Synthesis and Anti-Tobacco Mosaic Virus/Fungicidal/Insecticidal/Antitumor Bioactivities of Natural Product Hemigossypol and Its Derivatives

Article abstract of DOI:10.1021/acs.jafc.0c06058

To further study the structure-activity relationship of gossypol, hemigossypol (1) and its derivatives (2-23) were successfully designed via structure simplification and chemically synthesized. The anti-tobacco mosaic virus (TMV), fungicidal, and insectic

Full text of DOI:10.1021/acs.jafc.0c06058

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Synthesis and Anti-Tobacco Mosaic Virus/Fungicidal/Insecticidal/
Antitumor Bioactivities of Natural Product Hemigossypol and Its
Derivatives
Ling Li,* Jiyong Zou, Changjiang Xu, Shengyong You, Yongqiang Li, and Qingmin Wang*
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ABSTRACT: To further study the structure−activity relationship of gossypol, hemigossypol (1) and its derivatives (2−23) were
successfully designed via structure simplification and chemically synthesized. The anti-tobacco mosaic virus (TMV), fungicidal, and
insecticidal activities of them were tested systematically. Most of these derivatives exhibited excellent anti-TMV activity.
Furthermore, these compounds also exhibited broad-spectrum fungicidal activities against 14 kinds of phytopathogenic fungi. In
particular, hemigossypol acid lactone (7) was stable in the air. In terms of biological activity, it not only showed anti-TMV activity
(inhibitory rates of 70.3, 65.4 and 72.4% at 500 μg/mL for inactivation, curative, and protection activity in vivo, respectively)
comparable to ningnanmycin but also exhibited higher insecticidal activity against mosquito larvae (60%/0.25 mg/kg) than the
commercial species rotenone. None of hemigossypol and the tested derivatives showed antitumor activities.
KEYWORDS: natural product, hemigossypol, synthesis, anti-TMV activity, fungicidal activity, insecticidal activity
differently with Bcl-2.8 In our previous work,9−12 gossypol and
INTRODUCTION
■
its derivatives were first found to have good antiviral activity
Natural products are the outcome of nature’s chemical
against tobacco mosaic virus (TMV). Therefore, further
laboratory, which have been used in a variety of fields, such
research of SAR via structure simplification with gossypol as
as medicines, dyes, and pest control agents.1 A total of 64.9%
the lead compound would be very significant.
of cancer drugs between 1981 and 20192 and 41.8% of
Hemigossypol is the biosynthetic precursor of gossypol,13
registered pesticides from the years 1997 to 20103 were either
which is the dimer of it. Hemigossypol (Figure 2) was isolated
natural products or directly derived therefrom. However,
from the stele of cotton stems in response to inoculation with
physicochemical properties of natural products are often far
Verticillium albo-atrum in 1972.14 It was antifungal to V. albo-
from ideal; the synthesis of their derivatives is necessary to
atrum and more active than gossypol.15 Hemigossypol had not
improve bioavailability, enhance biological activity, and reduce
toxicity. Moreover, the generation of natural product analogues
been identified in healthy cottonseed.16−18 It is unstable in the
presence of oxygen, and its color would change upon standing
in the air. Therefore, the study on it is rarely little. To
investigate the necessity of the two symmetrical parts of
is also important for the determination of structure−activity
relationships (SARs) and the interaction of natural products
and their target biomolecules.4,5
gossypol to the biological activities and study the role that the
Gossypol belongs to complex polyphenolic compounds. Its
substituents of hemigossypol played in the biological activities,
structure consists of two naphthalene rings joined by a single
a series of hemigossypol derivatives were synthesized and their
internaphthyl bond between the 2- and 2′-carbon atoms
anti-TMV, fungicidal activities, insecticidal activities, and
(Figure 1).6 Gossypol is capable of inhibiting the growth of a
antitumor activities were also systematically evaluated.
variety of cell lines, and (−)-gossypol was usually more potent
in most biological evaluations in comparison to (+)-gossypol
MATERIALS AND METHODS
■
or racemic gossypol.7 Wang et al. performed computational
General Procedure. Reagents were purchased from commercial
docking of (−)-gossypol into the BH3 binding groove in Bcl-2
and found that the two halves of (−)-gossypol interact
sources and were used as received. All anhydrous solvents were dried
and purified by standard techniques just before use. The reaction
progress was monitored by thin-layer chromatography on silica gel
GF-254 with detection by ultraviolet (UV). Melting points were
Received: September 21, 2020
Revised: December 13, 2020
Accepted: January 15, 2021
Published: January 22, 2021
Figure 1. Enantiomeric structures of gossypol.
https://dx.doi.org/10.1021/acs.jafc.0c06058
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© 2021 American Chemical Society
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Figure 2. Structures of compounds 1−23.
determined on an X-4 binocular microscope melting point apparatus
and are uncorrected. 1H and 13C nuclear magnetic resonance (NMR)
spectra were recorded on a Bruker Ascend 300/400 MHz
spectrometer. Chemical shift values (δ) are given in parts per million
(ppm) and downfield from internal tetramethylsilane. High-resolution
mass spectrometry (HRMS) was recorded on Fourier transform ion
cyclotron resonance mass spectrometry (FT-ICR MS, 7.0 T,
Ionspec).
petroleum ether (60−90 °C) and ethyl acetate to give compound 6 as
a white solid (0.29 g, 0.87 mmol). Yield: 92.6%. mp: 132−133 °C. 1H
NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 6.63 (s, 1H), 3.98 (s, 3H),
3.93−3.88 (m, 10H), 2.48 (s, 3H), 1.48 (d, J = 7.1 Hz, 6H). 13C
NMR (100 MHz, CDCl3): δ 168.5, 153.5, 149.4, 147.5, 135.9, 134.0,
130.2, 120.4, 116.7, 115.4, 106.2, 60.5, 59.8, 55.4, 51.1, 26.2, 21.5,
21.0. HRMS (ESI): calculated for C19H25O5 [M + H]+, 333.1697;
found, 333.1701.
To a solution of compound 5 (0.50 g, 1.57 mmol) in
dichloromethane (30 mL), BBr3 (15.7 mL, 1.0 M, 15.7 mmol) was
added slowly via a constant pressure funnel at 0 °C under an argon
atmosphere. The solution was warmed to room temperature and then
refluxed for 10 h. The solution was added to ice water and extracted
with ethyl ether (30 mL). The aqueous layer was further extracted
with ethyl ether (30 mL × 2), and the combined organic extracts were
washed with water (80 mL) and brine, dried with MgSO4, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel to give compound 7 as a dark yellow
General Procedure for the Synthesis of Hemigossypol Acid
Derivatives 5−8. To a solution of compound 2 (2.00 g, 6.61 mol) in
t-butanol (100 mL) and tetrahydrofuran (100 mL), isopentene (6
mL) was added at 0 °C, and then a solution of NaClO2 (1.50 g ×
80%, 13.27 mmol) and NaH2PO4·2H2O (4.13 g, 26.46 mmol) in
water (40 mL) was added slowly via a constant pressure funnel at this
temperature. The solution was warmed to room temperature and then
stirred for 10 h. A solution of NH4Cl was added and extracted twice
with ethyl acetate. The organic layer was washed with brine, dried
over anhydrous MgSO4, and concentrated under reduced pressure.
The crude product was recrystallized using ethyl acetate and
petroleum ether to give compound 5 as a white solid (1.68 g, 5.28
1
solid. Yield: 78.5%. mp: 217−220 °C. H NMR (400 MHz, DMSO-
d6): δ 7.62 (s, 1H), 7.02 (s, 1H), 3.91−3.81 (m, 1H), 2.56 (s, 3H),
1.52−1.47 (m, 6H). 13C NMR (100 MHz, DMSO-d6): δ 165.1, 148.4,
147.7, 146.9, 135.4, 134.9, 122.8, 121.0, 116.9, 105.4, 99.3, 26.7, 22.4,
20.6. HRMS (ESI): calculated for C18H21O5 [M + H]+, 259.0965;
found, 259.0970.
1
mmol, 80.0%). Melting point (mp): 190−191 °C. H NMR (400
MHz, CDCl3): δ 7.54 (s, 1H), 6.69 (s, 1H), 4.02−3.91 (m, 10H),
2.50 (s, 3H), 1.50 (d, J = 7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3):
δ 175.5, 154.7 150.5, 148.4, 137.2, 135.2, 131.3, 121.0, 117.7, 116.5,
107.6, 61.7, 60.9, 56.1, 27.2, 22.6, 22.1. HRMS (ESI): calculated for
C18H21O5 [M − H]−, 317.1394; found, 317.1394.
To a solution of compound 5 (0.30 g, 1.16 mmol) in N,N-
dimethylformamide (40 mL), K2CO3 (0.35 g, 2.56 mmol) and BnBr
(0.44 g, 2.56 mmol) were added. After stirring at room temperature
for 10 h, water (100 mL) was added and extracted with
dichloromethane (80 mL × 2). The organic layer was washed with
water (100 mL × 3) and brine, dried over anhydrous MgSO4, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel to give compound 8 as a
To a solution of compound 5 (0.30 g, 0.94 mmol) in acetone (30
mL), K2CO3 (0.39 g, 2.83 mmol) and CH3I (0.27 g, 1.88 mmol) were
added. After stirring at room temperature for 7 h, acetone was
evaporated in vacuo. The residue was taken into water (15 mL) and
ethyl acetate (20 mL) and extracted with ethyl acetate (20 mL × 2).
The organic layer was washed with brine, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel and eluted with
1
white solid (0.48 g, 1.09 mmol). Yield: 94.2%. mp: 125−127 °C. H
NMR (400 MHz, CDCl3): δ 7.61 (s, 1H), 7.55−7.51 (m, 2H), 7.40−
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7.28 (m, 8H), 6.96 (s, 1H), 5.95 (s, 2H), 4.94 (s, 2H), 3.99−3.91 (m,
1H), 2.56 (s, 3H), 1.47 (d, J = 7.2 Hz, 6H). 13C NMR (100 MHz,
CDCl3): δ 164.6, 152.5, 148.1, 144.8, 135.8, 135.4, 135.2, 127.5,
127.5, 127.4, 127.4, 127.4, 127.2, 123.6, 123.2, 117.4, 106.3, 102.8,
74.8, 26.8, 22.1, 21.4. HRMS (ESI): m/z calculated for C29H27O4 [M
+ H]+, 439.1904; found, 439.1912.
To a solution of compound M-3 (4.00 g, 20.8 mmol) and dimethyl
succinate (3.95 g, 27.04 mmol) in anhydrous tetrahydrofuran (100
mL), t-BuOK (2.80 g, 24.96 mmol) was added, and the resulting
mixture was stirred at room temperature for 3 h. Then, water (100
mL) and diethyl ether (80 mL) were added. The organic phase was
added with 2 M hydrochloric acid to make pH ≈ 2 and separated.
The aqueous layer was extracted twice with ethyl acetate. The
combined organic phase was washed with water (100 mL) and brine
(100 mL), dried over anhydrous MgSO4, and concentrated in vacuo.
To a solution of the crude product in acetic anhydride (100 mL),
sodium acetate (2.56 g, 31.2 mmol) was added, and the resulting
mixture was refluxed for 2 h. After the mixture was cooled to room
temperature, water (100 mL) was added slowly at 0 °C. The yellow
slurry was filtered, and the cake was washed with water. The residue
was purified by column chromatography on silica gel to give
compound 14 (4.90 g, 14.9 mmol) as a yellow crystal. Yield:
Synthesis of Dinaphthol (12). To a solution of compound 10
(3.00 g, 6.87 mmol) in tetrahydrofuran (100 mL), LiAlH4 (0.52 g,
13.75 mmol) was added. After stirring at room temperature for 1 h, 2
M hydrochloric acid was added at 0 °C until the floccule disappeared.
The aqueous phase was separated and extracted with ethyl acetate (80
mL × 2). The organic layer was washed with brine, dried over
anhydrous MgSO4, and concentrated under reduced pressure to give
the crude product. A mixture of the crude product, 12 M hydrochloric
acid (0.3 mL), and 10% Pd/C (0.30 g) in methanol (120 mL) was
stirred under hydrogen (1 atm) at room temperature for 12 h. The
solution was filtrated and concentrated in vacuo. The residue was
purified by column chromatography on silica gel and eluted with
petroleum ether (60−90 °C) and ethyl acetate (50:1, v/v) to give
compound 12 as a light gray solid (1.36 g, 5.22 mmol). Yield: 76.0%.
mp: 147−149 °C. 1H NMR (400 MHz, CDCl3): δ 7.49 (s, 1H), 6.51
(d, J = 0.9 Hz, 1H), 5.94 (s, 1H), 5.05 (s, 1H), 3.92−3.83 (m, 1H),
3.82 (s, 2H), 2.80 (s, 3H), 2.40 (s, 3H), 1.56−1.52 (d, J = 7.3 Hz,
6H). 13C NMR (100 MHz, CDCl3): δ 153.7, 145.6, 144.6, 132.2,
131.2, 123.0, 121.2, 117.8, 115.6, 111.9, 62.0, 26.7, 22.3, 21.7, 14.4.
HRMS (ESI): m/z calculated for C16H21O3 [M + H]+, 261.1485;
found, 261.1486.
1
71.4%. mp: 153 °C. H NMR (400 MHz, CDCl3): δ 8.77 (d, J = 1.4
Hz, 1H), 7.64 (d, J = 1.4 Hz, 1H), 3.96 (s, 6H), 3.88−3.80 (m, J =
13.6 and 6.8 Hz, 1H), 2.61 (s, 3H), 2.40 (s, 3H), 1.43−1.39 (m, 6H).
13C NMR (100 MHz, CDCl3): δ 167.0, 166.8, 157.3, 147.6, 146.6,
130.8, 128.5, 125.2, 124.1, 119.6, 116.0, 111.1, 56.7, 52.2, 29.1, 23.8,
21.6, 12.7. HRMS (ESI): m/z calculated for C19H23O5 [M + H]+,
331.1540; found, 331.1546.
Compound 14 (4.00 g, 12.12 mmol) was dissolved in methanol
(50 mL) and water (15 mL), and then a solution of NaOH (0.80 g,
20 mmol) in water was added. The mixture was stirred until the
material disappeared. After cooling, methanol was evaporated in
vacuo. The residue was added with 2 M hydrochloric acid to make pH
≈ 2 and extracted with ethyl acetate (40 mL × 2). The organic layer
was washed with brine, dried over anhydrous MgSO4, and
concentrated under reduced pressure to give compound 15 (3.37 g,
General Procedure for the Synthesis of the Derivatives 14−
16. To a solution of carvacrol (18.85 g, 125.0 mol) in trichloro-
methane (180 mL), Br2 (6.40 mL, 19.98 g, 125.0 mmol) in
trichloromethane (60 mL) were added slowly via a constant pressure
funnel under refluxing. After the resulting mixture was refluxed for 0.5
h and then cooled to room temperature, a solution of Na2S2O3 (60
mL) was added. The resulting solution was stirred for 0.5 h, then
separated, and extracted with dichloromethane. The organic phase
was washed with saturated brine, dried over MgSO4, and
concentrated. The residue was purified by flash chromatography on
silica gel to give compound M-119 as a yellow oil (26.18 g, 114.25
1
11.70 mmol) as a yellow solid. Yield: 96.5%. mp: 207−208 °C. H
NMR (400 MHz, CDCl3): δ 8.43 (s, 1H), 7.37 (s, 1H), 7.24 (s, 1H),
5.83 (s, 1H), 3.96 (2 s, 6H), 3.83−3.74 (m, 1H), 2.82 (s, 3H), 1.42−
1.37 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 167.5, 156.5, 154.2,
145.7, 128.7, 128.2, 124.4, 119.8, 118.7, 111.4, 109.1, 56.9, 52.2, 29.1,
23.8, 13.9. HRMS (ESI): m/z calculated for C17H21O4 [M + H]+,
289.1434; found, 289.1435.
1
mmol). Yield: 91.4%. H NMR (400 MHz, CDCl3): δ 7.27 (s, 1H),
To a solution of compound 15 (0.40 g, 1.21 mmol) in
tetrahydrofuran (20 mL), LiAlH4 (0.14 g, 3.36 mmol) was added.
After stirring at room temperature for 1 h, 2 M hydrochloric acid was
added at 0 °C until the floccule disappeared. The aqueous phase was
separated and extracted with ethyl acetate (20 mL × 2). The organic
layer was washed with brine, dried over anhydrous MgSO4, and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel to give compound 16 as a
lavender solid (0.31 g, 1.19 mmol). Yield: 98.4%. mp: 153−156 °C.
1H NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 7.41 (s, 1H), 7.17
(s, 1H), 6.78 (s, 1H), 5.14 (t, J = 5.0 Hz, 1H), 4.52 (d, J = 5.0 Hz,
2H), 3.84 (s, 3H), 3.66−3.58 (m, 1H), 2.69 (s, 3H), 1.34−1.29 (m,
6H). 13C NMR (100 MHz, DMSO-d6): δ 156.1, 153.9, 143.1, 138.2,
129.5, 125.0, 118.3, 111.6, 111.3, 109.2, 63.7, 57.3, 28.9, 23.9, 14.6.
HRMS (ESI): m/z calculated for C16H21O3 [M + H]+, 261.1485;
found, 261.1490.
General Procedure for the Synthesis of the Derivatives 17
and 18. To a solution of compound M-2 (1.00 g, 4.12 mmol) in
acetone (20 mL), N-bromosuccinimide (2.92 g, 16.4 mmol) and
azodiisobutyronitrile (catalytic amount) in acetone (40 mL) were
added slowly via a constant pressure funnel under refluxing. After the
resulting mixture was refluxed until the purple of the reaction liquid
faded, water was added and acetone was evaporated in vacuo. The
residue was taken into petroleum ether (50 mL), separated, and
extracted with petroleum ether (50 mL × 2). The organic layer was
washed with brine, dried over anhydrous MgSO4, and concentrated
under reduced pressure. The above crude product was dissolved in
tetrahydrofuran (30 mL), and sodium methoxide (2.23 g, 41.2 mmol)
was added. After stirring at room temperature for 10 h,
tetrahydrofuran was evaporated in vacuo. The residue was taken
into diluted HCl and ethyl acetate, separated, and extracted with ethyl
acetate (50 mL × 2). The organic layer was washed with brine, dried
6.70 (s, 1H), 4.71 (s, 1H), 3.25 (dt, J = 13.5 and 6.8 Hz, 1H), 2.18 (s,
3H), 1.19 (d, J = 6.8 Hz, 6H).
To a solution of compound M-1 (6.30 g, 27.5 mmol) in acetone
(100 mL), K2CO3 (11.4 g, 82.5 mmol) and CH3I (2.8 mL, 7.81 g,
55.0 mmol) were added. After stirring at room temperature for 9 h,
acetone was evaporated in vacuo. The residue was taken into water
(100 mL) and dichloromethane (150 mL), separated, and extracted
with dichloromethane (100 mL × 2). The organic layer was washed
with brine, dried over anhydrous MgSO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy on silica gel to give compound M-219 as a colorless oil (5.82 g,
1
23.9 mmol). Yield: 87.0%. H NMR (400 MHz, CDCl3): δ 7.27 (s,
1H), 6.72 (s, 1H), 3.82 (s, 3H), 3.31 (dt, J = 13.7 and 6.8 Hz, 1H),
2.15 (s, 3H), 1.23 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3):
δ 157.3, 145.4, 134.0, 126.2, 113.9, 108.2, 55.4, 32.9, 22.9, 15.5.
To a solution of compound M-2 (5.82 g, 23.9 mmol) in anhydrous
tetrahydrofuran (150 mL), n-BuLi (10.5 mL, 2.4 M, 25.1 mmol) was
added at −78 °C, and the resulting mixture was stirred at this
temperature for 0.5 h under an argon atmosphere. Then, to the
mixture, N,N-dimethylformamide (3.49 g, 47.8 mmol) was added.
The solution was warmed to −30 °C over the course of 2 h and then
stirred at this temperature for 8 h. The reaction was quenched with
aqueous ammonium chloride (80 mL). After separation, the aqueous
phase was extracted with ethyl acetate (75 mL × 2). The organic layer
was washed with brine, dried over anhydrous MgSO4, and
concentrated under reduced pressure to give compound M-320
1
(4.00 g, 20.8 mmol). Yield: 87.0%. H NMR (400 MHz, CDCl3): δ
10.21 (s, 1H), 7.61 (s, 1H), 6.82 (s, 1H), 4.00 (dt, J = 13.7 and 6.9
Hz, 1H), 3.92 (s, 3H), 2.21 (s, 3H), 1.31 (d, J = 6.9 Hz, 6H). 13C
NMR (100 MHz, CDCl3): δ 190.8, 162.5, 152.3, 133.9, 125.9, 124.6,
106.8, 55.4, 27.6, 24.0, 15.6.
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over anhydrous MgSO4, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel to
give compound M-4 as a colorless oil (0.60 g, 2.19 mmol). Yield:
column chromatography on silica gel to give compound 19 as a white
solid (1.01 g, 2.67 mmol). Yield: 98.1%. mp: 114−115 °C. H NMR
1
(400 MHz, CDCl3): δ 8.45 (d, J = 1.0 Hz, 1H), 7.50−7.47 (m, 2H),
7.42−7.37 (m, 2H), 7.36−7.32 (m, 2H), 7.25 (s, 1H), 5.19 (s, 2H),
3.97 (s, 3H), 3.96 (s, 3H), 3.77 (dt, J = 13.6 and 6.8 Hz, 1H), 2.81 (s,
3H), 1.35 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 167.7,
158.5, 155.8, 145.3, 137.5, 129.6, 128.6, 128.5, 127.9, 127.5, 124.7,
120.2, 119.6, 113.2, 104.2, 71.9, 55.5, 52.1, 29.0, 23.7, 14.5. HRMS
(ESI): m/z calculated for C24H27O4 [M + H]+, 379.1904; found,
379.1908.
1
53.6%. H NMR (400 MHz, CDCl3): δ 7.48 (s, 1H), 6.76 (s, 1H),
4.42 (s, 2H), 3.83 (s, 3H), 3.41 (s, 3H), 3.34 (dt, J = 13.7 and 6.9 Hz,
1H), 1.24 (d, J = 6.9 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 156.7,
147.5, 132.6, 126.1, 114.4, 108.6, 68.8, 58.5, 55.6, 33.1, 22.9.
Compound 17 was synthesized using the same procedure of
compound 15, except that the reactant M-3 was replaced by
compound M-4. Compound 17: slight yellow solid. Yield: 74.0%.
mp: 91−92 °C. 1H NMR (400 MHz, CDCl3): δ 9.71 (s, 1H), 8.43 (s,
1H), 7.60 (s, 1H), 7.23 (s, 1H), 5.09 (s, 2H), 3.98 (s, 3H), 3.96 (s,
3H), 3.84 (dt, J = 13.8 and 6.9 Hz, 1H), 3.52 (s, 3H), 1.41 (d, J = 6.9
Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 166.4, 156.0, 153.2, 149.1,
128.4, 127.7, 124.9, 117.6, 112.5, 111.9, 109.1, 76.4, 76.0, 75.7, 64.1,
56.2, 55.7, 51.1, 28.3, 22.6. HRMS (ESI): m/z calculated for
C18H22NaO5 [M + Na]+, 341.1359; found, 341.1361.
Compound 18 was synthesized using the same procedure of
compound 17, except that the condition of the saponification reaction
in the last step is heating reflux. Compound 18: yellow solid. mp:
181−183 °C. 1H NMR (400 MHz, DMSO-d6): δ 12.49 (s, 1H), 7.84
(s, 1H), 7.09 (s, 1H), 6.93 (s, 1H), 4.35 (s, 1H), 3.83 (s, 3H), 3.26 (s,
3H), 3.18 (s, 2H), 3.05−2.96 (m, 1H), 1.18 (d, J = 6.7 Hz, 6H). 13C
NMR (100 MHz, DMSO-d6): δ 172.6, 168.8, 157.8, 148.5, 139.7,
129.1, 128.0, 125.1, 124.0, 108.0, 68.7, 58.1, 55.8, 33.8, 30.5, 23.5.
HRMS (ESI): m/z calculated for C17H20NaO5 [M − H]+, 303.1238;
found, 303.1241.
To a solution of compound 19 (0.30 g, 0.79 mmol) in
tetrahydrofuran (20 mL), LiAlH4 (0.06 g, 1.59 mmol) was added.
After stirring at room temperature for 1 h, 2 M hydrochloric acid was
added at 0 °C until the floccule disappeared. The aqueous phase was
separated and extracted with ethyl acetate (20 mL × 2). The organic
layer was washed with brine, dried over anhydrous MgSO4, and
concentrated under reduced pressure to give the crude product. A
mixture of the crude product, 12 M hydrochloric acid (0.05 mL), and
10% Pd/C (0.03 g) in methanol (25 mL) was stirred under hydrogen
(1 atm) at room temperature for 2 h. The solution was filtrated and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel and eluted with petroleum ether (60−
90 °C) and ethyl acetate (50:1, v/v) to give compound 20 as a white
1
solid (0.17 g, 0.72 mmol). Yield: 89.5%. mp: 84−85 °C. H NMR
(400 MHz, CDCl3): δ 7.44 (s, 1H), 7.02 (s, 1H), 6.69 (s, 1H), 4.79
(s, 1H), 3.93 (s, 3H), 3.66 (dt, J = 13.5 and 6.8 Hz, 1H), 2.75 (s, 3H),
2.50 (s, 3H), 1.38 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3):
δ 158.0, 150.1, 143.0, 132.4, 129.6, 125.0, 115.6, 114.3, 113.8, 108.3,
55.5, 28.6, 23.5, 22.1, 14.1. HRMS (ESI): m/z calculated for
C16H21O2 [M + H]+, 245.1536; found, 245.1534.
General Procedure for the Synthesis of the Derivatives 19−
23. To a solution of compound M-1 (26.18 g, 114.25 mmol) in
acetone (250 mL), K2CO3 (26.01 g, 188.2 mmol) and benzyl
bromide (15.6 mL, 22.45 g, 131.1 mmol) were added. After stirring at
room temperature for 12 h, acetone was evaporated in vacuo. The
residue was taken into water (150 mL) and petroleum ether (200
mL), separated, and extracted with petroleum ether (200 mL × 2).
The organic layer was washed with brine, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel to give compound
To a solution of compound 19 (0.30 g, 0.79 mmol) in ethyl acetate
(20 mL), 10% Pd/C (0.03 g) was added. The mixture was stirred
under hydrogen (1 atm) at room temperature for 7 h. The solution
was filtrated and concentrated in vacuo. The residue was purified by
column chromatography on silica gel to give compound 21 as a white
solid (0.204 g, 0.71 mmol). Yield: 89.9%. mp: 209 °C. 1H NMR (400
MHz, CDCl3): δ 8.44 (d, J = 0.9 Hz, 1H), 7.37 (d, J = 0.9 Hz, 1H),
7.08 (s, 1H), 3.98−3.94 (m, 6H), 3.77−3.69 (m, 1H), 2.74 (s, 3H),
1.36−1.34 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 167.8, 158.1,
153.1, 145.8, 129.7, 128.4, 124.3, 119.8, 114.9, 114.4, 104.6, 55.5,
52.2, 28.7, 23.7, 14.1. HRMS (ESI): m/z calculated for C17H21O4 [M
+ H]+, 289.1434; found, 289.1432.
1
M-6 as orange oil (39.31 g, 123.1 mmol). Yield: 98.5%. H NMR
(400 MHz, CDCl3): δ 7.45−7.36 (m, 4H), 7.34−7.31 (m, 1H), 7.30
(s, 1H), 6.77 (s, 1H), 5.06 (s, 2H), 3.29 (dt, J = 13.7 and 6.9 Hz, 1H),
2.21 (s, 3H), 1.20 (s, 3H), 1.18 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 156.4, 145.4, 137.2, 134.2, 129.1, 128.8, 128.6, 127.9,
127.3, 126.7, 114.3, 110.1, 70.2, 32.9, 22.9, 15.7.
Compound 22 was synthesized using the same procedure of
compound 21, except that the reactant was replaced by compound M-
Compound M-7 was synthesized as the same procedure of
compound 14, except that the reactant M-2 was replaced by
compound M-6. Compound M-7: yellow solid. Yield: 68.6%. mp:
1
7. Compound 22: gray solid. Yield: 91.8%. mp: 177−179 °C. H
NMR (400 MHz, CDCl3): δ 8.73 (d, J = 1.4 Hz, 1H), 7.65 (d, J = 1.4
Hz, 1H), 7.04 (s, 1H), 5.62 (s, 1H), 3.96 (s, 3H), 3.72 (dt, J = 13.6
and 6.8 Hz, 1H), 2.58 (s, 3H), 2.41 (s, 3H), 1.32 (d, J = 6.8 Hz, 6H).
13C NMR (100 MHz, CDCl3): δ 170.2, 167.0, 153.9, 147.4, 146.6,
131.2, 128.8, 125.2, 123.9, 119.8, 115.4, 112.0, 52.3, 28.7, 23.6, 21.6,
12.7. HRMS (ESI): m/z calculated for C18H21O5 [M + H]+,
317.1384; found, 317.1388.
1
127 °C. H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H), 7.65 (s, 1H),
7.49−7.44 (m, 2H), 7.40 (t, J = 7.0 Hz, 2H), 7.35 (d, J = 7.0 Hz, 1H),
7.28 (s, 1H), 7.26 (s, 1H), 5.21 (s, 2H), 3.96 (s, 3H), 3.85−3.76 (m,
1H), 2.67 (s, 3H), 2.41 (s, 3H), 1.39−1.32 (m, 6H).
Compound M-7 (2.00 g, 4.92 mmol) was dissolved in methanol
(30 mL) and water (10 mL), and then a solution of NaOH (0.40 g,
9.84 mmol) in water was added. The mixture was stirred until the
material disappeared. After cooling, methanol was evaporated in
vacuo. The residue was added with 2 M hydrochloric acid to make pH
≈ 2 and extracted with ethyl acetate (20 mL × 2). The organic layer
was washed with brine, dried over anhydrous MgSO4, and
concentrated under reduced pressure to give compound M-8 (1.74
g, 4.78 mmol) as a faint yellow solid. Yield: 97.3%. mp: 201−203 °C.
1H NMR (400 MHz, CDCl3): δ 8.42 (d, J = 1.0 Hz, 1H), 7.49 (d, J =
7.2 Hz, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.37−7.31 (m, 2H), 7.25 (s,
1H), 5.74 (s, 1H), 5.20 (s, 2H), 3.96 (s, 3H), 3.75 (dt, J = 13.6 and
6.8 Hz, 1H), 2.87 (s, 3H), 1.34 (d, J = 6.8 Hz, 6H).
To a solution of compound M-8 (0.35 g, 0.96 mmol) in methanol
(20 mL), 10% Pd/C (0.04 g) was added. The mixture was stirred
under hydrogen (1 atm) at room temperature for 4 h. The solution
was filtrated and concentrated in vacuo to give compound 23 as a gray
1
solid (0.26 g, 0.95 mmol). Yield: 98.5%. mp: 180−181 °C. H NMR
(400 MHz, DMSO-d6): δ 9.94 (s, 1H), 9.60 (s, 1H), 8.17 (d, J = 1.2
Hz, 1H), 7.30 (d, J = 1.2 Hz, 1H), 7.18 (s, 1H), 3.87 (s, 3H), 3.61
(dt, J = 13.6 and 6.8 Hz, 1H), 2.69 (s, 3H), 1.31 (d, J = 6.8 Hz, 6H).
13C NMR (100 MHz, DMSO-d6): δ 166.7, 155.6, 154.0, 144.0, 128.6,
127.3, 123.2, 117.0, 114.9, 114.3, 107.7, 51.9, 28.1, 23.4, 14.0. HRMS
(ESI): m/z calculated for C16H19O4 [M + H]+, 275.1278; found,
275.1280.
To a solution of compound M-8 (1.00 g, 2.72 mmol) in N,N-
dimethylformamide (30 mL), K2CO3 (1.13 g, 8.16 mmol) and CH3I
(0.33 mL, 0.93 g, 5.45 mmol) were added. After stirring at room
temperature for 3 h, water was added and extracted with
dichloromethane (100 mL × 2). The organic layer was washed
with water (100 mL × 3) and brine, dried over anhydrous MgSO4,
and concentrated under reduced pressure. The residue was purified by
Biological Assay. The anti-TMV, insecticidal, and fungicidal
activities of the compounds have been performed using our previously
reported methods.21,22
The effects of tested compounds on cancer cell lines were assessed
by the sulforhodamine B assay as previously described.23 Cells were
seeded into 96-well plates and grown for 24 h. The cells were then
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Scheme 1. Synthesis of Compounds 5−8
Scheme 2. Synthesis of Compound 12
Scheme 3. Synthesis of Compounds 14−16
Scheme 4. Synthesis of Compounds 17 and 18
treated with the compounds and grown for a further 72 h. The
antiproliferative activity was expressed as IC50, determined by the
Logit method from at least three independent experiments.
In the synthesis of hemigossypol acid derivatives 5−8
(Scheme 1), trimethoxyl hemigossypol (2) was used as the
starting material and oxidized aldehyde to carboxylic acid to
give compound 5 by Pinnick oxidation. Selection of the HClO
scavenger is very important to this reaction. When 2-methyl-2-
butene is used as the scavenger, no side reactions occur, but
with other scavengers, such as sulfamic acid and H2O2, the
naphthalene nucleus was partly or completely destroyed. The
demethylation of compound 5 by BBr3 gave hemigossypol acid
RESULTS AND DISCUSSION
■
Chemistry. Hemigossypol and its derivatives 1−4, 9−11,
and 13 (Figure 2) were prepared with our previously reported
method.24
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Scheme 5. Synthesis of Compounds 19−23
lactone (7) rather than hemigossypol acid. It was reacted with
benzyl bromide to produce compound 8. Trimethoxyl
hemigossypol acid methyl ester (6) was obtained by
esterification of compound 5.
Dinaphthol (12) (Scheme 2) can be obtained from
derivative 10 by two-stage reductions with LiAlH4 and then
hydrogen and Pd/C.
Generally, all of the analogues exhibited good antiviral
activity against TMV both in vitro and in vivo, and some of
them showed even higher antiviral activity than ribavirin. The
SARs showed the same tendency in the four test modes. In
other words, compounds that exhibited higher in vitro activity
also exhibited higher protection, inactivation, and curative
activities in vivo.
Hemigossypol (1) exhibited obviously higher activity than
gossypol at two concentrations. Its derivatives (2−13)
displayed different activity levels. Compound 2 whose hydroxyl
groups were protected with a methyl group showed lower
activity than hemigossypol. The different C-8 substituent
groups had a significant impact on the anti-TMV activity;
introduction of hydroxymethyl and ester reduced activity
levels, while methyoxylmethyl and carboxy groups increased
the activity. Hemigossypol acid lactone (7) exhibited higher
activities (67.8, 70.3, 65.4, and 72.4% at 500 μg/mL) than
hemigossypol, but the activity level decreased obviously when
hydroxyls were protected with benzyl (8). The compounds 9−
12, whose substituent group on the C-8 position is methyl, also
displayed anti-TMV activity, and increasing the number of
hydroxyls had beneficial effects on the antiviral activity (12 >
11 > 9 > 10). Compound 12 exhibited even slightly higher
activity than hemigossypol. The dimer (13) of compound 11,
whose skeleton is not a flat structure, showed low activity at
two concentrations.
On the whole, the derivatives 14−23 without a functional
group at the C-6 position had a lower activity level than
compounds 2−13. However, all of the compounds that had
hydroxyl on the C-1 position, except compound 17, displayed
nearly equivalent activity, with hemigossypol at 500 μg/mL.
Fungicidal Activities. These compounds also exhibited
good fungicidal activities against 14 kinds of plant fungi (Table
2). Hemeigossypol displayed excellent fungicidal activity
against all of the tested fungi. Its derivatives 2, 3, 7 and 11
showed slightly lower activity than it, whereas they were more
The derivatives 14−23 were synthesized using Stobbe
condensation, electrophilic cyclization, and selective reduction
as key steps. The preparation of them was shown in Schemes
3−5.
Bromination of carvacrol and protection of the hydroxyl
group using iodomethane gave intermediate M-2. Halogen−
lithium exchange of compound M-2 followed by formylation,
Stobbe condensation with dimethyl succinate, and electrophilic
cyclization with sodium acetate afforded compound 14.
Substituted naphthalen-1-yl acetate (14) was hydrolyzed to
obtained naphthol (15), which was reduced with lithium
aluminum hydride to produce compound 16. (Scheme 3) For
the synthesis of compounds 17 and 18, compound M-2 is first
oxidized to compound M-3, and then the same steps as
compounds 14 and 15 were employed (Scheme 4).
After benzylation of compound M-1, the intermediates M-7
and M-8 could be obtained with the similar steps as above.
Compound M-8 was methylated with CH3I to produce
compound 19. Compounds M-7, M-8, and 19 could be
reduced with different conditions to obtain compounds 20−23
(Scheme 5).
All synthesized compounds, except for compound 16, were
stored in the air at room temperature for 3 days, and the
chemical structure confirmed by NMR and appearance
remained unchanged.
Antiviral Biological Assay. The derivatives of hemi-
gossypol were evaluated for their antiviral activities against
TMV (Table 1). Gossypol and ribavirin were used as controls.
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Table 1. In Vitro and In Vivo Antiviral Activity against TMV
in vivo activity
compound
concentration (μg/mL)
in vitro curative effect (%)
inactivation effect (%)
curative effect (%)
protection effect (%)
1
2
3
4
5
6
7
8
9
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
46.9
20.7
41.7
9.8
35.7
0
55.9
26.7
39.8
10
36.5
8.4
53.2
18.3
50.8
26.4
49.6
17.9
70.3
33.6
44.4
15.5
36.9
12.7
25.3
0
49.8
18.3
36.2
15.2
30.2
0
48.9
20.5
48.5
19.2
43.9
0
65.4
30.1
41.3
19.8
40.4
6.6
25.9
0
48.6
18.8
51
14.3
31.3
0
28.7
6.9
48.6
22.4
38.3
8.3
31.3
0
56.8
24.8
46.6
22.5
31.5
0
72.4
36.2
50.2
14.7
34.1
8.1
28.6
0
45.7
24.4
55.8
18
28.6
0
34.2
0
44.5
0
38.3
16.6
42.4
8.9
35.7
16.3
58.4
16.4
42
15.2
43.7
19.1
32
51
15.6
43.2
21.4
37.6
0
67.8
37.9
40.3
8.9
32.3
0
21.5
0
45.6
21.3
47.2
19.7
27.2
0
38.1
0
46.1
19.3
27.5
0
32.7
0
37.1
0
44.2
0
48.2
13.3
42.2
15.4
33.3
0
42.3
10
32.4
0
10
11
49
23.4
53.9
22.5
30
0
34.5
0
43.8
9.1
32.4
0
35
0
12
13
14
15
39.8
13.5
31.7
0
36.1
10.3
33.9
0
16
17
18
30.8
8.9
19
52.8
13.6
48.9
26.3
46.8
11.7
38.3
7.9
50.3
0
20
46.1
20.9
43.9
14.5
36.2
10.4
39.4
13.3
29.1
0
21
22
0
23
36
39.1
12.6
28.6
0
39.5
18.2
57.2
20.5
15.8
35.3
7.7
37.5
12.1
65.2
24.3
gossypol
ribavirin
ningnanmycin
38.4
14.3
70.0
32.5
37.2
16.6
69.6
35.2
stable and more suitable as new lead compounds. On the
whole, the derivatives without a functional group at the C-6
position (20−23) had a lower activity level than compounds
1−3, 5, 6, 7, and 9−13. That is to say, the hydroxy or methoxy
group on the C-6 position was important to fungicidal
activities.
Insecticidal Activities. The insecticidal activities of the
target compounds 1, 2, 5, 7, 9, 10, and 13 against oriental
armyworm (Mythimna separata), cotton bollworm (Helicoverpa
armigera), corn borer (Ostrinia nubilalis), diamondback moth (
Plutella xylostella), and mosquito larvae (Culex pipiens pallens)
are listed in Table 3, with commercial species rotenone as the
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Table 2. Fungicidal Activities of Hemigossypol and Vergosin Derivatives against 14 Kinds of Phytopathogens
a
fungicidal activity (%)/50 mg/kg
compound
Rc
Fg
Ss
As
Pp
Fc
Rs
Fm
Pi
Rs
Pc
Bm
Ca
Wa
1
2
3
5
6
7
9
10
11
12
13
20
21
22
23
96.8
87.1
83.9
67.7
45.2
98.3
45.2
16.1
90.3
48.3
38.7
85.0
48.3
63.3
73.3
32.3
85.3
52.9
70.6
41.2
47.1
40.0
32.4
23.5
44.1
20.0
23.5
60.0
40.0
20.0
20.0
41.2
82.2
45.2
58.9
43.8
50.7
78.9
39.7
23.3
49.3
13.2
30.1
17.1
19.7
13.2
22.4
23.3
78.6
57.1
57.1
57.1
71.4
55.0
57.1
50.0
71.4
30.0
50.0
50.0
45.0
35.0
35.0
71.4
76.1
80.4
76.1
65.2
65.2
67.4
65.2
76.1
76.1
30.2
69.6
46.5
39.5
34.9
48.8
87.0
75.0
50.0
50.0
41.7
54.2
79.4
54.2
25.0
41.7
8.8
50.0
23.5
2.9
5.9
17.6
16.7
67.9
65.4
50.6
37.0
43.2
72.5
18.5
16.0
67.9
45.1
24.7
68.6
43.1
43.1
62.7
12.3
66.7
61.1
27.8
22.2
27.8
30.0
33.3
33.3
50.0
10.0
38.9
30.0
20.0
5.0
66.7
33.3
38.1
23.8
23.8
61.1
23.8
14.3
33.3
33.3
23.8
38.9
16.7
11.1
16.7
23.8
66.0
49.1
50.9
35.8
32.1
39.2
13.2
26.4
47.2
19.6
32.1
39.2
33.3
19.6
45.1
22.6
65.4
57.7
61.5
53.8
57.7
52.6
50.0
46.2
69.2
15.8
53.8
10.5
5.3
65.0
50.0
45.0
10.0
20.0
22.6
5.0
54.5
54.5
45.5
45.5
36.4
59.3
45.5
45.5
63.6
22.2
72.7
48.1
14.8
7.4
50.0
50.0
36.4
18.2
18.2
26.7
13.6
4.5
45.5
13.3
13.6
30.0
13.3
13.3
23.3
18.2
5.0
45.0
19.4
15.0
48.4
16.1
6.5
29.0
15.0
100
10.5
10.5
53.8
15.0
33.3
<50
18.5
54.5
<50
gossypol
carbendazim
100
100
100
<50
<50
<50
<50
100
100
<50
100
a
Rc, Rhizoctonia cerealis; Fg, Fusarium graminearum; Ss, Sclerotinia sclerotiorum; As, Alternaria solani; Pp, Physalospora piricola; Fc, Fusarium
oxysporium f. sp. cucumeris; Rs, Rhizoctonia solani; Fm, Fusarium moniliforme; Pi, Phytophthora infestans; Rs, Rhizoctonia solani; Pc, Phytophthora
capsici; Bm, Bipolaris maydis; Ca, Cercospora arachidicola Hori; and Wa, watermelon anthracnose.
Table 3. Insecticidal Activities of Hemigossypol Derivatives against Five Kinds of Insects
M. separata
a
H. armigera
a
O. nubilalis
a
P. xylostella
a
C. pipiens pallens
a
a
a
compound
C
(mg/kg)
P
(%)
P
(%)
P
(%)
P
(%)
C
(mg/kg)
P
(%)
1
2
5
600
600
600
15
5
70
25
30
40
25
45
40
50
0
60
10
10
10
5
10
5
35
30
100
50
100
100
100
100
100
60
10
20
65
100
100
100
100
20
7
600
50
65
75
0
2
1
0.5
0.25
10
10
10
10
5
2
1
0.5
9
10
13
rotenone
600
600
600
600
200
100
50
5
25
30
5
20
35
100
55
10
20
45
100
75
0
0
60
100
90
40
100
100
100
20
a
C, concentration; P, larvicidal activity.
control. It could be seen that all of the compounds showed the
same activity level against oriental armyworm, cotton boll-
worm, and corn borer. Only compounds 1, 5, and 13 displayed
insecticidal activity against diamondback moth at 600 mg/kg.
All of the compounds also exhibited insecticidal activity against
mosquito larvae, especially hemigossypol acid lactone (7),
showing 60% mortality at 0.25 mg/kg and higher than
rotenone.
Antitumor Activities. Hemigossypol and parts of its
derivatives were evaluated using the sulforhodamine B (SRB)
method for A549 and BEL-7402 cells. As shown in Table 4, all
of the compounds exhibited no activities against both A549
and BEL-7402. In other word, the binaphthyl framework of
gossypol is necessary for antitumor activity.
In summary, a series of hemigossypol derivatives were
designed, synthesized, and first assayed for their anti-TMV,
fungicidal, insecticidal, and antitumor activities. All of the
compounds exhibited good to excellent anti-TMV activities.
Hemigossypol (1) displayed higher activity than gossypol at
two concentrations. Especially, the anti-TMV activities of
hemigossypol acid lactone (7) were much higher than those of
ribavirin, and its stability were better than hemigossypol;
therefore, it can be used as a lead structure for the
development of anti-TMV drugs. Moreover, some of these
compounds, especially compounds 1, 2, 3, 7, and 11, exhibited
good fungicidal activity against 14 kinds of fungi. Most of the
compounds also displayed insecticidal activities. Especially,
compound 7 showed 60% mortality against mosquito larvae at
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Table 4. Inhibition Rate and IC50 of Hemigossypol and Its Derivatives against A549 and BEL-7402
A549
inhibition rate (%)
BEL-7402
inhibition rate (%)
1
compound
10
1
0.1
0.19
IC50 (μM)
10
0.1
IC50 (μM)
1
2
3
5
7
9
10
11
−3.39
3.11
−1.04
−6.55
−1.75
−5.42
−3.52
−16.82
0.78
−1.46
−1.15
77.50
>10
>10
>10
>10
>10
>10
>10
>10
6.25
0.1
−3.74
−5.11
−3.09
−7.83
0.78
−6.77
−1.17
−3.57
69.81
95.89
−2.54
−7.50
−2.52
−7.29
−2.59
−7.78
−3.33
−5.13
44.33
62.31
−2.65
−5.91
−2.54
−3.71
−4.20
−8.34
−6.60
−5.74
3.87
>10
>10
>10
>10
>10
>10
>10
>10
5.4
−7.21
−1.64
−4.04
−5.14
−16.80
−3.68
−1.91
−16.03
49.46
−0.85
−3.29
−1.11
−11.03
1.67
−3.14
70.79
92.49
gossypol acetic acid
ADR
27.64
0.47
0.25 μg/mL. All of the compounds exhibited no antitumor
activities, which suggests that the binaphthyl framework of
gossypol is necessary. Further studies on structural optimiza-
tion are in progress in our laboratory.
https://pubs.acs.org/10.1021/acs.jafc.0c06058
Funding
The authors are grateful to the National Natural Science
Foundation of China (21732002 and 21772104), the Key
Research Project of Jiangxi Province (20192BBF60038), and
the Science and Technology Program of Jiangxi Academy of
Sciences (2020-YZD-1) for generous financial support for our
programs.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jafc.0c06058.
Spectra data of compounds 5−8, 12, and 14−23 (PDF)
Notes
The authors declare no competing financial interest.
AUTHOR INFORMATION
■
Corresponding Authors
REFERENCES
■
Ling Li − Institute of Applied Chemistry, Jiangxi Academy of
Sciences, Nanchang, Jiangxi 330096, People’s Republic of
China; State Key Laboratory of Elemento-Organic Chemistry,
Research Institute of Elemento-Organic Chemistry, College of
Chemistry, Collaborative Innovation Center of Chemical
Science and Engineering (Tianjin), Nankai University,
Tianjin 300071, People’s Republic of China; orcid.org/
0000-0002-8444-5765; Phone: 0086-791-88133587;
Email: liling@jxas.ac.cn
Qingmin Wang − State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry,
College of Chemistry, Collaborative Innovation Center of
Chemical Science and Engineering (Tianjin), Nankai
University, Tianjin 300071, People’s Republic of China;
orcid.org/0000-0002-6062-3766; Phone: 0086-22-
23503952; Email: wangqm@nankai.edu.cn
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Authors
Jiyong Zou − Institute of Applied Chemistry, Jiangxi Academy
of Sciences, Nanchang, Jiangxi 330096, People’s Republic of
China; orcid.org/0000-0003-1074-2879
Changjiang Xu − Institute of Applied Chemistry, Jiangxi
Academy of Sciences, Nanchang, Jiangxi 330096, People’s
Republic of China
Shengyong You − Institute of Applied Chemistry, Jiangxi
Academy of Sciences, Nanchang, Jiangxi 330096, People’s
Republic of China
Yongqiang Li − State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry,
College of Chemistry, Collaborative Innovation Center of
Chemical Science and Engineering (Tianjin), Nankai
University, Tianjin 300071, People’s Republic of China
Complete contact information is available at:
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