Diaryl and heteroaryl sulfides: Synthesis via sulfenyl chlorides and evaluation as selective anti-breast-cancer agents

Article abstract of DOI:10.1021/jo402586v

A mild protocol for the synthesis of diaryl and heteroaryl sulfides is described. In a one-pot procedure, thiols are converted to sulfenyl chlorides and reacted with arylzinc reagents. This method tolerates functional groups including aryl fluorides and chlorides, ketones, as well as N-heterocycles including pyrimidines, imidazoles, tetrazoles, and oxadiazoles. Two compounds synthesized by this method exhibited selective activity against the MCF-7 breast cancer cell line in the micromolar range.

Full text of DOI:10.1021/jo402586v

Article
pubs.acs.org/joc
Diaryl and Heteroaryl Sulfides: Synthesis via Sulfenyl Chlorides and
Evaluation as Selective Anti-Breast-Cancer Agents
Ivelina M. Yonova,† Charlotte A. Osborne,† Naomi S. Morrissette,‡ and Elizabeth R. Jarvo*,†
†Department of Chemistry, University of California, Irvine, California 92697-2025, United States
‡Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-2025, United States
S
* Supporting Information
ABSTRACT: A mild protocol for the synthesis of diaryl and heteroaryl sulfides
is described. In a one-pot procedure, thiols are converted to sulfenyl chlorides
and reacted with arylzinc reagents. This method tolerates functional groups
including aryl fluorides and chlorides, ketones, as well as N-heterocycles
including pyrimidines, imidazoles, tetrazoles, and oxadiazoles. Two compounds
synthesized by this method exhibited selective activity against the MCF-7 breast
cancer cell line in the micromolar range.
arylzinc reagents. A series of heterocyclic diaryl thioethers
were designed and prepared as combretastatin A-4 analogues;
two of these compounds demonstrated micromolar activity
against the MCF-7 breast cancer cell line.
In the past two decades, there have been numerous advances
in the synthesis of this class of compounds, and particularly in
the field of metal-catalyzed carbon−sulfur bond formation
(Figure 2a). Copper- and palladium-catalyzed cross-coupling
INTRODUCTION
■
Diaryl thioethers, and particularly those containing heterocyclic
moieties, are a common structural motif in natural products and
medicinal agents (Figure 1). For example, thioethers have
Figure 2. Strategies for the synthesis of diaryl sulfides.
reactions offer a broad scope of reactivity; however, these
methods often require elevated temperatures.7−9 Mechanism-
based reaction design has been employed to accelerate
transformations such that they occur under milder reaction
conditions. For example, the Fu and Peters laboratories
disclosed a copper-catalyzed, photoinduced synthesis of diaryl
sulfides that proceeds at 0 °C.10
Figure 1. Representative bioactive diaryl sulfides.
An umpolung approach employs electrophilic sulfur reagents
(Figure 2b and c). Recent reports detail reactions of disulfides
with aryl iodides, boronic acids, or silanes in the presence of
stoichiometric reducing agents (Figure 2b).11−14 Sulfenyl
chlorides are used less frequently, likely due to their instability.
therapeutic potential for treatment of HIV,1 breast cancer,2
inflammatory diseases,3,4 diabetes,5 and Alzheimer’s disease.6
Despite their abundance, until recently few general methods
were available for their synthesis under mild conditions that
would tolerate sensitive heterocycles. In this manuscript, we
report synthesis of diaryl sulfides by in situ formation of highly
reactive sulfenyl chlorides and subsequent trapping with
Received: November 22, 2013
Published: February 25, 2014
© 2014 American Chemical Society
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d
Schlosser and co-workers demonstrated reactions of indoles
with sulfenyl chlorides prepared in situ.15 The high reactivity of
sulfenyl chlorides allows the reaction to occur at 0 °C. Recently,
expansion of the scope of this reaction to include Grignard
reagents was reported by Lee and co-workers (Figure 2c).16
Contemporaneously, on the basis of our work with N-
chloroamines,17,18 we developed sulfenylation of organozinc
reagents as a functional-group tolerant19 strategy for synthesis
of diaryl sulfides.
Scheme 2. Reactivity of Heteroaryl Thiols
RESULTS AND DISCUSSION
■
A variety of in situ-formed alkyl and aryl sulfenyl chlorides react
with phenylzinc bromide to afford the respective thioethers in
good yields (Scheme 1). Substrates containing ortho-
a
Scheme 1. Reactivity of Alkyl and Aryl Thiols
a
b
c
Used (4-OMe)C6H4MgBr. Used (4-F)C6H4MgBr. Used (3-CN)-
d
C6H4MgBr. Isolated yields after silica gel chromatography.
respectively). Furthermore, both electron-rich and electron-
poor Grignard reagents react smoothly to afford the desired
thioether products in good yields (21 and 22, respectively).
meta-Cyanophenylmagnesium reagent is well-tolerated, afford-
ing 23 in good yield.
a
Isolated yields after silica gel chromatography.
We sought to synthesize combretastatin A-420,21 analogues
using our method since it tolerates a diverse range of
heterocycles and would further SAR studies of these
compounds. Diaryl sulfide analogues of combretastatin
containing N-heterocyclic moieties have been reported to be
active against MCF-7 breast cancer cell lines (e.g., 2).2,22−25 We
examined reactions of a variety of heteroaryl sulfides with 3,4,5-
trimethoxyphenylzinc bromide, biasing our small library of
analogues toward inclusion of the 3,4,5-trimethoxyphenyl
scaffold, a privileged motif commonly found in anticancer
compounds that target microtubules.26,27 We were pleased to
see that the corresponding arylzinc bromide reacts with a
variety of in situ-formed heteroaryl sulfenyl chlorides to afford
the respective trimethoxyphenyl-substituted thioethers in
modest to good yields (24−27).
disubstituted aryl rings pose a significant challenge for most
metal-catalyzed methods, yet our reaction conditions furnish 9
in 93% yield. Halogenation, and particularly fluorination, is well
tolerated. Electron-rich thiols such as 4-methoxy thiophenol are
competent in the transformation, although the desired product
12 is afforded in slightly diminished yield due to competitive
formation of diaryl disulfide. 4-Nitrothiophenol proved to be a
challenging substrate, as it is prone to decomposition under the
reaction conditions, thus affording 13 in a modest yield. One
benefit of using aryl zinc reagents in contrast to aryl Grignard
reagents is the increased functional group compatibility. For
example, 1-(4-mercapto-phenyl)-ethanone reacted smoothly to
provide desired diaryl sulfide 14 with no observed competitive
addition to the ketone.
In an effort to ensure that our method is compatible with the
sensitive heterocyclic moieties frequently found in bioactive
compounds, we examined several heteroaromatic thiols
(Scheme 2). A broad range of heterocycles react with
phenylzinc bromide to provide good to excellent yields of the
corresponding sulfides, including benzothiazole, benzoxazole,
pyrimidine, tetrazole, oxadiazole, and imidazole functional
groups (15−20). Notably, when phenylmagnesium bromide
was used instead of phenylzinc bromide, compounds 15, 16,
and 20 were obtained in diminished yields (65, 57, and 59%
Having synthesized a variety of combretastatin A-4
analogues, we set out to evaluate these compounds for anti-
breast-cancer activity. Select products from Schemes 1 and 2
were tested for anticancer activity against the MCF-7 breast
cancer cell line relative to the normal MCF-10A stromal cell
line using a proliferation-based procedure (Figure 3).28 Results
are compared to activity of the estrogen receptor antagonist,
faslodex (ICI 182,780).29,30 Two compounds demonstrated
selective inhibition of cancer cell proliferation. Diaryl sulfide 25,
containing benzoxazole and 3,4,5-trimethoxyphenyl moieties,
was a potent inhibitor of MCF-7 cell proliferation (EC50 = 4.5
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were prepared from their respective halide precursors in THF. 3-
Cyanophenylmagnesium bromide was prepared by magnesium-
halogen exchange with isopropylmagnesium bromide in the presence
of LiCl.33 Molarities of organomagnesium and organozinc reagents
were determined by titration.33 N-Chlorosuccinimide (NCS) was
recrystallized from benzene and stored in an amber vial for up to two
weeks.
General Procedure A for Sulfenylation of Arylzinc Reagents.
To a solution of NCS (0.073 g, 0.55 mmol) in DCM (1.0 mL) was
added thiol (0.50 mmol), and the solution was stirred for 30 min in
the absence of direct light. The solution was taken up using a Teflon
needle and added dropwise to a solution of arylzinc reagent in THF
(1.25 mmol). Upon completion, as judged by TLC, the reaction
mixture was quenched with MeOH and concentrated in vacuo, and the
residue was adsorbed onto 3 mL of silica gel and purified by flash
column chromatography.
General Procedure B for Sulfenylation of Arylmagnesium
Reagents. To a solution of NCS (0.073 g, 0.55 mmol) in DCM (1.0
mL) was added thiol (0.50 mmol), and the solution was stirred for 30
min in the absence of direct light. The solution was taken up using a
Teflon needle and added dropwise to a solution of arylmagnesium
reagent in THF (1.25 mmol). Upon completion, as judged by TLC,
the reaction mixture was quenched with MeOH and concentrated in
vacuo, and the residue was adsorbed onto 3 mL of silica gel and
purified by flash column chromatography.
Figure 3. Evaluation of diaryl sulfides for anti-breast-cancer activity.
Anti-breast-cancer activity of compounds at 10 μM screened against
breast cancer (MCF-7) and normal breast cell lines (MCF-10A). Cell
proliferation is represented as relative cell numbers after treatment,
where a low percentage indicates potent anticancer activity for that
compound. All data are normalized to the DMSO vehicle control.
μM). In comparison, the simple phenyl analogues 16 and 15
were inactive. In contrast, trimethoxyphenyl-containing thio-
ether 27 performed poorly, while its phenyl analogue 19 was a
more potent cell proliferation inhibitor (EC50 = 7.9 μM).
Octyl(phenyl)sulfane (6). Title compound was prepared
according to general procedure A from octane thiol (0.087 mL, 0.50
mmol), NCS (0.073 g, 0.55 mmol) and PhZnBr (1.3 mmol, 1.7 mL).
Purification by flash column chromatography (3% EtOAc in hexanes)
afforded the title compound as a colorless oil (0.091 g, 82%). Spectral
data were consistent with reported values:34 TLC Rf = 0.7 (10%
CONCLUSION
■
We have developed a mild and efficient protocol for the
synthesis of alkyl and diaryl sulfides. This method tolerates a
wide array of heterocyclic moieties and is amenable to the
construction of highly functionalized diaryl and diheteroaryl
sulfides. Biological studies of select compounds have identified
two promising inhibitors of MCF-7 breast cancer cell
proliferation. Future efforts will focus on using this method-
ology to create a larger library of functionalized heterocyclic
sulfides and investigating their biological activity against a broad
range of cancer cell lines.
1
EtOAc in hexanes); H NMR (400 MHz, CDCl3) δ 7.33−7.25 (m,
4H), 7.15 (t, J = 7.0 Hz, 1H), 2.91 (t, J = 7.3 Hz, 2H), 1.68−1.61 (m,
2H), 1.42 (m, 2H), 1.27 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 137.2, 128.9 (2C), 125.7, 33.7, 31.9, 29.31, 29.27
(2C), 29.0, 22.8, 14.2.
Benzyl(phenyl)sulfane (7). Title compound was prepared
according to general procedure A from benzyl mercaptan (0.059
mL, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and PhZnBr (1.3 mmol,
1.7 mL). Purification by flash column chromatography (3% EtOAc in
hexanes) afforded the title compound as a colorless oil (0.087 g, 87%).
Spectral data were consistent with reported values:35 TLC Rf =
1
EXPERIMENTAL SECTION
0.5(10% EtOAc in hexanes); H NMR (400 MHz, CDCl3) δ 7.31−
■
7.18 (m, 9H), 7.16 (t, J = 7.2 Hz, 1H), 4.10 (s, 2H); 13C NMR (125
MHz, CDCl3) δ 137.6, 136.5, 129.9, 128.95, 128.94, 128.6, 127.3,
126.4, 39.1.
General Procedures. All reactions were carried out under an
atmosphere of N2 using glassware that was either oven- or flame-dried
prior to use. Dichloromethane (CH2Cl2) and tetrahydrofuran (THF)
were degassed with argon and then passed through two 4 × 36 in.
columns of anhydrous neutral A-2 alumina (8 × 14 mesh; activated
2-Napthyl(phenyl)sulfane (8). Title compound was prepared
according to general procedure A from thio-2-naphthol (0.080 g, 0.50
mmol), NCS (0.073 g, 0.55 mmol) and PhZnBr (1.3 mmol, 1.7 mL).
Purification by flash column chromatography (3% EtOAc in hexanes)
afforded the title compound as a colorless oil (0.110 g, 93%). Spectral
data were consistent with reported values:34 TLC Rf = 0.6 (10%
1
under a flow of argon at 350 °C for 12 h) to remove H2O. H NMR
spectra were recorded on 500 MHz (500 MHz 1H, 125.7 MHz 13C) or
400 MHz (400 MHz 1H, 100 MHz 13C) spectrometers. Proton
chemical shifts are reported in ppm (δ) relative to internal
tetramethylsilane (TMS, δ 0.00). Data are reported as follows:
chemical shift (multiplicity [singlet (s), broad singlet (br s), doublet
(d), doublet of doublets (dd), triplet (t), doublet of triplets (dt),
quartet (q), multiplet (m), apparent singlet (ap s), and apparent
doublet (ap d)], coupling constants [Hz], integration. Carbon
chemical shifts are reported in ppm (δ) relative to TMS with the
respective solvent resonance as the internal standard (CDCl3, δ 77.16
ppm). Unless otherwise indicated, NMR data were collected at 25 °C.
Infrared spectra (thin film or neat) are reported in terms of frequency
of absorption (cm−1). Melting points (mp) are uncorrected. Analytical
thin-layer chromatography (TLC) was performed using silica gel 60
F254 precoated plates (0.25 mm thickness). Visualization was
accomplished by irradiation with a UV lamp and/or staining with
KMnO4 solution. Flash chromatography was performed using silica gel
60 Å (170−400 mesh) from Fisher Scientific.
1
EtOAc in hexanes); H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H),
7.75−7.66 (m, 3H), 7.44−7.34 (m, 5H), 7.28−7.18 (m, 3H); 13C
NMR (125 MHz, CDCl3) δ 136.0, 133.9, 133.1, 132.4, 131.0, 130.0,
129.3, 129.0, 128.8, 127.8, 127.5, 127.1, 126.7, 126.3.
2,6-Dimethylphenyl(phenyl)sulfane (9). Title compound was
prepared according to general procedure A from 2,6-dimethylth-
iophenol (0.069 mL, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and
PhZnBr (1.3 mmol, 1.7 mL). Purification by flash column
chromatography (3% EtOAc in hexanes) afforded the title compound
as a colorless oil (0.100 g, 93%). Spectral data were consistent with
reported values:36 TLC Rf = 0.5 (10% EtOAc in hexanes); H NMR
1
(400 MHz, CDCl3) δ 7.22−7.14 (m, 5H), 7.04 (t, J = 7.2 Hz, 1H),
6.92 (d, J = 7.6 Hz, 2H), 2.42 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
144.0, 138.1, 130.6, 129.4, 129.0, 128.6, 125.8, 124.7, 22.0.
4-Chlorophenyl(phenyl)sulfane (10). Title compound was
prepared according to general procedure A from 4-chlorobenzenethiol
(0.072 g, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and PhZnBr (1.3
mmol, 1.7 mL). Purification by flash column chromatography (3%
Phenylmagnesium bromide31 and phenylzinc bromide32 were
prepared according to reported procedures. 4-(Trifluoromethyl)-
phenylmagnesium bromide and 4-methoxyphenylmagnesium bromide
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EtOAc in hexanes) afforded the title compound as a colorless oil
(0.094 g, 85%). Spectral data were consistent with reported values:34
TLC Rf = 0.7 (10% EtOAc in hexanes); 1H NMR (400 MHz, CDCl3)
δ 7.35−7.29 (m, 4H), 7.28−7.22 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 135.2, 134.8, 133.1, 132.1, 131.4, 129.5, 129.4, 127.6.
(Perfluorophenyl)(phenyl)sulfane (11). Title compound was
prepared according to general procedure A from pentafluorothiophe-
nol (0.067 mL, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and PhZnBr
(1.3 mmol, 1.7 mL). Purification by flash column chromatography (3%
EtOAc in hexanes) afforded the title compound as a colorless
crystalline solid (0.114 g, 84%). Spectral data were consistent with
reported values:37 TLC Rf = 0.6 (5% EtOAc in hexanes); mp 45−48
°C; 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 2H), 7.32−7.24 (m, 3H);
13C NMR (125 MHz, CDCl3) δ 148.7 (m), 146.7 (m), 143.2 (m),
141.2 (m), 139.0 (m), 136.9 (m), 133.1, 130.7, 129.6, 128.1, 109.1
(m); 19F NMR (376 MHz, CDCl3) δ −131.9 (dd, J = 24.7 Hz, 7.0 Hz,
2F), −151.6 (t, J = 20.9 Hz, 1F), −160.6 (td, J = 22.2 Hz, 6.7 Hz, 2F);
IR (neat) 1482, 1093, 971 cm−1; HRMS (TOF MS CI+) m/z calcd for
C12H5F5S (M)+ 276.0032, found 276.0025.
(4-Methoxyphenyl)(phenyl)sulfane (12). Title compound was
prepared according to general procedure A from 4-methoxybenzene-
thiol (0.062 mL, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and PhZnBr
(1.3 mmol, 1.7 mL). Purification by flash column chromatography
(10% EtOAc in hexanes) afforded the title compound as a colorless oil
(0.071 g, 66%). Spectral data were consistent with reported values:34
TLC Rf = 0.5 (10% EtOAc in hexanes); 1H NMR (400 MHz, CDCl3)
δ 7.40 (d, J = 8.5 Hz, 2H), 7.22−7.11 (m, 5H), 6.87 (d, J = 8.6 Hz,
2H), 3.77 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.8, 138.7,
135.4, 129.0, 128.2, 125.8, 124.3, 115.0, 55.3.
procedure B to afford 57% yield (determined by 1H NMR in
comparison to the internal standard phenyltrimethylsilane). Spectral
data were consistent with reported values:39 TLC Rf = 0.5 (30%
1
EtOAc in hexanes); H NMR (500 MHz, CDCl3) δ 7.70 (m, 2H),
7.59 (m, 1H), 7.47−7.42 (m, 3H), 7.39 (m, 1H), 7.27−7.21 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 163.4, 152.0, 142.1, 134.5, 130.0,
129.8, 127.3, 124.5, 124.4, 119.2, 110.2.
2-(Phenylthio)pyrimidine (17). Title compound was prepared
according to general procedure A from 2-mercaptopyrimidine (0.056
g, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and PhZnBr (1.3 mmol, 1.7
mL). Purification by flash column chromatography (20% EtOAc in
hexanes) afforded the title compound as a colorless oil (0.081 g, 86%).
Spectral data were consistent with reported values:40 TLC Rf = 0.3
(30% EtOAc in hexanes); 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J =
5.0 Hz, 2H), 7.63 (m, 2H), 7.44 (m, 3H), 6.95 (t, J = 5.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 172.9, 157.7, 135.4, 129.45, 129.43, 129.3,
117.1.
1-Phenyl-5-(phenylthio)-1H-tetrazole (18). Title compound
was prepared according to general procedure A from 1-phenyl-1H-
tetrazole-5-thiol (0.089 g, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and
PhZnBr (1.3 mmol, 1.7 mL). Purification by flash column
chromatography (30% EtOAc in hexanes) afforded the title compound
as a colorless crystalline solid (0.102 g, 80%): TLC Rf = 0.4 (30%
EtOAc in hexanes); mp 129−133 °C; 1H NMR (400 MHz, CDCl3) δ
7.57−7.53 (m, 7H), 7.42−7.36 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 153.7, 134.0, 133.7, 130.5, 130.1, 129.86, 129.85, 126.9,
124.5; IR (neat) 3067, 2922, 1498, 1412, 1389, 1240 cm−1; HRMS
(TOF MS ES+) m/z calcd for C13H10N4S (M + Na)+ 277.0524, found
277.0524.
(4-Nitrophenyl)(phenyl)sulfane (13). Title compound was
prepared according to general procedure A from 4-nitrobenzenethiol
(0.082 g, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and PhZnBr (1.3
mmol, 1.7 mL). Purification by flash column chromatography (10%
EtOAc in hexanes) afforded the title compound as a colorless oil
(0.042 g, 37%). Spectral data were consistent with reported values:34
TLC Rf = 0.4 (5% EtOAc in hexanes); 1H NMR (400 MHz, CDCl3) δ
8.06 (dt, J = 9.6 Hz, J = 2.2 Hz, 2H), 7.53 (m, 2H), 7.46 (m, 3H), 7.18
(dt, J = 9.6 Hz, J = 2.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
148.6, 145.4, 134.8, 130.5, 130.1, 129.7, 126.7, 124.1.
2-Phenyl-5-(phenylthio)-1,3,4-oxadiazole (19). Title com-
pound was prepared according to general procedure A from 5-
phenyl-1,3,4-oxadiazaole-2-thiol (0.089 g, 0.50 mmol), NCS (0.073 g,
0.55 mmol) and PhZnBr (1.3 mmol, 1.7 mL). Purification by flash
column chromatography (20−50% EtOAc in hexanes) afforded the
title compound as a white solid (0.089 g, 70%). Spectral data were
consistent with reported values:41 TLC Rf = 0.5 (20% EtOAc in
1
hexanes); H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 7.0 Hz, 2H),
7.67 (m, 2H), 7.51−7.39 (m, 6H); 13C NMR (125 MHz, CDCl3) δ
166.4, 162.9, 133.7, 131.9, 129.9, 129.8, 129.1, 127.1, 126.8, 123.5.
1-Methyl-2-(phenylthio)-1H-imidazole (20). Title compound
was prepared according to general procedure A from 2-mercapto-1-
methylimidazole (0.057 g, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and
PhZnBr (1.3 mmol, 1.7 mL). Purification by flash column
chromatography (10% EtOAc in hexanes) afforded the title compound
as a colorless oil (0.081 g, 95%). Compound 20 was also prepared
from PhMgBr according to general procedure B to afford 59% yield
(determined by 1H NMR in comparison to the internal standard
phenyltrimethylsilane). Spectral data were consistent with reported
values:39 TLC Rf = 0.2 (30% EtOAc in hexanes); 1H NMR (500 MHz,
CDCl3) δ 7.25 (m, 2H), 7.18−7.13 (m, 4H), 7.06 (d, J = 1.0 Hz, 1H),
3.62 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 138.1, 135.0, 130.2,
129.3, 128.0, 126.6, 123.9, 33.9.
4-Phenylsulfanylacetophenone (14). Title compound was
prepared according to general procedure A from 1-(4-sulfanylphenyl)-
ethan-1-one (60 μL, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and
PhZnBr (1.3 mmol, 2.6 mL). Purification by flash column
chromatography (5% EtOAc in hexanes) afforded the title compound
as a pale yellow solid (0.072 g, 63%). Spectral data were consistent
with reported values:38 TLC Rf = 0.3 (5% EtOAc in hexanes); H
1
NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.5 Hz, 2H), 7.50−7.47 (m,
2H), 7.40−7.38 (m, 3H), 7.20 (d, J = 8.5 Hz, 2H), 2.54 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 197.3, 145.0, 134.5, 134.0, 132.1, 129.8,
129.0, 128.9, 127.5, 26.5; IR (neat) 2922, 1677, 1589, 690 cm−1.
2-Phenylthiobenzothiazole (15). Title compound was prepared
according to general procedure A from 2-mercaptobenzothiazole
(0.084 g, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and PhZnBr (1.3
mmol, 1.7 mL). Purification by flash column chromatography (15%
EtOAc in hexanes) afforded the title compound as a colorless oil
(0.087 g, 71%). Compound 15 was also prepared from PhMgBr
according to general procedure B to afford 65% yield (determined by
1H NMR in comparison to the internal standard phenyltrimethylsi-
lane). Spectral data were consistent with reported values:39 TLC Rf =
0.5 (30% EtOAc in hexanes); 1H NMR (400 MHz, CDCl3) δ 7.87 (d,
J = 8.4 Hz, 1H), 7.72 (m, 2H), 6.63 (d, J = 8.0 Hz, 1H), 7.52−7.43 (m,
3H), 7.38 (m, 1H), 7.25 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
169.8, 154.0, 135.6, 135.4, 130.6, 130.01, 129.98, 126.2, 124.4, 122.0,
120.9.
2-(4-Methoxyphenylthio)pyrimidine (21). Title compound was
prepared according to general procedure B from 2-mercaptopyr-
imidine (0.056 g, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and (4-
OMe)PhMgBr (1.3 mmol, 1.8 mL). Purification by flash column
chromatography (20−30% EtOAc in hexanes) afforded the title
compound as a white solid (0.082 g, 75%). Spectral data were
consistent with reported values:40 TLC Rf = 0.4 (30% EtOAc in
1
hexanes); H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 4.4 Hz, 2H),
7.54 (d, J = 8.0 Hz, 2H), 6.95 (m, 3H), 3.83 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 173.5, 160.6, 157.6, 137.1, 120.0, 116.8, 114.9, 55.4.
2-(4-(Trifluoromethyl)phenylthio)pyrimidine (22). Title com-
pound was prepared according to general procedure B from 2-
mercaptopyrimidine (0.056 g, 0.50 mmol), NCS (0.073 g, 0.55 mmol)
and (4-CF3)PhMgBr (1.3 mmol, 2.1 mL). Purification by flash column
chromatography (10−30% EtOAc in hexanes) afforded the title
compound as a colorless oil (0.110 g, 86%): TLC Rf = 0.6 (30%
2-Phenylthiobenzoxazole (16). Title compound was prepared
according to general procedure A from 2-mercaptobenzoxazole (0.076
g, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and PhZnBr (1.3 mmol, 1.7
mL). Purification by flash column chromatography (15% EtOAc in
hexanes) afforded the title compound as a colorless oil (0.093 g, 82%).
Compound 16 was also prepared from PhMgBr according to general
1
EtOAc in hexanes); H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 4.8
Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.02 (t, J =
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4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 171.7, 157.8, 135.1,
134.6 (ap d, J = 1.4 Hz, 1C), 131.1 (q, J = 32.8 Hz, 1C), 126.1 (q, J =
3.7 Hz, 1C), 124.0 (q, J = 272.4 Hz, 1C), 117.6; 19F NMR (376 MHz,
CDCl3) δ −63.0; IR (thin film) 3039, 2927, 1566, 1389, 1329, 1170,
1122 cm−1; HRMS (TOF MS CI+) m/z calcd for C11H7F3N2S (M +
H)+ 257.0360, found 257.0353.
3-(Pyrimidin-2-ylthio)benzonitrile (23). Title compound was
prepared according to general procedure B from 2-mercaptopyr-
imidine (0.056 g, 0.50 mmol), NCS (0.073 g, 0.55 mmol) and (3-
CN)PhMgBr (1.3 mmol, 2.3 mL). Purification by flash column
chromatography (10−30% EtOAc in hexanes) afforded the title
compound as a white solid (0.074 g, 69%): TLC Rf = 0.4 (30% EtOAc
in hexanes); mp 71−73 °C; 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J
= 4.4 Hz, 2H), 7.95 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.6
Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 4.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 171.1, 157.7, 139.2, 138.3, 132.5, 131.7, 129.8,
118.1, 117.7, 113.4; IR (thin film) 3066, 2927, 2231, 1560, 1379, 1182
cm−1; HRMS (TOF MS CI+) m/z calcd for C11H7N3S (M + H)+
214.0439, found 214.0433.
(TOF MS ES+) m/z calcd for C17H16N2O4S (M +Na)+ 367.0728,
found 367.0722.
General Procedures for Biological Experiments. Biological
experiments were performed according to a modified procedure by
Sigman et al.28
Materials. The following reagents were obtained from commercial
sources as indicated: Dulbecco’s Modified Eagle’s Medium (DMEM)/
high glucose containing 4.5 g/L glucose and 4.0 mM L-glutamine
(HyClone); fetal bovine serum (FBS), heat-inactivated (Omega
Scientific); L-glutamine, 200 mM (Gibco); penicillin/streptomycin
solution 50× (Mediatech); DMEM/Ham’s Nutrient Mixture F12
containing 2.5 mM L-glutamine, 3151 mg/L dextrose, and 55 mg/L
sodium pyruvate (Sigma-Aldrich); horse serum (Sigma-Aldrich); 50
μM hydrocortisone solution (Sigma-Aldrich); human insulin solution
(Sigma-Aldrich); cholera toxin (Sigma-Aldrich); human Epidermal
Growth Factor (EGF), recombinant (Sigma-Aldrich); 0.25% Trypsin-
EDTA (Gibco); nuclease-free sterile water (Fisher Scientific);
molecular biology grade DMSO (Sigma-Aldrich); ICI 182,780
(faslodex) (Tocris Bioscience).
Cell Lines and Culture Conditions. MCF-7 cells were
maintained in DMEM/high glucose supplemented with 10% FBS, L-
glutamine, and penicillin/streptomycin. Experiments with MCF-7 cells
were performed in DMEM/high glucose supplemented with 2% FBS,
L-glutamine, and penicillin/streptomycin. MCF-10A cells were
maintained in standard medium according to a modified recipe by
Brugge et al.:42 DMEM/F12 supplemented with 5% horse serum, 10
μg/mL of human insulin, 0.5 μg/mL of hydrocortisone, 10 ng/mL of
EGF, 100 ng/mL of cholera toxin, and penicillin/streptomycin.
Experiments with MCF-10A cells were performed in the same
medium.
Evaluation of Compounds against MCF-7 Cells. MCF-7 cells
were centrifuged in 1× PBS for 20 min, and then the pellet was
resuspended in DMEM supplemented with 10% FBS and filtered
through a 40 μm nylon cell strainer (Fisher Scientific) to prevent
clumping. The cells were seeded at 1500 cells per well in 96-well flat
bottom plates suitable for fluorimetry, using 175 μL per well of
DMEM supplemented with 10% FBS, and grown for 24 h in 5% CO2
at 37 °C. The compounds (including the faslodex positive control)
were dissolved in molecular biology grade DMSO to achieve a 3.5 mM
stock solution and then sterile filtered through a 0.45 μm PVDF
syringe filter unit (Fisher Scientific). The 3.5 mM stock solutions were
subsequently diluted to a final concentration of 10 μM in DMEM
supplemented with 2% FBS. Additionally, the corresponding DMSO
vehicle control was diluted using the same medium.
After 24 h of growth, the cells were treated by replacing the normal
media with fresh media containing the individual compounds or
vehicle control (day 0). The outer rows of wells were not used to
eliminate the possibility of effects due to evaporation of media. The
cells were incubated with compound for 48 h and then treated again
by aspirating the media and adding fresh media containing the
compounds and controls (day 2). This procedure was repeated after
an additional 48 h (day 4). After incubating a final 24 h, the 96-well
plates were rinsed with 1× PBS, blotted dry, and then frozen at −78
°C overnight (day 5). On day 6, cell proliferation was measured using
the fluorescence-based CyQUANT Cell Proliferation Assay Kit
(Invitrogen).
Fluorimetry analysis was performed according to a modified
procedure by McGowan et al.43 Cells were stained with 200 μL/
well of 1× CyQUANT GR dye in cell lysis buffer for 10 min in the
dark at room temperature and quantified by fluorimetry at 535 nm
with 485 nm excitation. The fluorescence values were normalized to
the DMSO vehicle control. The normalized values were plotted as an
average standard deviation of 6 wells per compound.
2-(3,4,5-Trimethoxyphenylthio)pyrimidine (24). Title com-
pound was prepared according to general procedure A from 2-
mercaptopyrimidine (0.056 g, 0.50 mmol), NCS (0.073 g, 0.55 mmol)
and 3,4,5-trimethoxyphenylzinc bromide (1.3 mmol, 2.8 mL).
Purification by flash column chromatography (20−50% EtOAc in
hexanes, 1% Et3N) afforded the title compound as a white solid (0.059
g, 43%): TLC Rf = 0.1 (30% EtOAc in hexanes); mp 103−104 °C; 1H
NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.8 Hz, 2H), 6.99 (t, J = 4.8
Hz, 1H), 6.88 (s, 2H), 3.90 (s, 3H), 3.87 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 173.1, 157.8, 153.6, 139.2, 123.8, 117.1, 112.4, 61.0,
56.3; IR (neat) 2945, 2851, 1547, 1375, 1117 cm−1; HRMS (TOF MS
ES+) m/z calcd for C13H14N2O3S (M+Na)+ 301.0623, found
301.0616.
2-(3,4,5-Trimethoxyphenylthio)benzoxazole (25). Title com-
pound was prepared according to general procedure A from 2-
mercaptobenzoxazole (0.076 g, 0.50 mmol), NCS (0.073 g, 0.55
mmol) and 3,4,5-trimethoxyphenylzinc bromide (1.3 mmol, 2.8 mL).
Purification by flash column chromatography (5−15% EtOAc in
hexanes, 1% Et3N) afforded the title compound as a white solid (0.117
g, 74%): TLC Rf = 0.4 (30% EtOAc in hexanes); mp 129−130 °C; 1H
NMR (400 MHz, CDCl3) δ 7.62 (dd, J = 7.6 Hz, J = 5.6 Hz, 1H), 7.44
(dd, J = 8.8 Hz, J = 6.0 Hz, 1H), 7.27 (m, 2H), 6.94 (s, 2H), 3.90 (s,
3H), 3.88 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 163.6, 153.8,
152.0, 142.1, 139.8, 124.54, 124.45, 121.2, 119.2, 112.0, 110.2, 61.0,
56.4; IR (neat) 2931, 2837, 1489, 1451, 1406, 1232, 1129, 1121 cm−1;
HRMS (TOF MS ES+) m/z calcd for C16H15NO4S (M + Na)+
340.0620, found 340.0620.
1-Phenyl-5-(3,4,5-trimethoxyphenylthio)-1H-tetrazole (26).
Title compound was prepared according to general procedure A
from 1-phenyl-1H-tetrazole-5-thiol (0.089 g, 0.50 mmol), NCS (0.073
g, 0.55 mmol) and 3,4,5-trimethoxyphenylzinc bromide (1.3 mmol, 2.8
mL). Purification by flash column chromatography (30−50% EtOAc
in hexanes, 1% Et3N) afforded the title compound as a white solid
(0.105 g, 61%): TLC Rf = 0.3 (30% EtOAc in hexanes); mp 110−111
1
°C; H NMR (400 MHz, CDCl3) δ 7.57 (m, 5H), 6.78 (s, 2H), 3.86
(s, 3H), 3.82 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 153.9, 153.8,
139.9, 133.8, 130.5, 129.9, 124.7, 120.7, 111.7, 61.0, 56.4; IR (neat)
3042, 2951, 2860, 1585, 1408, 1231, 1125 cm−1; HRMS (TOF MS ES
+) m/z calcd for C16H16N4O3S (M + Na)+ 367.0841, found 367.0836.
2-Phenyl-5-(3,4,5-trimethoxyphenylthio)-1,3,4-oxadiazole
(27). Title compound was prepared according to general procedure A
from 5-phenyl-1,3,4-oxadiazaole-2-thiol (0.089 g, 0.50 mmol), NCS
(0.073 g, 0.55 mmol) and 3,4,5-trimethoxyphenylzinc bromide (1.3
mmol, 2.8 mL). Purification by flash column chromatography (5−25%
EtOAc in hexanes, 1% Et3N) afforded the title compound as a white
solid (0.100 g, 58%): TLC Rf = 0.3 (30% EtOAc in hexanes); mp 142
°C; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 6.8 Hz, 2H), 7.51 (m,
3H), 6.93 (s, 2H), 3.88 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
166.5, 163.3, 153.9, 139.8, 132.0, 129.2, 126.9, 123.6, 121.0, 111.5,
61.1, 56.5; IR (neat) 3009, 2943, 2850, 1582, 1463, 1128 cm−1; HRMS
Evaluation of Compounds against MCF-10A Cells. MCF-10A
cells were centrifuged in 1× PBS for 20 min, and then the pellet was
resuspended in DMEM/F12 and filtered through a 40 μm nylon cell
strainer (Fisher Scientific) to prevent clumping. The cells were seeded
at 9000 cells per well in 96-well flat bottom plates suitable for
fluorimetry, using 175 μL per well of DMEM/F12, and grown for 24 h
in 5% CO2 at 37 °C. The 3.5 mM stock solutions of compound in
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DMSO were subsequently diluted to a final concentration of 10 μM in
DMEM/F12. Additionally, the corresponding DMSO vehicle control
was diluted using the same medium.
(3) Liu, G.; Link, J. T.; Pei, Z.; Reilly, E. B.; Leitza, S.; Nguyen, B.;
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A.; Noble, A. J.; O’Beirne, D.; Patel, Z. M.; Perkins, J.; Rowan, P.;
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Patent WO/1998/27092 A1, June 25, 1998.
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D. J. Med. Chem. 2000, 43, 2217.
(7) For a review, see: Eichman, C. C.; Stambuli, J. P. Molecules 2011,
Addition of compounds was performed as specified above for days
0−6. Fluorimetry analysis was performed as specified above for MCF-7
cells, with the exception of staining MCF-10A cells with 200 μL/well
of 5× CyQUANT GR dye in cell lysis buffer for 10 min in the dark at
room temperature before quantification by fluorimetry. The
fluorescence values were normalized to the DMSO vehicle control.
The normalized values were plotted as an average standard deviation
of 6 wells per compound.
Dose−Response of Compounds 19 and 25. MCF-7 cells were
centrifuged in 1× PBS for 20 min, and then the pellet was resuspended
in DMEM supplemented with 10% FBS and filtered through a 40 μm
nylon cell strainer (Fisher Scientific) to prevent clumping. The cells
were seeded at 1500 cells per well in 96-well flat bottom plates suitable
for fluorimetry, using 175 μL per well of DMEM supplemented with
10% FBS, and grown for 24 h in 5% CO2 at 37 °C. The compounds 19
and 25 were dissolved in molecular biology grade DMSO to achieve a
42 mM stock and then sterile filtered through a 0.45 μm PVDF syringe
filter unit (Fisher Scientific). The 42 mM stock solutions in DMSO
were subsequently diluted to 120 μM in DMEM supplemented with
2% FBS and then serially diluted to achieve 10 different
concentrations. Additionally, the corresponding DMSO vehicle
controls for each concentration were serially diluted using the same
medium.
16, 590.
(8) For representative example of copper-catalyzed, see: Kwong, F.
Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517.
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Fernan
1663.
́
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Prep. Proced. Int. 2007, 39, 447.
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N.; Onami, T. J. Org. Chem. 2004, 69, 915.
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Taniguchi, N. Synlett 2006, 1351.
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Luo, P.-S.; Yu, M.; Tang, R.-Y.; Zhong, P.; Li, J.-H. Tetrahedron Lett.
2009, 50, 1066.
Addition of compounds was performed as specified above for days
0−6. Fluorimetry analysis was performed as specified above for the
evaluation of compounds against MCF-7 cells. The fluorescence values
were normalized to the DMSO vehicle controls corresponding to each
concentration. The normalized values were plotted as an average
standard deviation of 4 wells per concentration, and these data were
analyzed using the dose−response nonlinear regression fitting function
(log[inhibitor] vs response with variable slope (four parameters)).
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(16) While this work was in progress, Lee and co-workers disclosed a
method for the synthesis of diaryl sulfides utilizing in situ-formed
sulfenyl chlorides and organomagnesium reagents: Cheng, J.-H.;
Ramesh, C.; Kao, H.-L.; Wamg, Y.-J.; Chan, C.-C.; Lee, C.-F. J. Org.
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ASSOCIATED CONTENT
■
S
* Supporting Information
(17) Barker, T. J.; Jarvo, E. R. J. Am. Chem. Soc. 2009, 131, 15598.
(18) Barker, T. J.; Jarvo, E. R. Angew. Chem., Int. Ed. 2011, 50, 8325.
(19) For demonstration of functional group tolerance of organozinc
reagents, see: Bernhardt, S.; Manolikakes, G.; Kunz, T.; Knochel, P.
Angew. Chem., Int. Ed. 2011, 50, 9205.
(20) Lin, C. M.; Ho, H. H.; Pettit, G. R.; Hamel, E. Biochemistry
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Dose−response curves and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
(21) Tron, G. C.; Pirali, T.; Sorba, G.; Pagliai, F.; Busacca, S.;
Genazzani, A. A. J. Med. Chem. 2006, 49, 3033.
*E-mail: erjarvo@uci.edu.
Notes
(22) Barbosa, E. G.; Bega, L. A. S.; Beatriz, A.; Sarkar, T.; Hamel, E.;
do Amaral, M. S.; de Lima, D. P. Eur. J. Med. Chem. 2009, 44, 2685.
(23) La Regina, G.; Bai, R.; Rensen, W. M.; Di Cesare, E.; Coluccia,
A.; Piscitelli, F.; Famiglini, V.; Reggio, A.; Nalli, M.; Pelliccia, S.; Da
Pozzo, E.; Costa, B.; Granata, I.; Porta, A.; Maresca, B.; Soriani, A.;
Iannitto, M. L.; Santoni, A.; Li, J.; Cona, M. M.; Chen, F.; Ni, Y.;
Brancale, A.; Dondio, G.; Vultaggio, S.; Varasi, M.; Mercurio, C.;
Martini, C.; Hamel, E.; Lavia, P.; Novellino, E.; Silvestri, R. J. Med.
Chem. 2013, 56, 123.
(24) Lu, Y.; Li, C.-M.; Wang, Z.; Chen, J.; Mohler, M. L.; Li, W.;
Dalton, J. T.; Miller, D. D. J. Med. Chem. 2011, 54, 4678.
(25) Lee, H.-Y.; Chang, J.-Y.; Nien, C.-Y.; Kuo, C.-C.; Shih, K.-H.;
Wu, C.-H.; Chang, C.-Y.; Lai, W.-Y.; Liou, J.-P. J. Med. Chem. 2011, 54,
8517.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the University of California
Cancer Research Coordinating Committee, NCI Award
P30CA062203, and NCI Award F31CA177212 (C.A.O.). We
thank R. J. Ochoa for advice and assistance with biochemical
assays, Prof. J. A. Prescher, Prof. X. Zi, and C. A. Blair for
helpful discussions, and Prof. M. J. Buchmeier for use of the
fluorimeter. Dr. J. Greaves is acknowledged for mass
spectrometry data.
(26) Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T. Med.
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