Synthesis and Antitumor Activity of Novel 1-Substituted 3-(4,5-Substituted 1,2,4-Triazol-3-yl)-β-carboline Derivatives

Article abstract of DOI:10.1055/s-0037-1610291

Schiff bases, 1,2,4-triazolo[4,3-d[[1,2,3,4]thiatriazoles, and 1,2,4-triazolo[3,4-b[[1,3,4]thiadiazoles carrying the β-carboline nucleus were synthesized from 3-(4-amino-5-mercapto-1,2,4-triazol-3-yl)-β-carbolines. The compounds were evaluated for their in vitro antitumor activity against eight human cancer cell lines. The 1,2,4-triazolo[4,3-d[[1,2,3,4]thiatriazole derivatives showed a broad spectrum of antitumor activity, with GI ₅₀ values lower than 13 μM for all cell lines tested. In general, all tested compounds showed potent activity against the breast (MCF-7) cancer cell line, with GI ₅₀ values in the range of 2.07 to 4.58 μM.

Full text of DOI:10.1055/s-0037-1610291

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–E
paper
A
en
Synthesis
G. Brand et al.
Paper
Synthesis and Antitumor Activity of Novel 1-Substituted
-(4,5-Substituted 1,2,4-Triazol-3-yl)-β-carboline Derivatives
3
George Branda
Carla M. B. Gomesa
Willian F. Costaa
Mary A. Fogliob
Ana L. T. G. Ruizc
Maria H. Sarragiotto*a
a
Departamento de Química, Universidade Estadual de Maringá, Av. Colombo
5790, Maringá - PR, 87020-900, Brazil
mhsarragiotto@uem.br
Faculdade de Ciências Farmacêuticas, Universidade Estadual de Campinas,
Campinas - SP, 13083-859, Brazil
Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA),
Universidade Estadual de Campinas, Campinas - SP, 13083-970, Brazil
b
c
Received: 04.07.2018
Accepted after revision: 30.08.2018
Published online: 26.09.2018
In our previous work24–27 we demonstrated that deriva-
tives bearing an appropriately substituted phenyl group at
position 1 and various substituents at position 3 of the β-
carboline nucleus showed potent antitumor activity. The
incorporation of a 4-amino-5-mercapto-1,2,4-triazole moi-
ety at C-3 resulted in 1-(substituted phenyl)-3-(4-amino-5-
mercapto-1,2,4-triazol-3-yl)-β-carbolines 1f (Scheme 1)
with significant antitumor activity.24
DOI: 10.1055/s-0037-1610291; Art ID: ss-2018-m0455-op
Abstract Schiff bases, 1,2,4-triazolo[4,3-d][1,2,3,4]thiatriazoles, and
1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles carrying the β-carboline nucleus
were synthesized from 3-(4-amino-5-mercapto-1,2,4-triazol-3-yl)-β-
carbolines. The compounds were evaluated for their in vitro antitumor
activity against eight human cancer cell lines. The 1,2,4-triazolo[4,3-
d][1,2,3,4]thiatriazole derivatives showed a broad spectrum of antitu-
mor activity, with GI50 values lower than 13 μM for all cell lines tested. In
general, all tested compounds showed potent activity against the
breast (MCF-7) cancer cell line, with GI50 values in the range of 2.07 to
O
R =
O
R =
O
N
N
NH
NH
4.58 μM.
H
O
1g
1a
Key words β-carbolines, 4,5-substituted 1,2,4-triazoles, Schiff bases,
1,2,4-triazolo[4,3-d][1,2,3,4]thiatriazoles, antitumor activity
R
R =
N
NH
3
O
R =
O
N
N
H
The β-carboline nucleus is present in many synthetic
N
S
1
N
NH
NH2
and naturally occurring compounds displaying a large spec-
trum of important pharmacological and biological proper-
O
1
b
1
f
1
1–3
ties such as antitrypanosomal and antileishmanial, her-
4
,5
6–8
bicidal and fungicidal, antiviral,
antiplatelet aggrega-
O
O
9,10
anti-Parkinson11 and Dyrk1A
R =
N
NH
R =
S
tion and antithrombotic,
N
12,13
NH
inhibition.
O
O
R =
N
NH
Ph
1
c
Among the reported properties, it is worth mentioning
the potential of β-carboline derivatives as anticancer
agents, which has stimulated studies on their synthesis and
1e
O
S
1d
14–23
Scheme 1 General structures of β-carboline derivatives synthesized in
structure–activity relationship (SAR).
These studies re-
previous work
vealed that the introduction of appropriate substituents at
the 1-, 3- and 9-positions of the β-carboline ring can result
in more potent drugs with reduced toxicity and neurotoxic
effects.
The presence of the amino and mercapto nucleophilic
centers in the 4-amino-5-mercapto-1,2,4-triazole side
chain at position 3 of β-carbolines makes it a useful site for
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

B
Synthesis
G. Brand et al.
Paper
N
N
N
N 5"
3
"
a
SCH3
b
SCH3
N
N
N
NH2
N
N
N
H
N
H
1
'
1'"
R
2
'
4
'
4'"
N
N
3
5"
3"
4 R = H
5 R = Cl
SH
N
N
N
3
N
NH2
c
S
N
N
N
H
1
1'
N
N
R
N
H
R
2a R = H; 2b R = Cl
6a R = H; 6b R = Cl
N
N
N
R
N
5
"
3
"
S
N
S
6
N
d
"
N
N
HN
N
N
S
N
H
SH
H
R
7a R = H; 7b R = Cl
Scheme 2 Reagents and conditions: a) MeI, KOH, EtOH, r.t., 48 h; b) PhCHO or 2-ClC H CHO, DMF, reflux, 48 h; c) NaNO , HCl, 0–5 °C, 12 h; d) CS ,
6
4
2
2
KOH, MeOH, 0–5 °C, then reflux, 48 h.
the synthesis of triazole-fused derivatives. Besides, Schiff
bases can be obtained from the 4-amino group of this het-
erocyclic nucleus.
4-amino-5-mercapto-1,2,4-triazole derivatives having other
substituents at the 3-position, Schiff base formation was
not observed. The H NMR spectra obtained for the crude
1
Prompted by these observations, and to provide addi-
tional data for SAR studies, we decided to explore the po-
tential of β-carbolines 2 as precursors for new 3-(4,5-sub-
stituted 1,2,4-triazol-3-yl)-β-carboline derivatives. Thus, in
this work we synthesized Schiff bases 4 and 5, 1,2,4-triazo-
lo[4,3-d][1,2,3,4]thiatriazoles 6a,b, and 1,2,4-triazolo[3,4-
b][1,3,4]thiadiazoles 7a,b, all carrying the β-carboline nu-
cleus. The new compounds 4, 5, 6a and 6b were assayed for
their in vitro activity against eight human cancer cell lines,
and against human normal keratinocytes (HaCaT, noncan-
cer cell line).
products indicated a complex mixture, showing no signals
for the benzylideneamino group.
To avoid undesired reactions of the 5-mercapto group,
β-carboline 2a was S-methylated with methyl iodide, under
basic conditions,24 affording product 3. Refluxing of a DMF
solution of S-alkylated 3, in the presence of benzaldehyde
or 2-chlorobenzaldehyde, furnished the corresponding
Schiff bases 4 and 5, after purification by column chroma-
tography. The NMR spectra of Schiff bases 4 and 5 showed
signals at δH 8.98–9.00 and δ 162.4–169.1, corresponding
C
to the imine hydrogen and carbon of the benzylideneamino
The synthesis of Schiff bases 4 and 5, of 1,2,4-triazo-
lo[4,3-d][1,2,3,4]thiatriazoles 6a,b, and of 1,2,4-triazo-
lo[3,4-b][1,3,4]thiadiazoles 7a,b, all carrying the β-carbo-
line nucleus, is outlined in Scheme 2. The 3-(4-amino-5-
mercapto-1,2,4-triazol-3-yl)-β-carbolines 2a,b were ob-
tained via Pictet–Spengler condensation of L-tryptophan
methyl ester with benzaldehyde or 2-chlorobenzaldehyde,
according to our previously reported procedure.
Firstly, attempts towards the synthesis of Schiff bases
were made from 3-(4-amino-5-mercapto-4H-1,2,4-triazol-
groups, together with signals at δH 2.71–2.73 and δH 11.7
assigned to the SCH and NH groups, respectively, of the tri-
3
azole and β-carboline moieties.
Preparation of the 1,2,4-triazolo[4,3-d][1,2,3,4]thiatri-
azole derivatives 6a,b was carried out by treatment of 2a,b
with sodium nitrite in hydrochloric acid, according to the
31
report by El Shehry and co-workers. The absence of SH
and NH2 signals in the 1H NMR spectra, together with
changes observed for the C-3′′ and C-5′′ chemical shifts of
6a,b in the 13C NMR spectra, in relation to their precursors
2a,b, provided evidence for the formation of the triazolothia-
triazole nucleus. For example, in 6a the peaks for C-3′′ and
24
3-yl)-1-phenyl-9H-β-carboline (2a), which was subjected
to condensation with benzaldehyde or 2-chlorobenzalde-
hyde under various conditions, such as H SO catalysis, us-
C-5′′ appear at δ 157.4 and 158.3, while in 2a these car-
2
4
C
28,29
ing ethanol/water as solvent,
and p-TsOH catalysis, in
bons resonate at δ 147.3 (C-3′′) and 163.8 (C-5′′).
C
3
0
DMF as solvent. However, in contrast to the reported
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

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Synthesis
G. Brand et al.
Paper
Table 1 GI50 Values (μM) for Previously Reported β-Carbolines 2a, 2b and 3, and for New Synthesized Compounds 4, 5, 6a and 6ba
Cell lines
Compound
R
Lung
NCI-H460
Colon
HT-29
Prostate
PC-3
Breast
MCF-7
Renal
786-0
Glioma
U-251
OvarianResistant
NCI/ADR-res
Ovarian
OVCAR-3
HaCaT
2
2
a
H
1.59
15.4
>100
3.19
7.84
1.16
2.97
0.014
15.0
33.0
10.9
24.7
>100
3.02
4.21
2.70
7.98
0.058
15.0
70.1
>100
3.73
2.07
2.76
4.58
0.045
10.9
39.5
>100
6.87
8.52
2.88
9.16
0.034
NT
NT
NT
NT
12.0
6.80
NT
NT
b
Cl
–
3
4
5
>100
17.77
>100
1.98
NT
NT
>100
6.43
NT
H
Cl
H
Cl
1.53
13.75
3.45
5.74
0.015
1.11
5.06
3.47
3.99
0.11
1.91
0.09
0.08
1.16
0.018
21.92
12.63
12.35
0.17
6
a
6
b
12.28
0.32
Doxorubicinb
a
NT = not tested.
Doxorubicin = positive control.
b
The synthesis of β-carbolines 7a,b bearing the 1,2,4-tri-
azolo[3,4-b][1,3,4]thiadiazole group was achieved by treat-
ing the 1,2,4-triazoles 2a,b with carbon disulfide and potas-
sium hydroxide. The NMR data for 7a revealed a tauto-
meric thiol–thione equilibrium, as evidenced by the
presence of a singlet at δH 13.9 (6′′-SH) and signals at δC
the other hand, comparison of the average activity (mean
GI ) against the normal cell line (HaCaT) revealed that the
compounds are more toxic to normal cells than to other cell
lines, as well as for doxorubicin.
50
32
To summarize, Schiff's bases and triazolo-thiatriazole
derivatives carrying the β-carboline nucleus were easily
prepared in one step from the readily available 3-(4-amino-
5-mercapto-1,2,4-triazol-3-yl)-β-carbolines 2a,b. The po-
tent anticancer activity presented for synthesized com-
pounds, together with their easiness of synthesis, makes
these compounds promising anticancer agents. These in-
vestigations corroborated the previous reports that the an-
titumor activity of β-carboline derivatives is dependent of
the substituents at the positions 1 and 3 of the β-carboline
ring.
1
43.2 (C-6′′–SH) and δ 155.5 (C-6′′=S).
C
The new compounds 4, 5, 6a and 6b were evaluated in
vitro against a panel of eight human cancer cell lines con-
sisting of lung (NCI-H460), colon (HT-29), prostate (PC-3),
breast (MCF-7), renal (786-0), glioma (U-251), ovarian re-
sistant (NCI/ADR-res) and ovarian (OVCAR-3), and against a
normal cell line (HaCaT, immortalized human skin kerati-
nocytes). The GI50 values obtained for the new β-carboline
derivatives, and those previously reported for the 3-(4-ami-
no-5-mercapto-1,2,4-triazol-3-yl)-β-carbolines 2a,b and
24
for the S-methylated derivative 3, are summarized in Ta-
ble 1. The assay results demonstrated that the triazolothia-
triazoles 6a and 6b and the new Schiff base 4 show a broad
spectrum of antitumor activity, with GI50 values lower than
All reagents were purchased from commercial suppliers. Reactions
were monitored by thin-layer chromatography conducted on Merck
TLC plates (silica gel 60 F254). NMR spectra were recorded on a Varian
1
Mercury plus BB spectrometer at 300 MHz (for H) and 75 MHz (for
18 μM for all cell lines assayed.
13
C), with TMS as internal standard and deuterated solvents, DMSO-d6
The data for compounds 4, 5, 6a and 6b show a highest
and CDCl . Mass spectra (ESI-MS) were recorded on a Thermo Elec-
3
growth inhibitory activity towards ovarian resistant
NCI/ADR-res) and breast cancer (MCF-7) cell lines for these
tron Corporation Focus DSQ II spectrometer. Melting points were de-
termined on a Microquímica MQAPF-301 apparatus and are uncor-
rected.
(
compounds, with GI50 values in the range of 1.11 to 5.06
μM.
Comparison of the GI50 values for the newly synthesized
3-[4-Benzylideneamino-5-(methylthio)-4H-1,2,4-triazol-3-yl]-1-
phenyl-9H-β-carbolines 4 and 5; General Procedure
compounds with those for 2a and 2b24 (Table 1) revealed
To a solution of 3-[4-amino-5-(methylthio)-4H-1,2,4-triazol-3-yl]-1-
phenyl-9H-β-carboline (3; 186.0 mg, 0.5 mmol) in DMF (5 mL) was
added benzaldehyde (63.7 mg, 0.6 mmol) or 2-chlorobenzaldehyde
that compounds 6a and 6b display a better antitumor activ-
ity, indicating that formation of the fused triazolothiatri-
azole system leads to an enhancement of antitumor activi-
ty, providing evidence that a free thiol and amino is a key
structural feature of this class of inhibitors.
The assay results for compounds 7a and 7b were not
conclusive due to the lack of solubility of these compounds
in the assay medium, and these results are not included. On
(84.3 mg, 0.6 mmol). The solution was refluxed for 48 h then poured
onto crushed ice with stirring. The precipitate was collected by filtra-
tion and washed with water. The crude product was purified by col-
umn chromatography (silica gel; hexane/EtOAc, 40% to 100%) to af-
ford the corresponding Schiff base 4 or 5.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

D
Synthesis
G. Brand et al.
Paper
3-{4-[(E)-Benzylideneamino]-5-(methylthio)-4H-1,2,4-triazol-3-
3-(1-Aryl-9H-β-carbolin-3-yl)-1,2,4-triazolo[3,4-b][1,3,4]thiadi-
yl}-1-phenyl-9H-β-carboline (4)
azole-6-thiols/thiones 7a and 7b; General Procedure
White solid; yield: 73.6 mg (32%); mp 210.6–213.9 °C.
To a solution of 2a (143.2 mg, 0.4 mmol) or 2b (156.8 mg, 0.4 mmol)
1
in methanolic KOH (2 M, 10 mL), at 0–5 °C, was added CS
2
(0.027 mL,
H NMR (300 MHz, DMSO-d ): δ = 11.70 (s, 1 H, NH), 8.98 (s, 1 H),
.89 (s, 1 H), 8.45 (d, J = 7.5 Hz, 1 H), 7.88 (d, J = 8.0 Hz, 2 H), 7.77 (d,
6
0.45 mmol) dropwise with stirring. The reaction mixture was re-
8
fluxed for 48 h, then cooled to r.t. and poured onto crushed ice. The
solution was acidified with concentrated HCl, and the precipitate was
collected by filtration, washed with water and recrystallized from
EtOH to give 7a and 7b, respectively.
J = 8.0 Hz, 2 H), 7.69–7.52 (m, 5 H), 7.39–7.30 (m, 2 H), 7.22 (t, J = 7.5
Hz, 2 H), 2.71 (s, 3 H).
13
C NMR (75.5 MHz, DMSO-d ): δ = 169.1, 150.2, 149.8, 141.5, 141.4,
6
1
37.1, 135.4, 132.9, 132.8 (2 x C), 132.0, 130.1, 129.1 (3 x C) 129.0 (2 x
C) , 128.7, 128.6, 128.3 (2 x C), 122.0, 120.9, 120.1, 114.0, 112.6, 14.0.
ESI-MS: m/z = 461.05 [M + H]+.
3
-(1-Phenyl-9H-β-carbolin-3-yl)-1,2,4-triazolo[3,4-b][1,3,4]thia-
diazole-6-thiol (7a)
Yellow solid; yield: 85.9 mg (54%); mp 234.9–235.5 °C.
3
-{4-[(E)-2-Chlorobenzylideneamino]-5-(methylthio)-4H-1,2,4-
1
H NMR (300 MHz, DMSO-d ): δ = 13.90 (s, 1 H, SH), 12.10/11.90 (s, 1
6
triazol-3-yl}-1-phenyl-9H-β-carboline (5)
H, NH), 9.18/8.82 (s, 1 H), 8.38 (d, J = 6.0 Hz, 1 H), 8.21/8.09 (d, J = 6.0
Hz, 2 H), 7.76–7.67 (m, 5 H), 7.40–7.30 (m, 1 H).
White solid; yield: 87.1 mg (35%); mp 149.5–150.4 °C.
1
H NMR (300 MHz, DMSO-d ): δ = 11.70 (s, 1 H, NH), 9.00 (s, 1 H),
13C
6
NMR (75.5 MHz, DMSO-d ): δ = 163.9, 155.5/143.2, 147.4,
6
8.87 (s, 1 H), 8.44 (d, J = 7.5 Hz, 1 H), 8.15 (d, J = 9.0 Hz, 1 H,) 7.79 (d,
141.75/141.71, 141.6, 133.3, 129.2, 129.1, 129.2, 129.0, 128.9, 128.6
122.1/121.8, 120.9/120.8, 120.3, 114.3/114.0, 113.1/112.8,
134.2/133.8, 129.9/129.5, 137.8/136.8.
J = 9.0 Hz, 2 H), 7.69 (d, J = 7.5 Hz, 1 H), 7.51 (m, J = 7.5 Hz, 2 H), 7.42–
7.37 (m, 3 H), 7.37–7.25 (2m, 3 H), 2.73 (s, 3 H).
13
C NMR (75.5 MHz, DMSO-d ): δ = 162.4, 150.5, 150.1, 141.5, 141.4,
ESI-MS: m/z = 401.03 [M + H]+.
6
1
1
37.2, 135.3, 135.1, 134.2, 132.9, 130.2, 130.0, 129.2, 128.8, 128.7,
28.3, 128.2, 128.1, 127.9, 122.1, 120.9, 120.2, 114.4, 112.6, 14.0.
3-[1-(2-Chlorophenyl)-9H-β-carbolin-3-yl]-1,2,4-triazolo[3,4-b]-
ESI-MS: m/z = 495.00 [M + H]+.
[
1,3,4]thiadiazole-6-thiol (7b)
Yellow solid; yield: 94.1 mg (54%); mp 261.4–263.5 °C.
3
-(1-Aryl-9H-β-carbolin-3-yl)-1,2,4-triazolo[4,3-d][1,2,3,4]thiatri-
1
H NMR (300 MHz, DMSO-d ): δ = 13.90 (s, 1 H, SH), 11.70 (s, 1 H,
6
azoles 6a and 6b; General Procedure
NH), 8.93 (s, 1 H), 8.40 (d, J = 6.0 Hz, 1 H), 7.71–7.76 (m, 2 H), 7.60–
A solution of 2a (179.0 mg, 0.5 mmol) or 2b (196.0 mg, 0.5 mmol) in
7.64 (m, 4 H), 7.32–7.37 (m, 1 H).
37% HCl (5 mL) was cooled to 0 °C and a cold solution of NaNO (34.5
2
13
C NMR (75.5 MHz, DMSO-d ): δ = 164.3, 147.7, 142.0 (2 x C), 141.0,
mg, 0.5 mmol) in water (0.5 mL) was gradually added. The reaction
mixture was stirred at 0–5 °C for 2 h, kept for 10 h at 5 °C then diluted
with water. The precipitate was collected by filtration and recrystal-
lized from EtOH to give 6a and 6b, respectively.
6
1
1
39.5, 136.5, 134.7, 134.3, 132.9, 132.4, 131.2, 130.4, 129.5, 128.1,
22.6, 121.1, 120.7, 115.2, 112.8.
ESI-MS: m/z = 435.01 [M + H]+.
3-(1-Phenyl-9H-β-carbolin-3-yl)-1,2,4-triazolo[4,3-d][1,2,3,4]thia-
Antitumor Assays
triazole (6a)
Compounds 4, 5, 6a and 6b were evaluated in vitro against a panel of
eight human cancer cell lines consisting of lung (NCI-H460), colon
(HT-29), prostate (PC-3), breast (MCF-7), renal (786-0), glioma (U-
White solid; yield: 131.1 mg (70%); mp 251.6–252.8 °C.
1
H NMR (300 MHz, DMSO-d ): δ = 11.86 (s, 1 H, NH), 8.88 (s, 1 H),
6
251), ovarian resistant (NCI/ADR-res), and ovarian (OVCAR-3), kindly
8
7
.41 (d, J = 6.0 Hz, 1 H), 8.23 (d, J = 6.0 Hz, 2 H), 7.71–7.58 (m, 5 H),
.28 (t, J = 6.0 Hz, 1 H).
provided by the National Cancer Institute (Frederick, MA, USA). In ad-
dition, a normal cell line (HaCaT, immortalized human skin keratino-
cytes) was used. Stock and experimental cultures were grown in me-
dium containing 5 mL RPMI 1640 (GIBCO BRL) supplemented with 5%
fetal bovine serum (GIBCO BRL). Penicillin/streptomycin mixture
13
C NMR (75.5 MHz, DMSO-d ): δ = 158.3, 157.4, 142.4, 142.1, 137.7,
6
135.6, 133.9, 130.5, 129.5, 129.4, 129.3 (C-3′/5′), 129.2 (2 x C), 122.6,
121.5, 120.6, 113.1, 112.9.
ESI-MS: m/z = 371.95 [M + 3 H]+.
–1
–1
–1
(1000 U·mL :1000 μg·mL , 1 mL·L RPMI) was added to the experi-
–1
mental cultures. Cells in 96-well plates (100 μL cells·well ) were ex-
3
-[1-(2-Chlorophenyl)-9H-β-carbolin-3-yl]-1,2,4-triazolo[4,3-d]-
posed to sample concentrations in DMSO/RPMI (0.25, 2.5, 25, 250
–1
[
1,2,3,4]thiatriazole (6b)
μg·mL ) in triplicate at 37 °C, 5% CO
2
in air, for 48 h. The final DMSO
concentration did not affect cell viability. Doxorubicin (0.025 to
White solid; yield: 137.2 mg (70%); mp 170.4–172.0 °C.
–1
2
5 μg·mL ) was used as a positive control. Before (T plate) and after
0
1
H NMR (300 MHz, DMSO-d ): δ = 11.60 (s, 1 H, NH), 8.97 (s, 1 H),
6
the sample addition (T1 plates), cells were fixed with 50% trichloro-
acetic acid, and cell proliferation was determined by spectrophoto-
metric quantification (540 nm) of cellular protein using the sulfor-
hodamine B assay. All compounds were tested in triplicate for each
concentration. Using the dose–response curve for each cell line, the
concentration that inhibits cell growth by 50% (GI50) was determined
through nonlinear regression analysis using ORIGIN software version
8.43 (d, J = 6.0 Hz, 1 H), 7.72 (d, J = 6.0 Hz, 2 H, H-3′ and H-6′), 7.63–
7.58 (m, 4 H), 7.31–7.25 (m, 1 H).
13
C NMR (75.5 MHz, DMSO-d ): δ = 158.2, 157.4, 142.0, 141.7, 136.6,
6
135.3, 135.0, 133.2, 132.6, 131.2, 130.1, 129.6, 129.4, 127.9, 122.8,
121.3, 120.6, 113.7, 112.8.
+
ESI-MS: m/z = 377.84 [M – N + 3 H] .
2
33
8
.0 (OriginLab Corporation). Compounds with GI50 values >100 μM
were considered inactive.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E

E
Synthesis
G. Brand et al.
Paper
Funding Information
(15) Cao, R. H.; Guan, X.; Shi, B. X.; Chen, Z.; Ren, Z. H.; Peng, W.;
Song, H. C. Eur. J. Med. Chem. 2010, 45, 2503.
This work was supported by Fundação Araucária (Brazil, PR) and
Fundação de Amparo à Pesquisa de São Paulo (FAPESP).
(16) Zhang, G. X.; Cao, R. H.; Guo, L.; Ma, Q.; Fan, W. X.; Chen, X. M.;
)(
Li, J. R.; Shao, G.; Qiu, L. Q.; Ren, Z. H. Eur. J. Med. Chem. 2013, 65,
21.
(
17) Shi, B. X.; Cao, R. H.; Fan, W. X.; Guo, L.; Ma, Q.; Chen, X. M.;
Acknowledgment
Zhang, G. X.; Qiu, L. Q.; Song, H. C. Eur. J. Med. Chem. 2013, 60,
1
0.
We thank Fundação Araucária, CAPES and CNPq for fellowships (G.B.,
C.M.B.G.). The authors are thankful to Dr Eduardo J. Pilau and Dr Carla
Porto for the ESI-MS spectra.
(
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–E