m, 6H). 13C NMR (100 MHz, CDCl3)
d 190.5,159.1,
56.2, 95.0, 114.3, 121.4, 122.2, 122.8, 124.3, 125.2, 128.3, 129.9, 131.3,
131.6, 131.9, 136.2, 141.8, 158.9, 161.2, 161.5, 190.8. HRMS (ESI) m/z
Calcd for C28H34O4Na [MþNa]þ 457.2355; found: 457.2355.
158.6, 158.1, 141.8, 141.1, 135.9, 132.2, 131.8, 131.4, 129.8, 129.6, 125.9,
124.3, 123.7, 123.4, 122.7, 122.3, 119.1, 116.4, 99.5, 94.2, 66.0, 56.1,
39.8, 39.5, 32.0, 28.0, 26.7, 26.6, 26.3, 25.7, 25.6, 23.5, 17.7, 16.8, 16.2.
HRMS (ESI) m/z Calcd for C39H53O6 [MþH]þ 617.3842; found:.
617.3852.
5.1.19. (E)-1-(2-hydroxy-4-(methoxymethoxy)-5-(3-methylbut-2-
en-1-yl)phenyl)-3-(4-(methoxymethoxy)phenyl)prop-2-en-1-one
(11a)
5.1.23. (E)-1-(4-(methoxymethoxy)-5-(3-methylbut-2-en-1-yl)-2-
((3-methylbut-2-en-1-yl)oxy)phenyl)-3-(4-(methoxymethoxy)
phenyl)prop-2-en-1-one (12a)
The procedure is the same as the preparation of compound 12d
by using compound 11a (480 mg, 0.19 mmol) as substrate to give
compound 12a (500 mg, 89%) as a yellow oil. 1H NMR and EIMS
identical to literature data [23].
To a solution of compound 6 (100.00 mg, 0.22 mmol) in MeOH
(2 mL), was added 1N aqueous hydrochloric acid (1 mL) at 0 ꢀC. The
reaction was cooled to r.t and MeOH was removed in vacuo. Ethyl
acetate (10 mL) was then added and the layers were separated. The
aqueous layer was extracted with Ethyl acetate (2x10 mL) and the
combined organic layers were dried MgSO4 concentrated in vacuo
to give a residue which was purified by flash chromatography on
silica gel(eluant:n-hexane/EtOAc ¼ 15:1) to afford Compound 11a
(75.00 mg, 83%) as a yellow solid, 1H NMR and EIMS identical to
literature data [9].
5.1.24. (E)-1-(5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-4-
(methoxymethoxy)-2-((3-methylbut-2-en-1-yl)oxy)phenyl)-3-(4-
(methoxymethoxy)phenyl)prop-2-en-1-one (12c)
The procedure is the same as the preparation of compound 12b
by using compound 11b (480.00 mg, 0.190 mmol) as substrate to
give compound 12c (500.00 mg, 91%) as a yellow oil.1H NMR
5.1.20. (E)-1-(5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-2-hydroxy-4-
(methoxymethoxy)phenyl)-3-(4-(methoxymethoxy)phenyl)prop-2-
en-1-one (11b)
The procedure is the same as the preparation of Compound 11a
by using compound 7 (100.00 mg, 0.22 mmol) as substrate to give
compound 11b (75.00 mg, 82%), as yellow solid, 1H NMR and EIMS
identical to literature data [9].
(400 MHz, CDCl3)
d
7.63 (d, J ¼ 7.7 Hz, 2H), 7.59 (s, 1H), 7.52 (d,
J ¼ 8.7 Hz, 2H), 7.03 (d, J ¼ 8.7 Hz, 2H), 6.73 (s, 1H), 5.56e5.45 (m,
1H), 5.36e5.27 (m, 1H), 5.26 (s, 2H), 5.21 (s, 2H), 5.18e5.13 (m, 1H),
5.09 (m, 1H), 4.59 (d, J ¼ 6.8 Hz, 2H), 3.49 (s, 3H), 3.48 (s, 3H), 3.30
(d, J ¼ 7.2 Hz, 2H), 2.06 (m, 4H), 1.77 (s, 3H), 1.73 (m, 6H), 1.66 (s,

446
H.-M. Wang et al. / European Journal of Medicinal Chemistry 92 (2015) 439e448
3H), 1.58 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
190.42, 159.1, 158.6,
28.5, 26.7, 25.8, 25.6, 23.4, 18.0, 17.7, 16.3. HRMS (ESI) m/z Calcd for
C
158.2, 141.1, 138.6, 135.9, 132.2, 129.8, 126.1, 124.3, 123.4, 122.3,
119.4, 116.4, 94.3, 94.3, 65.9, 56.1, 39.8, 28.03, 26.72, 25.8, 25.7, 18.3,
17.7, 16.2. HRMS (ESI) m/z Calcd for C34H44O6H [MþH]þ 549.3216;
found:549.3222.
34H45O6 [MþH]þ 549.3216; found: 549.3211.
5.1.28. (E)-1-(5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-3-((Z)-3,7-
dimethylocta-2,6-dien-1-yl)-2,4-dihydroxyphenyl)-3-(4-
hydroxyphenyl)prop-2-en-1-one (2b)
5.1.25. (E)-1-(2-hydroxy-4-(methoxymethoxy)-3,5-bis(3-
methylbut-2-en-1-yl)phenyl)-3-(4-(methoxymethoxy)phenyl)prop-
2-en-1-one (13a)
To a solution of compound 13b (60.00 mg, 0.10 mmol) in THF
(6 mL), was added 98% H2SO4 (0.5 mL), isopropanol (1 ml) at 0 ꢀC,
then stirred for 2 h at room temperature, After completion of re-
action, the reaction mixture was concentrated under vacuum to get
a reside which was purified by silica gel column chromatography to
afford compound 2b (45.00 mg, 79%, purity: 100%) as a yellow
To a stirred solution of compound 12a (3.00 g, 7.27 mmol) in dry
toluene (15 mL) was slowly added 100e200 mesh Forisil® at room
temperature, then the reaction mixture was string at 140 ꢀC for 4 h,
After completion of reaction, the reaction mixture was concen-
trated under vacuum to get a reside which was purified by silica gel
column chromategraphy to afford compound 13a (60.00 mg, 2%) as
powder. 1H NMR (400 MHz, CDCl3)
d 13.71 (s, 1H), 7.83 (d,
J ¼ 15.4 Hz,1H), 7.55 (d, J ¼ 8.9 Hz, 3H), 7.46 (d, J ¼ 15.4 Hz,1H), 6.88
(dd, J ¼ 8.5, 5.2 Hz, 2H), 6.28 (s, 1H), 5.29 (d, J ¼ 5.7 Hz, 3H), 5.11 (dt,
J ¼ 23.7, 6.7 Hz, 2H), 3.48 (d, J ¼ 7.1 Hz, 2H), 3.33 (d, J ¼ 7.1 Hz, 2H),
2.12 (m, 8H), 1.83 (s, 3H), 1.81e1.74 (m, 3H), 1.68 (s, 6H), 1.59 (s, 6H).
a yellow oil. 1H NMR (400 MHz, CDCl3)
d 13.28 (s, 1H), 7.86 (d,
J ¼ 15.5 Hz, 1H), 7.64e7.55 (m, 3H), 7.47 (d, J ¼ 15.4 Hz, 1H), 7.09 (d,
J ¼ 8.7 Hz, 2H), 5.32 (t, J ¼ 7.0 Hz, 1H), 5.28e5.24 (m, 1H), 5.23 (s,
2H), 5.02 (s, 2H), 3.61 (s, 3H), 3.50 (s, 3H), 3.42 (d, J ¼ 6.4 Hz, 2H),
3.38 (d, J ¼ 7.0 Hz,2H), 1.79 (s, 6H), 1.75 (s, 3H), 1.70 (s, 3H). 13C NMR
13C NMR (100 MHz, CDCl3)
d 192.1, 162.4, 160.3, 157.9, 143.67, 138.9,
138.4, 131.9, 130.5, 128.3, 127.9, 123.9, 121.8, 121.4, 119.0, 118.3, 116.0,
114.3, 113.6, 77.3, 77.0, 76.7, 39.8, 39.8, 32.1, 28.8, 26.9, 26.4, 25.7,
23.5, 21.9, 17.7,16.3. HRMS (ESI) m/z Calcd for C35H44O4Na [MþNa]þ
551.3137; found:. 551.3148.
(101 MHz, CDCl3)
d 192.9, 162.2, 160.5, 159.4, 144.3133.1, 128.6,
128.1, 125.6, 123.7, 122.8, 122.4, 118.7, 116.8, 116.6, 99.9, 94.2, 57.7,
56.2, 28.5, 25.8, 25.7, 23.4, 18.0. HRMS (ESI) m/z Calcd for C29H37O6
[MþH]þ 481.2590; found: 481.2599.
5.1.29. (E)-1-(5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-2-hydroxy-4-
(methoxymethoxy)-3-(3-methylbut-2-en-1-yl)phenyl)-3-(4-
(methoxymethoxy)phenyl)prop-2en1-one (2c)
The procedure is the same as the preparation of compound 13b
by using compound 12c (300.00 mg, 0.55 mmol) as substrate to
give compound 13c and no purification to the next step. The pro-
cedure is the same as the preparation of compound 2b by using
compound 13c (60.00 mg, 0.11 mmol) as substrate to give com-
pound 2c (43.00 mg, 85%, purity: 98%) as a yellow powder. 1H NMR
5.1.26. (E)-1-(5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-3-((Z)-3,7-
dimethylocta-2,6-dien-1-yl)-2-hydroxy-4-(methoxymethoxy)
phenyl)-3-(4-(methoxymethoxy)phenyl)prop-2-en-1-one (13b)
To a stirred solution of compound 12b (617.00 mg, 1 mmol) in
dry toluene (15 mL) was slowly added 100e200 mesh Forisil® at
room temperature, then the reaction mixture was string at 140 ꢀC
for 4 h, After completion of reaction, the reaction mixture was
concentrated under vaccum to get a reside which was purified by
silica gel column chromategraphy to afford compound 13b
(400 MHz, CDCl3)
d
13.68 (d, J ¼ 3.8 Hz, 1H), 7.83 (d, J ¼ 15.4 Hz, 1H),
7.55 (dd, J ¼ 8.5, 5.5 Hz, 3H), 7.45 (d, J ¼ 15.4 Hz, 1H), 6.96e6.78 (m,
2H), 6.23 (d, J ¼ 4.1 Hz, 1H), 5.30 (dd, J ¼ 19.1, 11.9 Hz, 3H), 5.13 (dd,
J ¼ 15.6, 7.5 Hz, 1H), 3.46 (d, J ¼ 7.1 Hz, 2H), 3.33 (d, J ¼ 7.1 Hz, 2H),
2.28e2.04 (m, 4H), 1.84 (s, 3H), 1.78 (dd, J ¼ 12.4, 5.2 Hz, 6), 1.68 (s,
(60.00 mg, 9%) as a yellow oil; 1H NMR (400 MHz, CDCl3)
d 13.28 (d,
J ¼ 10.8 Hz, 1H), 7.86 (d, J ¼ 15.4 Hz, 1H), 7.68e7.54 (m, 3H), 7.47 (d,
J ¼ 15.4 Hz, 1H), 7.08 (dd, J ¼ 8.6, 6.8 Hz, 2H), 5.35 (d, J ¼ 6.1 Hz, 1H),
5.25 (s, 1H), 5.22 (t, J ¼ 4.9 Hz, 3H), 5.15 (t, J ¼ 6.7 Hz, 1H), 5.06 (t,
J ¼ 6.8 Hz, 1H), 5.02 (s, 2H), 3.60 (d, J ¼ 2.3 Hz, 3H), 3.50 (d,
J ¼ 0.8 Hz, 4H), 3.48e3.36 (m, 4H), 2.23e1.91 (m, 8H), 1.79 (s, 3H),
1.75 (s,3H), 1.66 (m, 6H), 1.58 (m, 6H). 13C NMR (101 MHz, CDCl3)
3H), 1.60 (s, 6). 13C NMR (100 Hz, CDCl3)
d 192.1, 162.5, 162.4, 160.1,
157.9, 143.7, 138.7, 135.1, 134.9, 132.0, 130.5, 128.5, 128.3, 127.9,
123.8, 122.6, 121.8, 121.5, 121.5, 118.9, 118.7, 118.3, 116.0, 114.6, 113.7,
77.3, 77.0, 76.7, 39.8, 32.1, 29.1, 28.9, 26.8, 26.5, 25.9, 25.8, 25.7, 23.5,
22.0, 18.0, 17.7, 16.3. HRMS (ESI) m/z Calcd for C30H37O4 [MþH]þ
461.2692; found:. 461.2704.
d
192.9, 162.3, 160.6, 159.4, 144.4, 144.3, 137.2, 135.6, 131.9, 131.3,
130.3, 128.6, 127.9, 125.4, 124.3, 124.1, 124.0, 123.7, 123.3, 122.6,
122.4, 118.7, 118.6, 116.7, 116.6, 99.9, 94.2, 57.7, 56.2, 39.8, 39.7, 28.2,
27.2, 26.7, 25.7, 23.4, 17.7, 16.3. HRMS (ESI) m/z Calcd for C39H53O6
[MþH]þ 617.3842; found:617.3852.
5.1.30. Medicagenin (2a)
To a solution of compound 13a (60.00 mg, 0.10 mmol) in THF
(6 mL), was added 98% H2SO4 (0.5 mL), isopropanol (1 ml) at 0 ꢀC,
then stirred for 2 h at room temperature, After completion of re-
action, the reaction mixture was concentrated under vacuum to get
a reside which was purified by silica gel column chromatography to
afford compound 2a (40.00 mg, 82%, purity: 97%) as a yellow
powder. 1H and 13C NMR identical with literature data [6]; HRMS
(ESI) m/z Calcd for C25H28O4 [MþH]þ 415.1885; found:. 415.1883.
5.1.27. (E)-1-(3-((Z)-3,7-dimethylocta-2,6-dien-1-yl)-2-hydroxy-4-
(methoxymethoxy)-5-(3-methylbut-2-en-1-yl)phenyl)-3-(4-
(methoxymethoxy)phenyl)prop-2-en-1-one (13d)
To a stirred solution of compound 12d (548.00 mg, 1.00 mmol)
in dry toluene (15 mL) was slowly added 100e200 mesh Forisil®
(500.00 mg) at room temperature, then the reaction mixture was
string at 90 ꢀC for 4 h, After completion of reaction, the reaction
mixture was concentrated under vacuum to get a reside which was
purified by silica gel column chromatography to afford compound
13d (90.00 mg, 17%) as a yellow oil; 1H NMR (400 MHz, CDCl3)
5.1.31. (E)-1-(3-((Z)-3,7-dimethylocta-2,6-dien-1-yl)-2,4-
dihydroxy-5-(3-methylbut-2-en-1-yl)phenyl)-3-(4-hydroxyphenyl)
prop-2-en-1-one (2d)
d
13.27 (s, 1H), 7.86 (d, J ¼ 15.4 Hz, 2H), 7.65e7.53 (m, 3H), 7.47 (d,
The procedure is the same as the preparation of Medicagenin 2
by using compound 13d (60.00 mg, 0.11 mmol) as substrate to give
compound 2d (43.00 mg, 85%, purity: 98%) as a yellow powder. 1H
J ¼ 15.4 Hz, 2H), 7.09 (d, J ¼ 8.7 Hz, 2H), 5.32 (dd, J ¼ 7.7, 6.4 Hz, 1H),
5.26 (d, J ¼ 4.9 Hz, 1H), 5.23 (s, 2H), 5.06 (t, J ¼ 6.8 Hz, 1H), 5.02 (s,
2H), 3.61 (s, 3H), 3.49 (s, 3H), 3.43 (d, J ¼ 6.1 Hz, 2H), 3.38 (d,
J ¼ 6.8 Hz, 2H), 2.29e1.88 (4, 1H), 1.79 (m, 3H), 1.75 (s, 3H), 1.64 (s,
NMR (400 MHz, CDCl3)
d
13.71 (s, 1H), 7.83 (d, J ¼ 15.4 Hz, 1H),
7.64e7.51 (m, 3H), 7.46 (d, J ¼ 15.4 Hz, 1H), 6.89 (d, J ¼ 8.6 Hz, 2H),
5.30 (m, 2H), 5.06 (d, J ¼ 6.6 Hz, 1H), 3.48 (d, J ¼ 7.1 Hz, 2H), 3.32 (d,
J ¼ 7.2 Hz, 2H), 2.21e2.02 (m, 4H), 1.83 (s, 3H), 1.79 (m, 6H), 1.68 (s,
3H), 1.57 (m, 6H). 13C NMR (100 MHz, CDCl3)
d 192.9, 162.2, 160.6,
159.4, 144.3, 135.6, 133.1, 131.3, 130.2, 128.6, 128.1, 125.6, 124.3,
123.8, 122.9, 122.4, 118.7, 116.8, 116.6, 99.9, 94.2, 57.7, 56.2, 39.7,
3H), 1.60 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 192.1, 162.4, 160.3,

H.-M. Wang et al. / European Journal of Medicinal Chemistry 92 (2015) 439e448
447
157.9, 143.7, 139.1, 134.3, 131.9, 130.5, 128.4, 127.9, 123.8, 122.1, 121.3,
119.1, 118.3, 116.0, 114.2, 113.6, 28.9, 26.4, 25.8, 25.7, 21.9, 17.9, 17.7,
16.3. HRMS (ESI) m/z Calcd for C30H37O4 [MþH]þ 461.2692; found:.
461.2705.
(s, 3H), 3.76 (s, 3H), 3.68 (s, 3H), 3.43 (d, J ¼ 6.4 Hz, 2H), 3.36 (d,
J ¼ 6.8 Hz, 2H), 2.01e2.13 (m, 8H),1.80 (s, 3H), 1.74 (s, 3H),1.65e1.73
(m, 6H),1.57e1.63 (m, 6H). 13C NMR (101 MHz, CDCl3)
d 192.8,161.5,
160.0,157.1,143.6,132.3,131.6,130.8,130.3,129.6,129.3,129.1,127.8,
124.1, 123.4, 122.5, 114.4, 77.3, 77.0, 76.7, 63.1, 61.3, 55.4, 39.7, 27.9,
26.7, 25.8, 25.7, 23.6, 17.7, 16.3. HRMS (ESI) m/z Calcd for
5.1.32. (E)-1-(2,4-dimethoxy-3,5-bis(3-methylbut-2-en-1-yl)
phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (33)
C
38H50O4Na [MþNa]þ 593.3607; found:593.3607.
To a stirred solution of compound 2a (100.00 mg, 1.00 mmol)
and NaH (41.00 mg, 4.50 mmol) in dry DMF (5 mL) was slowly
added CH3I (126.00 mg, 1.30 mmol) at 0 ꢀC and stirred for 2 h. The
reaction mixture was monitored by TLC. After completion of the
reaction, the reaction mixture was diluted with CH2Cl2 (20 mL). The
organic layer was washed with H2O (3 ꢂ 10 mL), dried over Mg2SO4
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography to afford compound 33
(100.00 mg, 89%, purity: 98%) as a colorless oil; 1H NMR (400 MHz,
5.2. Biology evaluation
5.2.1. Antitumor activity
Human leukemia K562 cells (or human umbilical vein endo-
thelial cells (HUVEC)) were dispensed into a 96 well microplate at
100
treated with the compounds at various concentrations (0, 0.01, 0.1,
1, 10, 100 M). After 48 h of treatment, 20 L of 5 mg/mL MTT so-
lution was added to each well, and incubated for another 4 h. The
cells in each well were then solubilized with DMSO (100 L for each
mL per well, and incubated for 2 h (or 24 h for HUVEC), and then
m
m
CDCl3)
d
, 7.67 (d, J ¼ 16 Hz,1H), 7.57 (d, J ¼ 8.8 Hz, 2H), 7.31e7.51 (m,
2H), 6.92 (d, J ¼ 8.8 Hz, 2H), 5.19e5.29 (m, 2H), 3.84 (s, 3H), 3.76 (s,
m
3H), 3.67 (s, 3H), 3.41 (d, J ¼ 6.8 Hz, 2H), 3.31 (d, J ¼ 6.8 Hz, 2H), 1.80
well) and the optical density (OD) was recorded at 570 nm (or
490 nm for HUVEC). DMSO was used as positive control and the IC50
values were derived from the mean OD values of the triplicate tests
versus using Graph Pad Prism 5.0.
(s, 3H), 1.71e1.73 (m, 9H). 13C NMR (101 MHz, CDCl3)
d 192.8, 161.6,
159.9,157.1,143.6,132.3,131.6,130.8,130.3,129.6,129.3,129.1,127.8,
124.1, 123.4, 122.5, 114.4, 77.3, 77.0, 76.7, 63.1, 61.3, 55.4, 28.1, 25.8,
25.7, 23.7, 18.0, 17.9. HRMS (ESI) m/z Calcd for C28H34O4Na [MþH]þ
457.2355; found:. 457.2362.
5.2.2. Flow cytometric analysis of apoptosis
Apoptotic cells were assayed by using the Annexin-V-FITC
Apoptosis Detection Kit (BD Biosciences, USA) according to the
manufacturer's instruction. In brief, K562 cells were treated with
5.1.33. (E)-1-(3-((Z)-3,7-dimethylocta-2,6-dien-1-yl)-2,4-
dimethoxy-5-(3-methylbut-2-en-1-yl)phenyl)-3-(4-
methoxyphenyl)prop-2-en-1-one (34)
DMSO or chalcone derivatives (30 mM) for 48 h. Cells were then
The procedure is the same as the preparation of compound 33
by using compound 2d (100.00 mg, 0.22 mmol) as substrate to give
compound 34 (92.00 mg, 85%, purity: 98%) as a yellow oil. 1H NMR
harvested, washed twice with ice-cold PBS and resuspended in
1 ꢂ Binding buffer to reach a final concentration of 1 ꢂ106 cells/ml.
Cells were stained by adding 5 mL of Annexin-V-FITC and 5 mL of PI
(50 mg/mL), sit for 15 min at room temperature in the dark and
analyzed by flow cytometry.
(400 MHz, CDCl3)
d, 7.67 (d, J ¼ 16 Hz, 1H), 7.56 (d, J ¼ 8.8 Hz, 2H),
7.31e7.51 (m, 2H), 6.92 (d, J ¼ 8.8 Hz, 2H), 5.20e5.29 (m, 2H),
5.04e5.08 (m, 2H), 3.85 (s, 3H), 3.76 (s, 3H), 3.68 (s, 3H), 3.43 (d,
J ¼ 6.8 Hz, 2H), 3.35 (d, J ¼ 7.2 Hz, 2H), 1.99e2.10 (m, 4H), 1.80 (s,
3H), 1.73 (m, 6H), 1.64 (s, 3H), 1.58 (s, 3H). 13C NMR (101 MHz,
Acknowledgments
CDCl3)
d 192.8, 161.6, 160.0, 157.2, 143.6, 132.3, 131.6, 130.8, 130.3,
The authors sincerely thank the financial support from National
Natural Science Foundation of China (21202118, 31301142), Inter-
national Science & Technology Cooperation Program of China
(2013DFA31160) and the Ministry of Education Changjiang Scholars
and Innovative Research Team Development Plan (IRT1166).
129.6, 129.3, 129.1, 127.8, 124.1, 123.4, 122.5, 114.4, 77.3, 77.0, 76.7,
63.1, 61.3, 55.4, 39.7, 28.1, 26.6, 25.8, 25.7, 23.6, 17.9, 17.7, 16.3. HRMS
(ESI) m/z Calcd for C33H42O4Na [MþH]þ 525.2981; found:525.2953.
5.1.34. (E)-1-(5-((Z)-3,7-dimethylocta-2,6-dien-1-yl)-2,4-
dimethoxy-3-(3-methylbut-2-en-1-yl)phenyl)-3-(4-
methoxyphenyl)prop-2-en-1-one (35)
Appendix A. Supplementary data
The procedure is the same as the preparation of compound 33
by using compound 2c (100.00 mg, 0.22 mmol) as substrate to give
compound 35 (92.00 mg, 85%, purity: 98%) as a yellow oil. 1H NMR
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.ejmech.2015.01.
007. These data include MOL files and InChiKeys of the most
important compounds described in this article.
(400 MHz, CDCl3)
d
, 7.66 (d, J ¼ 16 Hz, 1H), 7.56 (d, J ¼ 8.8 Hz, 2H),
7.30e7.34 (m, 2H), 6.91 (d, J ¼ 8.8 Hz, 2H), 5.06e5.31 (m, 3H), 3.85
(s, 3H), 3.76 (s, 3H), 3.68 (s, 3H), 3.41 (d, J ¼ 6.4 Hz, 2H), 3.36 (d,
J ¼ 6.8 Hz, 2H), 2.02e2.13 (m, 4H), 1.80 (s, 3H), 1.73 (m, 6H), 1.65 (s,
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