Discovery of Topsentin Alkaloids and Their Derivatives as Novel Antiviral and Anti-phytopathogenic Fungus Agents

Article abstract of DOI:10.1021/acs.jafc.6b04020

Topsentin alkaloids and their derivatives were designed, synthesized, and characterized on the basis of NMR and mass spectroscopy. The antiviral activities against tobacco mosaic virus (TMV) and anti-phytopathogenic fungus activities of these alkaloids were evaluated for the first time. Alkaloids 1c, 1e, 2b, and 2d displayed significantly higher antiviral activities against TMV than Ribavirin, emerging as new lead compounds for anti-TMV research. Further fungicidal activity tests against 14 kinds of phytopathogenic fungi revealed that these alkaloids displayed broad-spectrum fungicidal activities. Topsentin derivative 2d with 4-5 mg/kg EC₅₀ values against Sclerotinia sclerotiorum (Lib.), Rhizoctonia solani (Kuhn), and Botrytis cinerea (Pers.) emerged as a new lead compound for fungicidal research. Current studies provide support for the application of topsentin alkaloids as novel agrochemicals.

Full text of DOI:10.1021/acs.jafc.6b04020

Article
pubs.acs.org/JAFC
Discovery of Topsentin Alkaloids and Their Derivatives as Novel
Antiviral and Anti-phytopathogenic Fungus Agents
†
,§
,†
§
§
§
,§
Xiaofei Ji, Ziwen Wang,* Ji Dong, Yuxiu Liu, Aidang Lu, and Qingmin Wang*
†
Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Key Laboratory of Inorganic−Organic Hybrid
Functional Materials Chemistry (Tianjin Normal University), Ministry of Education, College of Chemistry, Tianjin Normal
University, Tianjin 300387, China
§
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Collaborative Innovation
Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China
*
S Supporting Information
ABSTRACT: Topsentin alkaloids and their derivatives were designed, synthesized, and characterized on the basis of NMR and
mass spectroscopy. The antiviral activities against tobacco mosaic virus (TMV) and anti-phytopathogenic fungus activities of
these alkaloids were evaluated for the first time. Alkaloids 1c, 1e, 2b, and 2d displayed significantly higher antiviral activities
against TMV than Ribavirin, emerging as new lead compounds for anti-TMV research. Further fungicidal activity tests against
1
4 kinds of phytopathogenic fungi revealed that these alkaloids displayed broad-spectrum fungicidal activities. Topsentin derivative 2d
with 4−5 mg/kg EC values against Sclerotinia sclerotiorum (Lib.), Rhizoctonia solani (Kuhn), and Botrytis cinerea (Pers.) emerged
as a new lead compound for fungicidal research. Current studies provide support for the application of topsentin alkaloids as novel
agrochemicals.
5
0
KEYWORDS: topsentin alkaloids, natural product, anti-TMV activity, antifungal activity, agrochemical
INTRODUCTION
should limit the development of pest resistance; unique modes
of action; ready absorption by plants; short environmental
■
Plant diseases, caused by viral pathogens, fungi, bacteria, and
oomycetes, always affect people’s daily life and health.
Tobacco mosaic virus (TMV) is the earliest discovered and
most well-studied plant virus. It is known to infect at least 125
individual plant species, such as tobacco, peppers, tomatos,
cucumbers, ornamental flowers, and so on. Furthermore, TMV
can be used as the template virus for the discovery of antiviral
agents for other viruses. For example, phenanthroindolizidine
alkaloids with anti-TMV activities were also found to have
good human immunodeficiency virus inhibitory effect. Banana
panama diseases, caused by the fungus Fusarium oxysporum, led
to enormous costs to the world in the 1950s. The late blight
caused by the oomycete Phytophthora infestans led to the Irish
10
1
−3
persistence; and low mammalian toxicity. In the process of
looking for novel bioactive natural products, marine organisms
attracted the attention of biochemists. Among them, sponges
3
11
are the richest phyla in biological species. Topsentins 1 and
4,5-dihydrotopsentins 2 (Figure 1) were isolated from several
marine sponges (Mediterranean Topsentia genitrix, Carribbean
3
12,13
or Korean Spongosorites sp., etc.).
These metabolites have
widely attracted the focus of biologists because of their potent
4
properties such as anti-inflammatory, antitumor, and antiviral
13−16
activities.
However, there is no report of the application of
1
these alkaloids in plant disease prevention as far as we know.
In this work, topsentin alkaloids and their derivatives were
prepared and systematically evaluated for their anti-TMV and
anti-phytopathogenic fungus activities.
1
potato famine in the 1840s. The rust diseases of wheat, caused
by rust fungi Puccinia graminis and Puccinia Striiformis, are the1
most common and widespread diseases of wheat worldwide.
Plant pathogens can propagate rapidly via wind, insects, water,
and humans over great distances. Therefore, plant diseases,
caused by viral, fungal, and bacterial pathogens, are known as
MATERIALS AND METHODS
■
Chemicals. The reagents were purchased from commercial sources
and were used as received. All anhydrous solvents were dried and
purified by standard techniques prior to use.
“
plant cancer”. The protection of plants from these diseases is
3
very difficult.
Instruments. The melting points of the synthesized compounds
were tested on an X-4 binocular microscope (Beijing Tech Instruments
Co., Beijing, China). NMR spectra were obtained on Bruker AV 400
spectrometer (Bruker Corp., Switzerland) in CDCl or DMSO-d
Ribavirin (Figure 1), a successfully registered antiviral agent, is
widely used for preventing TMV diseases. Nevertheless, the
5
antiviral effect of Ribavirin is <50% at 500 μg/mL. Due to the
unsatisfactory cure rate (30−60%) of commercial antiviral
agents, biologists have sought to develop novel and effective
3
6
solution with tetramethylsilane as the internal standard. High-resolution
6
−9
virucides. However, few virucides have yet been found. Thus,
there is a continuing need for the development of novel antiviral
agents.
Received: September 8, 2016
Revised: November 9, 2016
Accepted: November 13, 2016
Natural products and their analogues are particularly attractive
due to their advantages as follows: complex chemistries that
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.jafc.6b04020
J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
Figure 1. Structures of topsentin alkaloids and Ribavirin.
mass spectra were obtained with an FT-ICR MS spectrometer (Ionspec,
General Procedures for the Preparation of 3-(1,2-Diazidoethyl)-1-
tosyl-1H-indoles (8). Diethyl azodiformate (4.89 mmol) and diphenyl
phosphoryl (4.89 mmol) were added to the solution of ethane-1,2-diols
7
.0 T).
General Procedures for the Preparation of 2-(1H-Indol-3-yl)-2-
oxoacetyl Chlorides (4). The solution of oxalyl chloride (26 mmol)
7 (1.63 mmol) and Ph P (4.89 mmol) in toluene (100 mL). The mixture
3
in ethyl ether (40 mL) was added dropwise to the solution of indoles
was stirred at room temperature for 12 h and evaporated. The residue
3
(20 mmol) in ethyl ether (80 mL) at 0 °C. The mixture was stirred for
was purified by column chromatography on silica gel with petroleum
1
.5 h at 0 °C and then filtered to give 4 as a white powder, which was
ether/ethyl acetate (40:1 to 30:1, v/v) as eluent to give 8.
For 8a: colorless oil; yield 79%; H NMR (400 MHz, CDCl ) δ 8.00
1
used directly for the next step.
3
General Procedures for the Preparation of Ethyl 2-(1H-Indol-3-yl)-
(d, J = 8.3 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.57 (d, J =
7.9 Hz, 1H), 7.39−7.35 (m, 1H), 7.29 (d, J = 7.3 Hz, 1H), 7.24 (d, J =
8.2 Hz, 2H), 4.87 (dd, J = 7.4, 5.1 Hz, 1H), 3.69−3.58 (m, 2H), 2.34(s, 3H).
2
-oxoacetates (5). The mixture of oxoacetyl chlorides 4 (20 mmol) in
absolute ethanol (80 mL) was stirred for 0.5 h at 0 °C and then filtered
1
to give oxoacetates 5 as a white powder.
For 8b: white powder; mp 90−92 °C; yield 61%; H NMR
1
For 5a: mp 181−182 °C; yield 78%; H NMR (400 MHz, DMSO-d )
(400 MHz, CDCl ) δ 8.18 (d, J = 1.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H),
6
3
δ 12.40 (s, 1H), 8.43 (d, J = 3.3 Hz, 1H), 8.17 (dd, J = 6.6, 2.2 Hz, 1H),
7.66−7.60 (m, 1H), 7.41 (dt, J = 8.5, 5.0 Hz, 2H), 7.27 (d, J = 8.4 Hz,
2H), 4.83 (dd, J = 6.9, 5.3 Hz, 1H), 3.72−3.49 (m, 2H), 2.37 (s, 3H).
General Procedures for the Preparation of 1-(1-Tosyl-1H-indol-3-
yl)ethane-1,2-diamines (9). The mixture of 8 (2.91 mmol) and Ph3P
(6.75 mmol) in toluene (15 mL) was refluxed for 15 min and then
7
2
.56 (dd, J = 6.5, 2.0 Hz, 1H), 7.34−7.24 (m, 2H), 4.37 (q, J = 7.1 Hz,
H), 1.34 (t, J = 7.1 Hz, 3H).
For 5b: mp 174 °C (dec); yield 86%; H NMR (400 MHz, DMSO-
1
d6) δ 12.48 (s, 1H), 8.47 (d, J = 3.2 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H),
7
7
.75 (d, J = 1.5 Hz, 1H), 7.43 (dd, J = 8.5, 1.7 Hz, 1H), 4.36 (q, J =
.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).
General Procedures for the Preparation of Ethyl 2-Oxo-2-(1-Tosyl-
H-indol-3-yl)acetates (6). Tosyl chloride (5 mmol) was added to the
cooled to room temperature, and H O (1.5 mL) was added. The
2
resulting solution was stirred at reflux for 12 h and extracted with 5%
HCl solution three times (20 mL × 3). The combined aqueous phase
was washed with petroleum ether (50 mL), adjusted to basic (pH 10)
with 5% NaOH solution, and then extracted with CH Cl three times
1
solution of oxoacetates 5 (5 mmol), Et N (1.4 mmol), and DMAP
3
2
2
(
0.4 mmol) in CH Cl (40 mL). The mixture was stirred for 2 h at room
(50 mL × 3). The combined organic layer was concentrated to give
2
2
temperature, and then saturated NH Cl (50 mL) was added. The layers
were separated, and the aqueous layer was extracted with CH Cl2
1,2-diamines 9.
4
1
2
For 9a: light yellow powder; mp 104−105 °C; yield 76%; H NMR
(400 MHz, CDCl ) δ 8.00 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 7.9 Hz, 2H),
(80 mL). The combined organic layer was washed successively with
3
saturated NaHCO solution (150 mL), H O (150 mL), and brine
7.57 (d, J = 7.5 Hz, 1H), 7.52 (s, 1H), 7.36−7.29 (m, 1H), 7.26 (d, J =
3
2
(
150 mL) and then dried over Na SO anhydrous, filtered, and concen-
8.1 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 4.30−4.12 (m, 1H), 3.10−3.01
2 4
trated to give acetates 6.
(m, 1H), 2.96−2.80 (m, 1H), 2.34 (s, 3H), 1.60 (brs, 4H).
1
1
For 6a: light brown powder; mp 108−110 °C; yield 94%; H NMR
For 9b: light yellow oil; yield 62%; H NMR (400 MHz, CDCl ) δ
3
(
400 MHz, CDCl ) δ 8.85 (s, 1H), 8.36 (d, J = 7.2 Hz, 1H), 7.96 (d, J =
8.17 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.49 (s, 1H), 7.45 (d, J = 8.4 Hz,
1H), 7.33 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 4.24−4.12 (m,
1H), 3.02 (dd, J = 12.8, 4.4 Hz, 1H), 2.83 (dd, J = 12.7, 6.9 Hz, 1H), 2.36
(s, 3H), 1.64 (brs, 4H).
General Procedures for the Preparation of 2-(1H-Indol-3-yl)-2-
oxoacetaldehydes (10). The solution of tributyltin hydride (50 mmol)
in ethyl acetate (75 mL) was added dropwise to the solution of oxoacetyl
chlorides 4 (50 mmol) in ethyl acetate (50 mL) at 0 °C under an Ar
atmosphere. The mixture was stirred at 0 °C for 30 min and at room
temperature for 15 h; petroleum ether (500 mL) was added and then
filtered to afford 2-oxoacetaldehydes 10 as a yellow powder, which was
used directly for the next step.
3
8
.0 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.44−7.35 (m, 2H), 7.30 (d, J =
8.0 Hz, 2H), 4.46 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H).
1
For 6b: white powder; mp 141−142 °C; yield 77%; H NMR (400
MHz, CDCl ) δ 8.82 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 8.13 (d, J =
1
3
.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.48 (dd, J = 6.8, 1.6 Hz, 1H), 7.34
(
d, J = 8.0 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.46 (t, J =
6.4 Hz, 3H).
General Procedures for the Preparation of 1-(1-Tosyl-1H-indol-3-
yl)ethane-1,2-diols (7). NaBH (10 mmol) was added to the solution of
acetates 6 (2 mmol) in MeOH (40 mL) at 0 °C. The mixture was stirred
at room temperature for 12 h, and then saturated NH Cl (100 mL)
was added. The solution was extracted with ethyl acetate three times
4
4
General Procedures for the Preparation of 4,5-Dihydrotopsentins
2. The solution of 1,2-diamines 9 (1.65 mmol) in acetonitrile (30 mL)
was added to the solution of 2-oxoacetaldehydes 10 (1.5 mmol) in
acetonitrile (20 mL). Then the mixture was stirred for 30 min at 0 °C,
and the solution of NCS (1.65 mmol) in acetonitrile (20 mL) was
added. The mixture was stirred at room temperature for 12 h, saturated
aqueous Na S O solution (10 mL) was added, and then the solution
(
80 mL × 3). The combined organic layer was washed successively
with saturated NaHCO solution (150 mL), H O (150 mL), and brine
3
2
(
150 mL) and then dried over MgSO anhydrous, filtered, and concen-
4
trated to give ethane-1,2-diols 7.
1
For 7a: light brown powder; mp 87−89 °C; yield 90%; H NMR
(
400 MHz, CDCl ) δ 7.97 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 2H),
3
2
2
3
7.59 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.22
was concentrated. To the residue was added saturated aqueous
(
3
t, J = 7.7 Hz, 1H), 7.19 (d, J = 7.7 Hz, 2H), 5.05−5.03 (m, 1H), 3.89−
NaHCO solution (50 mL), followed by filtration to give 11. The
solution of 11 and 2 N NaOH (21.32 mmol) in MeOH (3 mL) was
3
.78 (m, 2H), 2.45 (brs, 2H), 2.31 (s, 3H).
1
For 7b: light brown oil; yield 98%; H NMR (400 MHz, CDCl ) δ
stirred at 70 °C for 30 min, and H O (50 mL) was added. The mixture
3
2
8.06 (s, 1H), 7.65 (d, J = 7.5 Hz, 2H), 7.59 (s, 1H), 7.31−7.20 (m, 1H),
7.20−7.11 (m, 1H), 7.03 (d, J = 7.3 Hz, 2H), 4.96 (s, 1H), 4.42 (s, 1H),
4.08−4.04 (m, 2H), 4.02−3.73 (m, 2H), 2.19 (s, 3H).
was extracted with ethyl acetate three times (60 mL × 3). The combined
organic layer was washed successively with H O (100 mL) and brine
2
(100 mL) and then dried over MgSO4 anhydrous, filtered, and
B
DOI: 10.1021/acs.jafc.6b04020
J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Journal of Agricultural and Food Chemistry
Article
Figure 2. Synthesis of intermediate 9.
concentrated. The residue was purified by column chromatography on
silica gel with dichloromethane as eluent to give 2.
For topsentin D (2a): yellow powder; mp 222−225 °C; yield 35%;
1
H NMR (400 MHz, DMSO-d ) δ 12.15 (s, 1H), 10.98 (s, 1H), 8.90 (s,
6
1
1
6
3
1
1
H), 8.28 (d, J = 5.5 Hz, 1H), 7.58−7.56 (s, 2H), 7.40 (d, J = 8.4 Hz,
H), 7.32 (s, 1H), 7.26 (dd, J = 4.8, 2.6 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H),
.97 (t, J = 7.3 Hz, 1H), 5.36 (t, J = 9.2 Hz, 1H), 4.19−4.14 (m, 1H),
13
.79−3.63 (m, 1H); C NMR (100 MHz, DMSO-d ) δ 179.6, 162.0,
6
38.4, 136.8, 136.4, 126.1, 125.5, 123.2, 122.5, 122.4, 121.3, 121.1, 118.9,
18.5, 117.1, 113.7, 112.5, 111.7, 27.7, 26.3; HRMS (ESI) calcd for
Figure 3. Synthesis of 10.
+
C H N O (M + H) 329.1397, found 329.1405.
20
17
4
1
For spongotine A (2b): yellow powder; mp 254−256 °C; yield 51%;
For topsentin A (1a): yellow powder; mp 291−293 °C; yield 19%; H
1
H NMR (400 MHz, DMSO-d ) δ 12.11 (s, 1H), 11.11 (s, 1H), 8.89 (s,
6
NMR (400 MHz, DMSO-d + 1% TFA) δ 14.34 (brs, TFA), 12.53 (s,
6
1
7
H), 8.27 (s, 1H), 7.57 (s, 1H), 7.52 (br, 2H), 7.34 (s, 1H), 7.25 (s, 2H),
1H), 11.67 (s, 1H), 8.91 (s, 1H), 8.34−8.36 (m, 1H), 8.13−8.04 (m,
13
.10 (d, J = 7.2 Hz, 1H), 5.32 (m, 1H), 4.03 (m, 1H), 3.62 (m, 1H);
C
3H), 7.63−7.60 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.36−7.31 (m, 2H),
13
NMR (100 MHz, DMSO-d ) δ 180.2, 162.6, 138.8, 138.2, 136.8, 126.6,
7.26−7.18 (m, 2H); C NMR (100 MHz, DMSO-d + 1% TFA) δ
6
6
1
5
25.0, 124.0,123.7, 122.8, 121.8, 121.2, 118.1, 114.7, 114.4, 114.2, 113.0,
171.5, 140.6, 138.7, 136.8, 136.4, 130.9, 125.7, 125.7, 124.1, 124.0, 123.0,
122.3, 121.2, 120.4, 119.3, 115.8, 113.5, 112.8, 112.2, 102.3; HRMS
+
0.0, 31.2; HRMS (ESI) calcd for C H BrN O (M + H) 407.0502,
20
16
4
+
found 407.0506.
(ESI) calcd for C H N O (M + H) 327.1240, found 327.1248.
20
15
4
For topsentin B1 (topsentin) (2c): yellow powder; mp 213−215 °C;
For bromodeoxytopsentin (1b): yellow powder; mp 227 °C (dec);
yield 42%; H NMR (400 MHz, DMSO-d + 1% TFA) δ 12.46 (s, 1H),
1
1
yield 53%; H NMR (400 MHz, DMSO-d ) δ 11.97 (s, 1H), 10.98 (s,
6
6
1
(
(
H), 8.76 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.39
d, J = 8.0 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.02
d, J = 2.4 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 6.89 (dd, J = 2.0 Hz, 1H),
11.75 (s, 1H), 11.10 (brs, TFA), 8.95 (s, 1H), 8.36 (d, J = 4.9 Hz, 1H),
8.11 (s, 1H), 8.03 (s, 1H), 8.01 (d, J = 6.3 Hz, 1H), 7.72 (s, 1H), 7.60 (d,
J = 4.9 Hz, 1H), 7.32 (m, 3H); 13C NMR (100 MHz, DMSO-d + 1%
6
5
.35 (t, J = 9.6 Hz, 1H), 4.15 (m, 1H), 3.80 (s, 3H), 3.73−3.71 (m, 1H);
TFA) δ 174.0, 143.2, 137.8, 137.3, 136.5, 132.4, 126.3, 125.4, 123.5,
122.7, 122.4, 121.4, 118.2, 114.6, 113.6, 112.5, 105.7, 99.5; HRMS (ESI)
1
3
C NMR (100 MHz, DMSO-d ) δ 207.0, 179.9, 162.5, 157.1, 138.1,
6
+
1
1
(
38.0, 137.3, 126.0, 123.0, 122.4, 121.6, 120.4, 119.4, 119.0, 117.5, 114.3,
12.4, 112.2, 96.2, 55.7, 31.2; HRMS (ESI) calcd for C H N O
2
calcd for C H BrN O (M + H) 405.0346, found 405.0348.
20
14
4
1
For 1c: yellow powder; mp 245 °C (dec); yield 62%; H NMR
(400 MHz, DMSO-d + 1% TFA) δ 14.96 (brs, TFA), 12.47 (s, 1H),
2
1
19
4
+
M + H) 359.1503, found 359.1508.
6
1
For 2d: yellow powder; mp 228−230 °C; yield 27%; H NMR
400 MHz, DMSO-d ) δ 12.10 (s, 1H), 11.23 (s, 1H), 8.76 (s, 1H), 8.15
11.75 (s, 1H), 8.60 (s, 1H), 8.19−8.16 (m, 3H), 8.03 (d, J = 6.7 Hz, 1H),
(
(
7.54 (d, J = 7.1 Hz, 1H), 7.32−7.18 (m, 2H), 7.11 (s, 1H), 6.99 (d, J =
6
13
d, J = 8.8 Hz, 1H), 7.62 (s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H),
7.9 Hz, 1H), 3.85 (s, 3H); C NMR (100 MHz, DMSO-d + 1% TFA) δ
6
7
.14 (d, J = 8.4 Hz, 1H), 7.06 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.40 (t, J =
171.7, 161.9, 157.4, 141.1, 138.1, 136.6, 131.2, 125.8, 124.3, 122.5, 122.1,
120.5, 119.8, 119.5, 116.2, 113.9, 112.7, 112.4, 102.8, 96.0, 55.4; HRMS
13
1
0.0 Hz, 1H), 4.21−4.16 (m, 1H), 3.81 (s, 3H), 3.76−3.70 (m, 1H); C
+
NMR (100 MHz, DMSO-d ) δ 179.0, 162.1, 156.7, 137.7, 137.4, 124.5,
(ESI) calcd for C H N O (M + H) 357.1346, found 357.1351.
6
21 17
4
2
1
1
5
23.7, 121.9, 121.5, 120.6, 119.9, 117.1, 114.3, 114.0, 113.8, 112.0, 95.7,
For 1d: yellow powder; mp 230 °C (dec); yield 31%; H NMR
+
5.2, 30.6; HRMS (ESI) calcd for C H BrN O (M + H) 437.0608,
(400 MHz, DMSO-d + 1% TFA) δ 12.32 (s, 1H), 11.77 (s, 1H), 10.80
21
18
4
2
6
found 437.0607.
(brs, TFA), 8.74 (s, 1H), 8.02−8.16 (m, 4H), 7.72 (s, 1H), 7.31 (s, 1H),
13
General Procedures for the Preparation of Topsentins 1a−d
7.09 (s, 1H), 6.96 (s, 1H), 3.83 (s, 3H); C NMR (100 MHz, DMSO-d
6
(
Method A). IBX (1.5 mmol) was added to the solution of
+ 1% TFA) δ 171.8, 157.7, 141.3, 138.4, 138.4, 137.7, 130.8, 127.1,
4,5-dihydrotopsentins 2 (1 mmol) in DMSO (5 mL) under an Ar
123.6, 123.6, 122.4, 121.5, 120.0, 116.5, 115.5, 115.3, 114.1, 113.0, 103.2,
+
atmosphere. The solution was stirred at room temperature for 5 h,
and saturated aqueous Na S O solution (10 mL) and H O (100 mL)
were added, followed by extraction with ethyl acetate three times
96.2, 55.6; HRMS (ESI) calcd for C H BrN O (M + H) 435.0451,
21
16
4
2
2
2
3
2
found 435.0452.
General Procedures for the Preparation of Topsentins 1a and 1e
(Method B). The mixture of 2-oxoacetaldehydes 10 (10 mmol) and
ammonium acetate (70 mmol) in ethanol (20 mL) was stirred at room
temperature for 20 h under an Ar atmosphere and then concen-
trated. The residue was recrystallized from CH Cl to give topsentins 1a
(
50 mL × 3). The combined organic layer was washed successively with
2
H O (100 mL) and brine (100 mL) and then dried over MgSO4
anhydrous, filtered, and concentrated. The residue was purified by
column chromatography on silica gel with dichloromethane/methanol
2
2
(
50:1, v/v) as eluent to give topsentins 1a−d.
and 1e.
C
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Journal of Agricultural and Food Chemistry
Article
Figure 4. Synthesis of topsentins 1.
1
18.2, 116.6, 115.8, 115.3, 115.2, 113.9, 105.0; HRMS (ESI) calcd for
+
C H Br N O (M + H) 482.9451, found 482.9446.
20
13
2
4
Preparation of 1f. The mixture of 1c (0.5 g, 1.4 mmol) and AlCl3
(
1.31 g, 9.83 mmol) in CH Cl (150 mL) was stirred at 0 °C for 30 min,
2
2
and then EtSH (0.71 mL) was added. The mixture was stirred at 0 °C
for 5 h, and methanol (10 mL) was added and then concentrated.
The residue was taken into H O (100 mL) and extracted with ethyl
2
acetate three times (50 mL × 3). The combined organic layer was
washed successively with H O (100 mL) and brine (100 mL) and then
Figure 5. Synthesis of 1a and 1e.
2
dried over MgSO anhydrous, filtered, and concentrated. The residue
4
was purified by column chromatography on silica gel with dichloro-
For 1a: yield 66%.
methane/methanol (30:1, v/v) as eluent to give 1f (0.19 g, 40%): mp
For dibromodeoxytopsentin 1e: deep green powder; mp 278 °C
1
1
283−285 °C; H NMR (400 MHz, DMSO-d + 1% TFA) δ 14.79
(
(
(
8
(
dec); yield 18%; H NMR (400 MHz, DMSO-d + 1% TFA) δ 13.63
6
6
(
(
brs, TFA), 12.27 (s, 1H), 11.72 (s, 1H), 8.56 (s, 1H), 8.14 (s, 2H), 8.06
d, J = 8.6 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H),
brs, TFA), 12.63 (s, 1H), 11.80 (s, 1H), 8.90 (d, J = 2.6 Hz, 1H), 8.26
d, J = 8.6 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 8.11 (s, 1H), 8.02 (d, J =
.6 Hz, 1H), 7.83 (s, 1H), 7.74 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.32
7.23 (dt, J = 14.8, 7.0 Hz, 2H), 6.95 (s, 1H), 6.84 (d, J = 8.2 Hz, 1H);
13
13
d, J = 8.4 Hz, 1H); C NMR (100 MHz, DMSO-d + 1% TFA) δ 173.6,
C NMR (100 MHz, DMSO-d + 1% TFA) δ 171.8, 155.0, 141.4,
6
6
142.5, 139.3, 138.0, 137.8, 132.3, 126.4, 125.9, 125.6, 123.8, 123.4, 121.8,
138.1, 137.4, 136.4, 125.3, 124.1, 122.2, 121.9, 120.3, 119.4, 118.6, 116.6,
Figure 6. Synthesis of 1f.
Figure 7. Synthesis of 1g−k.
D
DOI: 10.1021/acs.jafc.6b04020
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Journal of Agricultural and Food Chemistry
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Figure 8. Tautomeric forms of topsentins 1.
Figure 9. NOE spectra and chemical shift assignment of compounds 1g and 1h.
1
16.3, 113.7, 112.8, 112.2, 110.9, 97.8; HRMS (ESI) calcd for
Preparation of 1h. The mixture of topsentin A 1a (0.49 g, 1.5 mmol)
and NaH (60%, 0.42 g, 10.5 mmol) in THF (150 mL) was stirred at 0 °C
for 15 min and at room temperature for 1 h and then cooled to 0 °C.
+
C H N O (M + H) 343.1190, found 343.1185.
Preparation of 1g. The mixture of topsentin A 1a (0.16 g, 0.5 mmol),
Et N (0.5 mL, 3 mmol), and Boc O (0.44 g, 2 mmol) in CH Cl
20
15
4
2
To the mixture was added CH I (0.47 mL, 7.5 mmol). The mixture was
3
2
2
2
3
(
150 mL) was stirred at room temperature for 5 h, and H O (100 mL)
stirred at room temperature for 1 h and then cooled to 0 °C, and then
2
was added followed by extraction with ethyl acetate three times
50 mL × 3). The combined organic layer was washed successively
saturated NH
ethyl acetate three times (80 mL × 3). The combined organic layer
was washed successively with saturated aqueous NaHCO solution
(100 mL), H O (100 mL), and brine (100 mL) and then dried over
MgSO anhydrous, filtered, and concentrated. The residue was purified
4
Cl (200 mL) was added. The solution was extracted with
(
with H O (100 mL) and brine (100 mL) and then dried over MgSO4
anhydrous, filtered, and concentrated. The residue was purified by
column chromatography on silica gel with petroleum ether/ethyl acetate
3
2
2
4
(
10:1, v/v) as eluent to give 1g (0.26 g, 83%): mp 161−162 °C;
by column chromatography on silica gel with petroleum ether/ethyl
1
H NMR (400 MHz, CDCl ) δ 8.59 (s, 1H), 8.49−8.46 (m, 1H), 8.26
(
acetate (15:1, v/v) as eluent to give 1h (0.37 g, 67%): mp 202−204 °C;
3
1
d, J = 7.7 Hz, 1H), 8.19 (d, J = 7.2 Hz, 1H), 8.05 (s, 1H), 7.99 (d, J =
H NMR (400 MHz, CDCl ) δ 9.01 (s, 1H), 8.58 (d, J = 6.4 Hz, 1H),
3
7
(
1
1
8
6
.5 Hz, 1H), 7.84 (s, 1H), 7.45−7.32 (m, 4H), 1.68 (s, 18H), 1.53
8.01 (d, J = 7.7 Hz, 1H), 7.52 (s, 1H), 7.37−7.30 (m, 4H), 7.29−7.25
(m, 1H), 7.25−7.20 (m, 2H), 4.11 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H);
s, 9H); 13C NMR (100 MHz, CDCl ) δ 179.7, 149.6, 149.0, 146.9,
3
13
45.4, 136.8, 135.9, 135.7, 135.1, 128.0, 127.7, 125.8, 124.7, 124.7, 123.6,
23.1, 122.6, 120.3, 119.0, 115.8, 115.5, 115.1, 113.7, 86.7, 85.53,
C NMR (100 MHz, CDCl ) δ 178.2, 143.4, 140.7, 137.3, 137.1, 136.3,
3
128.0, 126.5, 125.9, 123.2, 122.7, 122.7, 121.9, 121.0, 120.2, 119.8,
114.8, 109.7, 109.6, 36.3, 33.6, 32.9; HRMS (ESI) calcd for C H N O
+
4.0, 28.2, 28.1, 27.5; HRMS (ESI) calcd for C H N O (M + H)
35
39
4
7
23 21
4
+
27.2813, found 627.2804.
(M + H) 369.1710, found 369.1713.
E
DOI: 10.1021/acs.jafc.6b04020
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Article
1
1
37.2, 136.9, 132.0, 126.4, 125.8, 124.7, 124.4, 123.3, 122.8, 121.8, 120.8,
19.9, 117.1, 114.0, 113.2, 112.7.
For 1k: yellow powder; mp 268−270 °C; yield 88%; H NMR (400
Table 1. In Vitro Antiviral Activities of Ribavirin and
Topsentins 1 and 2 against TMV
1
concn
inhibition
a
concn
inhibition
a
MHz, DMSO-d ) δ 12.54 (s, 1H), 11.67 (s, 1H), 8.80 (s, 1H), 8.35−
6
compd (μg/mL)
rate (%)
compd
1i
(μg/mL)
rate (%)
8
.27 (m, 1H), 8.14 (s, 2H), 8.04 (d, J = 7.7 Hz, 1H), 7.67−7.58 (m, 1H),
1
1
1
1
1
1
1
1
a
b
c
d
e
f
500
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
34 ± 2
0
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
20 ± 2
0
7.53 (d, J = 7.9 Hz, 1H), 7.39−7.29 (m, 2H), 7.23 (dt, J = 14.9, 6.9 Hz,
2
1
1
H); 13C NMR (100 MHz, DMSO-d ) δ 172.8, 141.9, 139.0, 137.2,
1
6
36.9, 131.9, 126.4, 125.8, 124.7, 124.4, 123.3, 122.7, 121.8, 120.8, 119.9,
17.1, 114.0, 113.2, 112.7.
30 ± 2
0
1j
0
1
0
Biological Assay. Each bioassay was repeated three times at 25 ±
°C. Activity results were estimated according to a percentage scale of
−100 (0, no activity; 100, total kill).
32 ± 1
0
1k
21 ± 1
0
1
0
1
34 ± 3
0 ± 2
46 ± 1
13 ± 2
35 ± 1
0
2a
28 ± 2
0
Antiviral Biological Assay. The antiviral activities against TMV
1
and phytotoxic activities were performed using previously reported
methods.
Antifungal Biological Assay. The details of antifungal activity tests
1
7,18
2b
36 ± 3
0
1
1
9
2c
38 ± 2
0
are described in the literature.
1
g
h
36 ± 2
0
2d
47 ± 2
14 ± 2
39 ± 2
11 ± 1
RESULTS AND DISCUSSION
■
1
Chemistry. Although the synthesis of topsentins has been
40 ± 2
0
Ribavirin
14,20−23
reported in past decades,
these reported methods are
1
not suitable for structure−activity relationship study due to harsh
conditions, low yields, complex materials, or the many steps
required. A novel route for the preparation of topsentin
derivatives is needed. As shown in Figure 2, commercially
available indoles 3 reacted with oxalyl chloride to give chlorides
a
Average of three replicates; all results are expressed as the mean ± SD.
General Procedures for the Preparation of Topsentins 1i−k. The
solution of topsentin A 1a (0.21 g, 0.65 mmol) and corresponding acids
0.65 mmol) in CH Cl (20 mL) and methanol (20 mL) was refluxed
(
2
2
4
, which were treated with ethanol to obtain esters 5. Protection
for 2 h and concentrated. The residue was recrystallized from CH Cl to
2
2
of 5 and reduction gave ethane-1,2-diols 7, which underwent
Mitsunobu reaction and reduction to obtain the key inter-
mediates 9. After reduction of chlorides 4 with tributyltin
hydride, aldehydes 10 were obtained (Figure 3). As depicted
in Figure 4, condensation of 1,2-diamines 9 with aldehydes 10
gave glyoxalidines 11. Treatment of 11 with NaOH yielded
4,5-dihydrotopsentins 2, which were oxidized with IBX to afford
topsentins 1. Substrates with the same substituent (R = R ) also
can be prepared using the methods depicted in Figure 5 involving
NH OAc as the ammonia source. The demethylation of 1c was
carried out in different conditions, such as BBr , HBr, and so on.
give 1i−k.
1
For 1i: yellow powder; mp 267−270 °C; yield 94%; H NMR
(
(
400 MHz, DMSO-d ) δ 12.65 (s, 1H), 11.77 (s, 1H), 8.76 (s, 1H), 8.32
d, J = 5.4 Hz, 1H), 8.17 (s, 2H), 8.03 (d, J = 7.5 Hz, 1H), 7.64 (d, J =
6
5
.7 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.40−7.30 (m, 2H), 7.29−7.10
(
(
1
m, 2H), 2.98 (d, J = 14.7 Hz, 1H), 2.68 (t, J = 11.6 Hz, 1H), 2.65−2.47
m, 2H), 2.24 (d, J = 18.0 Hz, 1H), 1.93 (s, 1H), 1.85−1.78 (m, 2H),
13
1
2
.36−1.26 (m, 2H), 1.04 (s, 3H), 0.74 (s, 3H); C NMR (100 MHz,
DMSO-d ) δ 216.6, 172.7, 141.8, 139.0, 137.3, 136.9, 126.4, 126.0,
6
1
5
24.7, 124.4, 123.3, 122.7, 121.8, 120.8, 119.8, 117.0, 114.0, 113.3, 112.7,
8.6, 47.6, 47.3, 42.7, 42.6, 26.9, 24.6, 20.5, 20.0.
For 1j: yellow powder; mp 289−291 °C; yield 97%; H NMR
4
1
3
Using only AlCl /EtSH as demethylation agents can give the
(
400 MHz, DMSO-d ) δ 12.54 (s, 1H), 11.67 (s, 1H), 8.80 (s, 1H),
3
6
designed compound 1f in 40% yield (Figure 6). To investigate
the influence of N−H on bioactivity, compounds 1g and 1h
were designed and prepared (Figure 7). As mentioned in the
8
(
6
.35−8.27 (m, 1H), 8.14 (s, 2H), 8.04 (d, J = 7.7 Hz, 1H), 7.67−7.58
m, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.39−7.29 (m, 2H), 7.23 (dt, J = 14.9,
.9 Hz, 2H); 13C NMR (100 MHz, DMSO-d ) δ 172.8, 141.9, 139.0,
6
Table 2. In Vivo Antiviral Activities of Ribavirin and Topsentins 1 and 2 against TMV
a
a
concn
inactivation
a
curative effect
protection
a
concn
inactivation
a
curative effect
protection
a
compd
(μg/mL)
effect (%)
(%)
effect (%)
compd
1i
(μg/mL)
effect (%)
(%)
effect (%)
1
1
1
1
1
1
1
1
a
b
c
d
e
f
500
36 ± 2
0
31 ± 1
0
40 ± 2
5 ± 2
32 ± 2
0
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
29 ± 1
0
22 ± 2
0
36 ± 2
0
1
00
500
00
500
00
500
00
500
00
500
00
500
00
500
00
26 ± 2
0
36 ± 3
7 ± 2
46 ± 1
16 ± 2
27 ± 2
0
1j
14 ± 2
0
19 ± 2
0
21 ± 1
0
1
42 ± 2
19 ± 2
33 ± 1
0
42 ± 2
17 ± 1
25 ± 2
0
1k
32 ± 1
0
25 ± 2
0
35 ± 2
0
1
2a
35 ± 2
7 ± 1
44 ± 3
14 ± 2
23 ± 1
0
36 ± 2
0
31 ± 2
10 ± 1
48 ± 1
18 ± 2
36 ± 2
10 ± 2
44 ± 2
18 ± 2
37 ± 1
16 ± 1
1
42 ± 1
13 ± 2
25 ± 2
0
39 ± 3
15 ± 1
31 ± 1
0
46 ± 2
18 ± 3
34 ± 2
0
2b
40 ± 2
16 ± 2
30 ± 1
0
1
2c
1
g
h
35 ± 2
0
28 ± 2
0
30 ± 2
0
2d
40 ± 2
14 ± 3
36 ± 2
11 ± 1
42 ± 2
14 ± 2
35 ± 2
12 ± 2
1
36 ± 2
6 ± 2
25 ± 2
0
30 ± 2
0
Ribavirin
1
a
Average of three replicates; all results are expressed as mean ± SD.
F
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G
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2
3
literature, topsentins 1 have two types of mutual variations
(
against Cercospora arachidicola Hori, Physalospora piricola, and
Rhizoctonia cerealis than carbendazim. Compounds 1f, 1g, and 2d
with excellent fungicidal activities were further evaluated for their
1
Figure 8). H NMR spectra of topsentins 1 showed a splitting of
all signals, which could be suppressed by the addition of 1% of
CF COOH into the deuterated solvent. To investigate the con-
3
EC values (Table 4). Topsentin derivative 2d displayed the best
50
figuration of compounds 1g and 1h, a 2D NOESY experiment
was carried out (Figure 9). As shown in the 2D NOE spectra,
there were obvious correlation signals between δ 1.53 and 7.84
for 1g and between δ 4.07 and 7.19 for 1h, which indicated
Table 4. EC Values of Topsentins 1f, 1g, and 2d against Five
Kinds of Fungi
5
0
EC50 mg/kg
that the substituent groups CH and Boc were located at the
3
a
15-position. To investigate the influence of salification, topsentin
compd
S.S
R.S
B.C
P.P
R.C
derivatives 1i−k were designed and synthesized (Figure 7).
1
f
−
13
4
−
−
5
−
−
5
36
−
−
6
−
−
Phytotoxic Activity. The phytotoxic activities of topsentins
1g
2d
1
and 2 against the tested plant showed that these compounds are
safe at 500 μg/mL.
a
S.S, Sclerotinia sclerotiorum; R.S, Rhizoctonia solani; B.C, Botrytis
cinerea; P.P, Physalospora piricola; R.C, Rhizoctonia cerealis. −, not
tested.
Antiviral Activity. The results of anti-TMV activities of
topsentins 1 and 2 are listed in Tables 1 and 2 with commercial
plant virucide Ribavirin as the control.
In Vitro Anti-TMV Activity. As shown in Table 1, most of these
compounds displayed good antiviral activities, especially
compounds 1e and 2d, which exhibited higher antiviral activities
than Ribavirin, thus emerging as new lead compounds for anti-
viral research. The main difference between 1b and 1e lies in
the Br atom at the 7-position; 1e showed significantly higher
inhibitory effect than 1b, which indicated that the Br atom at
the 7-position is favorable for keeping high anti-TMV activities.
However, salification is bad for antiviral activities. The salt
derivatives 1i−k showed significantly lower inhibitory effect than
fungicidal activities against Sclerotinia sclerotiorum (Lib.),
Rhizoctonia solani (Kuhn), and Botrytis cinerea (Pers.).
In Vivo Fungicidal Activity. Topsentins 1 and 2 were further
evaluated for their in vivo fungicidal activities against a series of
pathogens including Corynespora cassiicola (Berk. et Curt.) on
cucumber, Phytophthora capsici (Leon) on capsici, Sclerotinia
sclerotiorum (Lib.) on rape, Rhizoctonia solani (Kuhn) on rice,
and Botrytis cinerea (Pers.) on cucumber. The results (Table 5)
Table 5. In Vivo Fungicidal Activities of Topsentins 1 and 2
against Five Kinds of Fungi
1a. The 12-position of topsentins may be a hydrogen bond
accept region. Topsentins 1a, 1g, and 1h displayed similar levels
of antiviral effect, which indicated that the modification of
topsentins at the 1-, 15-, and 18-positions is tolerant. Hydro-
genation of topsentins 1 at the 13- and 14-positions gave a
complex result for antiviral activities (inhibitory effect: 1a > 2a,
a
inhibition rate %/200 mg/kg
b
compd
C.C
P.C
S.S
R.S
B.C
1a
1b
1c
1d
1e
1f
26 ± 1
19 ± 2
28 ± 2
32 ± 1
22 ± 2
32 ± 3
30 ± 1
22 ± 2
33 ± 1
19 ± 2
28 ± 2
28 ± 1
26 ± 1
22 ± 1
38 ± 2
15 ± 2
5 ± 1
5 ± 1
15 ± 1
20 ± 2
15 ± 2
5 ± 1
5 ± 1
20 ± 2
5 ± 1
15 ± 2
35 ± 1
10 ± 1
15 ± 1
10 ± 2
10 ± 2
23 ± 2
17 ± 1
10 ± 1
29 ± 1
10 ± 1
35 ± 1
10 ± 2
20 ± 1
17 ± 1
29 ± 1
35 ± 1
10 ± 2
14 ± 1
46 ± 1
83 ± 2
11 ± 1
14 ± 2
27 ± 1
27 ± 2
23 ± 2
27 ± 1
22 ± 3
22 ± 3
18 ± 2
23 ± 1
27 ± 1
11 ± 1
11 ± 2
18 ± 2
47 ± 2
81 ± 1
18 ± 1
13 ± 2
16 ± 2
22 ± 1
24 ± 1
22 ± 2
27 ± 1
17 ± 1
16 ± 2
17 ± 1
22 ± 1
37 ± 2
18 ± 2
17 ± 2
37 ± 2
82 ± 2
1
a−d < 2a−d). Compound 2d exhibited the best TMV
inhibitory effect.
In Vivo Anti-TMV Activity. As depicted in Table 2, topsentins
and 2 also showed good in vivo activities. Compounds 1c, 1e,
b, and 2d showed significantly higher antiviral activities than
1
2
1g
1h
1i
Ribavirin.
Unlike in vitro antiviral assay results, introduction of a MeO
group at the 7-position of 1a increased the in vivo antiviral
activities (inhibitory effect: 1c > 1a). Demethylation of 1c at
the 7-position led to a decrease of in vivo antiviral activities
1j
1k
2a
2b
2c
2d
(
inhibitory effect: 1c > 1f). The in vivo antiviral activities of
compounds 1j and 2a are significantly higher than in vitro, which
indicated that compounds 1j and 2a may have good plant-
induced activities. The other structure−activity relationships in
vivo are similar to those in vitro.
c
azoxystrobin
100
100
a
b
Average of five replicates. C.C, Corynespora cassiicola (cucumber-
Fungicidal Activity. Topsentins 1 and 2 were also evaluated
for their fungicidal activities with commercial fungicides
chlorothalonil, carbendazim, and azoxystrobin as controls.
In Vitro Fungicidal Activity. The first in vitro antifungal
activities test showed that topsentins 1 and 2 exhibited broad-
spectrum fungicidal activities against 14 kinds of phytopatho-
genic fungi at 50 mg/kg (Table 3). These compounds displayed
high bioselectiviy. Compounds 1c, 1e, and 2b with excellent
antiviral activities displayed average fungicidal activities. However,
compound 2a with average antiviral activities showed >60%
fungicidal activities against most of the tested fungi at 50 mg/kg.
Compound 1f with a hydroxyl polar group at the 7-position
displayed higher fungicidal activities against Rhizoctonia cerealis
than commercial fungicides chlorothalonil and carbendazim.
Compounds 2a and 2b exhibited higher fungicidal activities
protection); P.C, Phytophthora capsici; S.S, Sclerotinia sclerotiorum
(rape protection); R.S, Rhizoctonia solani (rice protection); B.C,
Botrytis cinerea (cucumber protection). The dilution of azoxystrobin is
c
1
000 times.
revealed that topsentins 1 and 2 also displayed good in vivo
fungicidal activities, especially compound 2d, which emerged as a
new lead for fungicidal research.
In summary, a series of marine natural products and their
derivatives were designed, synthesized, and evaluated for their
antiviral and anti-phytopathogenic fungus activities for the
first time. Compounds 1c, 1e, 2b, and 2d with significantly
higher antiviral activities than Ribavirin emerged as new lead
compounds for antiviral research. Further fungicidal activity
tests revealed that these alkaloids displayed broad-spectrum
H
DOI: 10.1021/acs.jafc.6b04020
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Journal of Agricultural and Food Chemistry
Article
fungicidal activities. Topsentin derivative 2d, with the best
fungicidal activities against Sclerotinia sclerotiorum (Lib.),
Rhizoctonia solani (Kuhn), and Botrytis cinerea (Pers.), emerged
as a new lead for fungicidal research. The above results provide
fundamental support for the development of topsentins as
potential antiviral and fungicidal agents, and further studies on
the antiviral mechanism are currently underway in our
laboratories.
(9) Wu, J.; Zhu, Y. Y.; Zhao, Y. H.; Shan, W. L.; Hu, D. Y.; Chen, J. X.;
Liu, D. Y.; Li, X. Y.; Yang, S. Synthesis and antiviral activities of novel 1,4-
pentadien-3-one derivatives bearing an emodin moiety. Chin. Chem.
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(
10) Rodrigues, T.; Reker, D.; Schneider, P.; Schneider, G. Counting
on natural products for drug design. Nat. Chem. 2016, 8, 531−541.
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655−9706.
12) Bartik, K.; Braekman, J. C.; Daloze, D.; Stoller, C.; Huysecom, J.;
(
9
(
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jafc.6b04020.
Vandevyver, G.; Ottinger, R. Topsentins, new toxic bis-indole alkaloids
from the marine sponge Topsentia genitrix. Can. J. Chem. 1987, 65,
■
*
S
2
(
118−2121.
13) Oh, K. B.; Mar, W.; Kim, S.; Kim, J. Y.; Oh, M. N.; Kim, J. G.; Shin,
D.; Sim, C. J.; Shin, J. Bis(indole) alkaloids as sortase A inhibitors from
1
13
H and C NMR and HRMS spectra of topsentins 1 and 2
the sponge Spongosorites sp. Bioorg. Med. Chem. Lett. 2005, 15, 4927−
4
931.
and compounds 5−9 (PDF)
(14) Tsujii, S.; Rinehart, K. L.; Gunasekera, S. P.; Kashman, Y.; Cross,
S. S.; Lui, M. S.; Pomponi, S. A.; Diaz, M. C. Topsentin, bromotopsentin,
and dihydrodeoxybromotopsentin: antiviral and antitumor bis-
AUTHOR INFORMATION
■
(
indoly1)imidazoles from caribbean deep-sea sponges of the family
halichondriidae. Structural and synthetic studies. J. Org. Chem. 1988, 53,
446−5453.
15) Shin, J.; Seo, Y.; Cho, K. W.; Rho, J. R.; Sim, C. J. New bis(indole)
Corresponding Authors
(Z.W.) E-mail: wangziwen2725@163.com. Phone: 0086-22-
3503792. Fax: 0086-22-23503792.
(Q.W.) E-mail: wangqm@nankai.edu.cn. Phone: 0086-22-
3503952. Fax: 0086-22-23503952.
*
5
2
*
2
(
alkaloids of the topsentin class from the sponge Spongosorites genitrix. J.
Nat. Prod. 1999, 62, 647−649.
ORCID
(16) Alvarado, S.; Roberts, B. F.; Wright, A. E.; Chakrabarti, D. The
bis(indolyl)imidazole alkaloid nortopsentin A exhibits antiplasmodial
activity. Antimicrob. Agents Chemother. 2013, 57, 2362−2364.
Qingmin Wang: 0000-0002-6062-3766
Funding
(17) Wang, Z. W.; Wei, P.; Wang, L. Z.; Wang, Q. M. Design, synthesis,
We gratefully acknowledge assistance from the National Natural
Science Foundation of China (21132003, 21421062, 21372131,
and anti-tobacco mosaic virus (TMV) activity of phenanthroindolizi-
dines and their analogues. J. Agric. Food Chem. 2012, 60, 10212−10219.
(18) Wang, Z. W.; Feng, A.; Cui, M.; Liu, Y.; Wang, L.; Wang, Q. M.
First discovery and structure-activity relationship study of phenan-
throquinolizidines as novel antiviral agents against tobacco mosaic virus
2
1402142, 21302038, 21672117), the Tianjin Natural Science
Foundation (16JCZDJC32400, 15JCQNJC05600), the Scien-
tific Research Foundation of Tianjin Normal University
(TMV). PLoS One 2012, 7, e52933.
(
5KQM110021), and the Specialized Research Fund for the
(19) Zhao, H. P.; Liu, Y. X.; Cui, Z. P.; Beattie, D.; Gu, Y. C.; Wang, Q.
Doctoral Program of Higher Education (20130031110017).
M. Design, synthesis, and biological activities of arylmethylamine
substituted chlorotriazine and methylthiotriazine compounds. J. Agric.
Food Chem. 2011, 59, 11711−11717.
Notes
The authors declare no competing financial interest.
(20) Braekman, J. C.; Daloze, D.; Stoller, C. Synthesis of topsentin-A, a
bisindole alkaloid of the marine sponge Topsentia genitrix. Bull. Soc.
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I
DOI: 10.1021/acs.jafc.6b04020
J. Agric. Food Chem. XXXX, XXX, XXX−XXX