Rapid Synthesis of N-Tosylhydrazones under Solvent-Free Conditions and Their Potential Application Against Human Triple-Negative Breast Cancer

Article abstract of DOI:10.1002/open.201800206

Some N-tosylhydrazone derivatives were effectively synthesized under solvent-free conditions by using a grinding method at room temperature. The short reaction time, clean and mild process with simple workup and easy purification of the target compounds w

Full text of DOI:10.1002/open.201800206

DOI: 10.1002/open.201800206
Rapid Synthesis of N-Tosylhydrazones under Solvent-Free
Conditions and Their Potential Application Against Human
Triple-Negative Breast Cancer
Zengyang Xie,*[a] Yuying Song,[a] Lujia Xu,[a] Yukun Guo,[a] Min Zhang,[a] Limei Li,[a]
Kai Chen,*[b, c] and Xue Liu*[a]
Some N-tosylhydrazone derivatives were effectively synthe-
sized under solvent-free conditions by using a grinding
method at room temperature. The short reaction time, clean
and mild process with simple workup and easy purification of
the target compounds were salient features of the present pro-
tocol, which enables straightforward access to N-tosylhydra-
zones. Among the tosylhydrazone derivatives evaluated, com-
pound 3l exhibits excellent apoptosis-promoting and anticanc-
er potential against triple-negative breast cancer (TNBC) cell
lines. This research shows that our synthesized compound 3l
may be a desirable and effective therapeutic drug against
TNBC.
1. Introduction
Hydrazones possessing the active moiety (ÀNHÀN=CHÀ) are an
important class of organic molecules for drug development. In
past decades, these compounds have been synthesized and
their biological activities have also been evaluated. Some hy-
drazone derivatives have proven to possess antidepressant,[1]
antimicrobial,[2] antimalarial,[3] antiviral,[4] antischistosomiasis,[5]
antiplatelet,[6] vasodilator,[7] anti-inflammatory,[8] analgesi,[9] anti-
convulsant,[10] or antituberculosis[11] activities.
On the other hand, other synthetic hydrazones have demon-
strated antitumoral activity against various cancer cells. For ex-
ample, several hydrazone derivatives I, bearing the 3,4,5-trime-
thoxyphenyl moiety (Figure 1) have shown good antiprolifera-
tive activity against PC3 cells with an IC50 range of 0.2–
Figure 1. Structures of some reported anticancer hydrazones and target
tosylhydrazones 3a–q.
1.8 mm.[12] N’-(4-Bromo-5-methyl-2-oxoindolin-3-ylidene)-3,4,5-
trimethoxybenzohydrazide II, which also has a 3,4,5-trimethox-
yphenyl backbone, exhibits EC50 =0.24 mm against human col-
orectal carcinoma HCT116 cells.[13] More recently, nine hybrid
compounds with a coumarin hydrazide–hydrazone backbone
were synthesized by Abdel-Aziz et al.;[14] of which, compound
IIIa exhibited significant activity against colon cancer cells
(HT29, IC50 =7.98Æ0.05 mm), whereas compound IIIb displayed
the best antiproliferative activity against leukemia cells (K562,
IC50 =9.44Æ0.02 mm). Moreover, isatin-quinazoline hybrids,
such as compound IV, have been reported to have a selective
and potent growth inhibitory effect towards the liver cancer
cell line (HepG2, IC50 =1.0Æ0.2 mm).[15]
[a] Dr. Z. Xie, Y. Song, L. Xu, Y. Guo, M. Zhang, L. Li, Dr. X. Liu
College of Basic Medicine, Jining Medical University
Jining, 272067 (China)
E-mail: xiezyjnmc@126.com
xuelingjing@yeah.net
[b] Dr. K. Chen
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics
and Gene Regulation, Sun Yat-Sen Memorial Hospital
Sun Yat-Sen University
Guangzhou 510275 (China)
E-mail: chenkai23@mail.sysu.edu.cn
[c] Dr. K. Chen
Breast Tumor Center, Sun Yat-sen Memorial Hospital
Sun Yat-Sen University
Guangzhou 510275 (China)
E-mail: chenkai23@mail.sysu.edu.cn
Tosylhydrazones, which are special class of hydrazones, have
been used widely as versatile and useful partners in organic
synthesis.[16] In particular, under basic conditions, the tosylhy-
drazone units are easily converted into diazo compounds,[17]
which can undergo insertion reactions leading to the construc-
tion of various chemical bonds. For example, the formation of
CÀC,[18] CÀN,[19] CÀS,[20] CÀP,[21] CÀO,[22] CÀSn,[23] CÀSi,[24] CÀB,[25]
and NÀN[19d,e] bonds has been reported in the past few years.
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/open.201800206.
ꢀ 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited,
the use is non-commercial and no modifications or adaptations are
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It is well known that the conventional procedure for the syn-
thesis of tosylhydrazones remains the reaction of tosylhydra-
zides with corresponding aldehydes or ketones. However, most
of these methods possess limitations such as the use of organ-
ic solvents, elevated temperature, lower yields and a longer re-
action time. Recently, green and sustainable reaction systems
have been a focus of interest, because of their advantages of
being environmentally friendly and atom economical.[26]
Among these, solvent-free reactions are more attractive due to
their high selectivity, simple handling and easy purification.[27]
Furthermore, mechanochemical synthesis conducted by grind-
ing technique has been considered to be a versatile strategy
for chemical synthesis, and plays an important role in various
solvent-free reactions.[28]
Table 1. Optimization of reaction conditions for the synthesis of 3a.[a]
Entry
Solvent
Condition[b]
Time [min]
Yield[c] [%]
1
2
3
4
5
6
7
8
CH3CN
EtOH
EtOAc
toluene
CHCl3
THF
RT[c]
120
120
120
120
120
120
120
30
92
89
84
80
82
79
71
93
95
95
95
RT[c]
RT[c]
RT[c]
RT[c]
RT[c]
DMF
CH3CN
RT[c]
reflux
grinding
grinding
grinding
[d]
9
10
11
–
–
–
1
5
10
[d]
Triple-negative breast cancer (TNBC) is a complex and ag-
gressive subtype of breast cancer, in which exhibits low ex-
pression of estrogen receptor (ER), progesterone receptor (PR),
and human epidermal growth factor receptor 2 (HER2).[29] In
spite of the rapid advanced on clinical therapeutic strategies, a
lack of effectively individualized treatments and the discour-
agement of existing overall prognosis remain troublesome for
this subtype of breast cancer patient.[30] In addition, the side ef-
fects of anticancer agents and drug resistance of cancer cells
can lead to recurrence of the disease.[31] Thus, development of
new and high-efficiency anticancer drugs for TNBC is urgently
needed.
[d]
[a] Reaction conditions: 1a (1 mmol) and 2a (1 mmol) in 2 mL of solvent.
[b] RT=room temperature. [c] Isolated yields. [d] Solvent-free conditions.
obtained in 95% yield within 1 min (Table 1, entry 9). However,
a further increase in grinding time resulted in no further im-
provement in the yield (Table 1, entries 10 and 11). The above
experiments clearly demonstrated that the solvent-free grind-
ing technique afforded a higher yield of product in less time
than with other conditions.
To date, there has been no report on an investigation into
the anticancer activity of tosylhydrazone derivatives against
TNBC cell lines. Thus, in this study, we aim to determine
whether the tosylhydrazone derivatives possess antitumor ac-
tivity against TNBC. Herein, we report a remarkably rapid and
environmentally friendly protocol for the preparation of N-to-
sylhydrazones under solvent-free conditions by using a grind-
ing technique, which yielded 17 N-tosylhydrazones (3a–q). Of
these, compound 3l exhibited the best IC50 value of
30.7 mgmLÀ1, and we then demonstrated its antiproliferation
and pro-apoptosis effect in TNBC cells. Taken together, we
expect to find some new compounds to overcome the resist-
ance of TNBC, in order to bring new hope for cancer patients.
On the basis of the above-optimized reaction conditions, we
investigated the substrate scope of this protocol, and the re-
sults are summarized in Scheme 1. Various aldehydes (ketones)
1 were reactive and the corresponding target products 3 were
obtained in good-to-excellent yields. It was noteworthy that
this protocol exhibited excellent functional group tolerance,
both electron-rich and electron-deficient aromatic aldehydes
can be effectively coupled to the benzenesulfonohydrazide
(Scheme 1, 3a–j). Most interestingly, phenylacetaldehyde (ali-
phatic aldehyde) was proved to be a suitable coupling partner,
which delivered product 3k in 86% yield. We also found the
reaction system was not sensitive to the steric hindrance effect
of groups on the aromatic aldehydes and gave good yield
(Scheme 1, 3l). In addition, this methodology could be applica-
ble to the reactions of heteroaromatic aldehydes, and the cor-
responding products being obtained in satisfactory yields
(Scheme 1; 3m, 3n). Furthermore, acetophenone can also be
coupled to 2 under our experimental conditions to afford
product 3o. Finally, the reactions could occur under mild con-
ditions with aliphatic ketones, and ideal yields were achieved
when acetone and cyclohexanone were used as the substrates
(Scheme 1; 3p, 3q).
2. Results and Discussion
2.1. Chemistry
In our initial study, 4-chlorobenzaldehyde (1a) and 4-methyl-
benzenesulfonohydrazide (2a) were selected to test the tosyl-
hydrazone formation (molar ratio, 1a/2a=1:1). As shown in
Table 1, seven solvents (CH3CN, EtOH, EtOAc, toluene, CHCl3,
THF, and DMF) were tested at room temperature for 2 h,
whereby using CH3CN as a solvent afforded the highest yield
(Table 1, entries 1). Next, with CH3CN as the solvent, we investi-
gated the effect of reaction temperature. It was found that the
yield underwent no significant change when the reactants
were refluxed in CH3CN for 30 min (Table 1, entries 8). Inspired
by recent advances in solvent-free reactions, we performed the
above reaction in a mortar under solvent-free conditions by
using a grinding method. Tosylhydrazone derivative 3a was
The spectra for the synthesized compounds (3a–q) are
given in the Supporting Information. As a representative case,
the IR spectra of 3a shows a C=N stretching band at about
1
1595 cmÀ1. In the H NMR spectra, the characteristic PhCH=N
and SO2NH protons appeared as singlet peaks at 7.91 and
11.50 ppm, respectively. The protons belonging to the substitu-
ent groups and aromatic ring were observed according to the
expected chemical shift values.
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factors. Next, compound 3l was selected for the further detec-
tion of cell proliferation and apoptosis ability against TNBC.
Compound 3l was selected to evaluate the antiproliferation
activity of MDA-MB-231 cells. The results showed that com-
pound 3l (at the concentrations of 30, 60, and 100 mgmLÀ1
)
successfully inhibited cell proliferation over six consecutive
days, which was superior to the control group as shown in
Figure 3 (P<0.05). The above results reveal that N-tosylhydra-
zone compounds displayed significant cytotoxic activity and
may be a potential drug for the treatment of TNBC.
Figure 3. Compound 3l efficiently suppress the proliferation of MDA-MB-231
cells.
Scheme 1. Synthesis of N-tosylhydrazones under solvent-free conditions by
using a grinding method. The reaction was performed with 1 (1 mmol) and
2 (1 mmol) under solvent-free conditions. Yields refer to isolated yields.
The effect of N-tosylhydrazone 3l in promoting the apopto-
sis of MDA-MB-231 cells was evaluated by AnnexinV FITC/PI
staining and using a flow cytometer. As shown in Figure 4A,
after treating with N-tosylhydrazone 3l (at concentrations of
30 and 100 mgmLÀ1) for 24 h in MDA-MB-231 cells, the per-
centage of apoptosis, including both early (from 1.71 to 6.27/
7.71%) and late apoptotic phases (from 4.57 to 8.33/11.96%),
was significantly increased compared with untreated control
cells. The results of immunofluorescence staining (Figure 4B)
were in accordance with the previous flow cytometer studies
that equally exhibited the strongly pro-apoptosis ability of N-
tosylhydrazone 3l. The above findings prove that compound
3l exerts pro-apoptotic potential, which contributes to its anti-
proliferative activity.
2.2. Biological Evaluation
The IC50 value of N-tosylhydrazones (3a–q) were detected in
MDA-MB-231 cells using CCK8 reagents. Among the 17 N-tosyl-
hydrazone compounds (3a–q), compound 3l was the selected
candidates that displayed strong cytotoxic activity against
MDA-MB-231 cells (IC50 =30.7 mgmLÀ1) (Figure 2), exhibiting a
better IC50 value than any other compounds (see the Support-
ing Information, Table 1). Unfortunately, some compounds
failed to record an IC50 value, which could be attributed to the
solubility of N-tosylhydrazone compounds or other unknown
3. Conclusions
In summary, we have developed a new, mild, and environmen-
tally friendly protocol for the synthesis of N-tosylhydrazones at
room temperature under solvent-free conditions by using a
grinding technique. This coupling reaction proceeded rapidly
(1 min) and tolerated a wide range of functional groups. The
antiproliferative properties of the desired products were also
studied. Among these synthetic compounds, compound 3l
was selected to further evaluate the functions against TNBC
cell lines according to its regnant IC50 value (IC50 =
30.7 mgmLÀ1). Interestingly, compound 3l exhibited the high-
est cytotoxic activity and obvious pro-apoptosis functions
against TNBC cell lines, suggesting the novel therapeutic
schedule may be accompanied by the synthesis and applica-
Figure 2. The IC50 values for N-tosylhydrazones in MDA-MB-231 cells.
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mortar and ground manually with a pestle until the completion of
the reaction as indicated by thin-layer chromatography (TLC;
1 min). The resultant material was washed with petroleum ether
and filtered to give the desired product.
Cell Cultures
Breast cancer cell line MDA-MB-231 used in this study was cultured
by using DMEM media containing 100UmLÀ1 penicillin and
100mgmLÀ1 streptomycin and with 10% FBS in a controlled atmos-
phere of 5% CO2, 95% humidified air at 378C. The cells were sub-
cultivated approximately every 2–3 days at 80% confluence, using
0.25% (w/v) trypsin and then seeded in a proper culture plates for
the following study.
Cytotoxic Activity Assays
MDA-MB-231 (1ꢁ104 cells per well) cells were seeded into 96-well
plates for incubation overnight (378C with 5% CO2). The medium
was removed and replaced with various concentrations of the 17
N-tosylhydrazone compounds (6.25, 12.5, 25, 50, 100, and
200 mgmLÀ1) for 24 h at 378C. After that, 20 mL of CCK-8 solution
was added to each well and incubated for 2 h at 378C. Finally, the
results were detected at 450 nm using a microplate reader. The
50% inhibitory concentration (IC50) represents the concentration of
the modulators that was required for 50% inhibition.
Figure 4. N-Tosylhydrazone compound 3l promotes the apoptosis of MDA-
MB-231 cell line. A) AnnexinV FITC/PI staining was used to determine the
apoptosis of MDA-MB-231 cells with different concentrations of N-tosylhy-
drazone 3l (30 and 100 mgmLÀ1) according to flow cytometry. B) Immuno-
fluorescence staining was used to evaluate cells apoptosis.
Cell Proliferation Assay
A CCK-8 assay was performed to evaluate cell viability after treat-
ing with compounds over six consecutive days, according to the
manufacturer’s instructions. Briefly, MDA-MB-231 cells were seeded
in 96-well plates at a density of 2ꢁ103 cells per well (378C with
5% CO2). Following overnight incubation, compounds were added
tion of compound 3l. Further research concerning the applica-
tion of compound 3l will focus on its functional identification
and therapeutic effect evaluation, in order to provide new
ideas for the treatment of TNBC.
to each well at a concentration of 0, 30, 60, as well as 100 mgmLÀ1
,
and then cultured for 1, 2, 3, 4, 5, and 6 days. At the indicated in-
tervals, 20 mL of Cell Counting Kit-8 (Beyotime) was added to each
well and incubated for 2 h at 378C. The absorbance was detected
at 450 nm by using a PerkinElmer EnSpireꢂ Multimode Plate
Reader (PerkinElmer).
Experimental Section
General Information
Infrared (IR) spectra were recorded on an IRAffinity-1S spectrome-
ter with KBr pellets. 1H and 13C NMR spectra were recorded on a
Bruker Avance III HD 400 MHz spectrometer in [D6]DMSO solution.
ESI mass spectra were collected on a ThermoFisher LCQ Fleet Mass
Spectrometer. TLC analyses were performed on commercial glass
plates bearing a 0.25 mm layer of Merck Silica gel 60F254. Unless
otherwise noted, materials obtained from commercial suppliers
AnnexinV FITC/PI Apoptosis Assay
Apoptotic cells were further analyzed by using the AnnexinV FITC/
PI assay. Briefly, MDA-MB-231 cells were treated with compound 3l
for 12 h with a concentration of 30.7 and 100 mgmLÀ1. Cells were
then harvested through trypsin and washed twice with PBS before
being stained with AnnexinV FITC and PI for 10 min. Then, cells
were analyzed by using a flow cytometer BD FACS Canto II, and
FlowJo7.6.4 software was used to quantify the apoptosis of cells.
Cell apoptosis was also evaluated by using immunofluorescence
microscopy (EVOS ꢂ FL Auto).
1
were used without further purification. Chemical shifts for H NMR
are expressed in parts per million (ppm) relative to tetramethylsi-
lane (d 0.0 ppm). Chemical shifts for 13C NMR are expressed in ppm
relative to [D6]DMSO (d 39.98 ppm). Data are reported as follows:
chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, m=
multiplet), coupling constant (Hz), and integration. All reactions
were carried out under air unless noted.
Statistical Analysis
Typical Procedure for the Synthesis of N-Tosylhydrazones by
All experiments were performed at least three times. MeanÆstan-
dard deviation was used for statistical treatment of data using
Graph Pad Prism (5.0, CA, USA) software, with P<0.05 considered
to be significant difference.
Grinding
A mixture of aromatic aldehyde (ketone) (1 mmol) and 4-methyl-
benzenesulfonohydrazide (1 mmol) was thoroughly mixed in a
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Spectral Data of Products (3a–q)
N’-Benzylidene-4-methylbenzenesulfonohydrazide, 3g
White solid; Yield: 250 mg (91%); IR (KBr) u 3223, 1597, 1429,
N’-(4-Chlorobenzylidene)-4-methylbenzenesulfonohydrazide,
3a
1
1360, 1165, 1043, 955 cmÀ1; H NMR (400 MHz, [D6]DMSO) d 11.40
(s, 1H), 7.91 (s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.61–7.51 (m, 2H),
7.42–7.38 (m, 5H), 2.36 (s, 3H); 13C NMR (100 MHz, [D6]DMSO) d
147.4, 143.9, 136.6, 134.1, 130.5, 130.1, 129.3, 127.7, 127.2, 21.5;
ESI-MS m/z: 275.17 [M+H]+.
White solid; Yield: 293 mg (95%); IR (KBr) u 3183, 1595, 1466,
1
1331, 1167, 1086, 814 cmÀ1; H NMR (400 MHz, [D6]DMSO) d 11.50
(s, 1H), 7.91 (s, 1H), 7.76 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H),
7.46 (d, J=8.5 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 2.36 (s, 3H);
13C NMR (100 MHz, [D6]DMSO) d 146.1, 143.9, 136.6, 135.0, 133.1,
130.2, 128.9, 127.7, 21.5; ESI-MS m/z: 309.17 [M+H]+.
N’-(2-Methylbenzylidene)-4-methylbenzenesulfonohydra-
zide, 3h
N’-(3-Chlorobenzylidene)-4-methylbenzenesulfonohydrazide,
3b
White solid; Yield: 260 mg (90%); IR (KBr) u 3183, 1595, 1458,
1
1360, 1325, 1167, 1055, 953 cmÀ1; H NMR (400 MHz, [D6]DMSO) d
11.41 (s, 1H), 8.15 (s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.56 (d, J=7.7 Hz,
1H), 7.41 (d, J=8.2 Hz, 2H), 7.31–7.15 (m, 3H), 2.35 (s, 3H), 2.31 (s,
3H); 13C NMR (100 MHz, [D6]DMSO) d 146.5, 143.9, 137.0, 136.6,
132.1, 131.4, 130.2, 130.1, 127.7, 126.7, 126.6, 21.5, 19.7; ESI-MS
m/z: 289.17 [M+H]+.
White solid; Yield: 287 mg (93%); IR (KBr) u 3156, 1595, 1439,
1
1358, 1325, 1175, 1059, 949 cmÀ1; H NMR (400 MHz, [D6]DMSO) d
11.65 (s, 1H), 7.91 (s, 1H), 7.78 (d, J=8.2 Hz, 2H), 7.60 (d, J=9.8 Hz,
1H), 7.52 (d, J=6.8 Hz, 1H), 7.46–7.37 (m, 4H), 2.35 (s, 3H);
13C NMR (100 MHz, [D6]DMSO) d 145.7, 144.0, 136.5, 136.3, 134.0,
131.2, 130.2, 127.7, 126.6, 125.8, 21.5; ESI-MS m/z: 309.08 [M+H]+.
N’-(4-Methylbenzylidene)-4-methylbenzenesulfonohydra-
zide, 3i
N’-(2-Chlorobenzylidene)-4-methylbenzenesulfonohydrazide,
3c
White solid; Yield: 265 mg (92%); IR (KBr) u 3215, 1595, 1433,
1
1362, 1165, 1047, 937 cmÀ1; H NMR (400 MHz, [D6]DMSO) d 11.35
White solid; Yield: 281 mg (91%); IR (KBr) u 3192, 1593, 1452,
1329, 1169, 1078, 955 cmÀ1; H NMR (400 MHz, [D6]DMSO) d 11.76
(s, 1H), 8.26 (s, 1H), 7.81–7.72 (m, 3H), 7.47–7.35 (m, 5H), 2.36 (s,
3H); 13C NMR (100 MHz, [D6]DMSO) d 144.1, 143.1, 136.5, 133.3,
132.0, 131.3, 130.4, 130.2, 128.1, 127.7, 127.0, 21.5; ESI-MS m/z:
309.08 [M+H]+.
(s, 1H), 7.87 (s, 1H), 7.76 (d, J=8.2 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H),
7.40 (d, J=8.2 Hz, 2H), 7.20 (d, J=7.9 Hz, 2H), 2.35 (s, 3H), 2.30 (s,
3H); 13C NMR (100 MHz, [D6]DMSO) d 147.6, 143.9, 140.4, 136.6,
131.4, 130.1, 129.8, 127.7, 127.2, 21.5, 21.4; ESI-MS m/z: 289.17
[M+H]+.
1
N’-(4-Methoxybenzylidene)-4-methylbenzenesulfonohydra-
zide, 3j
N’-(4-Fluorobenzylidene)-4-methylbenzenesulfonohydrazide,
3d
Yellow solid; Yield: 295 mg (97%); IR (KBr) u 3225, 1609, 1520,
White solid; Yield: 275 mg (94%); IR (KBr) u 3211, 1601, 1510, 1360,
1
1
1423, 1165, 1036, 949 cmÀ1; H NMR (400 MHz, [D6]DMSO) d 11.28
1319, 1159, 1053, 930 cmÀ1; H NMR (400 MHz, [D6]DMSO) d 11.48
(s, 1H), 7.89 (s, 1H), 7.79 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H),
7.38 (d, J=8.2 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 3.75 (s, 3H), 2.35 (s,
3H); 13C NMR (100 MHz, [D6]DMSO) d 161.2, 147.5, 143.8, 136.7,
130.1, 128.8, 127.7, 126.8, 114.7, 55.7, 21.4; ESI-MS m/z: 305.17
[M+H]+.
(s, 1H), 7.93 (s, 1H), 7.78 (d, J=8.2 Hz, 2H), 7.62 (dd, J=8.6, 5.7 Hz,
2H), 7.39 (d, J=8.2 Hz, 2H), 7.21 (t, J=8.8 Hz, 2H), 2.34 (s, 3H);
13C NMR (100 MHz, [D6]DMSO) d 164.8, 162.3, 146.4, 143.9, 136.6,
130.8, 130.7, 130.1, 129.4, 129.3, 127.7,116.4, 116.2, 21.4; ESI-MS
m/z: 293.17 [M+H]+.
4-Methyl-N’-(2-phenylethylidene)benzenesulfonohydrazide,
N’-(4-Bromobenzylidene)-4-methylbenzenesulfonohydrazide,
3k
3e
White solid; Yield: 248 mg (86%); IR (KBr) u 3209, 1599, 1435,
;
1357, 1162, 1013 cmÀ1 1H NMR (400 MHz, [D6]DMSO) d 10.98 (s,
White solid; Yield: 329 mg (93%); IR (KBr) u 3184, 1593, 1470,
1
1331, 1169, 1069, 812 cmÀ1; H NMR (400 MHz, [D6]DMSO) d 11.57
1H), 7.69 (d, J=8.1 Hz, 2H), 7.43–7.38 (m, 3H), 7.30–7.18 (m, 5H),
6.99 (d, J=6.7 Hz, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, [D6]DMSO)
d 150.6, 143.8, 136.8, 136.5, 130.1, 129.2, 128.9, 127.8, 127.1, 38.5,
21.5; ESI-MS m/z: 289.17 [M+H]+.
(s, 1H), 7.89 (s, 1H), 7.76 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H),
7.51 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 2.38 (s, 3H);
13C NMR (100 MHz, [D6]DMSO) d 146.2, 143.9, 136.6, 133.4, 132.3,
130.2, 129.1, 127.7, 123.8, 21.5; ESI-MS m/z: 353.17 [M+H]+.
N’-(3-Bromobenzylidene)-4-methylbenzenesulfonohydrazide,
4-Methyl-N’-(naphthalen-1-ylmethylene)benzenesulfonohy-
3 f
drazide, 3l
White solid; Yield: 325 mg (92%); IR (KBr) u 3142, 1597, 1518,
Yellow solid; Yield: 292 mg (90%); IR (KBr) u 3150, 1597, 1508,
1
1
1362, 1329, 1167, 1057, 949 cmÀ1; H NMR (400 MHz, [D6]DMSO) d
1321, 1171, 1063, 941 cmÀ1; H NMR (400 MHz, [D6]DMSO) d 11.57
11.67 (s, 1H), 7.90 (s, 1H), 7.78 (d, J=8.2 Hz, 2H), 7.72 (s, 1H), 7.55
(t, J=6.4 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.33 (t, J=7.9 Hz, 1H),
2.33 (s, 3H); 13C NMR (100 MHz, [D6]DMSO) d 145.7, 144.0, 136.6,
133.0, 131.4, 130.2, 129.5, 127.7, 126.1, 122.6, 21.5; ESI-MS m/z:
353.08 [M+H]+.
(s, 1H), 8.58 (d, J=8.2 Hz, 1H), 8.51 (s, 1H), 7.97 (d, J=8.0 Hz, 2H),
7.85 (d, J=8.2 Hz, 2H), 7.72 (d, J=7.1 Hz, 1H), 7.63–7.51 (m, 3H),
7.43 (d, J=8.0 Hz, 2H), 2.34 (s, 3H); 13C NMR (100 MHz, [D6]DMSO)
d 147.8, 144.0, 136.6, 133.9, 131.1, 130.2, 129.4, 129.2, 128.6, 127.9,
127.8, 126.8, 125.9, 124.7, 21.5; ESI-MS m/z: 325.17 [M+H]+.
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N’-(Furan-2-ylmethylene)-4-methylbenzenesulfonohydrazide,
3m
Keywords: anticancer
tosylhydrazones · triple negative breast cancer
·
grinding
·
solvent-free
·
Yellow solid; Yield: 256 mg (97%); IR (KBr) u 3196, 1595, 1487,
1346, 1161, 1049, 914 cmÀ1; H NMR (400 MHz, [D6]DMSO) d 11.45
1
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4-Methyl-N’-(thiophen-2-ylmethylene)benzenesulfonohydra-
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White solid; Yield: 264 mg (94%); IR (KBr) u 3167, 1605, 1439,
1
1341, 1173, 1055, 922 cmÀ1; H NMR (400 MHz, [D6]DMSO) d 11.40
(s, 1H), 8.11 (s, 1H), 7.75 (d, J=8.2 Hz, 2H), 7.57 (d, J=5.0 Hz, 1H),
7.39 (d, J=8.2 Hz, 2H), 7.35 (d, J=3.4 Hz, 1H), 7.08–7.03 (m, 1H),
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3o
White solid; Yield: 257 mg (89%); IR (KBr) u 3219, 1595, 1508,
1400, 1335, 1367,1057, 914 cmÀ1; H NMR (400 MHz, [D6]DMSO) d
10.52 (s, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.64–7.61 (m, 2H), 7.46–7.34
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1
4-Methyl-N’-(propan-2-ylidene)benzenesulfonohydrazide, 3p
White solid; Yield: 217 mg (96%); IR (KBr) u 3224, 1599, 1388,
;
1333, 1162, 1091, 927 cmÀ1 1H NMR (400 MHz, [D6]DMSO) d 9.99
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1404, 1333, 1162, 1037, 943 cmÀ1; H NMR (400 MHz, [D6]DMSO) d
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Acknowledgements
Financial support from the Natural Science Foundation of Shan-
dong Province (Grant Nos. ZR2016BL06 and ZR2017BH080), the
Youth Support Foundation of Jining Medical University (Grant
No. JYFC2018KJ057), and the Undergraduate Innovation Training
Programs of Jining Medical University (Grant No. cx2018006) is
gratefully acknowledged.
Conflict of Interest
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The authors declare no conflict of interest.
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Received: October 1, 2018
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FULL PAPERS
Z. Xie,* Y. Song, L. Xu, Y. Guo, M. Zhang,
L. Li, K. Chen,* X. Liu*
Daily grind: Some N-tosylhydrazone de-
rivatives are effectively synthesized
under solvent-free conditions by using a
grinding method. The short reaction
time, clean and mild process with
simple workup and easy purification of
target compounds are salient features
of the protocol, which enables straight-
forward access to N-tosylhydrazones.
Among the tosylhydrazone derivatives
evaluated, one compound exhibits ex-
cellent apoptosis-promoting and anti-
cancer potential against triple-negative
breast cancer (TNBC) cell lines, indicat-
ing that our synthesized compound
may be a desirable and effective thera-
peutic drug for TNBC.
&& – &&
Rapid Synthesis of N-Tosylhydrazones
under Solvent-Free Conditions and
Their Potential Application Against
Human Triple-Negative Breast Cancer
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