Synthesis and evaluation of 1-benzhydryl-sulfonyl-piperazine derivatives as inhibitors of MDA-MB-231 human breast cancer cell proliferation

Article abstract of DOI:10.1007/s00044-007-9022-y

A series of novel 1-benzhydryl-sulfonyl-piperazine derivatives 7(a-e) were designed by a nucleophilic substitution reaction of 1-benzhydryl-piperazine with various sulfonyl chlorides and characterized by ¹H nuclear magnetic resonance (NMR), liquid chromatography mass spectrometry (LC/MS), Fourier-transform infrared (FTIR), and elemental analysis. Our research is focused on identifying synthetically occurring chemotherapeutic substances capable of inhibiting, retarding, or reversing the process of multistage carcinogenesis. The title compounds were evaluated for their efficacy in inhibiting MDA-MB-231 breast cancer cell proliferation. Compound 1-benzhydryl-4-(4-tert-butyl-benzenesulfonyl)-piperazine (7d) showed significant inhibitory activity. Birkhaeuser 2007.

Full text of DOI:10.1007/s00044-007-9022-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2007) 16:179–187
DOI 10.1007/s00044-007-9022-y
ORIGINAL RESEARCH
Synthesis and evaluation of 1-benzhydryl-sulfonyl-
piperazine derivatives as inhibitors of MDA-MB-231
human breast cancer cell proliferation
C. S. Ananda Kumar Æ S. Nanjunda Swamy Æ N. R. Thimmegowda Æ
S. B. Benaka Prasad Æ George W. Yip Æ K. S. Rangappa
Received: 15 April 2007 / Accepted: 4 June 2007 / Published online: 1 August 2007
¨
Ó Birkhauser Boston 2007
Abstract A series of novel 1-benzhydryl-sulfonyl-piperazine derivatives 7(a-e)
were designed by a nucleophilic substitution reaction of 1-benzhydryl-piperazine
with various sulfonyl chlorides and characterized by 1H nuclear magnetic resonance
(NMR), liquid chromatography mass spectrometry (LC/MS), Fourier-transform
infrared (FTIR), and elemental analysis. Our research is focused on identifying
synthetically occurring chemotherapeutic substances capable of inhibiting, retard-
ing, or reversing the process of multistage carcinogenesis. The title compounds were
evaluated for their efficacy in inhibiting MDA-MB-231 breast cancer cell prolif-
eration. Compound 1-benzhydryl-4-(4-tert-butyl-benzenesulfonyl)-piperazine (7d)
showed significant inhibitory activity.
Keywords 1-benzhydryl-piperazine derivatives Á Sulfonyl chlorides Á
MDA-MB-231 Á Cell proliferation
Introduction
Breast cancer is a malignant cell growth in the breast. Breast cancer is the most
common type of cancer diagnosed in women, excluding skin cancer. Almost one
third (32%) of all cancers diagnosed in women are breast cancer. However, the
C. S. Ananda Kumar Á S. Nanjunda Swamy Á
N. R. Thimmegowda Á S. B. Benaka Prasad Á K. S. Rangappa
Department of Studies in Chemistry, University of Mysore, Mysore, India
G. W. Yip (&)
Department of Anatomy, National University of Singapore, Singapore, Singapore
e-mail: georgeyip@nus.edu.sg
K. S. Rangappa (&)
DOS in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
e-mail: rangappaks@gmail.com

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Med Chem Res (2007) 16:179–187
incidence of breast cancer varies by race and ethnicity. American, Indian, and
Native Alaskan women have the lowest incidence whereas Caucasian women have
the highest incidence of breast cancer diagnoses. In recent years, there has been an
explosion of life-saving treatment advances against breast cancer, bringing new
hope and excitement. Instead of only one or two options, there are now many
treatment choices that fight the complex mix of cells in each individual cancer. The
decisions between surgery, then perhaps radiation, hormonal (anti-estrogen)
therapy, and/or chemotherapy, can feel overwhelming.
Piperazines are currently the most important building blocks in drug discovery,
with a high number of positive hits encountered in biological screens of this
heterocycle and its congeners. The piperazine template forms the molecular
backbone, possesses versatile binding properties with a frequently occurring binding
motif, and provides potent and selective ligands for a range of different biological
targets in medicinal chemistry. The piperazine scaffold and its analogues are
important pharmacophores that can be found in biologically active compounds
across a number of different therapeutic areas (Berkheij et al., 2005; Guo et al.
2004). These include anticancer (Gillet et al. 1998; Gabriel et al., 2000; Hulme
et al., 1999), antifungal (Upadhayaya et al., 2004), antibacterial, antimalarial,
antipsychotic agents (Choudhary et al., 2006), HIV protease inhibitors (Vacca et al.,
1994; Askin et al., 1994; Rossel et al., 1995) and antidepressants (EGYT, 1975).
MST-16[4,4-1,2-(ethanediyl) bis(1-isobutoxycarbonyloxy-methyl-2,6-piperazinedi-
one)] was recently approved as an oral anticancer drug for clinical use in Japan
(Yoshida, 1999). The piperazine analogues have been shown to have potent
antiproliferative activity against colon, prostate, breast, lung, and leukemia tumors;
additional studies have demonstrated the ability of the lead piperazines to suppress
and eliminate experimental tumors in small-animal models performed by the
National Cancer Institute (NCI). Mechanistic evaluations have shown that
piperazines inhibit microtubule synthesis by a unique mechanism, inhibit cell cycle
progression, and inhibit angiogenesis, which is critical to a tumor cell’s ability to
grow and metastasize. The piperazines kill tumor cells directly through the
induction of apoptosis. The anti-tumor mode of action of the piperazines is quite
distinct from that of Taxol and in addition they are significantly more potent, active
against a variety of different tumor types, and are orally bioavailable, when
compared to Taxol. In the literature, we also found that diaryl piperazine derivatives
were identified as potent and selective dopamine D4 receptor antagonists (Mark
et al., 2004; Glase et al., 1997; Perrone et al., 2000), enterovirus inhibitors (Chern
et al., 2004), and inhibitors of dopamine uptake in the central nervous system
(Kimura et al., 2003a, b; Guo et al., 2004; Kimara et al. 2004). Piperazine
sulfonamides exhibit diverse pharmacological activity such as MMP-3 enzyme
inhibition and carbonic anhydrase inhibition (Chern et al., 2004; Amin and Welsh,
2003). In continuation of our research on the synthesis of bioactive heterocycles and
their biological evaluation (Nanjunda Swamy et al., 2006; Narendra Sharath
Chandra et al., 2006, 2007; Priya et al., 2005; Thimmegowda et al., 2007; Anil
Kumar et al., 2007, 2007), we describe here the synthesis of 1-benzhydryl-sulfonyl-
piperazine derivatives and their effect on inhibition of proliferation of MDA-MB-
231 human breast cancer cells.

Med Chem Res (2007) 16:179–187
181
Chemistry
1-benzhydryl-piperazine derivatives 7(a-e) were prepared by the method summa-
rized in Scheme 1. Initially compound 3, benzhydrol, was synthesized by a Grignard
reaction under nitrogen with benzaldehyde (1) and phenyl magnesium bromide (2);
the obtained yield was found to be 60%. Finally, we synthesized benzhydrol by
reduction of benzophenone using sodium borohydride and achieved a 90% yield.
Herein, we report the synthesis of 1-benzhydryl-piperazine from benzophenone for
the first time. Compound 3 was subsequently treated with thionyl chloride to give
the corresponding benzhydryl chloride (5), which was directly reacted with
piperazine and anhydrous potassium carbonate using dimethyl formamide as a
solvent at 80°C to give the target key intermediate 1-benzhydryl-piperazine (6). The
nucleophilic substitution reactions of (6) with different sulfonyl chlorides (R-SO2-
Cl) were carried out in the presence of triethylamine and dichloromethane as the
solvent with a good yield of 76–85% and good purity. Synthesized molecules 7(a-e)
were structurally characterized by 1H NMR, LC/MS, IR and elemental analysis. The
chemical structures, physical data and purity of all the synthesized compounds are
given in Table 1.
Results and discussion
Chemistry
The N-substitution of 1-benzhydryl-piperazine with different sulfonyl chlorides was
confirmed by the disappearance of the N-H group in IR and 1H NMR data.
Compounds 7(a-e) were also confirmed by IR data, which showed asymmetric
O
MgBr
a
H
b
OH
+
O
1
2
4
3
O
S
c
d
e
OH
N H
N
Cl
N
N
R
O
7(a-e)
3
5
6
Scheme 1. Reagents and conditions: (a) dry THF, room temperature, 4 hrs, under N2; (b) NaBH4,
methanol, room temperature, 5 hrs; (c) thionyl chloride, methylene dichloride (MDC), 0–5°C, 4 hrs; (d)
piperazine, K2CO3, DMF, 80°C, 8 hrs; (e) R-SO2Cl, 6(a-e), MDC, triethylamine, room temperature, 5–6
hr, where R-SO2Cl is:, 6a: Methanesulfonyl chloride, 6b: 4-methyl-benzenesulfonyl chloride, 6c: 4-
chloro-benzenesulfonyl chloride, 6d: 4-tert-butyl-benzenesulfonyl chloride, 6e: 3,5-dimethyl-isoxazole-4-
sulfonyl-chloride

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Table 1 Chemical structures, physical data, and purities of synthesized compounds
Compound
7a
R
Yield (%)
85
m.p. (°C)
Purity
99.21
CH3
192–194
CH3
7b
7c
7d
7e
82
80
84
76
173–175
153–155
198–200
179–181
99.14
98.65
99.62
98.90
Cl
CH3
CH3
CH3
H3C
O
N
H3C
Table 2 Percentage inhibition of MDA-MB-231 cell proliferation
Piperazine derivatives
% Inhibition SD
P value (Student’s t-test)
7a
7b
7c
7d
7e
3.79 0.2552
10 0.0086
0.25520
0.00860
0.86730
0.00030
0.001
1
0.8673
28.6 0.0003
20.6 0.001
stretching frequency of O=S=O at 1350 cm-1 and symmetric stretching frequency at
1280 cm-1. Several new derivatives of 1-benzhydryl-piperazine 7(a-e) were
synthesized and evaluated for their anti-cancer activities. The obtained products
were purified by column chromatography using hexane:ethyl acetate (8:2) as an
eluent.
Biology: in vitro cell viability assay – MTS assay
To check the anticancer activity, we carried out the reactions of 1-benzhydryl-
piperazine with different sulfonyl chlorides containing aliphatic, substituted
aromatic, and heterocyclic groups. Our results reveal that the title compounds
showed inhibition of proliferation of MDA-MB-231 human breast cancer cells
(Table 2). Among the tested compounds, the inhibitory activity was observed in the
following order 7d > 7e > 7b > 7a > 7c. Compounds 7d and 7e exhibited
28.6
proliferation of MDA-MB-231 breast cancer cells, respectively. Similarly com-
pounds 7a, 7b and 7c showed 3.79 0.2552% (P = 0.2552), 10 0.0086%
0.0003% (P = 0.00030) and 20.6
0.001% (P = 0.001) inhibition of
(P = 0.0086), and 1 0.8673% (P = 0.8673) inhibition, respectively. Compound 7d
exhibited good inhibition compared to compound 7b; the inhibition of the

Med Chem Res (2007) 16:179–187
183
compound 7d may be due to the presence of a tertiary butyl group, a strong electron-
donating group. Compound 7c showed less inhibition (1%), which might be due to
the presence of an electronegative chloro group. Similarly compound 7e showed
20.6% inhibition, which might due to the isoxazole ring containing methyl groups.
Compound 7a showed 3.79% inhibition with a methyl group only. From our results,
it could be concluded that inhibition increases with the number of electron-donating
groups, whereas in the presence of electron-withdrawing groups the observed
inhibition is not significant. Thus, we conclude that the presence of electron-
donating groups may be responsible for the observed inhibition. Further modifi-
cation of the groups in the basic scaffold to increase efficacy and in vivo work is
under progress.
Conclusion
Currently, a large variety of chemotherapeutic drugs are used to treat cancer.
Unfortunately, many compounds have limited efficacy due to problems of delivery
and penetration and a moderate degree of selectivity for cancer cells. From our
studies, it is clear that compound 7d inhibits MDA-MB-231 human breast cancer
cell proliferation. The 1-benzhydryl-sulfonyl-piperazine derivatives were obtained
with good yield and purity. This study sheds light on the identification of this new
series of agents for cancer therapy.
Experimental
Melting points were determined using a SELACO-650 hot-stage melting-point
apparatus and were used uncorrected. Infrared (IR) spectra were recorded using a
Jasco FTIR-4100 device. Nuclear magnetic resonance (1H NMR) spectra were
recorded on a Shimadzu AMX 400-Bruker, 400 MHz spectrometer using dimethyl
sulfoxide (DMSO) as a solvent and trimethylsilyl (TMS) as an internal standard
(chemical shift in d ppm). Spin multiplets are given as s (singlet), d (doublet), t
(triplet), dd (doublet of doublet), and m (multiplet). Mass and purity were recorded
on a LC-MSD-Trap-XCT. Elemental (CHNS) analyses were obtained on a Vario EL
III Elementar device. Silica gel column chromatography was performed using
Merck 7734 silica gel (60-120 mesh) and Merck thin-layer chromatography (TLC)
plates.
General procedure for the synthesis of 1-benzhydryl-piperazine (6)
A solution of piperazine dihydrochloride (10.0 g, 62.86 mmol) in dimethyl
formamide was taken, anhydrous potassium carbonate (43.44 g, 314.3 mmol) was
added to the solution and stirred for 10 min, and then benzhydryl chloride (11.46 g,
56.58 mmol) was added. The reaction mixture was heated to 80°C for 8 hrs, and
monitored by TLC. Upon completion, the solvent was removed under reduced
pressure and the residue was taken in water and extracted with ethyl acetate. Finally

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a water wash was given to the organic layer, followed by drying with anhydrous
sodium sulphate. The solvent was evaporated to obtain the crude product, which
was purified by column chromatography over silica gel (60-120 mesh) using
chloroform:methanol (9:1) as the eluent.
General procedure for the synthesis of 1-benzhydryl-sulfonyl-piperazine
derivatives 7(a-e)
A solution of 1-benzhydryl-piperazine 6 (1.0 eq) in dry dichloromethane was taken
and cooled to 0–5°C in an ice bath. Triethylamine (3.0 eq) was added to the cold
reaction mixture and stirred for 10 min, and then different sulfonyl chlorides (1.0
eq) were added. The reaction mixture was stirred for 5–6 hrs at room temperature,
and monitored by TLC. Upon completion, the solvent was removed under reduced
pressure and residue was taken in water and extracted with ethyl acetate. The
organic layer was washed with 10% ammonium chloride solution and finally a water
wash was given to the organic layer and dried with anhydrous sodium sulphate. The
solvent was evaporated to obtain the crude product, which was purified by column
chromatography over silica gel (60-120 mesh) using hexane:ethyl acetate (8:2) as
the eluent.
Synthesis of 1-benzhydryl-4-methanesulfonyl-piperazine (7a)
This was obtained from 1-benzhydryl-piperazine (6) (0.5 g, 1.98 mmol), metha-
nesulfonyl chloride (0.226 g, 1.98 mmol), triethylamine (0.601 g, 5.94 mmol). The
product obtained was a white crystalline solid (0.556 g, 85%). IR (KBr, cmÀ1):
3029, 2959, 2850, 1346, 1285. 1H NMR (DMSO, 400 MHz) d: 7.38 (d, 4H, Ar-H),
7.27 (t, 4H, Ar-H), 7.15 (t, 2H, Ar-H), 4.25 (s, 1H, -CH-), 2.92 (br s, 4H, -CH2-),
2.50 (br s, 4H, -CH2-), 2.7 (s, 3H, -CH3-). MS: 331.56. Anal. calcd. for
C18H22N2O2S (in %): C-65.43, H-6.71, N-8.48, S-9.70. Found C-65.40, H-6.68, N-
8.45, S-9.66.
Synthesis of 1-benzhydryl-4-(toluene-4-sulfonyl)-piperazine (7b)
This was obtained from 1-benzhydryl-piperazine (6) (0.5 g, 1.98 mmol), 4-methyl-
benzenesulfonyl chloride (0.377 g, 1.98 mmol), triethylamine (0.601 g, 5.94 mmol).
The product obtained was a white crystalline solid (0.644 g, 82%). IR (KBr, cmÀ1):
3029, 2962, 1398, 1346, 1280. 1H NMR (DMSO, 400 MHz) d: 7.63-7.7 (m, 4H, Ar-
H), 7.35 (d, 4H, Ar-H), 7.25 (t, 4H, Ar-H), 7.15 (t, 2H,Ar-H), 4.3 (s, 1H, -CH), 2.9
(br s, 4H, -CH2-), 2.4 (br s, 4H, -CH2-), 2.4 (s, 3H, -CH3-). MS: 407.3. Anal. calcd.
for C24H26N2O2S (in %): C-70.91, H-6.45, N-6.89, S-7.89. Found C-70.87, H-6.41,
N-6.86, S-7.87.
Synthesis of 1-benzhydryl-4-(4-chloro-benzenesulfonyl)-piperazine (7c)
This was obtained from 1-benzhydryl-piperazine (6) (0.5 g, 1.98 mmol), 4-
chlorobenzene sulfonyl chloride (0.417 g, 1.98 mmol), triethylamine (0.601 g, 5.94

Med Chem Res (2007) 16:179–187
185
mmol). The product obtained was an off-white crystalline solid (0.676 g, 80%). IR
(KBr, cmÀ1): 2961, 2889, 1350, 1279, 707. 1H NMR (DMSO, 400 MHz) d: 7.7-7.8
(m, 4H, Ar-H), 7.4 (d, 4H, Ar-H), 7.28 (t, 4H, Ar-H), 7.16 (t, 2H, Ar-H), 4.3 (s, 1H, -
CH), 3.0 (br s, 4H, -CH2-), 2.41 (br s, 4H, -CH2-). MS: 427.90. Anal. calcd. for
C23H23ClN2O2S (in %): C-64.70, H-5.43, N-6.56, S-7.51. Found C-64.66, H-5.40,
N-6.54, S-7.50.
Synthesis of 1-benzhydryl-4-(4-tert-butyl-benzenesulfonyl)-piperazine (7d)
This was obtained from 1-benzhydryl-piperazine (6) (0.5 g, 1.98 mmol), 4-tert-
butyl-benzenesulfonyl chloride (0.460 g, 1.98 mmol), triethylamine (0.601 g, 5.94
mmol). The product obtained was an off-white amorphous solid (0.746 g, 84%). IR
1
(KBr, cmÀ1): 3028, 2852, 1346, 1279, 1399. H NMR (DMSO, 400 MHz) d: 7.63-
7.7 (m, 4H, Ar-H), 7.35 (d, 4H, Ar-H), 7.25 (t, 4H, Ar-H), 7.15 (t, 2H,Ar-H), 4.3 (s,
1H, -CH), 2.94 (br s, 4H, -CH2-), 2.42 (br s, 4H, -CH2-), 1.3 (s, 9H, (-CH3)3-). MS:
449.58. Anal. calcd. for C27H32N2O2S (in %): C-72.29, H-7.19, N-6.24, S-7.15.
Found C-72.25, H-7.15, N-6.20, S-7.12.
Synthesis of 1-benzhydryl-4-(3,5-dimethyl-isoxazole-4-sulfonyl)-piperazine
(7e)
This was obtained from 1-benzhydryl-piperazine (6) (0.5 g, 1.98 mmol), 3,5-
dimethyl-isoxazole-4-sulfonyl-chloride (0.387 g, 1.98 mmol), triethylamine (0.601
g, 5.94 mmol). The product obtained was a white crystalline solid (0.619 g, 76%).
1
IR (KBr, cmÀ1): 3055, 2956, 2831, 1345, 1296. H NMR (DMSO, 400 MHz) d:
7.38 (d, 4H, Ar-H), 7.27 (t, 4H, Ar-H), 7.17 (t, 2H, Ar-H), 4.25 (s, 1H, -CH-), 3.05
(br s, 4H, -CH2-), 2.55 (br s, 4H, -CH2-), 2.4 (s, 6H, -CH3). MS: 412.1. Anal. calcd.
for C22H25N3O3S (in %): C-64.21, H-6.12, N-10.21, S-7.79. Found C-64.19, H-6.08,
N-10.20, S-7.76.
Biology
Culturing mammalian cell lines
MDA-MB-231 human breast cancer cells were grown in Roswell Park Memorial
Institute (RPMI) medium (Sigma), supplemented with 10% fetal bovine serum
(FBS). The cells were maintained at 37°C in a 5% CO2 incubator. They were
subsequently dislodged from the substratum by 1X trypsin treatment for 5 min
followed by inactivation using FBS.
Cell proliferation assay
The MTS assay was performed using the Promega CellTiter 961 aqueous
nonradioactive cell proliferation assay as previously described (Zou et al., 2004).
Briefly, MB-MB-231 cells were added to the wells of a 96-well plate at a density of

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Med Chem Res (2007) 16:179–187
2000 cells/well. The test compounds at 2 mM concentration dissolved in 1% DMSO
were added, and the cultures were continued for 72 hrs. Replenishment with fresh
compounds was done after the first 48 hrs. At the end of 72 hrs of treatment, the
cultured medium was removed and 20 ml/well of combined MTS/PMS solution was
added and incubated for 4 hrs. The absorbance at 490 nm was recorded using an
ELISA plate reader.
Acknowledgements The authors are grateful to the UGC, Govt. of India for financial support to K.S.R.
under project UGC-SAP (phase I) DRS programme DV4/375/2004-05, and to the National Medical
Research Council, Singapore for financial support from grants NMRC/0772/2003 and NMRC/1023/2005
(G.W.Y.). One of the authors, S.N.S, thanks the CSIR, Govt. of India for the award of a CSIR senior
research fellowship.
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