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Chinese Chemical Letters xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Chinese Chemical Letters

journal homepage: www.elsevier.com/locate/cclet

1
2 Original article

3 New phenolic compounds from the leaves of Artocarpus heterophyllus

4 Q1 Xiao-Ling Wang a, Xia-Xia Di b, Tao Shen b, Shu-Qi Wang b, Xiao-Ning Wang b,*
5 a
The Second Hospital of Shandong University, Jinan 250033, China
6 b
Department of Natural Product Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong
7 University, Jinan 250012, China

A R T I C L E I N F O A B S T R A C T

Article history: One new 2-arylbenzofuran derivative, artocarstilbene B (1), one new benzaldehyde derivative, (E)-3,5-
Received 3 May 2016 dihydroxy-4-(3-methylbut-1-enyl)benzaldehyde (2), as well as 18 known compounds (3–20) were
Received in revised form 26 May 2016 obtained from the leaves of Artocarpus heterophyllus. Their structures were elucidated on the basis of
Accepted 12 June 2016
extensive spectroscopic techniques including 2D NMR and HR-ESIMS. Many compounds exhibited
Available online xxx
moderate to weak inhibitory activity against the proliferation of the PC-3, NCI-H460, and A549 cancer
cell lines.
Keywords:
ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Artocarpus heterophyllus
2-Arylbenzofuran
Published by Elsevier B.V. All rights reserved.
Artocarstilbene B
(E)-3,5-Dihydroxy-4-(3-methylbut-1-
enyl)benzaldehyde
Cytotoxicity

8
9 1. Introduction and one 2-arylbenzofuran derivative were isolated from the twigs 31
of A. heterophyllus, among which some showed moderate 32
10 Artocarpus, belonging to the mulberry family Moraceae, is a inhibitory activity on the proliferation of the PC-3 and H460 cell 33
11 genus of approximately 60 trees and shrubs distributed in the lines [6]. In the course of our ongoing study, the 95% EtOH extract 34
12 Southeast Asian and Pacific regions. A. heterophyllus Lam, popularly of the leaves of A. heterophyllus was investigated and one new 2- 35
13 known as jackfruit, is one of the important trees in the home arylbenzofuran derivative, artocarstilbene B (1), one new benzal- 36
14 gardens of tropical India, Bangladesh, Nepal, Sri Lanka, Vietnam, dehyde derivative, (E)-3,5-dihydroxy-4-(3-methylbut-1-enyl)ben- 37
15 Thailand, Malaysia, Indonesia, Philippines, Africa, and Brazil [1]. It zaldehyde (2), as well as 18 known ones (3–20) (Fig. 1) were 38
16 is also an important fruit in southern China, distributed and obtained. Their structures were elucidated on the basis of 39
17 cultivated in Hainan, Guangdong, Guangxi, and Yunnan provinces extensive spectroscopic techniques including 1D and 2D NMR 40
18 [2]. Different parts of this species have been used for medicinal and HR-ESIMS. Herein, we report the structure elucidation as well 41
19 purposes, such as alleviating asthma and fever (the roots), relieving as the anti-proliferative activity of these compounds to the PC-3 42
20 biliousness and diarrhea (the seeds), acting as a sedative for (human prostate cancer), NCI-H460 (human lung cancer), and 43
21 convulsion (the wood), stimulating lactation in women and A549 (human lung adenocarcinoma epithelial) cells. 44
22 animals and acting as an antisyphilitic and vermifuge in humans
23 (the leaves), and relieving ulcers and wounds (the leaf ash)
2. Experimental 45
24 [3,4]. Wood and bark of this plant are rich sources of prenylated
25 flavonoids, stilbenoids, triterpenoids, and steroids [1]. Some of
2.1. General 46
26 these compounds have exhibited interesting biological activities,
27 such as cytotoxicity [5,6], antioxidative activity [7], anti-inflam-
MTT was purchased from Sigma Chemical Co. (St. Louis, MO, 47
28 matory activity [8], antimalarial activity [9], inhibition of tyrosi-
USA). Doxorubicin was purchased from Shenzhen Main Luck 48
29 nase and melanin biosynthesis [10,11], and inhibition of
Pharmaceuticals Inc. (Shenzhen, PR China). Optical rotations were 49
30 5a-reductase [12]. In our previous study, 10 chalcones, 8 flavones,
measured on a Perkin-Elmer 241 MC polarimeter. IR spectra were 50
recorded on a Nicolet iN 10 Micro FTIR spectrometer by 51
transmission mode. UV spectra were obtained on a Shimadzu 52
* Corresponding author. UV-2550 spectrophotometer. NMR spectra were measured on a 53
E-mail address: wangxn@sdu.edu.cn (X.-N. Wang). Bruker Avance DRX-600 spectrometer operating at 600 (1H) and 54

http://dx.doi.org/10.1016/j.cclet.2016.06.024
1001-8417/ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: X.-L. Wang, et al., New phenolic compounds from the leaves of Artocarpus heterophyllus, Chin. Chem.
Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.06.024
 G Model
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2 X.-L. Wang et al. / Chinese Chemical Letters xxx (2016) xxx–xxx

5' 4' by CC of C18 reversed-phase silica gel (30%!100% MeOH) to obtain 103
3'
4 (9.5 mg) and 8 (3.0 mg). Fr. 7 (10.3 g) was subjected to CC of MCI 104
HO 4'' 2'
1' (30%!100% MeOH) to obtain seven subfractions (Fr. 7.1–Fr. 7.7). 105
5'' Fr. 7.1 (0.9 g) was further purified by CC of Sephadex LH-20 106
O 3'' HO 3
4 OH (MeOH) and HPLC (MeOH-H2O, 78:22, 1.8 mL/min) to yield 15 107
7 2' 3'
HO 6 7a O 2'' 5 (20.9 mg, tR = 13.61 min). Fr. 7.4 was separated by Sephadex LH-20 108
2 1'
6 CC (MeOH) to obtain the major part, which was then separated by 109
4' 1'' 2
5 1 HPLC (MeOH-H2O, 78:22, 1.8 mL/min) to obtain 3 (7.6 mg, 110
3a 5'
3 6'
4
OH C tR = 15.90 min) and 5 (6.3 mg, tR = 21.82 min). Fr. 8 (6.1 g) was 111
H 7 O subjected to CC of MCI (30%!100% MeOH) to obtain six 112
1 2 subfractions (Fr. 8.1–Fr. 8.6). Fr. 8.1 (0.7 g) was separated by CC 113
of Sephadex LH-20 (MeOH) and CC of C18 reversed-phase silica gel 114
Fig. 1. Structure of compounds 1 and 2. (30%!100% MeOH) to obtain 9 (4.3 mg) and 11 (6.2 mg). Fr. 8.2 115
(0.9 g) was separated by preparative HPLC (MeOH-H2O, 75:25, 116
55 150 (13C) MHz with TMS as internal standard. HR-ESIMS were 1.8 mL/min) to yield 17 (6.0 mg, tR = 19.50 min), 1 (4.0 mg, 117
56 carried out on a LTQ-Orbitrap XL mass spectrometer. HPLC was tR = 20.85 min), 10 (8.1 mg, tR = 22.02 min), and 6 (5.2 mg, 118
57 performed on an Agilent 1260 HPLC system equipped with a tR = 24.02 min). Fr. 9 (2.3 g) was separated by CC of MCI 119
58 G1311C isopump, a G1315D DAD detector, and a YMC-Pack ODS-A (30%!100% MeOH) to obtain four subfractions (Fr. 9.1–Fr. 9.4). 120
59 column (10 mm  250 mm, 5 mm). All solvents used were of Fr. 9.2 (0.9 g) was separated by CC of C18 reversed-phase silica gel 121
60 analytical grade (Laiyang Chemical Reagent Co., Ltd., Shandong, PR (30%!100% MeOH) to obtain 18 (8.9 mg). Fr. 9.3 was crystallized 122
61 China). Silica gel (200–300 mesh; Qingdao Haiyang Chemical Co., to yield 20 (5.0 mg). 123
62 Ltd., Qingdao, People’s Republic of China), C18 reversed-phase silica Artocarstilbene B (1). Yellowish oil. IR (KBr)nmax: 3265, 2928, 124
63 gel (YMC ODS-A gel, YMC Co., Ltd.), MCI-gel (CHP20P, 75–150 mm, 1617, 1564, 1489, 1426, 1365, 1148, 971, 823 cm1. UV (MeOH) 125
64 Mitsubishi Chemical Industries Ltd.), and Sephadex LH-20 lmax (log e): 226 (4.03) nm. 1H NMR and 13C NMR data, see Table 1. 126
65 (Pharmacia Biotek, Denmark) were used for column chromatogra- ()-HR-ESIMS: m/z 323.0917 [MH] (Calcd. for C19H15O5, 127
66 phy (CC). Thin layer chromatography (TLC) was carried out with 323.0919). 128
67 high-performance TLC plates precoated with silica gel GF254 (E)-3,5-Dihydroxy-4-(3-methylbut-1-enyl)benzaldehyde (2). 129
68 (Qingdao Haiyang Chemical Co., Ltd.). Spots of TLC were observed Yellowish oil. IR (KBr) nmax: 3298, 2960, 2929, 1684, 1514, 130
69 under UV or visualized by spraying with H2SO4-EtOH (1:9) 1437, 1391, 1338, 1206, 1042, 842 cm1. UV (MeOH) lmax (log e): 131
70 followed by heating. 203 (3.77) nm. 1H NMR and 13C NMR data, see Table 1. ()-HR- 132
ESIMS: m/z 205.0869 [MH] (Calcd. for C12H13O3, 205.0865). 133
71 2.2. Plant material
2.4. Cell lines and cell culture 134
72 The leaves of A. heterophyllus were collected from Mengla
73 County, Yunnan Province, China, in July 2009. The plant material PC-3 cells (ATCC CRL-1435 human prostate adenocarcinoma), 135
74 was identified by Dr. Tao Shen, Shandong University. A voucher NCI-H460 cells (ATCC HTB 177 human lung carcinoma), and A549 136
75 specimen (AH02-2009-07) was deposited at the Department of cells (ATCC CCL-185 human lung adenocarcinoma epithelial) were 137
76 Natural Products Chemistry, School of Pharmaceutical Sciences, cultured in RPMI-1640 medium (HyClone, Thermo Fisher Scientific 138
77 Shandong University. Inc., Waltham, MA, USA). The medium was supplemented with 10% 139
fetal bovine serum (FBS) (Gibco, Invitrogen, Carlsbad, CA, USA), 140
78 2.3. Extraction and isolation 100 mg/mL penicillin and 100 mg/mL streptomycin. Cells were 141
cultured in a humidified atmosphere of 5% CO2 at 37 8C. 142
79 The leaves of A. heterophyllus (5.0 kg), air-dried and powdered,
80 were percolated with 95% EtOH (3 25 L, each for one week) at 2.5. Cytotoxicity assay 143
81 room temperature. The combined extracts were concentrated
82 under reduced pressure to afford a dark gum (123.8 g), which was The tetrazolium-based colorometric assay (MTT assay) was 144
83 suspended in warm water and partitioned successively with used to determine cell viability. The cancer cells were all cultured 145
84 petroleum ether (4 1.2 L) and EtOAc (4 1.2 L). The EtOAc soluble under standard culture conditions. The test compounds (1–20) or 146
85 part (57.3 g) was subjected to CC of silica gel eluted with petroleum vehicle control (dimethyl sulfoxide, DMSO) were added to 147
86 ether-EtOAc (20:1!1:2) to yield 12 fractions (Fr. 1–Fr. 12). Fr. 4 appropriate wells and the cells were incubated for 72 h. Then 148
87 (3.2 g) was crystallized to yield 19 (150.1 mg). Fr. 5 (7.7 g) was MTT solution was added into the assay plates (final concentration, 149
88 subjected to CC of MCI (30%!100% MeOH) to obtain five 0.5 mg/mL). After shaking for 10 s, plates were returned to 150
89 subfractions (Fr. 5.1–Fr. 5.5). Fr. 5.2 (820.0 mg) was further incubator and kept for 4 h. The supernatants were removed 151
90 separated by CC of Sephadex LH-20 (MeOH) and preparative HPLC carefully, followed by the addition of 100 mL of DMSO to each well 152
91 (MeOH-H2O, 88:12, 1.8 mL/min) to afford 16 (9.5 mg, to dissolve the precipitate. Then, the absorbance was measured at 153
92 tR = 10.61 min), 7 (9.0 mg, tR = 12.31 min), and 2 (1.2 mg, 570 nm with a Model 680 microplate reader (Bio-Rad, Hercules, 154
93 tR = 15.02 min). Fr. 6 (6.3 g) was subjected to CC of MCI CA, USA). The percent viability was expressed as absorbance in the 155
94 (30%!100% MeOH) to obtain six subfractions (Fr. 6.1–Fr. 6.6). presence of test compound as a percentage of that in the vehicle 156
95 Fr. 6.2 (1.1 g) was further separated by CC of Sephadex LH-20 control. Doxorubicin and DMSO were used as positive and negative 157
96 (MeOH) and preparative HPLC (MeOH-H2O, 80:20, 1.8 mL/min) to controls. 158
97 afford 12 (3.0 mg, tR = 8.06 min) and 14 (20.9 mg, tR = 10.02 min).
98 Fr. 6.3 (0.9 g) was first separated by CC of silica gel (petroleum 3. Results and discussion 159
99 ether-acetone, 10:1) to obtain the major part, which was purified
100 by CC of Sephadex LH-20 (MeOH) to afford 13 (1.6 mg). Fr. 6.6 Compound 1 was obtained as a yellowish oil. The high- 160
101 (1.3 g) was first separated by CC of silica gel (petroleum ether- resolution ESI-MS showed the pseudo molecular ion [MH] peak 161
102 acetone, 10:1) to obtain the major part, which was then separated at m/z 323.0917, corresponding to the molecular formula C19H16O5 162

Please cite this article in press as: X.-L. Wang, et al., New phenolic compounds from the leaves of Artocarpus heterophyllus, Chin. Chem.
Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.06.024
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X.-L. Wang et al. / Chinese Chemical Letters xxx (2016) xxx–xxx 3

Table 1
1 13
H NMR and C NMR data and detailed HMBC correlations for compounds 1 and 2.a

No. 1 2

dH (multi., J) dC HMBC dH (multi., J) dC HMBC

1 134.9
2 153.8 6.83 (s) 107.7 C-3, C-4, C-6, C-7
3 7.14 (s) 102.4 C-3a, C-7a, C-10 157.0
3a 121.2
4 7.38 (d, 8.5) 121.7 C-3, C-3a, C-5, C-7 118.4
5 6.74 (d, 8.5) 113.0 C-6, C-7 157.0
6 156.3 6.83 (s) 107.7 C-2, C-4, C-5, C-7
7 6.92 (br. s) 97.9 C-3a, C-5, C-6, C-7a 9.72 (s) 192.9 C-1, C-2, C-3, C-5, C-6
7a 155.8
10 130.8 6.58 (d, 16.0) 117.9 C-3, C-4, C-5, C-20 , C-30
20 6.82 (br. s) 103.7 C-2, C-30 , C-40 , C-60 6.82 (dd, 16.0, 6.0) 143.5 C-4, C-10 , C-30 , C-40 , C-50
30 153.9 2.40 (m) 33.1 C-10 , C-20 , C-40 , C-50
40 109.5 1.04 (d, 6.2, 3H) 23.0 C-20 , C-30 , C-50
50 154.3 1.05 (d, 6.2, 3H) 23.1 C-20 , C-30 , C-40
60 6.74 (br. s) 103.5 C-2, C-20 , C-40 , C-50
100 6.64 (d, 10.0) 118.3 C-30 , C-40 , C-50 , C-300 , C-400 , C-500
200 5.63 (d, 10.0) 126.6 C-30 , C-40 , C-300 , C-400 , C-500
300 79.2
400 3.45 (m, 2H) 67.0 C-200 , C-300 , C-500
500 1.29 (s, 3H) 23.2 C-200 , C-300 , C-400
–OH 5.00 (br. t, 5.0) C-300 , C-400 10.01 (br. s)
–OH 9.64 (s)
–OH 9.85 (s)
a
Recorded in DMSO-d6 at 600 and 150 MHz for 1H NMR and 13
C NMR, respectively. Multiplicities and J in Hz are in the parentheses.

163 (Calcd. for C19H15O5, 323.0919). The IR spectrum displayed C12H13O3, 205.0865). The IR spectrum showed absorption bands for 187
164 absorption bands for hydroxyl (3265 cm1) and benzene ring hydroxy (3298 cm1) and benzene (1684 and 1514 cm1) groups. 188
165 (1684 cm1 and 1564 cm1). The 1H NMR (Table 1) showed The 1H NMR (Table 1) showed signals for an aldehyde (dH 9.72, s), a 189
166 resonances for one 1,3,4,5-tetrasubstituted benzene ring (dH 6.82, symmetrical 1,2,3,5-tetrasubstituted benzene ring (dH 6.83, s, H-2 190
167 br. s and 6.74, br. s), one substituted benzofuran ring (dH 7.14, s, H- and H-6), a double bond (dH 6.58, d, J = 16.0 Hz and 6.82, dd, J = 16.0, 191
168 3; 7.38, d, J = 8.5 Hz, H-4; 6.74, d, J = 8.5 Hz, H-5; and 6.92, br. s, H- 6.0 Hz), and one isopropyl (dH 2.40, m; 1.04 and 1.05, each d, 192
169 7), one double bond (dH 6.64, d, J = 10.0 Hz and 5.63, d, J = 10.0 Hz), J = 6.2 Hz, each 3H). The 13C NMR showed signals for 12 carbons, 193
170 one methyl singlet (dH 1.29, s, 3H), and one oxygenated methylene including a symmetrically substituted benzene ring at dC 134.9 (C-1), 194
171 (dH 3.45, m, 2H). The 13C NMR showed resonances for 19 carbons, 107.7 (C-2, 6), 157.0 (C-3, 5), and 118.4 (C-4), as well as an aldehyde 195
172 which included one methyl, one oxygenated methylene, eight (dC 192.9) and a double bond (dC 117.9 and 143.5). The above 196
173 methine (all sp2), and nine quaternary (one sp3 and eight sp2) information indicated that compound 2 was a substituted benzal- 197
174 carbons as discerned from the HSQC spectrum. The NMR data dehyde. In the HMBC of 2 (Fig. 2), correlations of H-10 /C-3(C-5); H-20 / 198
175 (Table 1) for 1 was very similar to those of moracin D (16) [13]. The C-4, C-30 , and C-50 ; and H-7(dH 9.72)/C-1, C-2, and C-3 verified the 199
176 only difference was absence of one methyl in 16 and instead, one structure of 2 to be (E)-3,5-dihydroxy-4-(3-methylbut-1-enyl)ben- 200
177 oxygenated methylene (dH 3.45, m, 2H; dC 67.0) was observed in 1, zaldehyde. 201
178 indicating oxidation of a methyl to a hydroxymethyl in 1. In the The known compounds were identified by comparison of their 1H 202
179 HMBC of 1 (Fig. 2), the methylene protons were observed to NMR, 13C NMR and MS data with those reported in the literatures as 203
180 correlated with C-500 (dC 23.2), C-300 (dC 79.2), and C-200 (dC 126.6), one chalcone, artocarmitin B (3) [14], five flavones, artocarpin (4) 204
181 which also supported the above conclusion. Thus, compound 1 was [15], cudraflavone C (5) [16], albanin A (6) [17], cudraflavone (7) [18], 205
182 determined as 2-[5-hydroxy-(2-hydroxymethyl-2-methyl)benzo- and brosimone I (8) [18], two flavanones, norartocarpanone (9) [19] 206
183 pyran]-1-benzofuran-5-ol, and named artocarstilbene B. and euchrenone a7 (10) [20], six 2-arylbenzofuran derivatives, 207
184 Compound 2 was also obtained as a yellowish oil. The molecular moracin M (11) [21], moracin C (12) [13], albafuran B (13) [22], 208
185 formula was deduced as C12H14O3 from the HRESIMS of 2, which artoindonesianin B-1 (14) [23], demethylmoracin I (15) [24], and 209
186 showed a pseudo molecular ion [MH] at m/z 205.0869 (Calcd. for moracin D (16) [13], one stilbenoid, artocarbene (17) [25], one 210
lignan, 2,6,20 ,60 -tetramethoxy-4,40 -bis(2,3-epoxy-1-hydroxy-pro- 211
pyl)biphenyl (18) [26], one triterpenoid, griffithine A (19) [27], 212
5' 4'
3' and one steroid, 5a,6a-epoxy-24(R)-methylcholesta-7,22-dien-3b- 213
HO 4'' ol (20) [28] (Fig. S1 in Supporting information). 214
2'
5'' 1' Compounds 1–20 were evaluated for the in vitro inhibition of 215
O 3''
4
cell proliferation against the PC-3, NCI-H460, and A549 cancer cell 216
7
HO 7a O
2' 3'
2''
HO 3 OH lines using the MTT method. Compounds with IC50 value 217
6 2 1' 4' 5 <50 mmol/L were listed in Table 2. In our previous study [6], 218
1''
5 6 moderate to weak cytotoxicity was found for compounds 3–5 219
3a 2
4 3 6' 5' 1 against the PC-3 and NCI-H460 cells, and in this report they 220
OH C showed similar results. Besides this, 3–5 also exhibited cytotoxici- 221
H 7 O ty against the A549 cells. Compounds 10, 14, and 16 also showed 222
1 2 weak inhibitory activity (IC50 < 20 mmol/L) to some or all of the 223
three cancer cell lines. The other compounds were inactive in our 224
Fig. 2. Key HMBC (H!C) and 1H–1H COSY (–) correlations of 1 and 2. study (IC50 > 20 mmol/L). 225

Please cite this article in press as: X.-L. Wang, et al., New phenolic compounds from the leaves of Artocarpus heterophyllus, Chin. Chem.
Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.06.024
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4 X.-L. Wang et al. / Chinese Chemical Letters xxx (2016) xxx–xxx

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5 21.3  1.1 15.4  0.9 11.3  1.6
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Please cite this article in press as: X.-L. Wang, et al., New phenolic compounds from the leaves of Artocarpus heterophyllus, Chin. Chem.
Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.06.024