SUPPLEMENTARY MATERIAL
Cytotoxicity of Benzophenanthridine Alkaloids from the Roots of
Zanthoxylum nitidum (Roxb.) DC. var. fastuosum How ex Huang
Cheng-Fang Wanga,b, Li Fana, Mei Tiana, Shu-Shan Dub, Zhi-Wei Dengc,
Jiang-Bin Fenga, Yong-Yan Wangb and Xu Sua,*
a
China CDC Key Laboratory of Radiological Protection and Nuclear Emergency,
National Institute for Radiological Protection, Chinese Center for Disease Control
and Prevention, Xicheng District, Beijing 100088, China;
b
State Key Laboratory of Earth Surface Processes and Resource Ecology, Beijing
Normal University, No.19 Xinjiekouwai Street, Haidian District, Beijing 100875,
China;
c
Analytic and Testing Center, Beijing Normal University, No.19 Xinjiekouwai Street,
Haidian District, Beijing 100875, China.
*
Corresponding author. E-Mail: suxu@nirp.cn
Tel.: +86-10-6238-9938; Fax: +86-10-6238-9938.
Cytotoxicity of Benzophenanthridine Alkaloids from the Roots of
Zanthoxylum nitidum (Roxb.) DC. var. fastuosum How ex Huang
This work aimed to investigation benzophenanthridine alkaloids from the roots
of Zanthoxylum nitidum (Roxb.) DC. var. fastuosum How ex Huang for the
first time. Thirteen benzophenanthridines were isolated, and our results of the
cytotoxic activities indicated that compound 6 exhibited the best potency
against A549, Hela, SMMC-7721 and EJ, with the IC50 values of 27.50, 37.50,
16.95 and 60.42 µM, respectively. Compounds 7 and 11 also showed strong
cytotoxicity when tested against the four human cancer cell lines (A549, Hela,
SMMC-7721 and EJ). While only compounds 12 and 13 displayed cytotoxicity
in inhibiting BALL-1 proliferation among all the compounds. These results
suggested that benzophenanthridines may become a valid alternative of
potential basis for new anti-proliferative agents.
Keywords: benzophenanthridine alkaloids; Zanthoxylum nitidum (Roxb.) DC.
var. fastuosum How ex Huang; cytotoxic activity
Experimental Section
General
1
H- and
13
C-NMR spectrum was recorded on Bruker Avance DRX 500 NMR
spectrometer with TMS as the internal standard. ESI-MS and HR-ESI-MS were
obtained on a Bruker Q-TOF mass spectrometer. Silica gel (160–200 mesh, 200–300
mesh, Qingdao Marine Chemical Plant, Qingdao, China) used for column
chromatography and Sephadex LH-20 were supplied by Amersham Pharmacia
Biotech (Beijing, China). Analytical grade solvents were produced by Beijing
Chemical Factory (Beijing, China).
Plant Material
The fresh roots (4.0 kg) of Z. nitidum var. fastuosum were collected from Nanning,
Guangxi Province, China (22.26 N latitude and 108.76 E longitude), December 2011,
and identified by Dr Haibo Yin of Liaoning University of Traditional Chinese
Medicine. Voucher specimens (BNU-Dushushan-2011-12-15-005) were deposited at
the herbarium (BNU) in the College of Resources Sciences & Technology, Beijing
Normal University. The fresh materials were air dried for five days and then ground
to a powder.
Extraction and Isolation
The powder (2.0 kg) was extracted under ultrasound three times (each for half an
hour) with methanol (MeOH, 10L). The extract was concentrated under reduced
pressure to obtain a crude residue (150 g). The suspension was fractionated by silica
gel column chromatography (160–200 mesh, 850 g), using a gradient solvent system
of CHCl3/MeOH (50:1, 30:1, 20:1, 10:1, 1:1 and MeOH) to afford ten fractions
according to TLC detection on silica gel plates. Silica gel column chromatography
(200–300 mesh, 280 g) of Fr.1 (22 g) eluting with PE/EtOAc (30:1, 20:1, 10:1, 1:1
and EtOAc) gave compound 1 (150 mg), 5 (92 mg) and 12 (8 mg) at gradient 1:1, and
fifteen sub-fractions (1.1–1.15). Fr.1.4 (1.2 g) was chromatographed on a gel column
(200–300 mesh) eluting with PE/EtOAC (10:1) to give compound 11 (10 mg). Fr.1.7
(350 mg) and Fr.1.8 (760 mg) were subjected to silica gel column (200–300 mesh)
eluting with PE/EtOAC (5:1) to afford compound 2 (7 mg), 9 (28 mg) and 13 (5 mg),
and six sub-fractions (1.8.1–1.8.6). Fr.1.8.3 (113 mg) was separated on a Sephadex
LH-20 column eluted with CHCl3:MeOH (1:1) to give compound 8 (6 mg) and 10 (5
mg). Compound 4 (30 mg) was isolated from Fr.1.10 (380 mg) after purification by
chromatography on a silica gel column (200–300 mesh). Fr.1.12 (1.7 g) was subjected
to silica gel column (200–300 mesh, PE/EtOAc 3:1), then purified by chromatography
on a Sephadex LH-20 column (CHCl3/MeOH, 1:1) to give compound 6 (87 mg), 7(72
mg) and 3 (17 mg).
Structure Confirmation of Isolated Compounds
The NMR spectral data of thirteen known compounds, decarine (1) (Martin,
Rasoanaivo, & Raharisololalao, 2005), norchelerythrine (2) (Jaromir, Jiri, & Radek,
2004), oxyavicine (3) (Hu et al., 2013), arnottianamide (4) (Hsiao & Chiang, 1995),
6-hydroxydihydrochelerythrine
(5)
(Seckarova
et
al.,
2002),
6-methoxy-7-
hydroxydihydrochelerythrine (6) (Tarus et al., 2006), 6-methoxydihydrochelerythrine
(7) (Miao et al., 2011), 6-carboxymethyldihydrochelerythrine (8) (Ng, Gray, &
Waterman, 1987; Tsai, Ishikawa, Seki, & Chen, 2000), oxychelerythrine (9) (He et al.,
2002), 6-acetonyldihydrochelerythrine (10) (Ye, Feng, & Liu, 2009), 8-(1'-
hydroxyethyl)-7, 8-dihydrochelerythrine (11) (Geng et al., 2009), N-nornitidine (12)
(Martin, Rasoanaivo, & Raharisololalao, 2005), and noravicine (13) (Geen, Mann,
Mullane, & McKillop, 1998), were consistent with the literature data.
Decarine (1). Pale yellow needles. mp 241~242 ℃ . ESI-MS m/z: 320.1[M+H]+,
C19H13NO4. 1H-NMR(500 MHz, DMSO-d6) δppm: 10.11(1H, s, 8-OH), 9.59(1H, s,
H-6), 8.55(1H, s, H-4), 8.53(1H, d, J=9.0 Hz, H-11), 8.48(1H, d, J=9.0 Hz, H-10),
7.97(1H, d, J=9.0 Hz, H-12), 7.59(1H, d, J=9.0 Hz, H-9), 7.53(1H, s, H-1), 6.23(2H,
13
s, H-13), 4.03(3H, s, 7-OCH3).
C-NMR(125 MHz, DMSO-d6) δppm: 148.61(C-2),
148.37(C-3), 148.00(C-8), 146.28(C-6), 142.56(C-7), 139.10(C-4b), 129.64(C-12a),
128.74(C-4a), 127.55(C-12), 126.83(C-10a), 124.03(C-9), 122.10(C-6a), 120.49(C10b), 119.26(C-10), 119.14(C-11), 104.99(C-1), 101.96(C-13), 101.34(C-4), 61.67(7OCH3).
Norchelerythrine (2). Colorless crystal. mp 213~214℃. ESI-MS m/z: 334.1 [M+H]+,
C20H15NO4. 1H-NMR(500 MHz, CDCl3) δppm: 9.77(1H, s, H-6), 8.75(1H, s, H-4),
8.37(1H, d, J=9.0 Hz, H-10), 8.35(1H, d, J=9.0 Hz, H-11), 7.86(1H, d, J=9.0 Hz, H12), 7.61(1H, d, J=9.0 Hz, H-9), 7.28(1H, s, H-1), 6.16(2H, s, H-13), 4.15(3H, s, 8OCH3), 4.08(3H, s, 7-OCH3).
13
C-NMR(125 MHz, CDCl3) δppm: 149.37(C-8),
148.47(C-2), 148.23(C-3), 146.48(C-6), 145.26(C-7), 129.75(C-4b, 10b), 128.10(C12a), 127.05(C-12), 121.81(C-4a), 120.00(C-10a), 118.80(C-9), 118.25(C-10),
118.18(C-11), 110.00(C-6a), 104.36(C-1), 102.18(C-4), 101.32(C-13), 61.90(7OCH3), 56.83(8-OCH3).
Oxyavicine (3). White needles. mp 257~258 ℃ . ESI-MS m/z: 348.1 [M+H]+,
C20H13NO5. 1H-NMR(500 MHz, CDCl3) δppm: 7.95(1H, d, J=8.5 Hz, H-11),
7.93(1H, s, H-10), 7.66(1H, s, H-1), 7.64(1H, s, H-7), 7.58(1H, d, J=8.5 Hz, H-12),
7.21(1H, s, H-4), 6.16(2H, s, -OCH2O-), 6.13(2H, s, -OCH2O-), 4.00(3H, s, N-CH3).
C-NMR(125 MHz, CDCl3) δppm: 164.09(C=O), 152.41(C-8), 148.17(C-9),
13
147.58(C-3), 147.03(C-2), 135.84(C-10a), 131.95(C-12a), 131.05(C-4b), 123.29(C11), 120.89(C-4a), 120.75(C-10b), 118.54(C-12), 116.79(C-6a), 106.57(C-10),
104.76(C-4),
41.24(N-CH3).
102.67(C-1),
101.96(-OCH2O-),
101.57(-OCH2O-),
100.66(C-7),
Arnottianamide (4). Colorless needles. mp 264~265℃. ESI-MS m/z: 382.1 [M+H]+,
C21H19NO6. 1H-NMR(500 MHz, CDCl3) δppm: 8.19(1H, s, H-6), 7.75(1H, d, J=8.5
Hz, H-11), 7.34(1H, d, J=8.5 Hz, H-12), 7.22(1H, s, H-4), 7.11(1H, s, H-1), 6.82(1H,
d, J=8.5 Hz, H-10), 6.56(1H, d, J=8.5 Hz, H-9), 6.11(2H, s, H-13), 5.97(1H, s, -OH),
3.95(3H, s, 7-OCH3), 3.93(3H, s, 8-OCH3), 3.02(3H, s, N-CH3). 13C-NMR(125 MHz,
CDCl3) δppm: 164.51(C=O), 152.06(C-8), 149.33(C-2), 148.14(C-3), 146.70(C-6a),
135.81(C-7), 135.62(C-4a), 133.39(C-10b), 131.26(C-12a), 128.76(C-4b), 127.44(C12),
127.41(C-11),
125.11(C-10),
118.61(C-10a),
104.35(C-9),
103.99(C-4),
101.50(C-13), 99.30(C-1), 61.17(7-OCH3), 55.85(8-OCH3), 33.03(N- CH3).
6-Hydroxydihydrochelerythrine (5). Pale yellow needles. mp 198~199℃. ESI-MS
m/z: 388.1 [M+Na]+, C21H19NO5. 1H-NMR(500 MHz, CDCl3) δppm: 7.81(1H, d,
J=8.5 Hz, H-11), 7.72(1H, s, H-4), 7.65(1H, d, J=8.5 Hz, H-10), 7.50(1H, d, J=8.5
Hz, H-12), 7.16(1H, s, H-1), 7.05(1H, d, J=8.5 Hz, H-9), 6.08(2H, s, H-13), 5.73(1H,
s, H-6), 4.02(3H, s, 8-OCH3), 3.95(3H, s, 7-OCH3), 2.78(3H, s, N-CH3).
13
C-
NMR(125 MHz, CDCl3) δppm: 152.18(C-8), 147.90(C-3), 147.33(C-2), 146.63(C-7),
138.68(C-4b),
131.02(C-10b),
126.79(C-12a),
126.04(C-4a),
124.98(C-10a),
123.34(C-12), 122.67(C-6a), 120.14(C-11), 119.02(C-10), 112.86(C-9), 104.63(C-1),
101.02(C-13), 100.69(C-4), 84.52(C-6), 61.64(8-OCH3), 55.97(7-OCH3), 40.70(NCH3).
6-Methoxy-7-hydroxydihydrochelerythrine (6). Pale yellow powder. ESI-MS m/z:
388.1 [M+Na]+, C21H19NO5. 1H-NMR(500 MHz, CDCl3) δppm: 7.95(1H, s, H-4),
7.71(1H, d, J=8.5 Hz, H-11), 7.51(1H, d, J=8.5 Hz, H-10), 7.47(1H, d, J=8.5 Hz, H12), 7.19(1H, s, H-1), 6.87(1H, d, J=8.5 Hz, H-9), 6.63(1H, s, H-6), 6.14(2H, s, H13), 3.75(3H, s, 8-OCH3), 3.08(3H, s, N-CH3), 2.44(3H, s, 6-OCH3). 13C-NMR(125
MHz, CDCl3) δppm: 152.11(C-8), 148.06(C-2), 147.51(C-3), 146.34(C-7), 138.42(C4b), 131.20(C-12a), 126.93(C-4a), 126.16(C-6a), 125.52 (C-10a), 123.24(C-12),
123.01(C-10b), 119.83(C-11), 118.68(C-10), 112.32(C-9), 104.49(C-1), 101.10(C13), 100.85(C-4), 77.47(C-6), 60.40(6-OCH3), 55.66(8-OCH3), 40.85(N-CH3).
6-Methoxydihydrochelerythrine (7). Pale yellow needles. mp 197~198℃. ESI-MS
m/z: 781.3[2M+Na] +, C22H21NO5. 1H-NMR(500 MHz, CDCl3) δppm: 7.80(1H, d,
J=8.5 Hz, H-11), 7.73(1H, s, H-4), 7.65(1H, d, J=8.5 Hz, H-10), 7.50(1H, d, J=8.5
Hz, H-12), 7.15(1H, s, H-1), 7.07(1H, d, J=8.5 Hz, H-9), 6.09(1H, s, H-13a), 6.08(1H,
s, H-13b), 5.58(1H, s, H-6), 3.99(3H, s, 8-OCH3), 3.96(3H, s, 7-OCH3), 3.49(3H, s, 6OCH3), 2.78(3H, s, N-CH3).
13
C-NMR(125 MHz, CDCl3) δppm: 152.12(C-8),
147.95(C-3), 147.36(C-2), 146.69(C-7), 138.40(C-4b), 131.07(C-10b), 126.76(C12a), 125.73(C-4a), 124.89 (C-10a), 123.46(C-12), 122.56(C-6a), 120.05(C-11),
118.92(C-10), 113.01(C-9), 104.65(C-1), 101.02(C-13), 100.65(C-4), 86.11(C-6),
61.65(8-OCH3), 56.00(7-OCH3), 53.97(6-OCH3), 40.64(N-CH3).
6-Carboxymethyldihydrochelerythrine (8). White powder. ESI-MS m/z: 408.1
[M+H]+, C23H21NO6. 1H-NMR(500 MHz, DMSO-d6) δppm: 7.82(1H, d, J=8.5 Hz, H11), 7.67(1H, d, J=8.5 Hz, H-10), 7.56(1H, d, J=8.5 Hz, H-12), 7.42(1H, s, H-4),
7.32(1H, s, H-1), 7.11(1H, d, J=8.5 Hz, H-9), 6.15(1H, s, H-13a), 6.14(1H, s, H-13b),
4.86(1H, dd, J=3.5 Hz, H-6), 3.88(3H, s, 8-OCH3), 3.86(3H, s, 7-OCH3), 2.54(3H, s,
N-CH3), 2.21(1H, dd, J=3.5, 11.5 Hz, H-14a), 1.98(1H, q, J=3.5, 11.5 Hz, H-14b).
C-NMR(125 MHz, DMSO-d6) δppm: 172.44(C=O)，152.38(C-8), 148.18 (C-3),
13
147.76(C-2), 145.51(C-7), 139.19(C-4b), 131.10(C-10b), 127.81(C-12a), 127.20(C4a), 124.29(C-10a), 124.18(C-12), 123.14(C-6a), 120.24(C-11), 119.42 (C-10),
112.60(C-9), 104.59(C-1), 101.67(C-13), 100.40(C-4), 60.95(7-OCH3), 56.19(8OCH3), 54.94(C-6), 43.13(N-CH3), 39.49(C-14).
Oxychelerythrine (9). White needles. mp 192~193℃. ESI-MS m/z: 364.1 [M+H]+,
C21H17NO5. 1H-NMR(500 MHz, CDCl3) δppm: 8.01(1H, d, J=9.0 Hz, H-11),
8.00(1H, d, J=9.0 Hz, H-10), 7.57(1H, s, H-4), 7.55(1H, d, J=9.0 Hz, H-12), 7.41(1H,
d, J=9.0 Hz, H-9), 7.19(1H, s, H-1), 6.12(2H, s, H-13), 4.11(3H, s, 7-OCH3), 4.01(3H,
s, 8-OCH3), 3.93(3H, s, N-CH3).
13
C-NMR(125 MHz, CDCl3) δppm: 162.63(C=O),
152.71(C-8), 150.17(C-7), 147.50(C-3), 147.07(C-2), 131.69(C-4b), 128.94(C-10a),
123.30(C-12), 121.03 (C-4a), 118.47(C-11), 117.85(C-10), 117.81(C-9), 117.20(C10b), 114.39(C-12a), 111.45(C-6a), 104.67(C-1), 102.50(C-13), 101.50(C-4),
61.77(8-OCH3), 56.62(7-OCH3), 40.82(N-CH3).
6-Acetonyldihydrochelerythrine (10). Colorless crystal. mp 199~200 ℃ . ESI-MS
m/z ： 406.7[M+H]+, C24H23NO5. 1H-NMR(500 MHz, CDCl3) δppm: 7.73(1H, d,
J=9.0 Hz, H-10), 7.56(1H, s, H-4), 7.54(1H, d, J=9.0 Hz, H-12), 7.50(1H, d, J=9.0
Hz, H-11), 7.13(1H, s, H-1), 6.96(1H, d, J=9.0 Hz, H-9), 6.07(2H, s, H-13), 5.06(1H,
dd, H-6), 4.00(3H, s, 8-OCH3), 3.95(3H, s, 7-OCH3), 2.66(3H, s, N-CH3), 2.58(1H, dd,
-CH2-), 2.27(1H, dd, -CH2-), 2.09(3H, s, -CH3).
C-NMR(125 MHz, CDCl3) δppm:
13
207.70(C=O), 152.09(C-8), 148.43(C-3), 147.81(C-2), 145.52(C-7), 139.33(C-4b),
131.02(C-12a), 128.31(C-4a), 127.42(C-6a), 124.68(C-10a), 123.88(C-12), 123.32(C10b),
119.69(C-11),
118.79(C-10),
111.48(C-9),
104.32(C-1),
100.67(C-13),
100.62(C-4), 61.02(7-OCH3), 55.86(8-OCH3), 54.89(C-6), 46.84(-CH2-), 42.81(NCH3), 31.12(-CH3).
8-(1'-Hydroxyethyl)-7, 8-dihydrochelerythrine (11). Yellow crystal. mp 251~252℃.
ESI-MS m/z: 394.2[M+H]+, C23H23NO5. 1H-NMR(500 MHz, CDCl3) δppm: 7.72(1H,
d, J=8.5 Hz, H-11), 7.66(1H, s, H-1), 7.55(1H, d, J=8.5 Hz, H-10), 7.52(1H, d, J=8.5
Hz, H-12), 7.15(1H, s, H-4), 7.01(1H, d, J=8.5 Hz, H-9), 6.09(2H, d, J=1.2 Hz, H-13),
4.23(1H, d, J=9.0 Hz, H-6), 3.96(3H, s, 7-OCH3), 3.95(3H, s, 8-OCH3), 3.24(1H, m,
H-14), 2.72(3H, s, N-CH3), 1.13(3H, d, J=6.0 Hz, -CH3). 13C-NMR(125 MHz, CDCl3)
δppm: 152.17(C-8), 148.57(C-7), 147.59(C-3), 147.09(C-2), 137.96(C-4b), 131.05(C4a), 126.69(C-12a), 125.45(C-6a), 124.94(C-10a), 124.40(C-12), 123.98(C-10b),
119.77(C-11), 119.09(C-10), 111.83(C-9), 104.77(C-4), 101.19(C-1), 99.60(C-13),
66.89(7-OCH3), 64.61(8-OCH3), 60.83(C-14), 55.81(C-6), 42.24(N-CH3), 18.56(CH3).
N-nornitidine (12). Yellow needles. mp 279~280℃. ESI-MS m/z: 334.1 [M+H]+,
C20H15NO4. 1H-NMR(500 MHz, DMSO-d6) δppm: 9.33(1H, s, H-6), 8.65(1H, d,
J=9.0 Hz, H-11), 8.56(1H, s, H-4), 8.18(1H, s, H-10), 7.97(1H, d, J=9.0 Hz, H-12),
7.72(1H, s, H-7), 7.53(1H, s, H-1), 6.22(2H, s, H-13), 4.10(3H, s, 9-OCH3), 3.99(3H,
s, 8-OCH3).
13
C-NMR(125 MHz, DMSO-d6) δppm: 153.55(C-9), 150.43(C-6),
150.16(C-8), 148.47(C-2), 148.39(C-3), 140.06(C-10b), 129.74(C-4b), 128.78(C12a), 128.68(C-6a), 126.76(C-12), 122.39(C-10a), 120.17(C-4a), 119.72(C-11),
108.19(C-7), 104.98(C-1), 102.90(C-10), 101.92(C-13), 101.53(C-4), 56.61(8-OCH3),
56.19(9-OCH3).
Noravicine (13). Colorless needles. mp 310~311℃. ESI-MS m/z: 318.1 [M+H]+,
C19H11NO4. 1H-NMR(500 MHz, DMSO-d6) δppm: 9.28(1H, s, H-6), 8.55(1H, s, H4), 8.54(1H, d, J=9.0 Hz, H-11), 8.35(1H, s, H-10), 7.95(1H, d, J=9.0 Hz, H-12),
7.70(1H, s, H-7), 7.53(1H, s, H-1), 6.30(2H, s, H-14), 6.23(2H, s, H-13).13CNMR(125 MHz, DMSO-d6) δppm: 152.15(C-9), 150.45(C-6), 148.56(C-2, 3),
148.37(C-8), 140.18(C-4b), 130.84(C-10a), 129.87(C-4a), 128.50(C-12a), 127.05(C12),
123.65(C-6a),
120.76(C-10b),
119.67(C-11),
105.34(C-7),
105.02(C-1),
102.66(C-14), 101.99(C-13), 101.56(C-4), 100.61(C-10).
Cytotoxicity Assay
The cytotoxicity was determined by cell counting kit-8 (CCK-8) assay (Jiang et al.,
2013). The five tumor cell lines, human B-lineage acute lymphoblastic leukemia 1
cells (BALL-1), human lung adenocarcinoma cells (A549), human hepatocellular
carcinoma cells (SMMC-7721), human bladder tumor cells (EJ) and human cervical
carcinoma cells (Hela), were purchased from the Chinese Academy of Medical
Sciences (Beijing, China). All cells were grown and maintained in RPMI 1640
(Sigma, St. Louis, MO, USA) medium supplemented with 10% fetal bovine serum
(Grand Island, NY, USA), 100 IU/mL penicillin (Flow Lab, Beijing, China) and 100
μg/mL streptomycin (Flow Lab, Beijing, China) at 37 °C, 5% CO2. The cell
suspension was dispensed into a 96-well microplate at 100 μL per well (adherent cells
were 6 × 103 per well; suspension cells were 5 × 104 per well). After 4–6 h
preincubation in the incubator (Forma Series ΙΙ Water Jacket) to allow cellular
attachment, various concentrations of test solution were added and cells were
incubated for 48 h. At the end of the incubation, CCK-8 reagent (Cell Counting Kit-8,
Dojindo, Kumamoto, Japan, 10 μL) was added into each well followed by further
incubation for 2 h. The optical density (OD) was recorded at 450 nm using a
microplate reader (Multiskan GO, Thermo Scientific). Each determination represented
the average mean of six replicates. Doxorubicin (Adriamycin, Actavis Italy S.p.A.,
Beijing, China) was used as positive control. The 50% inhibitory concentration (IC50)
value was calculated the line equation of the dose-dependent curve of each
compound. The equation to calculate the inhibition rate was
RInhibition = 1 - (Rdosing cell group - Rcontrol group) / (Rcell control group - Rcontrol group)
Acknowledgements
This project was supported by the Nuclear Accident Health Risk Assessment and Health
Emergency Disposal Technology Research (2013BAK03B05).
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