Synthesis and in vitro antiproliferative activity of diphenyl(sulphonylpiperidin-4-yl)methanol derivatives

Article abstract of DOI:10.1007/s00044-009-9186-8

A series of novel diphenyl(piperidin-4-yl)methanol derivatives 10(a-n) were synthesized and characterized by ¹H NMR, LC/MS, FTIR, and elemental analyses. All the synthesized compounds were evaluated for cell proliferation by MTT assay. The antiproliferative effects of the synthesized compounds were tested against viable human skin fibroblast cell line and carcinoma cell lines, namely HeLa cells, HT-29 cells, MCF-7 cells, and HepG-2 cells in comparing the positive and negative control. Among the synthesized compounds, (10b) and (10g) have been identified as potent antiproliferative agents.

Full text of DOI:10.1007/s00044-009-9186-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2010) 19:220–235
DOI 10.1007/s00044-009-9186-8
ORIGINAL RESEARCH
Synthesis and in vitro antiproliferative activity
of diphenyl(sulphonylpiperidin-4-yl)methanol
derivatives
S. B. Benaka Prasad Æ K. Vinaya Æ
C. S. Ananda Kumar Æ Sanjay Swarup Æ
K. S. Rangappa
Received: 21 April 2008 / Accepted: 17 March 2009 / Published online: 6 May 2009
¨
Ó Birkhauser Boston 2009
Abstract A series of novel diphenyl(piperidin-4-yl)methanol derivatives 10(a–n)
1
were synthesized and characterized by H NMR, LC/MS, FTIR, and elemental
analyses. All the synthesized compounds were evaluated for cell proliferation by
MTT assay. The antiproliferative effects of the synthesized compounds were tested
against viable human skin fibroblast cell line and carcinoma cell lines, namely HeLa
cells, HT-29 cells, MCF-7 cells, and HepG-2 cells in comparing the positive and
negative control. Among the synthesized compounds, (10b) and (10g) have been
identified as potent antiproliferative agents.
Keywords Diphenyl(pyridin-4-yl)methanol Á Sulfonyl chloride Á
MTT assay Á Antiproliferative activity Á Cancer therapy Á Cell proliferation
Introduction
Cancer remains the leading cause of death in the world, and as a result there is a
pressing need for novel and effective treatments. Cancer cells differ from their normal
cells in a number of biochemical processes, particularly during the control of cell
growth and division. Antiproliferative and cytotoxic drugs play a major role in cancer
therapy, whether used alone or in combination with other treatment modalities, such as
surgery, radiation, and biological therapy. During the past 50 years, the mass
screening of synthetic derivatives or natural products has led to the discovery of the
currently utilized anticancer drugs. In the field of chemotherapeutic drugs, the search
S. B. Benaka Prasad Á K. Vinaya Á C. S. Ananda Kumar Á K. S. Rangappa (&)
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
e-mail: rangappaks@chemistry.uni-mysore.ac.in; rangappaks@gmail.com
S. Swarup
Department of Biological Sciences, National University of Singapore, Singapore, Singapore

Med Chem Res (2010) 19:220–235
221
for new, more active, more selective, and less toxic compounds is still very intense,
and new promising anticancer approaches are being tested (Sawyers, 2004; Li and Xu,
2005). Currently, combined anticancer therapies or multiacting drugs are clinically
preferred to traditional cytotoxic treatment, with the goal of overcoming resistance
and toxicity drawbacks. These events often prevent successful treatment and are
responsible for reduced survival times (Jimeno and Hidalgo 2006; Mencher and
Wang, 2005).
The accentuated interest in the piperidine class of opiate analgesics continues to
be expressed in the field of pharmaceuticals, and biological properties of these
agents have been the subject of ongoing investigations (Colapret et al., 1989). The
importance of nitrogen heterocycles, especially piperidine type, as subunits of
bioactive molecules stimulates the chemist for the development of new synthetic
methods (Cordell, 2000). During the last decade, combinatorial chemistry has
represented the most promising approach to allow entry to a great number of
biological targets arising from molecular biology and genomic studies (Ganesan,
2002). The piperidine scaffold is wide-ranging in its therapeutic uses and is
ubiquitously found in drugs. It is a key structural component of successful
Parkinson’s drug (Klockgether et al., 1996) and displays antipsychotic (Stephen
et al., 2002), metabolic (Lihu et al., 1998), antimicrobial (Baikenova et al., 2004;
Anna et al., 2002), antidepressants (Amat et al., 1996), antimalarial (Maniyan et al.,
2006), and anticonvulsant activity (Reddy et al., 1997; Matthew et al., 1998).
Recently, a class of sulfonamides has been used for the treatment of diseases arising
from abnormal cell growth and proliferation (Medina et al., 1998; Shan et al.,
1999). Based on the diverse biological activities of the piperidine sulfonamides and
a recent report from our laboratory (Anil Kumar et al., 2007a; Anil Kumar et al.,
2007b; Ananda Kumar et al., 2007; Priya et al., 2007), we present the
antiproliferative activity of the synthesized compounds against four human cancer
cell lines.
Chemistry
Synthesis of the target key intermediate (9) as outlined in Scheme 1 was accomplished
in high yield. Compound diphenyl(pyridin-4-yl)methanol (3) was prepared from 4-
benzoylpyridine by Grignard reaction (Dhananjay et al., 1993). In the second step N-
methylation of compound (3), 4-(Hydroxy-diphenyl-methyl)-1-methyl-pyridinium
iodide (5) of its salt was obtained. Sodium borohydride reduction of compound (5)
yielded (1,2,3,6-tetrahydro-1-methylpyridin-4-yl)diphenylmethanol (6) (Dhananjay
et al., 1993), which on catalytic transfer hydrogenation (Ra–Ni/Cyclohexanol) gave
(1-methyl piperidin-4-yl)diphenylmethanol (7). In the fifth step N-demethylation
of (7) with ethylchlorformate (Abdel-Menem and Portoghese, 1972) yielded the ethyl
4-(hydroxydiphenylmethyl)piperidine-1-carboxylate (8), which on hydrolysis gave
diphenyl(piperidin-4-yl)methanol (9). Compound (9) thus prepared is used for the
synthesis of its derivatives. Although the method involves several stages, the
reactions can be conveniently performed and may be scaled up. The method avoids the
use of high pressure. Diphenyl(piperidin-4-yl)methanol derivatives 10(a–n) were

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Med Chem Res (2010) 19:220–235
MgBr
(ii)
(i)
HO
N
CH3I
O
HO
N
I
N
1
2
4
5
3
(v)
(iv)
(iii)
HO
N
HO
N
HO
N
COOCH2CH3
6
7
8
O
(vi)
(vii)
HO
N
HO
NH
S
R
O
9
10 (a-n)
Scheme 1 Reagents and Conditions: (i). Dry THF, r.t, 3 hours. (ii). acetone, r.t, 3–4 hours. (iii). NaBH4,
MeOH, r.t, 4 hours. (iv). Ra–Ni/Cyclohexanol, reflux, 2 hours (v). CHCl3, K2CO3, C2H5COOCl, r.t,
overnight. (vi). C2H5OH, KOH, reflux under N2, 24 hours. (vii). R–SO2–Cl, TEA, MDC, 4 hours
prepared by the nucleophilic substitution reaction of diphenyl(piperidin-4-yl)meth-
anol (9) with different substituted aromatic, aliphatic and heterocyclic sulfonyl
chlorides (R–SO2–Cl) were performed in presence of triethylamine and dichloro-
methane as solvent with a good yield ranging from 82–91%. The absence of –N–H
proton peak in synthesized derivatives 10(a–n) in proton NMR confirms our products.
It also is confirmed by IR data, for sulfonamide series 10(a–n), which showed
asymmetric stretching frequency of O = S=O in the range 1350–1370 cm-1 and
symmetric stretching frequency at 1270–1290 cm-1. All the compounds were
1
characterized by H-NMR spectroscopy and LCMS. The yield, physical data, and
chemical structures of the synthesized compounds are shown in Table 1.
Results and discussion
New classes of sulfonamides have been used for the treatment of diseases arising
from abnormal cell growth and proliferation (Medina et al., 1998; Shan et al.,
1999). Most cancers are characterized by uncontrolled cell proliferation, lack of cell
differentiation, and loss of contact inhibition, which confers upon the tumor cell a
capability to invade local tissues and metastasize. The novel synthesized
diphenyl(piperidin-4-yl)methanol analogues 10(a–n) were evaluated for their cell

Med Chem Res (2010) 19:220–235
223
Table 1 Chemical structure, yield, and melting point of the synthesized compounds 10(a–n)
Compound
10a
R
Yield (%)
90
M. P (°C)
165–167
CH3
10b
89
185–187
N
O
H3C
CH3
10c
10d
85
90
237–239
172–174
CH3
10e
10f
89
88
142–144
135–137
CH3
CH3
10g
10h
87
91
215–217
236–238
F
Cl
CH3
Cl
10i
10j
83
88
205–207
275–277
10k
10l
83
87
180–182
194–196
Cl
O2N

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Med Chem Res (2010) 19:220–235
Table 1 continued
Compound
R
Yield (%)
M. P (°C)
10m
82
–
NO2
NO2
10n
86
161–163
antiproliferative activity against human MCF-7 breast carcinoma cell line, HT-29
colon carcinoma cell line, HeLa cervix carcinoma cell line, and HepG-2
hepatocellular carcinoma cell line. All the synthesized compounds were tested for
their cytotoxicity against normal skin fibroblast cells. In vitro cytotoxicity was
evaluated after 24 hours of cell treatment performing MTT assay. The percentage of
cells survived in all the test compounds are listed in Table 2.
Among the tested compounds, the minimum 38.68% cell survival activity was
shown by (10b) against MCF-7 carcinoma cell line. Compound (10j) exhibited
39.11% antiproliferation against HepG-2 carcinoma cell line. Similarly, compound
(10g) showed 39.22% antiproliferation against HeLa carcinoma cell line. Com-
pound (10g) showed good potency for all the carcinoma cell lines and exhibits
44.16%, 46.32%, 47.17%, and 39.22% cell survival activity against MCF-7, HepG-
Table 2 Evaluation of cytotoxicity toward carcinoma cells for the synthesized compounds 10(a–n)
Compound
NF-
103
MCF-
7
HepG-
2
HT-
29
HeLa
10a
10b
10c
10d
10e
10f
10g
10h
10i
65.63
53.82
63.98
63.0
70.24
38.68
60.54
65.80
68.65
70.46
44.16
NT
62.67
52.18
60.85
68.30
62.56
64.66
46.32
NT
45.11
73.61
74.70
73.88
74.21
77.63
47.17
NT
71.21
39.89
64.36
68.29
73.12
78.50
39.22
NT
59.98
59.98
51.76
NT
53.53
59.81
52.96
63.41
57.36
53.59
66.02
69.69
61.36
73.75
63.39
69.75
59.13
39.11
52.18
57.20
64.16
68.74
45.16
76.49
69.59
78.55
74.97
70.84
56.06
70.14
49.71
64.30
70.31
54.04
10j
10k
10l
10m
10n
NT = not tested

Med Chem Res (2010) 19:220–235
225
2, HT-29, and HeLa cell lines, respectively. Similarly, compound (10b) showed
potent antiproliferative activity and exhibits 38.68% and 39.89% cell survival
activity against MCF-7 and HeLa cell lines, respectively. Compounds (10a), (10i),
and (10k) showed moderate activity against HT-29, HT-29, and HeLa cell lines and
exhibits 45.11%, 45.16%, and 49.71% cell survival, respectively. Moreover, the
other tested compounds 10(c–f) and 10(l–n) showed very little inhibitory activity.
The extent of inhibition of carcinoma cell lines by 10(a–n) are schematically
presented in Figs. 1, 2, 3, 4, 5.
The inhibition by compound (10g) (39.22% cell survival) could be attributed to
electron donating fluorine and chlorine atoms present on the substituted benzene at
ortho and para position. The compound (10b) exhibited 38.68% cell survival, which
may be due to the presence of electron-donating dimethyl groups present on the
substituted isoxazole moiety. The hydrophobicity of chloro fluorophenyl, dimethyl,
and rigidity of the isoxazole ring is essential for a more efficient binding to the
active site of the enzyme.
Initial structure–activity relationship (SAR) studies were focused on the effects
of the substitutions on the aromatic ring. Compounds with electron-donating
substituents (10a, 10b, 10d, 10e, and 10g) showed enhanced activity compared with
120
100
80
60
40
20
0
No. of days (1)
Fig. 1 MTT assay for human normal skin cell line
Fig. 2 MTT assay for MCF-7
cell line

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Med Chem Res (2010) 19:220–235
Fig. 3 MTT assay for HepG-2
cell line
Fig. 4 MTT assay for HT-29
cell line
Fig. 5 MTT assay for HeLa
cell line
those bearing electron-withdrawing substituents 10(l–n). As shown in Table 2,
chloro fluorophenyl (10g) and dimethyisoxazole ring (10b) derivatives showed a
pronounced effect on all the cell lines. These results suggest that the electronic

Med Chem Res (2010) 19:220–235
227
features of the various substituents have an effect on how easily the drug can
interact with bioactive molecules. We synthesized compounds (10c), (10f), (10h),
and (10i) to understand the effect of alkyl chain substitution in compound (9). It was
observed that as the length of alkyl chain increases, decrease in the antiproliferative
activity was noted. Therefore, length of carbon side chain has shown no effect on
the increase in the antiproliferative activity. On the other hand, replacement of the
alkyl side chain by aromatic and heterocyclic substitution substantially increased the
antiproliferative activity.
Conclusions
Based on the experimental results, it seems that the introduction of an aryl sulfonyl
and alkyl moieties on the diphenyl(piperidin-4-yl)methanol system is of potential
interest to obtain novel antiproliferative compounds. This work allowed us to
identify a few active molecules able to inhibit in vitro growth of human cancer cell
lines. These compounds displayed a relatively weak cytotoxicity. All of these
findings support the need for further investigations to clarify the features underlying
the antiproliferative activities of these new diphenyl(piperidin-4-yl)methanol
derivatives. This work is under progress.
Experimental
Melting points were determined using Veego model VMP-III melting point
apparatus and are uncorrected. Infrared (IR) spectra were recorded using a Jasco
FTIR-4100 series. Nuclear magnetic resonance (1H NMR) spectra were recorded on
a Bruker AM-400, and chemical shifts are expressed in parts per million (ppm, for
d) relative to tetra methyl silane as an internal standard and DMSO-d6 as solvent.
Spin multiplets are given as s (singlet), d (doublet), t (triplet), q (quartet), and m
(multiplet). Mass and purity were recorded on a LC-MSD-Trap-XCT. Elemental
(CHNS) analysis was obtained on Vario EL III Elementar. Silica gel column
chromatography was performed using Merck 7734 silica gel (60–120 mesh) and
Merck made TLC plates. All of the reagents and chemicals were purchased from
Sigma Aldrich Chemicals Pvt Ltd.
Synthesis of diphenyl(pyridin-4-yl)methanol (3)
To a solution of compound (1) (1.0 equiv) in dry THF add phenylmagnesium
bromide (2) (1.0 equiv) and the mixture stirred for 2 hours at room temperature
under N2 atmosphere. The reaction was monitored by TLC, and after completion of
the reaction, reaction mass was quench with water filtered through celite bed. The
filtrate was extracted with ethyl acetate and organic layer was evaporated under
reduced pressure and got the crude product. The product was purified by column
chromatography.

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Med Chem Res (2010) 19:220–235
Synthesis of N-methylation of compound (5)
The compound (3) (1.0 equiv) was taken in the tenfold volume of acetone; then
methyl iodide (4.0 equiv) was added and the mixture was stirred for 3–4 hours.
After completion of the reaction, the reaction was monitored by TLC, and the
solvent was evaporated under reduced pressure. A yellow pyridinium salt (5) was
obtained.
Synthesis of (1,2,3,6-tetrahydro-1-methylpyridin-4-yl)diphenylmethanol (6)
The quaternary salt (5) (15 g, 37 mmol) was dissolved in 60 ml of methanol and
treated with sodium borohydride (4.19 g, 11 mmol) in small portions. Temperature
was maintained at\20 °C during the addition. The reaction was monitored by TLC;
after completion of the reaction, the solvent was evaporated under reduced pressure.
The reaction mixture was diluted with water (150 ml), and the precipitated solid
filtered, washed with water, and air dried. Recrystallization from chloroform:meth-
1
anol (1:1) gave compound 6 (10.2 g, 95%), mp: 178–180 °C. H-NMR (CDCl3,
400 MHz) d: 7.13 (m, 10H, Ar–H), 2.10 (t, 2H, –CH2), 2.16 (s, 3H, N–CH3), 2.4 (t,
2H, –CH2), 2.86 (d, 2H, N–CH2), 3.0 (bs, 1H, O–H), 5.2 (t, 1H, vinylic-H). IR (KBr,
cm-1): 3500 (–OH). Anal. calc. for C19H21NO (in %): C-81.68, H-7.58, N-5.01.
Found: C-81.65, H-7.54, N-4.96.
Synthesis of (1-methyl piperidin-4-yl)diphenylmethanol (7)
To a solution of (6) (10.0 g, 35 mmol) in cyclohexanol (75 ml) was added Raney
Nickel (2.05 g, 3.5 mmol, previously washed with t-butanol) and the mixture stirred
under reflux for 2 hours. The reaction mixture was cooled to room temperature and
filtered. Cyclohexanol was concentrated under reduced pressure and completion of
the reaction was monitored by TLC. The residue was extracted with chloroform
(3 9 25 ml) and the combined chloroform extracts were dried over anhydrous
sodium sulphate and recovered. Recrystallization from benzene-petether (3:15) gave
compound (7) (7.1 g, 85%) as a crystalline solid. mp: 131–133 °C. 1H-NMR
(CDCl3, 400 MHz) d: 7–7.5 (m, 10H, Ar–H), 3.14 (d, 2H, –CH2), 2.62 (t, 2H,
–CH2), 2.38 (m, 1H, –CH), 2.25 (s, 1H, –OH), 2.13 (s, 3H, N–CH3), 1.62 (d, 4H,
–CH2). IR (KBr, cm-1): 3500 (–OH). Anal. calc. for C19H23NO (in %): C-81.10, H-
8.24, N-4.98. Found: C-81.08, H-8.23, N-4.96.
Synthesis of ethyl 4-(hydroxydiphenylmethyl)piperidine-1-carboxylate (8)
Compound (7) (6 g, 21.3 mmol) was dissolved in 50 ml of chloroform, and to this
solution added K2CO3 (8.87 g, 63.96 mmol) and followed by ethyl chloroformate
(5.7 g, 21.3 mmol). The mixture was stirred overnight at room temperature. The
chloroform layer was washed successively with water and dilute HCl. Dried over
anhydrous Na2SO4, the completion of the reaction was monitored by TLC and the
mixture concentrated under reduced pressure gave compound (8) (5.1 g, 70%) as a
1
crystalline solid. mp: 152–154 °C. H-NMR (CDCl3, 400 MHz) d: 7–7.5 (m, 10H,

Med Chem Res (2010) 19:220–235
229
Ar–H), 1.2 (t, 3H, –OCH2CH3), 1.5–2 (m, 5H, –CH2–CH–CH2), 2.4–3 (m, 4H, –
CH2–N–CH2), 4.03 (q, 2H, –OCH2–CH3), 4.25 (bs, 1H, OH). IR (KBr, cm-1): 3500
(–OH), 1680 (NCOOEt). Anal. calc. for C21H25NO3 (in %): C-74.31, H-7.42, N-
4.13. Found: C-74.27, H-7.40, N-4.11.
Synthesis of diphenyl(piperidin-4-yl)methanol (9)
Ethyl 4-(hydroxydiphenylmethyl)piperidine-1-carboxylate (8)(5.0 g, 14.7 mmol)was
dissolved in 50 ml of ethanol, K2CO3 solution (30 ml, 50%) was added. The reaction
mixture was refluxed under N2 for 24 hours. The reaction mixture was 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 dried with
anhydrous sodium sulphate. The solvent was evaporated to get crude product, which
was purified by column chromatography over silica gel (60–120 mesh) using hexane:
ethyl acetate (8:2) as an eluent. Recrystallization from isopropanol-ether gave 9 (3 g,
1
75%). The presence of proton peak at 2.00 ppm in H NMR spectrum and N–H
stretching frequency at 3300 cm-1 in IR spectrum confirms the formation of the
product. M.P: 160–162°C. 1H-NMR (CDCl3, 400 MHz) d: 7.48 (m, 4H, Ar–H), 7.30
(m, 4H, Ar–H), 7.18 (m, 2H, Ar–H), 3.1 (d, 2H, –CH2), 2.68 (t, 2H, –CH2), 2.4 (m, 1H,
–CH2), 2.2 (s, 1H, –OH), 2.0 (s, 1H, –NH), 1.5 (d, 4H, –CH2). IR (KBr, cm-1): 3500
(–OH), 3300 (NH). MS (ESI) m/z: 268.16 (M ? H?). Anal. calc. for C18H21NO (in %):
C-80.86, H-7.92, N-5.24. Found: C-80.82, H-7.88, N-7.87.
General procedure for the synthesis of diphenyl(sulphonylpiperidin-4-
yl)methanol derivatives 10(a–n)
A solution of diphenyl(piperidin-4-yl)methanol (9) (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 minutes, then different sulfonyl chloride
(1.0 eq) was added. The reaction mixture was allowed to room temperature under
stirring for 5–6 hours. The reaction mixture was 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 water wash was given to organic layer and
dried with anhydrous sodium sulphate. The solvent was evaporated to get crude
product, which was purified by column chromatography over silica gel (60–120
mesh) using hexane: ethyl acetate (8:2) as an eluent.
Synthesis of diphenyl-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-methanol (10a)
The general synthetic method described earlier afforded (10a); the product obtained
was pale brown crystalline solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,
1.77 mmol), p-toluenesulfonyl chloride (0.338 g, 1.77 mmol), and triethylamine
(0.537 g, 5.31 mmol). 1H NMR (DMSO, 400 MHz) d: 7.7 (m, 4H, Ar–H), 7.48 (m,
4H, Ar–H), 7.35 (m, 4H, Ar–H), 7.18 (t, 2H, Ar–H), 3.13 (d, 2H, –CH2), 2.65 (t, 2H,
–CH2), 2.46 (m, 1H, –CH), 2.31 (s, 3H, –CH3), 2.2 (s, 1H, –OH), 1.5 (d, 4H, –CH2).

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Med Chem Res (2010) 19:220–235
IR (KBr, cm-1): 3500, 2856, 1350, 1276. MS (ESI) m/z: 422.17 (M ? H?). Anal.
calcd. for C25H27NO3S (in %): C-71.23, H-6.46, N-3.32, S-7.61. Found C-71.20, H-
6.40, N-3.28, S-7.58.
Synthesis of [1-(3,5-dimethyl-2,3-dihydro-isoxazole-4-sulfonyl)-piperidin-4-yl]-
diphenyl-methanol (10b)
The general synthetic method described earlier afforded (10b); the product obtained
was pale yellow crystalline solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,
1.77 mmol), 3,5-dimethyl-2,3-dihydro-isoxazole-4-sulfonyl chloride (0.349 g,
1.77 mmol), and triethylamine (0.537 g, 5.31 mmol). 1H NMR (DMSO,
400 MHz) d: 7.47 (m, 4H, Ar–H), 7.23 (m, 4H, Ar–H), 7.09 (t, 2H, Ar–H), 3.1
(d, 2H, –CH2), 3.61 (d, 2H, –CH2), 2.68 (t, 2H, –CH2), 2.62 (s, 3H, –CH3), 2.56
(s, 3H, –CH3), 2.4 (m, 1H, –CH), 2.31 (s, 2H, –CH2), 2.2 (s, 1H, –OH). IR (KBr,
cm-1): 3515, 1470, 1376, 1356, 1276. MS (ESI) m/z: 427.00 (M ? H?). Anal.
calcd. for C23H26N2O4S (in %): C-64.77, H-6.14, N-6.57, S-7.52. Found C-64.75,
H-6.10, N-6.53, S-7.48.
Synthesis of (1-methanesulfonyl-piperidin-4-yl)-diphenyl-methanol (10c)
The general synthetic method described earlier afforded (10c); the product obtained
was white amorphous solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,
1.77 mmol), methane sulfonyl chloride (0.202 g, 1.77 mmol), and triethylamine
1
(0.537 g, 5.31 mmol). H NMR (DMSO, 400 MHz) d: 7.48 (m, 4H, Ar–H), 7.30
(m, 4H, Ar–H), 7.18 (m, 2H, Ar–H), 3.12 (d, 2H, –CH2), 2.8 (s, 3H, –CH3), 2.68
(t, 2H, –CH2), 2.4 (m, 1H, –CH), 2.2 (s, 1H, –OH), 1.5 (d, 4H, –CH2). IR (KBr,
cm-1): 3522, 1479, 1383, 1346, 1266. MS (ESI) m/z: 346.14 (M ? H?). Anal.
calcd. for C19H23NO3S (in %): C-66.06, H-6.71, N-4.05, S-9.28. Found C-66.01, H-
6.67, N-4.01, S-9.26.
Synthesis of (1-benzenesulfonyl-piperidin-4-yl)-diphenyl-methanol (10d)
The general syntheticmethoddescribed earlier afforded(10d);the product obtained was
white amorphous solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g, 1.77 mmol),
benzenesulfonyl chloride (0.312 g, 1.77 mmol), and triethylamine (0.537 g,
5.31 mmol). 1H NMR (DMSO, 400 MHz) d: 7.9 (d, 2H, Ar–H), 7.55 (m, 3H, Ar–H),
7.48 (m, 4H, Ar–H), 7.30 (m, 4H, Ar–H), 7.18 (m, 2H, Ar–H), 3.1 (d, 2H, –CH2), 2.68
(t, 2H, –CH2), 2.4 (m, 1H, –CH), 2.2 (s, 1H, –OH), 1.5 (d, 4H, –CH2). IR (KBr, cm-1):
3493, 1361, 1263. MS (ESI) m/z: 408.16 (M ? H?). Anal. calcd. for C24H25NO3S (in
%): C-70.73, H-6.18, N-3.44, S-7.87. Found C-70.71, H-6.15, N-3.40, S-7.84.
Synthesis of diphenyl-[1-(4-propyl-benzenesulfonyl)-piperidin-4-yl]-methanol
(10e)
The general synthetic method described earlier afforded (10e); the product obtained
was white amorphous solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,

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231
1.77 mmol), 4-propyl-benzenesulfonyl chloride (0.387 g, 1.77 mmol), and trieth-
1
ylamine (0.537 g, 5.31 mmol). H NMR (DMSO, 400 MHz) d: 7.6 (d, 2H, Ar–H),
7.5 (d, 2H, Ar–H), 7.48 (m, 4H, Ar–H), 7.30 (m, 4H, Ar–H), 7.18 (m, 2H, Ar–H),
3.1 (d, 2H, –CH2), 2.68 (t, 2H, –CH2), 2.4 (m, 1H, –CH), 2.2 (s, 1H, –OH), 2.15
(t, 2H, –CH2), 1.64 (m, 2H, –CH2), 1.5 (d, 4H, –CH2), 0.92 (t, 3H, –CH3). IR (KBr,
cm-1): 3532, 1479, 1375, 1356, 1281. MS (ESI) m/z: 450.2 (M ? H?). Anal. calcd.
for C27H31NO3S (in %): C-72.13, H-6.95, N-3.14, S-7.13. Found C-72.09, H-6.90,
N-3.10, S-7.09.
Synthesis of diphenyl-[1-(propane-2-sulfonyl)-piperidin-4-yl]-methanol (10f)
The general synthetic method described earlier afforded (10f); the product obtained
was pale brown amorphous solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,
1.77 mmol), propane-2-sulfonyl chloride (0.252 g, 1.77 mmol), and triethylamine
(0.537 g, 5.31 mmol). 1H NMR (DMSO, 400 MHz) d: 1H-NMR (CDCl3, 400 MHz)
d: 7.42 (m, 4H, Ar–H), 7.35 (m, 4H, Ar–H), 7.22 (m, 2H, Ar–H), 3.4 (m, 1H, –CH),
3.13 (d, 2H, –CH2), 2.62 (t, 2H, –CH2), 2.43 (m, 1H, –CH), 2.26 (s, 1H, –OH), 1.52
(d, 4H, –CH2), 1.4 (s, 6H, –(CH3)2). IR (KBr, cm-1): 3528, 1466, 1380, 1351, 1275.
MS (ESI) m/z: 374.17 (M ? H?). Anal. calcd. for C21H27NO3S (in %): C-67.53, H-
7.29, N-3.75, S-8.58. Found C-67.49, H-7.25, N-3.70, S-8.55.
Synthesis of [1-(4-chloro-2-fluoro-benzenesulfonyl)-piperidin-4-yl]-diphenyl-
methanol (10g)
The general synthetic method described earlier afforded (10g); the product obtained
was white crystalline solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,
1.77 mmol), 4-chloro-2-fluoro-benzenesulfonyl chloride (0.405 g, 1.77 mmol), and
1
triethylamine (0.537 g, 5.31 mmol). H NMR (DMSO, 400 MHz) d: 7.57 (m, 4H,
Ar–H), 7.27 (m, 6H, Ar–H), 7.12 (t, 2H, Ar–H), 7.10 (d, 1H, Ar–H), 3.32 (m, 4H,
–CH2), 2.76 (m, 4H, –CH2), 2.43 (m, 1H, –CH), 2.2 (s, 1H, –OH). IR (KBr, cm-1):
3505, 1359, 1040, 1263, 712. MS (ESI) m/z: 460.11 (M ? H?). Anal. calcd. for
C24H23ClFNO3S (in %): C-62.27, H-5.04, N-3.05, S-6.97. Found C-62.22, H-5.01,
N-3.01, S-6.93.
Synthesis of [1-(butane-1-sulfonyl)-piperidin-4-yl]-diphenyl-methanol (10h)
The general synthetic method described earlier afforded (10h); the product obtained
was white amorphous solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,
1.77 mmol), butane-1-sulfonyl chloride (0.277 g, 1.77 mmol), and triethylamine
1
(0.537 g, 5.31 mmol). H NMR (DMSO, 400 MHz) d: 7.45 (m, 4H, Ar–H), 7.39
(m, 4H, Ar–H), 7.23 (m, 2H, Ar–H), 3.56 (t, 2H, –CH2), 3.07 (d, 2H, –CH2), 2.61
(t, 2H, –CH2), 2.46 (m, 1H, –CH), 2.22 (s, 1H, –OH), 1.85 (m, 2H, –CH2), 1.58 (d,
4H, –CH2), 1.3 (t, 2H, –CH2), 0.94 (t, 3H, –CH3). IR (KBr, cm-1): 3528, 1466,
1380, 1351, 1275. MS (ESI) m/z: 388.19 (M ? H?). Anal. calcd. for C22H29NO3S
(in %): C-68.18, H-7.54, N-3.61, S-8.27. Found C-68.15, H-7.50, N-3.58, S-8.22.

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Synthesis of (1-chloromethanesulfonyl-piperidin-4-yl)-diphenyl-methanol (10i)
The general synthetic method described earlier afforded (10i); the product obtained
was pale brown solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,
1.77 mmol), chloro-methane sulfonyl chloride (0.263 g, 1.77 mmol), and triethyl-
1
amine (0.537 g, 5.31 mmol). H NMR (DMSO, 400 MHz) d: 7.40 (m, 4H, Ar–H),
7.38 (m, 4H, Ar–H), 7.23 (m, 2H, Ar–H), 5.3 (s, 2H, –CH2), 3.09 (d, 2H, –CH2),
2.72 (t, 2H, –CH2), 2.39 (m, 1H, –CH), 2.2 (s, 1H, –OH), 1.58 (d, 4H, –CH2). IR
(KBr, cm-1): 3500, 1450, 1386, 1360, 1286, 728. MS (ESI) m/z: 380.10 (M ? H?).
Anal. calcd. for C19H22ClNO3S (in %): C-60.07, H-5.84, N-3.69, S-8.44. Found
C-60.02, H-5.80, N-3.65, S-8.39.
Synthesis of diphenyl-(1-phenylmethanesulfonyl-piperidin-4-yl)-methanol (10j)
The general synthetic method described earlier afforded (10j); the product obtained
was white amorphous solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,
1.77 mmol), phenyl-methanesulfonyl chloride (0.337 g, 1.77 mmol), and triethyl-
1
amine (0.537 g, 5.31 mmol). H NMR (DMSO, 400 MHz) d: 7.52 (m, 4H, Ar–H),
7.33 (m, 4H, Ar–H), 7.25 (m, 2H, Ar–H), 7.14 (m, 5H, Ar–H), 4.72 (s, 2H, –CH2),
3.16 (d, 2H, –CH2), 2.63 (t, 2H, –CH2), 2.44 (m, 1H, –CH), 2.2 (s, 1H, –OH), 1.56
(d, 4H, –CH2). IR (KBr, cm-1): 3509, 1445, 1377, 1369, 1286. MS (ESI) m/z:
422.17 (M ? H?). Anal. calcd. for C25H27NO3S (in %): C-71.23, H-6.46, N-3.23,
S-7.61. Found C-71.19, H-6.41, N-3.20, S-7.58.
Synthesis of [1-(4-chloro-benzenesulfonyl)-piperidin-4-yl]-diphenyl-methanol
(10k)
The general synthetic method described earlier afforded (10k); the product obtained
was white crystalline solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,
1.77 mmol), 4-chloro-benzenesulfonyl chloride (0.373 g, 1.77 mmol), and triethyl-
1
amine (0.537 g, 5.31 mmol). H NMR (DMSO, 400 MHz) d: 7.6 (m, 4H, Ar–H),
7.42 (m, 4H, Ar–H), 7.39 (m, 4H, Ar–H), 7.21 (m, 2H, Ar–H), 3.14 (d, 2H, –CH2),
2.63 (t, 2H, –CH2), 2.42 (m, 1H, –CH), 2.2 (s, 1H, –OH), 1.55 (d, 4H, –CH2). IR
(KBr, cm-1): 3500, 1360, 1286, 722. MS (ESI) m/z: 442.12 (M ? H?). Anal. calcd.
for C23H24ClNO3S (in %): C-65.22, H-5.47, N-3.17, S-7.26. Found C-65.18, H-
5.42, N-3.13, S-7.21.
Synthesis of [1-(2-nitro-benzenesulfonyl)-piperidin-4-yl]-diphenyl-methanol
(10l)
The general synthetic method described earlier afforded (10l); the product obtained
was white crystalline solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,
1.77 mmol), 2-nitrobenzene-1-sulfonyl chloride (0.391 g, 1.77 mmol), and trieth-
ylamine (0.537 g, 5.31 mmol). 1H NMR (DMSO, 400 MHz) d: 7.94 (d, 1H, Ar–H),
7.6–7.7 (m, 3H, Ar–H), 7.42 (m, 4H, Ar–H), 7.29 (m, 4H, Ar–H), 7.20 (t, 2H,
Ar–H), 2.77 (m, 4H, –CH2), 2.48 (m, 1H, –CH2), 1.65–1.5 (m, 4H, –CH2), 2.18

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233
(s, 1H, –OH). IR (KBr, cm-1): 3518, 1526, 1353, 1330, 1286. MS (ESI) m/z: 453.14
(M ? H?). Anal. calcd. for C24H24N2O5S (in %): C-63.70, H-5.35, N-6.19, S-7.09.
Found C-63.64, H-5.31, N-6.15, S-7.05.
Synthesis of [1-(3-nitro-benzenesulfonyl)-piperidin-4-yl]-diphenyl-methanol
(10m)
The general synthetic method described earlier afforded (10m); the product obtained
was pale brown amorphous solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,
1.77 mmol), 3–nitrobenzene-1-sulfonyl chloride (0.391 g, 1.77 mmol), and trieth-
ylamine (0.537 g, 5.31 mmol). 1H NMR (DMSO, 400 MHz) d: 7.91 (d, 1H, Ar–H),
7.6–7.7 (m, 3H, Ar–H), 7.48 (m, 4H, Ar–H), 7.21 (m, 4H, Ar–H), 7.23 (t, 2H,
Ar–H), 2.70 (m, 4H, –CH2), 2.42 (m, 1H, –CH2), 1.65–1.5 (m, 4H, –CH2), 2.11
(s, 1H, –OH). IR (KBr, cm-1): 3511, 1516, 1356, 1339, 1276. MS (ESI) m/z: 453.14
(M ? H?). Anal. calcd. for C24H24N2O5S (in %): C-63.70, H-5.35, N-6.19, S-7.09.
Found C-63.64, H-5.31, N-6.15, S-7.05.
Synthesis of [1-(4-nitro-benzenesulfonyl)-piperidin-4-yl]-diphenyl-methanol
(10n)
The general synthetic method described earlier afforded (10n); the product obtained
was pale yellow solid from diphenyl(piperidin-4-yl)methanol (9) (0.5 g,
1.77 mmol), 4-nitrobenzene-1-sulfonyl chloride (0.391 g, 1.77 mmol), and trieth-
ylamine (0.537 g, 5.31 mmol). 1H NMR (DMSO, 400 MHz) d: 7.86 (d, 1H, Ar–H),
7.6–7.7 (m, 3H, Ar–H), 7.39 (m, 4H, Ar–H), 7.28 (m, 4H, Ar–H), 7.31 (t, 2H,
Ar–H), 2.76 (m, 4H, –CH2), 2.40 (m, 1H, –CH2), 1.65–1.5 (m, 4H, –CH2), 2.15
(s, 1H, –OH). IR (KBr, cm-1): 3500, 1521, 1359, 1342, 1296. MS (ESI) m/z: 453.14
(M ? H?). Anal. calcd. for C24H24N2O5S (in %): C-63.70, H-5.35, N-6.19, S-7.09.
Found C-63.64, H-5.31, N-6.15, S-7.05.
Biology
We synthesized novel diphenyl(piperidin-4-yl)methanol derivatives 10(a–n) and
evaluated for their efficacy as antiproliferative agents on the growth of the five
different cell lines in a cell toxicity assay for percentage cell survival at 100 lM.
Percentage cell survival for compounds against NF-103, MCF-7, HepG-2, HT-29,
and HeLa cell proliferation at the concentration of 100 lM for 24 hours are shown
in Table 2.
Stock solutions (100 lM) of test compounds were first prepared in dimethyl-
sulfoxide (DMSO) and stored at -20 °C. On the day of experiment, these
concentrated solutions were diluted to the desired final concentrations immediately
before addition to cell culture wells. The final DMSO concentration was 0.1% in
each well and showed no interference with the biological activities tested.

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Med Chem Res (2010) 19:220–235
Cell culture and in vitro cell viability assay—MTT assay
NF-103, HeLa, HepG-2, and MCF-7 cells were cultured in DMEM with 10% FCS.
HT-29 cells were cultured in McCoy’s Medium with 10% FCS, CRL-170 cultured
in RPMI with 10% FCS and 1% v/v antibiotic. The proliferation of skin fibroblast
cells (NF-103), HeLa cells, HepG-2 cells, HT-29 cells, and MCF-7 cells can be
assayed at different time points besides 24 hours. The positive control used was
wells with DMEM (10% FBS added; 1% v/v antibiotic added) added, whereas the
negative control used was wells with DMEM (1% v/v antibiotic added; no FBS
added). Cell cultures were maintained in the Department of Biological Sciences,
National University of Singapore, Singapore. The absorbance was measured at
570 nm with a microtiter plate reader.
The potential effects on cell viability were investigated by using the MTT assay
(Scudiero et al., 1988) [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
bromide] as an indicator of metabolically active cells (Ananda Kumar et al.,
2009). Results were evaluated by comparing the absorbance of the wells containing
compound-treated cells with the absorbance of wells containing 0.1% DMSO alone
(solvent control). Conventionally, cell viability was estimated to be 100% in the
solvent control. All assays were performed in triplicate. Mean standard deviation
values were used to estimate cell viability.
Acknowledgments The authors thank the Council of Scientific and Industrial Research (CSIR), New
Delhi, for financial support under the project 01(1904)/03/EMR-II 2004. One of the authors (K. Vinaya) is
grateful to CSIR, New Delhi, for financial support under CSIR SRF order No. 09/119(0172)2K8 EMR-I.
Elemental Analysis and IR spectroscopic data were obtained from instruments funded by DST–FIST, and
UGC-SAP (phase I) No.F.540/10/DRS/2004-05 (SAP-I) is greatly acknowledged.
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