Design, synthesis, and biological evaluation of linear 1-(4-, 3- or 2-methylsulfonylphenyl)-2-phenylacetylenes: A novel class of cyclooxygenase-2 inhibitors

Article abstract of DOI:10.1016/j.bmc.2005.06.064

A group of regioisomeric 1-(methylsulfonylphenyl)-2-phenylacetylenes possessing a COX-2 SO₂Me pharmacophore at the para-, meta- or ortho-position of the C-1 phenyl ring, in conjunction with a C-2 phenyl or substituted-phenyl ring substituent (3

Full text of DOI:10.1016/j.bmc.2005.06.064

Bioorganic & Medicinal Chemistry 13 (2005) 6425–6434
Design, synthesis, and biological evaluation of linear 1-(4-, 3-
or 2-methylsulfonylphenyl)-2-phenylacetylenes: A novel class
of cyclooxygenase-2 inhibitors
Qiao-Hong Chen, P. N. Praveen Rao and Edward E. Knaus*
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta., Canada T6G 2N8
Received 21 June 2005; revised 29 June 2005; accepted 29 June 2005
Available online 15 August 2005
Abstract—A group of regioisomeric 1-(methylsulfonylphenyl)-2-phenylacetylenes possessing a COX-2 SO2Me pharmacophore at
the para-, meta- or ortho-position of the C-1 phenyl ring, in conjunction with a C-2 phenyl or substituted-phenyl ring substituent
(3-F, 3-OMe, 3-OH, 3-OAc, 4-Me), were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. These target lin-
ear 1,2-diarylacetylenes were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction followed by oxidation of
the respective 1-(methylthiophenyl)-2-phenylacetylene intermediate. In vitro COX-1/COX-2 isozyme inhibition structure–activity
studies identified 1-(3-methylsulfonylphenyl)-2-(4-methylphenyl)acetylene (12d) as a potent COX-2 inhibitor (IC50 = 0.32 lM) with
a high COX-2 selectivity index (SI > 320) comparable to the reference compound rofecoxib (COX-2 IC50 = 0.50 lM; COX-2
SI > 200). A molecular modeling study where (12d) was docked in the binding site of COX-2 showed that the MeSO2 COX-2 phar-
macophore was positioned in the vicinity of the secondary COX-2 binding site near Val523. The 1-(4-methylsulfonylphenyl)-2-(3-
acetoxyphenyl)acetylene (11f, COX-1 IC50 = 1.00 lM; COX-2 IC50 = 0.06 lM; COX-2 SI = 16.7) and 1-(3-methylsulfonylphenyl)-
2-(3-acetoxyphenyl)acetylene (12f, COX-1 IC50 = 6.5 lM; COX-2 IC50 = 0.05 lM; COX-2 SI = 130) regioisomers exhibited compa-
rable COX-2 inhibition, and moderately lower selective COX-2 selectivity, relative to the reference drug celecoxib (COX-1
IC50 = 33.1 lM; COX-2 IC50 = 0.07 lM; COX-2 SI = 472). The most potent anti-inflammatory agent 1-(3-methylsulfonylphenyl)-
2-(4-methylphenyl)acetylene (12d) exhibited moderate oral anti-inflammatory activity (ED50 = 129 mg/kg) at 3 h postdrug adminis-
tration relative to the reference drug celecoxib (ED50 = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. The structure–
activity data acquired indicate that the acetylene moiety constitutes a suitable scaffold (template) to design novel acyclic 1,2-diaryl-
acetylenes with selective COX-2, or dual COX-1/COX-2, inhibitory activities.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
para-position of one of the aryl rings often provides
optimum COX-2 selectivity and inhibitory potency.10
The selective COX-2 inhibitors celecoxib (1),1 rofecoxib
(2),2 valdecoxib (3),3 and etoricoxib (4)4,5 have been clin-
ically validated as anti-inflammatory therapeutics for
indications such as rheumatoid arthritis with less gastro-
intestinal and renal toxicity (see structures in Fig. 1).6–9
Tricyclic compounds possessing 1,2-diaryl substitution
on a central heterocyclic, or carbocyclic, ring system
constitute a major class of selective COX-2 inhibitors.
Structure–activity relationship (SAR) studies have
shown that a SO2Me or SO2NH2 substituent at the
Despite the relatively safe pharmacological profile of
selective COX-2 inhibitors, there is now increasing con-
cern regarding their use in patients at risk for an adverse
cardiovascular event such as myocardial infarction. For
example, the clinical use of rofecoxib and valdecoxib
were recently terminated due to adverse cardiovascular
side effects associated with their use.11 The adverse car-
diovascular effects of rofecoxib and valdecoxib appear
to be due to their high COX-2 selectivity. Hence, there
is a need for the design of COX inhibitors based on
new structural templates. Recently, we reported several
investigations describing the design, synthesis, and
anti-inflammatory properties for several classes of novel
acyclic olefins.12–17 The lead compound (5) in this group
of compounds exhibited excellent in vitro inhibitory
potency against COX-2 (IC50 = 0.014 lM) with no
Keywords: 1-(Methylsulfonylphenyl)-2-phenylacetylenes; Sonogashira
coupling reaction; Cyclooxygenase-2 inhibitors; Anti-inflammatory
and analgesic activities.
*
Corresponding author: Tel.: +1 780 492 5993; fax: +1 780 492
1217; e-mail: eknaus@pharmacy.ualberta.ca
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.06.064

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Q.-H. Chen et al. / Bioorg. Med. Chem. 13 (2005) 6425–6434
SO2NH2
R1
SO2Me
3
R
N
R2
N
4
SMe
+
C
C
H
F3C
O
6a, R = 4-Br
6b, R = 3-Br
6c, R = 3-I
6d, R = 2-I
7
O
Me
Celecoxib (1)
Rofecoxib (2)
a
SO2Me
R1
SO2NH2
Cl
Me
O
SMe
R2
C
C
N
N
8, para-SMe
9, meta-SMe
10, ortho-SMe
N
Me
b
Valdecoxib (3)
Etoricoxib (4)
R1
SO2Me
SO2Me
n-Bu
R2
C
C
7-13a, R1 = H, R2 = H
7-13b, R1 = F, R2 = H
7-13c, R1 = OMe, R2 = H
7-13d, R1 = H, R2 = Me
7-13e, R1 = OH, R2 = H
11-13f, R1 = OAc, R2 = H
11, para-SO2Me
12, meta-SO2Me
13, ortho-SO2Me
(5)
Figure 1. Some representative selective cyclooxygenase-2 (COX-2)
inhibitors.
c (11-13e)
inhibition of COX-1 (IC50 > 100 lM). Many compounds
within this group showed impressive activity in an in vivo
model of inflammation. It was therefore of interest, as
part of our ongoing program to design selective COX-2
inhibitors and acquire structure–activity correlations,
to determine whether replacement of the double bond
in this class of acyclic olefinic compounds by a linear
acetylene would retain COX-2 selectivity and in vivo
anti-inflammatory activity. Accordingly, we now de-
scribe the design, synthesis, in vitro COX-1 and COX-2
inhibitory activities, and in vivo anti-inflammatory activ-
ity for this class of 1-(4-,3- or 2-methylsulfonylphenyl)-2-
phenylacetylene regioisomers (11–13).
Scheme 1. Reagents and conditions: (a) Pd(PPh3)2Cl2, CuI, Et3N,
reflux or 50 ꢂC, overnight; (b) Oxoneꢁ, THF, MeOH, H2O, 25 ꢂC,
overnight; (c) CH3COCl, Et3N, THF, 25 ꢂC, 2 h.
cross-coupling reaction provides an effective method for
the preparation of a wide variety of functionally substi-
tuted 1-(methylthiophenyl)-2-phenylacetylenes in excel-
lent yield. This is particularly relevant in the case of
1-(2-methylthiophenyl)-2-phenylacetylenes (10) which
generally cannot be synthesized using the less reactive
2-bromothioanisole. Subsequent oxidation of the meth-
ylthio intermediates (8–10) using Oxoneꢁ (potassium
peroxymonosulfate) furnished the target 1-(methylsulfo-
nylphenyl)-2-phenylacetylenes (11a–e, 12a–e, and 13a–
e). During the course of these studies, it was observed
that the ortho-methylthio moiety present in 10a–e was
more difficult to oxidize (5 equiv. Oxoneꢁ, overnight)
than the para- or meta-methylthio group present in the
8a–e and 9a–e regioisomers (2 equiv. Oxonereg, 2 h).
Thus, it was necessary to increase the amount of Ox-
oneꢁ (5 equiv.) and prolong the reaction time (over-
night) in order to completely oxidize the ortho-
methylthio compounds (10a–e) to the desired ortho-
methylsulfonyl target products (13a–e) since oxidation
of the ortho-methylthio compounds (10a–e) using 2
equiv of Oxoneꢁs for 2 h yielded the methylsulfoxide
product rather than the desired methylsulfones. Acetyla-
tion of the 1-(methylsulfonylphenyl)-2-(3-hydroxyphe-
nyl)acetylenes (11e, 12e, and 13e) using acetyl chloride
in the presence of Et3N yielded the corresponding
2. Chemistry
The target 1-(methylsulfonylphenyl)-2-phenylacetylenes
(11a–f, 12a–f, and 13a–f) having a variety (R1 = H, F,
OMe, OH, OAc; R2 = H, Me) of substituents at the
meta- and/or para-position of the C-2 phenyl ring were
prepared using
a palladium-catalyzed Sonogashira
cross-coupling reaction18 as a key reaction step accord-
ing to the reaction sequence shown in Scheme 1. The
cross-coupling reaction between a bromo- or iodothio-
anisole (6) and a substituted-phenylacetylene (7) under
an argon atmosphere in triethylamine, using dichloro-
bis(triphenylphosphine)palladium(0)/cuprous iodide as
catalysts, afforded the respective 1-(methylthiophenyl)-
2-phenylacetylenes (8–10). The high reactivity of the 3-
iodo (6c) and 2-iodothioanisole (6d) in the Sonogashira

Q.-H. Chen et al. / Bioorg. Med. Chem. 13 (2005) 6425–6434
6427
1-(methylsulfonylphenyl)-2-(3-acetoxyphenyl)acetylene
regioisomers (11f, 12f, and 13f).
COX-2 inhibitor) ! 3-MeSO2 (12a, mixed COX-1/
COX-2 inhibitor) ! 2-MeSO2 (13a, selective COX-1
inhibitor). A similar isozyme selectivity profile was ob-
served for the C-2 3-fluorophenyl regioisomers (11b–
13b) as the position of the MeSO2 pharmacophore on
the C-1 phenyl ring is transposed from 4-MeSO2 (11b,
selective COX-2 inhibitor) ! 3-MeSO2 (12b, selective
COX-2 inhibitor) ! 2-MeSO2 (13b, non-selective
COX-1/COX-2 inhibitor). In contrast, the relative activ-
ity/selectivity profile for the C-2 3-methoxyphenyl
regioisomers (11c–13c) did not give rise to COX-1 inhib-
itory activity as one moved the MeSO2 substituent on
the C-1 phenyl ring [4-MeSO2 (11c, inactive COX-1/
COX-2 inhibitor) ! 3-MeSO2 (12c, selective COX-2
inhibitor) ! 2-MeSO2 13c, selective COX-2 inhibitor].
The effect of a C-2 4-methylphenyl substituent in regioi-
somers 11d–13d as a function of the MeSO2 substituent
position on the C-1 phenyl ring was highly variable
[4-MeSO2 (11d, equipotent inhibitor of COX-1 and
COX-2) ! 3-MeSO2 (12d, selective COX-2 inhibi-
tor) ! 2-MeSO2 (13d), significantly more potent and
selective inhibitor of COX-1]. Although regioisomers
11e–13e having a C-2 3-hydroxyphenyl substituent and
11f–13f having a C-2 3-acetoxyphenyl substituent inhib-
ited both COX-1 and COX-2, all compounds were more
potent and selective inhibitors of the COX-2 isozyme
irrespective of the position of the MeSO2 substituent
on the C-1 phenyl ring.
3. Results and discussion
A group of 1-(methylsulfonylphenyl)-2-phenylacetylene
regioisomers (11–13) were designed such that the COX-
2 SO2Me pharmacophore was located at the para-, meta-
or ortho-position of the C-1 phenyl ring on a linear acety-
lene template (scaffold). In addition, the substituent on
the C-2 phenyl ring was simultaneously varied (H, 3-F,
3-OMe, 3-OH, 3-OAc, and 4-Me) to determine the com-
bined effects of positional, steric, and electronic substitu-
ent properties upon COX-1 and COX-2 inhibitory
potency and COX isozyme selectivity. SAR data (IC50
values) acquired by determination of the in vitro ability
of the title compounds to inhibit the COX-1 and COX-2
isozymes showed that the position of the COX-2 SO2Me
pharmacophore on the C-1 phenyl ring and the nature
of the C-2 phenyl substituent were either individual, or
collective, determinants of COX-2 inhibitory potency
and selectivity (see Table 1).
A comparison of the SAR data for the 1-(4-, 3-, and 2-
methylsulfonylphenyl)-2-phenylacetylene regioisomers
(11a–13a) showed that the COX isozyme selectivity
shifts as one moves from the 4-MeSO2 (11a, selective
Table 1. In vitro COX-1 and COX-2 inhibition data for 1-(methylsulfonylphenyl)-2-phenylacetylenes (11a–f, 12a–f, and 13a–f)
R1
R1
R1
SO2Me
MeSO2
R2
C
C
R2
SO2Me
C
C
R2
C
C
13a-f
11a-f
12a-f
Compounds
R1
R2
IC50 (lM)a
COX-2 S.I.b
COX-1
COX-2
11a
11b
H
H
P100
P100
P100
0.32
11.3
1.0
0.89
6.0
P113
P16
N/A
1.0
F
H
11c
11d
OMe
H
H
P100
0.32
0.21
0.06
3.2
Me
H
11e
11f
OH
OAc
H
54
17
H
12a
12b
H
1.0
0.32
>54
>30
>320
2.6
F
H
>100
>100
>100
0.82
6.5
1.9
3.4
12c
12d
OMe
H
H
Me
H
0.32
0.32
0.05
>100
0.32
4.8
12e
12f
OH
OAc
H
H
130
<0.31
5.3
13a
13b
H
31.6
1.7
F
H
13c
13d
OMe
H
H
>100
0.10
31.6
1.0
>21
0.003
8.9
Me
H
31.6
3.5
13e
13f
OH
OAc
—
H
0.14
0.07
0.50
7.0
472
Celecoxib
Rofecoxib
—
—
33.1
>100
—
>200
a Values are means of two determinations acquired using an ovine COX-1/COX-2 assay kit (Catalog No. 560101, Cayman Chemicals Inc.,
Ann Arbor, MI, USA) and the deviation from the mean is <10% of the mean value.
b In vitro COX-2 selectivity index (COX-1 IC50/COX-2 IC50).

6428
Q.-H. Chen et al. / Bioorg. Med. Chem. 13 (2005) 6425–6434
The effect of a 3-substituent on the C-2 phenyl ring, with
respect to COX-2 selectivity, varied according to the
position of the MeSO2 substituent on the C-1 phenyl
ring where the relative COX-2 selectivity indexes
(SI) for the 4-MeSO2-phenyl compounds (11) were
H > OH > OAc > F >> OMe (inactive), for the 3-
MeSO2-phenyl compounds (12) were OAc > F > O-
Me > OH > H, and for the 2-MeSO2-phenyl compounds
(13) were OMe >OH P OAc P F >> H. These latter
SAR data indicate that the MeSO2 COX-2 pharmaco-
phore on the C-1 phenyl ring, and the 3-subsitutent on
the C-2 phenyl ring, are cooperative determinants of
selective COX-2 inhibition.
nylphenyl)-2-(4-methylphenyl)acetylene (12d) in the
COX-2 binding site (Fig. 2). Analysis of the most stable
enzyme–ligand conformation shows that the 3-MeSO2-
phenyl moiety is oriented in the vicinity of COX-2 sec-
ondary pocket where it is surrounded by the amino acids
Leu352, Ser353, Ala516, Phe518, Val523, and His90. One of
the SO2Me oxygen-atoms undergoes a weak hydrogen
bonding interaction with the NH of Phe518 (dis-
˚
tance = 3.66 A). The SO2Me methyl group is suitably
positioned to undergo a van der Waalꢀs interaction with
the methyl side chain of Ala516 (distance = 4.00 A). The
˚
linear acetylene scaffold, that is surrounded by Gly526
,
Ala527, and Val349, serves to orient the p-tolyl ring in a
region comprising of Tyr348, Ser530, and Leu531. The
interspatial distance between the center of the p-tolyl
A number of compounds such as 1-(4-methylsulfonyl-
phenyl)-2-phenylacetylene
ring and the OH of Ser530 is about 4.76 A. The CH3 sub-
˚
(11a,
IC50 = 0.89 lM;
SI > 113) and 1-(3-methylsulfonylphenyl)-2-(4-methyl-
phenyl)acetylene (12d, IC50 = 0.32 lM; SI > 320) were
potent and selective COX-2 inhibitors relative to the ref-
erence compound rofecoxib (IC50 = 0.50 lM; SI > 200).
In comparison, the 1-(4-methylsulfonylphenyl)-2-(3-
acetoxyphenyl)acetylene (11f, COX-1 IC50 = 1.00 lM;
COX-2 IC50 = 0.06 lM; COX-2 SI = 16.7), and 1-
(3-methylsulfonylphenyl)-2-(3-acetoxyphenyl)acetylene
(12f, COX-1 IC50 = 6.5 lM; COX-2 IC50 = 0.05 lM;
COX-2 SI = 130) regioisomers, having a C-2 3-acetoxy-
phenyl substituent, exhibited equipotent COX-2 inhibi-
tory activity relative to the reference drug celecoxib
(COX-1 IC50 = 33.1 lM; COX-2 IC50 = 0.07 lM;
COX-2 S.I. = 472) as showed in Table 1.
stituent of the 4-Me-C6H4-moiety is oriented in a small
lipophilic region where it can undergo van der Waalꢀs
interactions with the side chains of amino acid residues
such as Leu534, Val344, and Ile345 (distance <5 A).
˚
Pharmacological studies were carried out to access the
in vivo anti-inflammatory and analgesic activities of
1-(3-methylsulfonylphenyl)-2-(4-methylphenyl)acetylene
(12d), and two of the most potent COX-2 inhibitors (11f
and 12f), based on in vitro enzyme inhibition data (see
data in Table 2). In the carrageenan-induced rat paw
edema assay, compound 12d was the most potent anti-
inflammatory agent (ED50 = 129.3 mg/kg) within this
group of compounds at 3 h postdrug administration
(oral dose) relative to the reference drug celecoxib
(ED50 = 10.8 mg/kg). One plausible explanation for the
observation that the 2-(3-acetoxyphenyl)-compound
A molecular modeling experiment was carried out to
determine the binding interactions of 1-(3-methylsulfo-
Figure 2. 1-(3-Methylsulfonylphenyl)-2-(4-methylphenyl)acetylene (12 d) (ball and stick) docked in the active site of murine COX-2. Hydrogen atoms
of the amino acid residues have been removed to improve clarity.

Q.-H. Chen et al. / Bioorg. Med. Chem. 13 (2005) 6425–6434
6429
Table 2. In vivo anti-inflammatory and analgesic activities for 1-(methylsulfonylphenyl)-2-phenylacetylenes (11f, 12d, and 12f)
AcO
AcO
SO2Me
SO2Me
C
C
SO2Me
Me
C
C
C
C
11f
12d
12f
Compounds
Anti-inflammatory activitya
Analgesic activityb
% inhibition at 3 h (75 mg/kg po dose)
ED50 (mg/kg)
% inhibition at 30 min
% inhibition at 60 min
11f
12d
Inactive
—
—
43.7 19.8
—
69.3 12.1c
—
65.8 7.1
—
79.5 2.0c
38.9 3.5
28.5 5.0
79.9 1.9c
129.3
—
10.8
12f
Celecoxib
a Inhibitory activity in a carrageenan-induced rat paw edema assay. The results are expressed as the means SEM (n = 4) following a 75 mg/kg oral
dose of the test compound.
b Inhibitory activity in the rat 4% NaCl-induced abdominal constriction assay. The results are expressed as the means SEM (n = 4) following a
75 mg/kg oral dose of the test compound.
c 50 mg/kg oral dose.
(11f) is an effective in vitro inhibitor of both COX-1 and
COX-2, but that it is an inactive anti-inflammatory
agent at a 75 mg/kg oral dose, is that 11f undergoes in vi-
vo O-deacetylation to an inactive phenolic metabolite.
On the other hand, the corresponding regioisomer 12f
showed modest anti-inflammatory activity where a
28% inhibition of inflammation was observed following
a 75 mg/kg oral dose. In a rat model 4% NaCl-induced
abdominal constriction assay, a 75 mg/kg po dose of
1-(3-methylsulfonylphenyl)-2-(4-methylphenyl)acetylene
(12d) exhibited good analgesic activity where writhing
was reduced by 43 and 66% at 30 and 60 min postdrug
administration relative to the reference drug celecoxib
(69 and 79% inhibition at 30 and 60 min postdrug
administration for a 50 mg/kg oral dose).
spectra were recorded as films on NaCl plates using a
Nicolet 550 Series II Magna FT-IR spectrometer. H
1
NMR spectra were measured on a Bruker AM-300 spec-
trometer in CDCl3 or DMSO-d6 with TMS as the inter-
nal standard, where J (coupling constant) values are
estimated in hertz (Hz). Spin multiples are given as s
(singlet), d (double), t (triplet), q (quartet), m (multi-
plet), and br (broad). Microanalyses were performed
for C, H (MicroAnalytical Service Laboratory, Depart-
ment of Chemistry, University of Alberta) and were
within 0.4% of theoretical values. Silica gel column
chromatography was performed using Merck silica gel
60 ASTM (70–230 mesh). 3-Iodothioanisole (6c) was
synthesized in 54% yield starting from 3-(methylthio)an-
iline using the procedure of Ullmann.19 2-Iodothioani-
sole (6d) was prepared in 63% yield via a two-step
halogen exchange reaction [(i) t-BuLi, -78 ꢂC; (ii) I2]
employing 2-bromothioanisole.20 All other reagents,
purchased from the Aldrich Chemical Company (Mil-
waukee, WI), were used without further purification.
Male Sprague–Dawley rats, used in the anti-inflamma-
tory and analgesic screens, were purchased from Animal
Health Services at the University of Alberta, and exper-
iments were carried out using protocols approved by the
Animal Welfare Committee, University of Alberta.
4. Conclusions
A new class of linear 1,2-diarylacetylenes was designed
for evaluation as COX-2 inhibitors. In vitro enzyme
inhibition structure–activity studies indicated that (i)
the acetylene moiety present in the 1-(methylsulfonyl-
phenyl)-2-phenylacetylene structure is a suitable scaffold
(template) to design COX-2 inhibitors, (ii) SAR data for
the 1-(4-, 3- and 2-methylsulfonylphenyl)-2-phenylacety-
lene regioisomers (11a–13a) showed that the COX isozy-
me selectivity shifts as one moves from the 4-MeSO2
(selective COX-2 inhibitor) ! 3-MeSO2 (mixed COX-
1/COX-2 inhibitor) ! 2-MeSO2 (selective COX-1 inhib-
itor), and (iii) 1-(3-methylsulfonylphenyl)-2-(4-methyl-
phenyl)acetylene (12d) was a selective in vitro COX-2
inhibitor (COX-2 IC50 = 0.32 lM; SI > 320) that exhib-
6. General procedure for the synthesis of 1-(4-, 3-, and
2-methylthiophenyl)-2-phenylacetylenes (8–10)
Cuprous iodide (35 mg, 0.18 mmol) was added to a solu-
tion
of
dichloro-bis(triphenylphosphine)palladium
(63 mg, 0.09 mmol), a bromothioanisole 6a or 6b
(609 mg, 3 mmol) or an iodothioanisole 6c or 6d
(750 mg, 3 mmol), and an acetylene 7a–e (4.5 mmol) in
Et3N (8 mL). The reaction was allowed to proceed over-
night with stirring at 90 ꢂC (for bromothioanisole 6a
and 6b) or 50 ꢂC (for iodothioanisole 6c and 6d) under
an argon atmosphere, cooled to 25 ꢂC, and then Et3N
was removed under reduced pressure. The residue ob-
tained was purified by silica gel column chromatography
using hexane/dichloromethane as the eluent to furnish
the respective title compound (8, 9, or 10). Some physi-
ited
moderate
in
vivo
anti-inflammatory
(ED50 = 129.3 mg/kg po) and analgesic (60% inhibition
at 60 min postdrug administration for a 75 mg/kg oral
dose) activities.
5. Experimental section
Melting points were determined on a Thomas–Hoover
capillary apparatus and are uncorrected. Infrared (IR)

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Q.-H. Chen et al. / Bioorg. Med. Chem. 13 (2005) 6425–6434
cal and spectroscopic data for 8a–e, 9a–e, and 10a–e are
listed below.
hydroxyphenyl H-4), 6.99 (t, J = 2.4 Hz, 1H, 3-hydroxy-
phenyl H-2), 7.11 (d, J = 7.6 Hz, 1H, 3-hydroxyphenyl
H-6), 7.20–7.26 (m, 3 H, 4-methylthiophenyl H-3, H-5,
3-hydroxyphenyl H-5), 7.44 (d, J = 8.2 Hz, 2H, 4-meth-
ylthiophenyl H-2, H-6). Anal. calcd for C15H12OS: C,
74.97; H, 5.03. Found: C, 74.63; H, 5.03.
6.1. 1-(4-Methylthiophenyl)-2-phenylacetylene (8a)
The product was obtained as yellow crystals using a
Sonogashira coupling reaction of 7a with 4-bromothio-
anisole in 47% yield; mp 86–87 ꢂC (Lit.21 83–84 ꢂC); IR
6.6. 1-(3-Methylthiophenyl)-2-phenylacetylene (9a)
1
(film): 2218 (C„C), 1593, 1492 (Ar) cmꢀ1; H NMR
(CDCl3) d 2.49 (s, 3H, SCH3), 7.21 (d, J = 8.2 Hz, 2H,
4-methylthiophenyl H-3, H-5), 7.36–7.41 (m, 3H, phenyl
H-3, H-4, H-5), 7.45 (d, J = 8.2 Hz, 2H, 4-methylthi-
ophenyl H-2, H-6), 7.52 (m, 2H, phenyl H-2, H-6).
The product was obtained as a pale yellow liquid by the
Sonogashira coupling reaction of 7a with 3-bromothio-
anisole in 65% yield; IR (film): 2220 (C„C), 1602, 1581,
1499 (Ar) cmꢀ1; 1H NMR (CDCl3) d 2.52 (s, 3H, SCH3),
7.21–7.56 (m, 9H, 3-methylthiophenyl and phenyl
hydrogens). Anal. calcd for C15H12S: C, 80.31; H,
5.39. Found: C, 80.39; H, 5.38.
6.2. 1-(4-Methylthiophenyl)-2-(3-fluorophenyl)acetylene
(8b)
The product was obtained as a yellow solid using a
Sonogashira coupling reaction of 7b with 4-bromothio-
anisole in 55% yield; mp 66–68 ꢂC; IR (film): 2200
6.7. 1-(3-Methylthiophenyl)-2-(3-fluorophenyl)acetylene
(9b)
(C„C), 1575, 1502 (Ar) cmꢀ1
;
1H NMR (CDCl3) d
The product was obtained as a pale yellow oil using the
Sonogashira coupling reaction of 7b with 3-iodothioani-
sole in 84% yield; IR (film): 2209 (C„C), 1612, 1584,
1483 (Ar) cmꢀ1; 1H NMR (CDCl3) d 2.52 (s, 3H, SCH3),
7.02–7.41 (m, 8H, 3-methylthiophenyl and 3-fluoro-
phenyl hydrogens). Anal. calcd for C15H11FS: C, 74.35;
H, 4.58. Found: C, 74.16; H, 4.40.
2.60 (s, 3H, SCH3), 7.09–7.55 (m, 8H, 4-methylthiophe-
nyl and 3-fluorophenyl hydrogens). Anal. calcd for
C15H11FS: C, 74.35; H, 4.58. Found: C, 74.03; H, 4.72.
6.3. 1-(4-Methylthiophenyl)-2-(3-methoxyphenyl)acety-
lene (8c)
The product was obtained as a yellow oil by a Sono-
gashira coupling reaction of 7c with 4-bromothioanisole
in 54% yield; IR (film): 2206 (C„C), 1595, 1499 (Ar)
6.8. 1-(3-Methylthiophenyl)-2-(3-methoxyphenyl)acet-
ylene (9c)
1
cmꢀ1; H NMR (CDCl3) d 2.51 (s, 3H, SCH3), 3.83 (s,
The product was obtained as a pale yellow solid by the
Sonogashira coupling reaction of 7c with 3-bromothio-
anisole in 47% yield; IR (film): 2213 (C„C), 1595,
3H, OCH3), 6.90 (dd, J = 8.2, 2.7 Hz, 1H, 3-methoxy-
phenyl H-4), 7.12 (br s, 1H, 3-methoxyphenyl H-2),
7.13 (br d, J = 8.2 Hz, 1H, 3-methoxyphenyl H-6), 7.21
(d, J = 8.2 Hz, 2H, 4-methylthiophenyl H-3, H-5), 7.26
(t, J = 8.2 Hz, 1H, 3-methoxyphenyl H-5), 7.45 (d,
J = 8.2 Hz, 2H, 4-methylthiophenyl H-2, H-6).
1567, 1492 (Ar) cmꢀ1 1H NMR (CDCl3) d 2.51 (s,
;
3H, SCH3), 3.82 (s, 3H, OCH3), 6.89–7.41 (m, 8H,
3-methylthiophenyl and 3-methoxyphenyl hydrogens).
6.9. 1-(3-Methylthiophenyl)-2-(4-methylphenyl)acetylene
(9d)
6.4. 1-(4-Methylthiophenyl)-2-(4-methylphenyl)acetylene
(8d)
The product was obtained as a pale yellow oil using
the Sonogashira coupling reaction of 7d with 3-
bromothioanisole in 48% yield, or by the Sonogashira
coupling reaction of 7d with 3-iodothioanisole in 85%
yield; IR (film): 2227 (C„C), 1588, 1567, 1506 (Ar)
The product was obtained as a pale yellow solid employ-
ing the Sonogashira coupling reaction of 7d with 4-
bromothioanisole in 26% yield; mp 100–101 ꢂC; IR
1
(film): 2220 (C„C), 1609, 1519 (Ar) cmꢀ1; H NMR
(CDCl3) d 2.38 (s, 3H, Ar-CH3), 2.50 (s, 3H, SCH3),
7.16 (d, J = 7.6 Hz, 2H, 4-methylphenyl H-3, H-5),
7.20 (d, J = 8.2 Hz, 2H, 4-methylthiophenyl H-3, H-5),
7.42 (d, J = 7.6 Hz, 2H, 4-methylphenyl H-2, H-6),
7.43 (d, J = 8.2 Hz, 2H, 4-methylthiophenyl H-2, H-6).
Anal. calcd for C16H14S: C, 80.63; H, 5.92. Found: C,
80.57; H, 5.87.
cmꢀ1 1H NMR (CDCl3) d 2.38 (s, 3H, Ar-CH3),
;
2.51 (s, 3H, SCH3), 7.15–7.45 (m, 8H, 3-methylthi-
ophenyl and 4-methylphenyl hydrogens). Anal. calcd
for C16H14S: C, 80.63; H, 5.92. Found: C, 81.02; H,
6.27.
6.10. 1-(3-Methylthiophenyl)-2-(3-hydroxyphenyl)acet-
ylene (9e)
6.5. 1-(4-Methylthiophenyl)-2-(3-hydroxyphenyl)acety-
lene (8e)
The product was obtained as a yellow oil employing
the Sonogashira coupling reaction of 7e with 3-iodo-
thioanisole in 90% yield; IR (film): 3377 (OH), 2215
The product was obtained as a yellow foam using the
Sonogashira coupling reaction of 7e with 4-bromothio-
anisole in 42% yield; mp 90–92 ꢂC; IR (film): 3421
(C„C), 1592, 1502 (Ar) cmꢀ1 1H NMR (CDCl3) d
;
2.51 (s, 3H, SCH3), 5.16 (br s, 1H, OH, exchanges with
D2O), 6.84 (dd, J = 7.9, 2.5 Hz, 1H, 3-hydroxyphenyl
H-4), 7.01 (s, 1H, 3-hydroxyphenyl H-2), 7.12 (d,
J = 7.6 Hz, 1H, 3-hydroxyphenyl H-6), 7.20–7.31 (m,
1
(OH), 2209 (C„C), 1603, 1437 (Ar) cmꢀ1; H NMR
(CDCl3) d 2.51 (s, 3H, SCH3), 4.83 (br s, 1H, OH,
exchanges with D2O), 6.83 (dd, J = 7.9, 2.4 Hz, 1H, 3-

Q.-H. Chen et al. / Bioorg. Med. Chem. 13 (2005) 6425–6434
6431
4H, 3-methylthiophenyl H-4, H-5, H-6, 3-hydroxyphe-
nyl H-5), 7.40 (s, 1H, 3-methylthiophenyl H-2). Anal.
calcd for C15H12OS: C, 74.97; H, 5.03. Found: C,
74.67; H, 4.93.
6.16. General procedure for the synthesis of 1-(4-methyl-
sulfonylphenyl)-2-phenylacetylenes (11a–e) and 1-(3-methyl-
sulfonylphenyl)-2-phenylacetylenes (12a–e)
An aqueous solution of Oxoneꢁ (1.28 g, 2 mmol, 9 mL)
was added to a stirred solution of a 1-(4-, or 3-methyl-
thiophenyl)-2-phenylacetylene compound (8 or 9,
1 mmol) in methanol (15 mL) and THF (15 mL), and
the reaction was allowed to proceed with stirring at
25 ꢂC for 1.5 h. Addition of H2O (200 mL), extraction
with EtOAc (3 · 80 mL), drying the combined EtOAc
extracts (Na2SO4), and removal of the solvent in vacuo
afforded the crude product. Purification of the product
by recrystallization from hexanes/acetone, or silica gel
column chromatography using hexanes/acetone (3:1)
as eluent, gave the respective title compound (11a–e
and 12a–e) in 80–95% yield. The physical and spectral
data for 11a–e and 12a–e are summarized below.
6.11. 1-(2-Methylthiophenyl)-2-phenylacetylene (10a)
The product was obtained as a yellow liquid either by
the Sonogashira coupling reaction of 7a with 2-bromo-
thioanisole in 25% yield, or by the Sonogashira coupling
reaction of 7a with 2-iodothioanisole in 89% yield; IR
1
(film): 2206 (C„C), 1602, 1499 (Ar) cmꢀ1; H NMR
(CDCl3) d 2.53 (s, 3H, SCH3), 7.10–7.63 (m, 9H, 2-
methylthiophenyl and phenyl hydrogens).
6.12. 1-(2-Methylthiophenyl)-2-(3-fluorophenyl)acetylene
(10b)
The product was obtained as a yellow oil using the
Sonogashira coupling reaction of 7b with 2-iodothioani-
sole in 86% yield; IR (film): 2200 (C„C), 1621, 1584,
6.17. 1-(4-Methylsulfonylphenyl)-2-phenylacetylene (11a)
1492 (Ar) cmꢀ1 1H NMR (CDCl3) d 2.53 (s, 3H,
;
Yield, 83%; pale yellow crystals; mp 158–160 ꢂC; IR
(film): 2227 (C„C), 1650, 1561, 1451 (Ar), 1320 (SO2)
SCH3), 7.02–7.50 (m, 8H, 2-methylthiophenyl and
3-fluorophenyl hydrogens). Anal. calcd for C15H11FS:
C, 74.35; H, 4.58. Found: C, 74.58; H, 4.61.
cmꢀ1 1H NMR (CDCl3) d 3.08 (s, 3H, SO2 CH3),
;
7.29–7.41 (m, 3H, phenyl H-3, H-4, H-5), 7.53–7.59
(m, 2H, phenyl H-2, H-6), 7.71 (d, J = 8.5 Hz, 2H,
4-methylsulfonylphenyl H-2, H-6), 7.93 (d, J = 8.5 Hz,
2H, 4-methylsulfonylphenyl H-3, H-5).
6.13. 1-(2-Methylthiophenyl)-2-(3-methoxyphenyl)acety-
lene (10c)
6.18. 1-(4-Methylsulfonylphenyl)-2-(3-fluorophenyl)acet-
ylene (11b)
The product was obtained as a yellow oil from the Sono-
gashira coupling reaction of 7c with 2-iodothioanisole in
70% yield; IR (film): 2200 (C„C), 1603, 1575, 1492 (Ar)
1
Yield, 82%; pale yellow solid; mp 130–132 ꢂC; IR (film):
cmꢀ1; H NMR (CDCl3) d 2.52 (s, 3H, SCH3), 3.84 (s,
2296 (C„C), 1609, 1588, 1499 (Ar), 1320 (SO2) cmꢀ1
;
3H, OCH3), 6.89–7.51 (m, 8H, 2-methylthiophenyl and
3-methoxyphenyl hydrogens).
1H NMR (CDCl3) d 3.08 (s, 3H, SO2 CH3), 7.07–7.14
(m, 1H, 3-fluorophenyl H-4), 7.24 (dd, J = 8.0, 1.8 Hz,
1H, 3-fluorophenyl H-2), 7.33–7.40 (m, 2H, 3-fluorophe-
nyl H-5, H-6), 7.71 (d, J = 8.2 Hz, 2H, 4-methylsulfonyl-
phenyl H-2, H-6), 7.94 (d, J = 8.2 Hz, 2H, 4-
methylsulfonylphenyl H-3, H-5). Anal. calcd for
C15H11FO2S: C, 65.69; H, 4.02. Found: C, 65.39; H, 4.14.
6.14. 1-(2-Methylthiophenyl)-2-(4-methylphenyl)acety-
lene (10d)
The product was obtained as a pale yellow oil using the
Sonogashira coupling reaction of 7d with 2-iodothioani-
sole in 72% yield; IR (film): 2209 (C„C), 1593, 1520,
6.19. 1-(4-Methylsulfonylphenyl)-2-(3-methoxyphenyl)acet-
ylene (11c)
1
1465 (Ar) cmꢀ1; H NMR (CDCl3) d 2.38 (s, 3H, Ar-
CH3), 2.52 (s, 3H, SCH3), 7.12 (dt, J = 7.6, 1.2 Hz,
1H, 2-methylthiophenyl H-4), 7.18 (d, J = 8.2 Hz, 1H,
2-methylthiophenyl H-6), 7.17 (d, J = 8.2 Hz, 2H, 4-
methylphenyl H-3, H-5), 7.30 (dt, J = 7.6, 1.5 Hz, 1H,
2-methylthiophenyl H-5), 7.48 (d, J = 7.9 Hz, 3H, 2-
methylthiophenyl H-3, 4-methylphenyl H-2, H-6). Anal.
calcd for C16H14S Æ 1/8H2O: C, 79.87; H, 5.97. Found:
C, 79.79; H, 6.01.
Yield, 82%; pale yellow needle; mp 137–139 ꢂC; IR
(film): 2207 (C„C), 1570, 1487 (Ar), 1315 (SO2) cmꢀ1
;
1H NMR (CDCl3) d 3.08 (s, 3H, SO2 CH3), 3.84 (s,
3H, OCH3), 6.96 (dd, J = 8.0, 2.1 Hz, 1H, 3-methoxy-
phenyl H-4), 7.09 (d, J = 2.1 Hz, 1H, 3-methoxyphenyl
H-2), 7.16 (d, J = 8.0 Hz, 1H, 3-methoxyphenyl H-6),
7.30 (t, J = 8.0 Hz, 1H, 3-methoxyphenyl H-5), 7.71 (d,
J = 8.2 Hz, 2H, 4-methylsulfonylphenyl H-2, H-6),
7.93 (d, J = 8.2 Hz, 2H, 4-methylsulfonylphenyl H-3,
H-5). Anal. calcd for C16H14O3S: C, 67.11; H, 4.93.
Found: C, 66.97; H, 4.80.
6.15. 1-(2-Methylthiophenyl)-2-(3-hydroxyphenyl)acety-
lene (10e)
The product was obtained as a pale yellow oil using the
Sonogashira coupling reaction of 7e with 2-iodothioani-
sole in 92% yield; IR (film): 3375 (OH), 2200 (C„C),
6.20. 1-(4-Methylsulfonylphenyl)-2-(4-methylphenyl)acet-
ylene (11d)
1
1658, 1575, 1437 (Ar) cmꢀ1; H NMR (CDCl3) d 2.52
(s, 3H, SCH3), 6.82–7.49 (m, 8H, 2-methylthiophenyl
and 3-hydroxyphenyl hydrogens). Anal. calcd for
C15H12OS: C, 74.97; H, 5.03. Found: C, 74.64; H, 4.76.
Yield, 90%; pale yellow needles, mp 193–194 ꢂC; IR
(film): 2234 (C„C), 1567, 1513 (Ar), 1313 (SO2) cmꢀ1
;
1H NMR (CDCl3) d 2.40 (s, 3H, Ar-CH3), 3.08 (s, 3H,

6432
Q.-H. Chen et al. / Bioorg. Med. Chem. 13 (2005) 6425–6434
SO2 CH3), 7.20 (d, J = 7.6 Hz, 2H, 4-methylphenyl H-3,
H-5), 7.46 (d, J = 7.6 Hz, 2H, 4-methylphenyl H-2, H-6),
7.70 (d, J = 8.5 Hz, 2H, 4-methylsulfonylphenyl H-2, H-
6), 7.92 (d, J = 8.5 Hz, 2H, 4-methylsulfonylphenyl H-3,
H-5). Anal. calcd for C16H14O2S: C, 71.08; H, 5.22.
Found: C, 70.72; H, 5.20.
fluorophenyl H-4), 7.25 (d, J = 8.5 Hz, 1H, 3-fluorophe-
nyl H-2), 7.31–7.39 (m, 2H, 3-fluorophenyl H-5, H-6),
7.59 (t, J = 7.9 Hz, 1H, 3-methylsulfonylphenyl H-5),
7.79 (d, J = 7.9 Hz, 1H, 3-methylsulfonylphenyl H-6),
7.92 (d, J = 7.9 Hz, 1H, 3-methylsulfonylphenyl H-4),
8.12 (s, 1H, 3-methylsulfonylphenyl H-2). Anal. calcd
for C15H11FO2S: C, 65.68; H, 4.04. Found: C, 65.48;
H, 4.02.
6.21. 1-(4-Methylsulfonylphenyl)-2-(3-hydroxyphenyl)acet-
ylene (11e)
6.25. 1-(3-Methylsulfonylphenyl)-2-(3-methoxyphe-
nyl)acetylene (12c)
Yield,90%;palebrowncrystals;mp196–198 ꢂC;IR(film):
3429(OH),2131(C„C),1595,1567,1451(Ar),1306(SO2)
cmꢀ1
;
1H NMR (CDCl3 + DMSO) d 3.06 (s, 3H,
Yield, 80%; yellow oil; IR (film): 2227 (C„C), 1609,
1
SO2CH3), 6.87 (dd, J = 8.2, 1.2 Hz, 1H, 3-hydroxyphenyl
H-4), 7.02–7.05 (m, 2H, 3-hydroxyphenyl H-2, H-6), 7.19
(t, J = 7.9 Hz, 1H, 3-hydroxyphenyl H-5), 7.67 (d,
J = 8.2 Hz, 2H, 4-methylsulfonylphenyl H-2, H-6), 7.90
(d, J = 8.2 Hz, 2H, 4-methylsulfonylphenyl H-3, H-5),
8.40 (br s, 1H, OH, exchanges with D2O). Anal. calcd for
C15H12O3S: C, 66.16; H, 4.44. Found: C, 65.79; H, 4.60.
1574, 1492 (Ar), 1320 (SO2) cmꢀ1; H NMR (CDCl3)
d 3.08 (s, 3H, SO2CH3), 3.84 (s, 3H, OCH3), 6.94 (dd,
J = 8.0, 2.7 Hz, 1H, 3-methoxyphenyl H-4), 7.07 (br s,
1H, 3-methoxyphenyl H-2), 7.14 (dt, J = 7.6, 1.2 Hz,
1H, 3-methoxyphenyl H-6), 7.29 (t, J = 7.6 Hz, 1H, 3-
methoxyphenyl H-5), 7.57 (t, J = 7.9 Hz, 1H, 3-meth-
ylsulfonylphenyl H-5), 7.79 (dt, J = 7.9, 1.2 Hz, 1H, 3-
methylsulfonylphenyl H-6), 7.90 (dt, J = 7.9, 1.2 Hz,
1H, 3-methylsulfonylphenyl H-4), 8.11 (t, J = 1.2 Hz,
1H, 3-methylsulfonylphenyl H-2). Anal. calcd for
C16H14O3S1/8H2O: C, 66.59; H, 4.98. Found: C, 66.46;
H, 4.84.
6.22. 1-(4-Methylsulfonylphenyl)-2-(3-acetoxyphenyl)acet-
ylene (11f)
Acetyl chloride (0.1 mL, 1.5 mmol) and Et3N (0.1 mL,
0.75 mmol) were added to a solution of 1-(4-meth-
ylsulfonylphenyl)-2-(3-hydroxyphenyl)acetylene
(11e,
6.26. 1-(3-Methylsulfonylphenyl)-2-(4-methylphenyl)acet-
ylene (12d)
204 mg, 0.75 mmol) in THF (6 mL), and the reaction
was allowed to proceed at 25 ꢂC with stirring for 2 h.
Then EtOAc (200 mL) was added and this solution
was washed with H2O (2 · 60 mL). The organic frac-
tion was dried (NaSO4), and the solvent was removed
in vacuo to afford 11f (190 mg, 80% yield) as pale yel-
low crystals; mp 122–123 ꢂC; IR (film): 2220 (C„C),
1767 (C@O), 1602, 1574, 1478 (Ar), 1300 (SO2)
Yield, 88%; pale solid; mp 94–96 ꢂC; IR (film): 2234
1
(C„C), 1602, 1526 (Ar), 1313 (SO2) cmꢀ1; H NMR
(CDCl3) d 2.39 (s, 3H, Ar-CH3), 3.09 (s, 3H, SO2CH3),
7.20 (d, J = 7.9 Hz, 2H, 4-methylphenyl H-3, H-5), 7.45
(d, J = 7.9 Hz, 2H, 4-methylphenyl H-2, H-6), 7.56 (t,
J = 7.6 Hz, 1H, 3-methylsulfonylphenyl H-5), 7.78 (d,
J = 7.6 Hz, 1H, 3-methylsulfonylphenyl H-6), 7.89 (d,
J = 7.6 Hz, 1H, 3-methylsulfonylphenyl H-4), 8.10 (s,
1H, 3-methylsulfonylphenyl H-2). Anal. calcd for
C16H14O2S: C, 71.08; H, 5.22. Found: C, 70.75; H, 5.14.
cmꢀ1 1H NMR (CDCl3) d 2.33 (s, 3H, COCH3),
;
3.08 (s, 3H, SO2 CH3), 7.11–7.15 (m, 1H, 3-acetoxy-
phenyl H-4), 7.29 (br s, 1H, 3-acetoxyphenyl H-2),
7.31–7.44 (m, 2H, 3-acetoxyphenyl H-5, H-6), 7.70
(d, J = 8.5 Hz, 2H, 4-methylsulfonylphenyl H-2, H-6),
7.90 (d, J = 8.5 Hz, 2H, 4-methylsulfonylphenyl H-3,
H-5). Anal. calcd for C17H14O4S: C, 64.95; H, 4.49.
Found: C, 64.61; H, 4.67.
6.27. 1-(3-Methylsulfonylphenyl)-2-(3-hydroxyphenyl)acet-
ylene (12e)
Yield, 90%; white crystals; mp 99–100 ꢂC; IR (film):
3422 (OH), 2220 (C„C), 1581, 1492 (Ar), 1306 (SO2)
6.23. 1-(3-Methylsulfonylphenyl)-2-phenylacetylene (12a)
1
cmꢀ1; H NMR (CDCl3) d 3.09 (s, 3H, SO2CH3), 5.02
Yield, 89%; pale yellow solid; mp 100–102 ꢂC; IR (film):
(br s, 1H, OH, exchanges with D2O), 6.88 (dd, J = 7.9,
2.4 Hz, 1H, 3-hydroxyphenyl H-4), 7.02 (br s, 1H, 3-
hydroxyphenyl H-2), 7.13 (d, J = 7.9 Hz, 1H, 3-
hydroxyphenyl H-6), 7.25 (t, J = 7.9 Hz, 1H, 3-hydroxy-
phenyl H-5), 7.57 (t, J = 7.9 Hz, 1H, 3-meth-
ylsulfonylphenyl H-5), 7.78 (d, J = 7.9 Hz, 1H,
3-methylsulfonylphenyl H-6), 7.90 (d, J = 7.9 Hz, 1H,
3-methylsulfonylphenyl H-4), 8.11 (br s, 1H, 3-meth-
ylsulfonylphenyl H-2). Anal. calcd for C15H12O3S: C,
66.16; H, 4.44. Found: C, 65.83; H, 4.13.
2227 (C„C), 1603, 1492 (Ar), 1327 (SO2) cmꢀ1 1H
;
NMR (CDCl3) d 3.09 (s, 3H, SO2CH3), 7.34–7.41 (m,
3H, phenyl H-3, H-4, H-5), 7.52–7.60 (m, 3H, phenyl
H-2, H-6, 3-methylsulfonylphenyl H-5), 7.79 (d,
J = 7.6 Hz, 1H, 3-methylsulfonylphenyl H-6), 7.90 (br
d, J = 7.9 Hz, 1H, 3-methylsulfonylphenyl H-4), 8.12
(t, J = 1.2 Hz, 1H, 3-methylsulfonylphenyl H-2). Anal.
calcd for C15H12O2S: C, 70.29; H, 4.72. Found: C,
70.50; H, 4.97.
6.24. 1-(3-Methylsulfonylphenyl)-2-(3-fluorophenyl)acet-
ylene (12b)
6.28. 1-(3-Methylsulfonylphenyl)-2-(3-acetoxyphenyl)acet-
ylene (12f)
Yield, 95%; pale brown oil; IR (film): 2218 (C„C),
Acetyl chloride (0.1 mL, 1.5 mmol) and Et3N (0.1 mL,
0.75 mmol) were added to a solution of 1-(3-meth-
1603, 1584, 1483 (Ar), 1318 (SO2) cmꢀ1 1H NMR
;
(CDCl3) d 3.09 (s, 3H, SO2CH3), 7.06–7.13 (m, 1H, 3-
ylsulfonylphenyl)-2-(3-hydroxyphenyl)acetylene
(12e,

Q.-H. Chen et al. / Bioorg. Med. Chem. 13 (2005) 6425–6434
6433
185 mg, 0.68 mmol) in THF (6 mL), and the reaction
was allowed to proceed at 25 ꢂC with stirring for 2 h.
EtOAc (200 mL) was added and this solution was
washed with H2O (2 · 60 mL). The organic fraction
was dried (NaSO4), and the solvent was removed in vac-
uo to afford 12f (190 mg, 89%) as a white solid; mp 78–
79 ꢂC; IR (film): 2218 (C„C), 1768 (C@O), 1658, 1566
6.32. 1-(2-Methylsulfonylphenyl)-2-(3-methoxyphenyl)acet-
ylene (13c)
Yield, 82%; semisolid; IR (film): 2215 (C„C), 1607,
1
1570, 1487 (Ar), 1307 (SO2) cmꢀ1; H NMR (CDCl3)
d 3.33 (s, 3H, SO2CH3), 3.85 (s, 3H, OCH3), 6.96 (dd,
J = 8.2, 1.8 Hz, 1H, 3-methoxyphenyl H-4), 7.14 (br s,
1H, 3-methoxyphenyl H-2), 7.21 (d, J = 7.6 Hz, 1H,
3-methoxyphenyl H-6), 7.31 (t, J = 7.6 Hz, 1H, 3-meth-
oxyphenyl H-5), 7.53 (dt, J = 7.6, 1.2 Hz, 1H, 2-meth-
ylsulfonylphenyl H-4), 7.63 (dt, J = 7.6, 1.2 Hz, 1H,
2-methylsulfonylphenyl H-5), 7.74 (dd, J = 7.6, 1.2 Hz,
1H, 2-methylsulfonylphenyl H-6), 8.13 (dd, J = 7.9,
1.2 Hz, 1H, 2-methylsulfonylphenyl H-3). Anal. calcd
for C16H14O3S: C, 67.11; H, 4.93. Found: C, 66.96; H,
4.88.
1
(Ar), 1318 (SO2) cmꢀ1; H NMR (CDCl3) d 2.33 (s,
3H, CO CH3), 3.09 (s, 3H, SO2CH3), 7.11–7.14 (m,
1H, 3-acetoxyphenyl H-4), 7.29 (br s, 1H, 3-acetoxyphe-
nyl H-2), 7.36-7.43 (m, 2H, 3-acetoxyphenyl H-5, H-6),
7.58 (t, J = 7.9 Hz, 1H, 3-methylsulfonylphenyl H-5),
7.78 (d, J = 7.9 Hz, 1H, 3-methylsulfonylphenyl H-6),
7.91 (d, J = 7.9 Hz, 1H, 3-methylsulfonylphenyl H-4),
8.10 (br s, 1H, 3-methylsulfonylphenyl H-2). Anal. calcd
for C17H14O4S: C, 64.95; H, 4.49. Found: C, 64.66; H,
4.35.
6.33. 1-(2-Methylsulfonylphenyl)-2-(4-methylphenyl)acet-
ylene (13d)
6.29. General procedure for the synthesis of 1-(2-methylsul-
fonylphenyl)-2-phenylacetylenes (13a–e)
Yield, 83%; pale yellow solid; mp 94–95 ꢂC; IR (film):
2222 (C„C), 1585, 1510, 1480 (Ar), 1322 (SO2) cmꢀ1
;
An aqueous solution of Oxoneꢁ (3.07 g, 5 mmol, 9 mL)
was added to a stirred solution of the 1-(2-methylthio-
phenyl)-2-phenylacetylene compound (10, 1 mmol) in
methanol (15 mL) and THF (15 mL), and the reaction
was allowed to proceed with stirring at 25 ꢂC overnight.
Addition of H2O (200 mL), extraction with EtOAc
(3 · 80 mL), drying the combined EtOAc extracts
(Na2SO4), and removal of the solvent in vacuo afforded
the crude product. Purification of the product by silica
gel column chromatography using hexanes/acetone
(3:1, v/v) as eluent gave the respective title compound
(13a–e) in 79–86 % yield. Some of the physical and spec-
tral data for 13a–e are listed below.
1H NMR (CDCl3) d 2.39 (s, 3H, Ar-CH3), 3.32 (s, 3H,
SO2CH3), 7.20 (d, J = 7.6 Hz, 2H, 4-methylphenyl H-
3, H-5), 7.48–7.53 (m, 3H, 4-methylphenyl H-2, H-6,
2-methylsulfonylphenyl H-4), 7.61 (dt, J = 7.6, 1.2 Hz,
1H, 2-methylsulfonylphenyl H-5), 7.72 (dd, J = 7.6,
1.2 Hz, 1H, 2-methylsulfonylphenyl H-6), 8.14 (dd,
J = 7.9, 0.9 Hz, 1H, 2-methylsulfonylphenyl H-3). Anal.
calcd for C16H14O2S: C, 71.08; H, 5.22. Found: C, 71.03;
H, 5.14.
6.34. 1-(2-Methylsulfonylphenyl)-2-(3-hydroxyphenyl)acet-
ylene (13e)
Yield, 86%; colorless syrup; IR (film): 3407 (OH), 2215
1
(C„C), 1585, 1487 (Ar), 1315 (SO2) cmꢀ1; H NMR
6.30. 1-(2-Methylsulfonylphenyl)-2-phenylacetylene (13a)
(CDCl3) d 3.36 (s, 3H, SO2CH3), 5.56 (br s, 1H, OH,
exchanges with D2O), 6.88–6.92 (m, 1H, 3-hydroxyphe-
nyl H-4), 7.12 (d,J = 2.4 Hz, 1H, 3-hydroxyphenyl H-2),
7.16 (dd, 1H, J = 7.6, 1.2 Hz, 3-hydroxyphenyl H-6),
7.24 (t, J = 7.6 Hz, 1H, 3-hydroxyphenyl H-5), 7.53
(dt, J = 7.6, 1.2 Hz, 1H, 2-methylsulfonylphenyl H-4),
7.63 (dt, J = 7.6, 1.2 Hz, 1H, 2-methylsulfonylphenyl
H-5), 7.73 (dd, J = 7.6, 1.2 Hz, 1H, 2-methylsulfonyl-
phenyl H-6), 8.15 (dd, J = 7.9, 1.2 Hz, 1H, 2-meth-
ylsulfonylphenyl H-3). Anal. calcd for C15H12O3S: C,
66.16; H, 4.44. Found: C, 65.99; H, 4.33.
Yield, 79%; pale yellow solid; mp 99–100 ꢂC; IR (film):
2218 (C„C), 1566, 1502 (Ar), 1309 (SO2) cmꢀ1 1H
;
NMR (CDCl3) d 3.33 (s, 3H, SO2 CH3), 7.35–7.41 (m,
3H, phenyl H-3, H-4, H-5), 7.53 (dt, J = 7.9, 1.2 Hz,
1H, 2-methylsulfonylphenyl H-4), 7.57–7.66 (m, 3H,
phenyl H-2, H-6, 2-methylsulfonylphenyl H-5), 7.74
(dd, J = 7.6, 1.2 Hz, 1H, 2-methylsulfonylphenyl H-6),
8.15 (dd, J = 7.9, 1.2 Hz, 1H, 2-methylsulfonylphenyl
H-3). Anal. calcd for C15H12O2S: C, 70.29; H, 4.72.
Found: C, 70.09; H, 4.79.
6.31. 1-(2-Methylsulfonylphenyl)-2-(3-fluorophenyl)acet-
ylene (13b)
6.35. 1-(2-Methylsulfonylphenyl)-2-(3-acetoxyphenyl)acet-
ylene (13f)
Yield, 83%; pale yellow oil; IR (film): 2215 (C„C),
Acetyl chloride (0.1 mL, 1.5 mmol) and Et3N (0.1 mL,
0.75 mmol) were added to a solution of 13e (204 mg,
0.70 mmol) in THF (6 mL), and the reaction was al-
lowed to proceed at 25 ꢂC with stirring for 2 h. EtOAc
(200 mL) was added and this solution was washed with
H2O (2 · 60 mL). The organic fraction was dried
(NaSO4), and the solvent was removed in vacuo to af-
ford 13f (200 mg, 85%) as a pale yellow solid; mp 129–
130 ꢂC; IR (film): 2215 (C„C), 1757 (C@O), 1600,
1607, 1585, 1495 (Ar), 1307 (SO2) cmꢀ1 1H NMR
;
(CDCl3) d 3.31 (s, 3H, SO2CH3), 7.08–7.16 (m, 1H,
3-fluorophenyl H-4), 7.29–7.42 (m, 3H, 3-fluorophenyl
H-2, H-5, H-6), 7.56 (dt, J = 7.6, 1.2 Hz, 1H, 2-meth-
ylsulfonylphenyl H-4), 7.64 (dt, J = 7.6, 1.2 Hz, 1H,
2-methylsulfonylphenyl H-5), 7.74 (d, J = 7.6 Hz, 1H,
2-methylsulfonylphenyl H-6), 8.16 (dd, J = 7.6, 1.2 Hz,
1H, 2-methylsulfonylphenyl H-3). Anal. calcd for
C15H11FO2S: C, 65.68; H, 4.04. Found: C, 65.53; H,
3.84.
1
1585, 1487 (Ar), 1315 (SO2) cmꢀ1; H NMR (CDCl3)
d 2.33 (s, 3H, COCH3), 3.31 (s, 3H, SO2CH3), 7.13–

6434
Q.-H. Chen et al. / Bioorg. Med. Chem. 13 (2005) 6425–6434
Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P.
C. J. Med. Chem. 1997, 40, 1347.
7.17 (m, 1H, 3-acetoxyphenyl H-4), 7.35 (t, J = 1.8 Hz,
1H, 3-acetoxyphenyl H-2), 7.41 (t, J = 7.9 Hz, 1H,
3-acetoxyphenyl H-5), 7.49 (dt, J = 7.9, 1.2 Hz, 1H,
3-acetoxyphenyl H-6), 7.54 (dt, J = 7.6, 1.5 Hz, 1H,
2-methylsulfonylphenyl H-4), 7.63 (dt, J = 7.6, 1.2 Hz,
1H, 2-methylsulfonylphenyl H-5), 7.73 (dd, J = 7.6,
1.2 Hz, 1H, 2-methylsulfonylphenyl H-6), 8.15 (dd,
J = 7.6, 1.2 Hz, 1H, 2-methylsulfonylphenyl H-3). Anal.
calcd for C17H14O4S: C, 64.95; H, 4.49. Found: C, 64.62;
H, 4.50.
2. Prasit, P.; Wang, Z.; Brideau, C.; Chan, C. C.; Charleson,
S.; Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutchin-
son, A. W.; Gauthier, J. Y.; Gordon, R.; Guay, J.; Gresser,
M.; Kargman, S.; Kennedy, B.; Leblanc, Y.; Leger, S.;
Mancini, J.; OꢀNeill, G. P.; Quellet, M.; Percival, M. D.;
Perrier, H.; Riendeau, D.; Rodger, I.; Tagari, P.; Therien,
M.; Vickers, P.; Wong, E.; Xu, L. J.; Young, R. N.;
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3. Talley, J. A.; Brown, D. L.; Carter, J. S.; Masferrer, M. J.;
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Dube, D.; Ethier, D.; Falgueyret, J.-P.; Friesen, R. W.;
Gordon, R.; Greig, G.; Guay, I.; Manacini, J.; Ouellet,
M.; Wong, E.; Xu, L.; Boyce, S.; Visco, D.; Girad, Y.;
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7. Molecular modeling (docking) study
Docking experiments were performed using Insight II
software Version 2000.1 (Accelrys Inc.) running on a
Silicon Graphics Octane
2 R14000A workstation
according to a previously reported method.16
5. Davies, I. W.; Marcoux, J.-F.; Corley, E. G.; Journet, M.;
Cai, D. –W.; Palucki, M.; Wu, J.; Larsen, R. D.; Rossen,
K.; Pye, P. J.; Dimichele, L.; Dormer, P.; Reider, P. J.
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7. Rodrigues, C. R.; Veloso, M. P.; Verli, H.; Fraga, C. A.;
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849.
8. Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.;
Burgos-Vargas, R.; Davies, B.; Day, R.; Ferraz, M. B.;
Hawkey, C. J.; Hochberg, M. C.; Kvien, T. K.; Schnitzer,
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9. Silverstein, F. E.; Faich, G.; Goldstein, J. L.; Simon, L. S.;
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D.; Lefkwith, J. B.; Verburg, K. M.; Geis, G. S. JAMA
2000, 284, 1247.
8. In vitro cyclooxygenase (COX) inhibition assay
The ability of the test compounds listed in Table 1 to
inhibit ovine COX-1 and COX-2 (IC50 value, lM) was
determined using an enzyme immuno assay (EIA) kit
(catalog number 560101, Cayman Chemical, Ann
Arbor, MI, USA) according to our previously reported
method.13
9. Anti-inflammatory assay
Anti-inflammatory activity was performed using a
method described by Winter et al.22
10. Talley, J. Prog. Med. Chem. 1999, 36, 201.
´
11. Dogne, J. M.; Supuran, C. T.; Pratico, D. J. Med. Chem.
2005, 48, 2251.
10. Analgesic assay
12. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med.
Chem. Lett. 2004, 14, 1953.
13. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med.
Chem. 2004, 12, 5929.
Analgesic activity was determined using a 4% sodium
chloride-induced writhing abdominal constriction assay
previously reported.23
14. Uddin, M. J.; Rao, P. N. P.; Rahim, M. A.; McDonald,
R.; Knaus, E. E. Bioorg. Med. Chem. Lett. 2004, 14, 4911.
15. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med.
Chem. 2005, 13, 417.
Acknowledgments
We are grateful to (i) the Canadian Institutes of Health
Research (CIHR) (MOP-14712) for financial support of
this research, (ii) Rx&D-HRF/CIHR for a postdoctoral
fellowship (to Q.H.C.), and to the Alberta Heritage
Foundation for Medical Research (AHFMR) for a
postdoctoral fellowship award (to Q.H.C.).
16. Uddin, M. J.; Rao, P. N. P.; McDonald, R.; Knaus, E. E.
Bioorg. Med. Chem. Lett. 2005, 15, 439.
17. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E.; McDonald, R.
J. Med. Chem. 2004, 47, 6108.
18. Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara,
N. Synthesis 1980, 627.
19. Larock, R. C.; Harrison, L. W. J. Am. Chem. Soc. 1984,
106, 4218.
20. Mongin, O.; Papamicael, C.; Hoyler, N.; Gossauer, A.
J. Org. Chem. 1998, 63, 5568.
References and notes
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22. Winter, C. A.; Risley, E. A.; Nuss, G. W. Proc. Soc. Exp.
Biol. Med. 1962, 111, 544.
23. Fukawa, K.; Kawano, O.; Hibi, M.; Misaka, N.; Ohba, S.;
Hatanaka, Y. J. Pharmacol. Methods 1980, 4, 251.
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