Design, synthesis and antiproliferative activities of diaryl thiourea derivatives as anticancer agents

Article abstract of DOI:10.1002/cjoc.201200708

Two new series of diaryl thiourea containing sorafenib derivatives 9a-9t were designed and synthesized, and their antiproliferative activities against PC-3, HCT116 and MDA-MB-231 cell lines were evaluated. All compounds generally showed antiproliferative activity to PC-3 cells, most of the analogs exhibited potent antiproliferative activity to HCT116 cells, and compounds 9e, 9f, 9o and 9p demonstrated inhibitory activities against all three cell lines. The structures of all the newly synthesized compounds were determined by ¹H NMR, ¹³C NMR and HRMS. Two series of diaryl thiourea derivatives have been designed, prepared, and tested for cytotoxicity against human tumor cells PC-3, HCT116 and MDA-MB-231. The results showed that all compounds generally had antiproliferative activity against PC-3 cells, and some compounds demonstrated competitive antiproliferative activities to sorafenib. Copyright

Full text of DOI:10.1002/cjoc.201200708

FULL PAPER
DOI: 10.1002/cjoc.201200708
Design, Synthesis and Antiproliferative Activities of Diaryl
Thiourea Derivatives as Anticancer Agents
Yao, Jianwena,b(姚建文)
Chen, Daquana(陈大全)
He, Zuopenga(何作鹏)
Chen, Jinga(陈静)
Sun, Weib(孙伟) Xu, Wenfang*,b(徐文方)
a Department of Medicinal Chemistry, School of Pharmacy, Yantai University, Yantai, Shandong 264005, China
b Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan,
Shandong 250012, China
Two new series of diaryl thiourea containing sorafenib derivatives 9a—9t were designed and synthesized, and
their antiproliferative activities against PC-3, HCT116 and MDA-MB-231 cell lines were evaluated. All compounds
generally showed antiproliferative activity to PC-3 cells, most of the analogs exhibited potent antiproliferative ac-
tivity to HCT116 cells, and compounds 9e, 9f, 9o and 9p demonstrated inhibitory activities against all three cell
lines. The structures of all the newly synthesized compounds were determined by 1H NMR, 13C NMR and HRMS.
Keywords sorafenib analogs, diaryl thiourea, structure-activity relationships, antiproliferative activity
Introduction
H
H
F3C
Cl
N
N
N
Since cancer is a multi-genetic disease, multi-target
therapeutics against selective multiple targets can be
more efficacious and less vulnerable to adaptive resis-
tance.[1-3] Sorafenib, an oral multi-kinase inhibitor, can
control formation and progression of tumors by inhibit-
ing the Ras/Raf/MEK pathway, and act directly on tu-
mor angiogenesis through the inhibition of VEGFR-2,
PDGFR-β, Flt-3 and c-KIT.[4-8] Due to the advantages of
broad-spectrum anticancer potency, safety and less
prone to resistance, there is an increasing interest in the
optimization of sorafenib.[9-15]
As a type 2 kinase inhibitor, sorafenib can be con-
nected with DFG-out motif of the kinases by two hy-
drogen bonds of urea group.[16,17] Aimed at urea group,
we designed a series of thiourea derivatives based on
the bioisosteric theory (Figure 1).[18] Among these de-
rivatives, only those with R1 being methyl group
showed the inhibitory activity against MDA-MB-231
cell. While in recent study, we found that the pyrrolidine
containing derivatives could also inhibit the growth of
MDA-MB-231 cell. In the present paper, two series of
pyrrolidine containing sorafenib derivatives (Figure 1)
were designed and synthesized. The antitumor effect of
all the newly synthesized compounds on the in vitro
growth of three cell lines, namely human prostate cell
(PC-3), human colorectal carcinoma (HCT116) and
human breast cancer cell (MDA-MB-231) was evalu-
ated, and some structure-activity relationships have also
been established.
O
NH
O
CH
O
Sorafenib
R2
H
H
N
N
N
S
NH R1
O
O
Previously reported diarylthiourea derivatives
R2
H
H
N
N
N
S
N
X
O
Series A: X = O
Series B: X = S
Figure 1 Structures of sorafenib and thiourea derivatives.
Experimental
All materials were purchased from commercial sup-
pliers and used without further purification. Solvents
were distilled prior to use and flash chromatography
was performed using silica gel (60 Å, 200—300 mesh).
Compounds 3, 4 and 8 were synthesized according to
the literature method.[18] All reactions were monitored
by thin-layer chromatography on 0.25 mm silica gel
plates (60GF-254) and visualized with UV light, or
*
E-mail: wfxu@yahoo.cn; Tel.: 0086-531-88382264; Fax: 0086-531-88382264
Received July 11, 2012; accepted August 24, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200708 or from the author.
Chin. J. Chem. 2012, 30, 2423—2430 © 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Yao et al.
FULL PAPER
chloride ferric. Melting points were determined on an
electrothermal melting point apparatus and were uncor-
(t, J＝6.7 Hz, 4H, CH2CH2), 3.46 (t, J＝6.8 Hz, 2H,
NCH2), 3.59 (t, J＝6.7 Hz, 2H, NCH2), 7.09 (dd, J＝5.4,
2.4 Hz, 1H, pyridine-H), 7.12 (d, J＝2.4 Hz, 1H, pyri-
dine-H), 7.22 (d, J＝8.4 Hz, 2H, PhH), 7.45 (dd, J＝8.4,
2.4 Hz, 1H, PhH), 7.58 (d, J＝8.4 Hz, 1H, PhH), 7.62 (d,
J＝8.4 Hz, 2H, PhH), 7.70 (d, J＝2.4 Hz, 1H, PhH),
8.49 (d, J＝5.4 Hz, 1H, pyridine-H), 9.57 (s, 1H, NH),
10.12 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ:
23.9, 26.5, 46.9, 48.9, 111.0, 113.5, 121.5, 126.4, 127.9,
129.4, 131.5 (d), 131.9, 136.2, 137.1, 150.4, 150.6,
1
rected. H NMR, 13C NMR spectra were determined on
a Brucker Avance 600/300 spectrometer using TMS as
an internal standard in DMSO-d6 or CDCl3 solutions.
Chemical shifts (δ) are reported, downfield from
trimethylsilane. ESI-MS were determined on an API
4000 spectrometer. High-resolution mass spectral
(HRMS) data were conducted by Shandong Analysis
and Test Center, and are reported as m/z (relative inten-
sity).
156.9, 165.4, 165.5, 181.0; HRMS (AP-ESI) m/z: calcd
＋
for C23H21Cl2N4O2S [M ＋ H]
487.0764.
487.0757, found
General procedure for the synthesis of 5a and 5b
To a solution of 4-aminophenol or 4-aminobenzene-
thiol (36.7 mmol) in dry N,N-dimethylformamide (DMF,
60 mL), potassium tert-butoxide (38.0 mmol), 4a (37.0
mmol) and K2CO3 (23.5 mmol) were added respectively,
and the mixture was stirred at room temperature for 1 h
under nitrogen atmosphere, then the resulting mixture
was heated to 80—85 ℃for 10 h. After the temperature
was cooled to room temperature, the mixture was di-
luted with water (300 mL), and extracted with EtOAc
(100 mL×3). The combined ethyl acetate extracts were
washed with brine (100 mL×2), dried over anhydrous
sodium sulfate, and concentrated under reduced pres-
sure to give 5a and 5b.
1-(3,4-Difluorophenyl)-3-(4-(2-(pyrrolidine-1-car-
bonyl)pyridin-4-yloxy)phenyl)thiourea (9b)
1
Grey solid, yield 68.8%, m.p. 169—170 ℃; H
NMR (600 MHz, DMSO-d6) δ: 1.82—1.84 (m, 4H,
CH2CH2), 3.44—3.46 (m, 2H, N-CH2), 3.58—3.61 (m,
2H, N-CH2), 7.08 (dd, J＝6.0, 3.0 Hz, 1H, pyridine-H),
7.12 (d, J＝2.4 Hz, 1H, pyridine-H), 7.20—7.25 (m, 3H,
Ph-H), 7.38—7.43 (m, 1H, Ph-H), 7.58 (d, J＝9.0 Hz,
2H, Ph-H), 7.67—7.71 (m, 1H, Ph-H), 8.48 (d, J＝5.4
Hz, 1H, pyridine-H), 9.96 (s, 1H, NH), 9.98 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d6) δ: 24.4, 27.0, 47.4, 49.4,
111.5, 114.0, 114.1, 114.3, 117.8, 118.0, 121.5 (q, J＝12
Hz), 122.0, 126.9, 137.4 (dd, J＝33, 12 Hz), 137.7,
150.9, 151.1, 157.4, 165.9, 166.0, 181.0; HRMS
(AP-ESI) m/z: calcd for C23H21F2N4O2S [M ＋H] ＋
455.1348, found 455.1341.
(4-(4-Aminophenoxy)pyridin-2-yl)(pyrrolidin-1-yl)-
methanone (5a)
Light-brown solid, yield 79.1%, m.p. 110—113 ℃;
1H NMR (400 MHz, DMSO-d6) δ: 1.89 (t, J＝6.6 Hz,
4H), 3.63 (t, J＝6.9 Hz, 2H), 3.67 (t, J＝6.4 Hz, 2H),
3.80 (br s, 2H), 6.68, 6.87 (AA'BB', q, J＝8.7 Hz, 4H),
6.84 (dd, J＝5.5, 2.4 Hz, 1H), 7.26 (d, J＝2.4 Hz, 1H),
8.38 (d, J＝5.6 Hz, 1H); ESI-MS m/z 284.1 [M＋H]＋.
1-(4-Fluorophenyl)-3-(4-(2-(pyrrolidine-1-carbonyl)-
pyridin-4-yloxy)phenyl)thiourea (9c)
Light-brown solid, yield 75.8%, m.p. 156—159℃;
1H NMR (600 MHz, DMSO-d6) δ: 1.82—1.84 (m, 4H,
CH2CH2), 3.45 (t, J＝6.4 Hz, 2H, N-CH2), 3.60 (t, J＝
6.4 Hz, 2H, N-CH2), 7.07 (dd, J＝5.4, 2.4 Hz, 1H, pyri-
dine-H), 7.12 (d, J＝2.4 Hz, 1H, pyridine-H), 7.17—
7.21 (m, 4H, ), 7.46—7.48 (m, 2H), 7.56 (d, J＝8.4 Hz,
2H), 8.49 (d, J＝5.4 Hz, 1H, pyridine-H), 9.83 (s, 1H,
NH), 9.87 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
δ: 23.4, 26.0, 46.4, 48.4, 110.5, 113.0, 114.9, 115.2,
121.0, 125.8, 126.2, 126.3, 135.6 (d), 137.0, 149.7,
150.1, 156.4, 164.9, 165.0, 180.1; HRMS (AP-ESI) m/z:
calcd for C23H22FN4O2S [M＋H]＋ 437.1442, found
437.1445.
(4-(4-Aminophenylthio)pyridin-2-yl)(pyrrolidin-1-
yl)methanone (5b)
1
Yellow solid, yield 87.6%, m.p. 171—173 ℃; H
NMR (400 MHz, DMSO-d6) δ: 1.79—1.83 (m, 4H),
3.43 (t, J＝6.9 Hz, 2H), 3.53 (t, J＝6.6 Hz, 2H), 5.71
(br s, 2H), 6.68 (d, J＝8.5 Hz, 2H), 7.06 (dd, J＝5.2, 2.0
Hz, 1H), 7.13 (d, J＝1.6 Hz, 1H), 7.22 (d, J＝8.5 Hz,
2H), 8.31 (d, J＝5.4 Hz, 1H); ESI-MS m/z 300.1 [M＋
H]＋.
General procedure for the synthesis of 9a—9t
1-(4-(2-(Pyrrolidine-1-carbonyl)pyridin-4-yloxy)-
phenyl)-3-(3-(trifluoromethyl)phenyl)thiourea (9d)
To a 10 mL DCM solution of 5 (5.3 mmol), a 8 mL
DCM solution of 8 (5.4 mmol) was slowly added at
0—5 ℃. The mixture was stirred for 2 h in ice bath,
then stirred for another 18 h at room temperature. Pe-
troleum ether (60 mL) was poured into the mixture, af-
ter filtration, the solids were washed, and dried under
vacuum for 5 h at 50—60 ℃, to afford pure 9a—9t.
Light-brown solid, yield 81.4%, m.p. 134—136 ℃;
1H NMR (600 MHz, DMSO-d6) δ: 1.82—1.84 (m, 4H,
CH2CH2), 3.45—3.46 (m, 2H, N-CH2), 3.59—3.61 (m,
2H, N-CH2), 7.08 (dd, J＝5.4, 2.4 Hz, 1H, pyridine-H),
7.12 (s, 1H, pyridine-H), 7.22 (d, J＝7.2 Hz, 2H, Ph-H),
7.47 (d, J＝7.8 Hz, 1H, Ph-H), 7.56—7.58 (m, 3H,
Ph-H), 7.76 (d, J＝8.0 Hz, 1H, Ph-H), 7.95 (s, 1H,
Ph-H), 8.49 (d, J＝5.4 Hz, 1H, pyridine-H), 10.09 (s,
1H, NH), 10.12 (s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6) δ: 23.9, 26.5, 46.9, 48.9, 111.0, 113.5, 120.3
1-(2,4-Dichlorophenyl)-3-(4-(2-(pyrrolidine-1-car-
bonyl)pyridin-4-yloxy)phenyl)thiourea (9a)
Light yellow solid in the yield of 68.4%, m.p.
1
174—176 ℃; H NMR (400 MHz, DMSO-d6) δ: 1.82
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Design, Synthesis and Antiproliferative Activities of Diaryl Thiourea Derivatives as Anticancer Agents
(d), 121.1 (d), 121.6, 126.3, 127.9, 129.3, 129.7, 130.0,
137.2, 140.9, 150.4, 150.6, 156.9,165.4, 165.5, 180.4;
HRMS (AP-ESI) m/z: calcd for C24H22F3N4O2S [M＋
H]＋ 487.1410, found 487.1409.
CH2CH2), 3.45 (t, J＝6.6 Hz, 2H, N-CH2), 3.58 (t, J＝
6.6 Hz, 2H, N-CH2), 7.08 (dd, J＝5.4, 2.4 Hz, 1H, pyri-
dine-H), 7.12 (d, J＝2.4 Hz, 1H, pyridine-H), 7.21 (d,
J＝8.4 Hz, 2H, Ph-H), 7.34 (d, J＝8.4 Hz, 2H, Ph-H),
7.58—7.61 (m, 4H, Ph-H), 8.50 (d, J＝5.4 Hz, 1H, pyri-
dine-H), 9.98 (s, 1H, NH), 10.00 (s, 1H, NH); 13C NMR
(75 MHz, DMSO-d6) δ: 24.4, 27.0, 47.4, 49.4, 111.5,
114.0, 122.0, 122.1, 126.2, 126.7, 137.8, 139.6, 145.6
(d), 150.7, 151.1, 157.4, 165.9, 166.0, 180.9; HRMS
(AP-ESI) m/z: calcd for C24H22F3N4O3S [M＋
H]＋ 503.1360, found 437.1445.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-(4-(2-(pyrroli-
dine-1-carbonyl)pyridin-4-yloxy)phenyl)thiourea (9e)
Off-white solid, yield 67.1%, m.p. 167—168 ℃; 1H
NMR (400 MHz, DMSO-d6) δ: 1.83 (t, J＝6.6 Hz, 4H,
CH2CH2), 3.46 (t, J＝6.6 Hz, 2H, N-CH2), 3.61 (t, J＝
6.6 Hz, 2H, N-CH2), 7.10 (dd, J＝5.4, 2.4 Hz, 1H, pyri-
dine-H), 7.13 (d, J＝2.4 Hz, 1H, pyridine-H), 7.25 (d,
J＝8.4 Hz, 2H, Ph-H), 7.56 (d, J＝8.4 Hz, 2H, Ph-H),
7.83 (s, 1H, Ph-H), 8.26 (s, 2H, Ph-H), 8.50 (d, J＝5.4
Hz, 1H, pyridine-H), 10.31 (s, 1H, NH), 10.39 (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6) δ: 23.4, 26.0, 46.4,
48.4, 110.6, 113.1, 121.2, 123.6 (d), 126.1, 129.8, 130.2,
136.2, 141.8, 150.1, 150.3, 156.4, 164.9, 180.0; HRMS
(AP-ESI) m/z: calcd for C25H21F6N4O2S [M ＋H] ＋
555.1284, found 555.1278.
1-(4-(2-(Pyrrolidine-1-carbonyl)pyridin-4-yloxy)-
phenyl)-3-m-tolylthiourea (9i)
Grey solid, yield 62.7%, m.p. 169—171 ℃; 1H
NMR (600 MHz, DMSO-d6) δ: 1.82—1.84 (m, 4H,
CH2CH2), 2.30 (s, 3H, Ph-CH3), 3.46 (t, J＝6.6 Hz, 2H,
N-CH2), 3.59 (t, J＝6.6 Hz, 2H, N-CH2), 6.96 (d, J＝
7.8 Hz, 1H, Ph-H), 7.06—7.07 (m, 1H, pyridine-H),
7.11 (d, J＝3 Hz, 1H, pyridine-H), 7.18—7.21 (m, 2H,
Ph-H), 7.23 (d, J＝7.2, 1H, Ph-H), 7.26 (d, J＝8.4 Hz,
2H, Ph-H), 7.56—7.58 (m, 2H, Ph-H), 8.49 (d, J＝5.4
Hz, 1H, pyridine-H), 9.82 (s, 1H, NH), 9.84 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d6) δ: 21.98, 24.4, 27.0,
47.4, 49.4, 111.4, 113.9, 121.9, 125.20, 126.2, 126.7,
129.3, 138.1, 138.7, 140.2, 150.6, 151.1, 157.4, 165.9,
166.0, 180.6; HRMS (AP-ESI) m/z: calcd for
C24H25N4O2S [M＋H]＋ 433.1692, found 433.1688.
1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-
(pyrrolidine-1-carbonyl)pyridin-4-yloxy)phenyl)thio-
urea (9f)
1
Grey solid, yield 78.0%, m.p. 181—182 ℃; H
NMR (600 MHz, DMSO-d6) δ: 1.82—1.84 (m, 4H,
CH2CH2), 3.46 (t, J＝6.6 Hz, 2H, N-CH2), 3.60 (t, J＝
6.6 Hz, 2H, N-CH2), 7.08 (dd, J＝5.4, 2.4 Hz, 1H, pyri-
dine-H), 7.13 (d, J＝2.4 Hz, 1H, pyridine-H), 7.24 (d,
J＝8.4 Hz, 2H, Ph-H), 7.56 (d, J＝8.4 Hz, 2H, Ph-H),
7.69 (d, J＝8.4 Hz, 1H, Ph-H), 7.82 (dd, J＝8.4, 2.4 Hz,
1H, Ph-H), 8.09 (d, J＝2.4 Hz, 1H, Ph-H), 8.50 (d, J＝
5.4 Hz, 1H, pyridine-H), 10.16 (s, 1H, NH), 10.20 (s,
1H, NH); 13C NMR (75 MHz, DMSO-d6) δ: 23.4, 26.0,
46.4, 48.4, 110.6, 113.0, 121.1, 122.4 (q), 125.1, 125.9,
126.0, 126.8, 128.5, 131.5, 136.5, 139.2, 150.0,150.1,
156.4, 164.8, 164.9, 179.9; HRMS (AP-ESI) m/z: calcd
for C24H21ClF3N4O2S [M ＋H] ＋ 521.1021, found
521.1029.
1-(4-(2-(Pyrrolidine-1-carbonyl)pyridin-4-yloxy)-
phenyl)-3-p-tolylthiourea (9j)
Grey solid, yield 66.9%, m.p. 162—164 ℃; 1H
NMR (600 MHz, DMSO-d6) δ: 1.82—1.84 (m, 4H,
CH2CH2), 2.28 (s, 3H, Ph-CH3), 3.46 (t, J＝6.6 Hz, 2H,
N-CH2), 3.59 (t, J＝6.6 Hz, 2H, N-CH2), 7.06—7.08 (m,
1H, pyridine-H), 7.11 (d, J＝1.2 Hz, 1H, pyridine-H),
7.15 (d, J＝7.8 Hz, 2H, Ph-H), 7.17—7.19 (m, 2H,
Ph-H), 7.33 (d, J＝8.4 Hz, 2H, Ph-H), 7.57—7.58 (m,
2H, Ph-H), 8.49 (d, J＝5.4 Hz, 1H, pyridine-H), 9.78 (s,
1H, NH), 9.79 (s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6) δ: 21.5, 24.4, 27.0, 47.4, 49.4, 111.4, 113.9,
121.9, 124.9, 126.6, 129.9, 134.8, 137.7, 138.1, 150.5,
151.1, 157.4, 165.9, 166.0, 180.7; HRMS (AP-ESI) m/z:
calcd for C24H25N4O2S [M ＋H] ＋ 433.1692, found
433.1689.
1-(4-Methoxyphenyl)-3-(4-(2-(pyrrolidine-1-carbon-
yl)pyridin-4-yloxy)phenyl)thiourea (9g)
1
Beige solid, yield 83.2%, m.p. 165—167 ℃; H
NMR (600 MHz, DMSO-d6) δ: 1.82 (s, 4H, CH2CH2),
3.46 (t, J＝6.6 Hz, 2H, N-CH2), 3.58 (t, J＝6.6 Hz, 2H,
N-CH2), 3.75 (s, 3H, OCH3), 6.91 (d, J＝8.4 Hz, 2H,
Ph-H), 7.06—7.07 (m, 1H, pyridine-H), 7.12 (d, J＝1.8
Hz, 1H, pyridine-H), 7.18 (d, J＝8.4 Hz, 2H, Ph-H),
7.32 (d, J＝9.0 Hz, 2H, Ph-H), 7.57 (d, J＝7.8 Hz, 2H,
Ph-H), 8.48 (d, J＝6.0 Hz, 1H, pyridine-H), 9.68 (s, 1H,
NH), 9.70 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
δ: 23.4, 26.0, 46.4, 48.4, 55.2, 110.5, 112.9, 113.7, 120.9,
125.7, 126.0, 132.0, 137.2, 149.5, 150.1, 156.4, 156.6,
164.9, 165.1, 180.0; HRMS (AP-ESI) m/z: calcd for
C24H25N4O3S [M＋H]＋ 449.1642, found 449.1651.
1-(2,4-Dichlorophenyl)-3-(4-(2-(pyrrolidine-1-carb-
onyl)pyridin-4-ylthio)phenyl)thiourea (9k)
1
Yellow solid, yield 84.3%, m.p. 154—156 ℃; H
NMR (600 MHz, DMSO-d6) δ: 1.80—1.82 (m, 4H,
CH2CH2), 3.43 (t, J＝6.6 Hz, 2H, N-CH2), 3.55 (t, J＝
6.6 Hz, 2H, N-CH2), 7.15 (dd, J＝5.4, 2.4 Hz, 1H, pyri-
dine-H), 7.24 (d, J＝1.8 Hz, 1H, pyridine-H), 7.46 (dd,
J＝8.4, 2.4 Hz, 1H, Ph-H), 7.60 (d, J＝7.8 Hz, 3H,
Ph-H), 7.72 (d, J＝1.8 Hz, 1H, Ph-H), 7.78 (d, J＝8.4
Hz, 2H, Ph-H), 8.38 (d, J＝4.8 Hz, 1H, pyridine-H),
9.72 (s, 1H, NH), 10.32 (s, 1H, NH); 13C NMR (75
MHz, DMSO-d6) δ: 23.4, 26.0, 46.3, 48.4, 119.1, 121.0,
122.5, 124.2, 127.4, 129.0, 131.0, 131.1, 131.4, 135.5,
1-(4-(2-(Pyrrolidine-1-carbonyl)pyridin-4-yloxy)-
phenyl)-3-(4-(trifluoromethoxy)phenyl)thiourea (9h)
Off-white solid, yield 79.2%, m.p. 170—172 ℃; 1H
NMR (600 MHz, DMSO-d6) δ: 1.83—1.84 (m, 4H,
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Yao et al.
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135.7, 141.2, 148.0, 150.9, 154.4, 164.9, 180.2; HRMS
(AP-ESI) m/z: calcd for C23H21Cl2N4OS2 [M＋H]＋
503.0529, found 503.0528.
CH2CH2), 3.44 (t, J＝6.6 Hz, 2H, N-CH2), 3.55 (t, J＝
6.6 Hz, 2H, N-CH2), 7.16 (dd, J＝5.4, 2.4 Hz, 1H, pyri-
dine-H), 7.27 (d, J＝1.8 Hz, 1H, pyridine-H), 7.61 (d,
J＝8.4 Hz, 2H, Ph-H), 7.70 (d, J＝8.4 Hz, 2H, Ph-H),
7.83 (s, 1H, Ph-H), 8.26 (s, 2H, Ph-H), 8.39 (d, J＝5.4
Hz, 1H, pyridine-H), 10.44 (s, 1H, NH), 10.52 (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6) δ: 23.4, 26.0, 46.3,
48.4, 119.2, 121.4, 121.7, 123.1, 123.6 (d), 124.6, 129.9,
130.8, 135.7, 140.7, 141.6, 148.0, 150.7, 154.4, 164.9,
179.8; HRMS (AP-ESI) m/z: calcd for C25H21F6N4OS2
[M＋H]＋ 571.1056, found 571.1067.
1-(3,4-Difluorophenyl)-3-(4-(2-(pyrrolidine-1-carb-
onyl)pyridin-4-ylthio)phenyl)thiourea (9l)
Light yellow solid, yield 70.8%, m.p. 166—170 ℃;
1H NMR (600 MHz, DMSO-d6) δ: 1.81 (t, J＝6.6 Hz,
4H, CH2CH2), 3.44 (t, J＝6.6 Hz, 2H, N-CH2), 3.55 (t,
J＝6.6 Hz, 2H, N-CH2), 7.15 (dd, J＝5.4, 2.4 Hz, 1H,
pyridine-H), 7.25—7.26 (m, 2H, aryl-H), 7.40—7.45 (m,
1H, Ph-H), 7.58—7.60 (m, 2H, Ph-H), 7.68—7.73 (m,
3H, Ph-H), 8.38 (d, J＝4.8 Hz, 1H, pyridine-H), 10.13
(s, 1H, NH), 10.20 (s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6) δ: 23.4, 26.0, 46.3, 48.4, 113.0, 113.3, 116.9,
117.2 119.1, 120.5 (q), 121.0, 122.3, 124.2, 135.6, 136.2
(dd), 141.3, 148.0, 150.9, 154.4, 164.9, 179.7; HRMS
(AP-ESI) m/z: calcd for C23H21F2N4OS2 [M ＋H] ＋
471.1120, found 471.1119.
1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(2-(pyr-
rolidine-1-carbonyl)pyridin-4-ylthio)phenyl)thio-
urea (9p)
Light-yellow solid, yield 67.6%, m.p. 164—165 ℃;
1H NMR (600 MHz, DMSO-d6) δ: 1.81 (t, J＝6.6 Hz,
4H, CH2CH2), 3.44 (t, J＝6.6 Hz, 2H, N-CH2), 3.55 (t,
J＝6.6 Hz, 2H, N-CH2), 7.16 (dd, J＝5.4, 1.8 Hz, 1H,
pyridine-H), 7.26 (d, J＝1.8 Hz, 1H, pyridine-H), 7.60
(d, J＝9.0 Hz, 2H, Ph-H), 7.69—7.71 (m, 3H, Ph-H),
7.82 (dd, J＝8.4, 2.4 Hz, 1H, Ph-H), 8.09 (d, J＝2.4 Hz,
1H, Ph-H), 8.39 (d, J＝5.4 Hz, 1H, pyridine-H), 10.31
(s, 1H, NH), 10.38 (s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6) δ: 23.4, 26.0, 46.3, 48.4, 119.2, 120.8, 121.0,
122.4 (q), 122.7, 125.4 (d), 126.1, 126.5, 128.5, 131.6,
135.7, 139.0, 141.0, 148.0, 150.8, 154.4, 164.9, 179.6;
HRMS (AP-ESI) m/z: calcd for C24H21ClF3N4OS2 [M＋
H]＋ 537.0792, found 537.0788.
1-(4-Fluorophenyl)-3-(4-(2-(pyrrolidine-1-carbonyl)-
pyridin-4-ylthio)phenyl)thiourea (9m)
Off-white solid (yield 70.1%), m.p. 162—164 ℃;
1H NMR (600 MHz, DMSO-d6) δ: 1.81 (t, J＝6.6 Hz,
4H, CH2CH2), 3.44 (t, J＝6.6 Hz, 2H, N-CH2), 3.55 (t,
J＝6.6 Hz, 2H, N-CH2), 7.14 (dd, J＝5.4, 1.8 Hz, pyri-
dine-H), 7.20 (t, J＝8.4 Hz, 2H, Ph-H), 7.24 (d, J＝1.8
Hz, 1H, pyridine-H), 7.47—7.49 (m, 2H, Ph-H), 7.57 (d,
J＝8.4 Hz, 2H, Ph-H), 7.72 (d, J＝8.4 Hz, 2H, Ph-H),
8.38 (d, J＝5.4 Hz, 1H, pyridine-H), 10.00 (s, 1H, NH),
10.08 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ:
23.4, 26.0, 46.3, 48.4, 115.0, 115.3, 119.1, 120.9, 122.0,
124.1, 126.2, 126.3, 135.5 (d), 135.6, 141.5, 148.0,
151.0, 154.4, 157.6, 160.9, 165.0, 179.8; HRMS
(AP-ESI) m/z: calcd for C23H22FN4OS2 [M ＋H] ＋
453.1214, found 453.1206.
1-(4-Methoxyphenyl)-3-(4-(2-(pyrrolidine-1-carbon-
yl)pyridin-4-ylthio)phenyl)thiourea (9q)
1
Off-white solid, yield 68.4%, m.p. 187—189 ℃; H
NMR (600 MHz, DMSO-d6) δ: 1.80—1.82 (m, 4H,
CH2CH2), 3.44 (t, J＝6.6 Hz, 2H, N-CH2), 3.55 (t, J＝
6.6 Hz, 2H, N-CH2), 3.75 (t, J＝7.8 Hz, 3H, O-CH3),
6.92—6.94 (m, 2H, Ph-H), 7.14 (dd, J＝5.4, 1.8 Hz, 1H,
pyridine-H), 7.24 (d, J＝1.2 Hz, 1H, pyridine-H), 7.34
(d, J＝9.0 Hz, 2H, Ph-H), 7.56 (d, J＝8.4 Hz, 2H,
Ph-H), 7.73 (d, J＝8.4 Hz, 2H, Ph-H), 8.37 (d, J＝5.4
Hz, 1H, pyridine-H), 9.87 (s, 1H, NH), 9.93 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d6) δ: 24.4, 27.0, 47.3, 49.4,
56.2, 114.7, 120.0, 121.8, 122.6, 125.0, 126.9, 132.8,
136.6, 142.7, 149.0, 152.1, 155.3, 157.7, 165.9, 180.6;
HRMS (AP-ESI) m/z: calcd for C24H25N4O2S2 [M＋H]＋
465.1414, found 465.1418.
1-(4-(2-(Pyrrolidine-1-carbonyl)pyridin-4-ylthio)-
phenyl)-3-(3-(trifluoromethyl)phenyl)thiourea (9n)
Off-white solid, yield 62.2%, m.p. 178—180 ℃; 1H
NMR (600 MHz, DMSO-d6) δ: 1.81 (t, J＝6.6 Hz, 4H,
CH2CH2), 3.44 (t, J＝6.6 Hz, 2H, N-CH2), 3.55 (t, J＝
6.6 Hz, 2H, N-CH2), 7.15—7.16 (m, 1H, pyridine-H),
7.26 (d, J＝1.8 Hz, 1H, pyridine-H), 7.49 (d, J＝7.8 Hz,
1H, Ph-H), 7.57—7.61 (m, 3H, Ph-H), 7.71 (d, J＝8.4
Hz, 2H, Ph-H), 7.78 (d, J＝8.4 Hz, 1H, PhH), 7.96 (s,
1H, Ph-H), 8.39 (d, J＝5.4 Hz, 1H, pyridine-H), 10.12
(s, 1H, NH), 10.17 (s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6) δ: 23.4, 26.0, 46.3, 48.5, 119.1, 119.8 (q),
120.8 (d), 121.0, 122.4, 124.2, 127.3, 128.8, 129.2,
129.6, 135.7, 140.2, 141.2, 148.0, 150.9, 154.4, 165.0,
179.7; HRMS (AP-ESI) m/z: calcd for C24H22F3N4OS2
[M＋H]＋ 503.1182, found 503.1187.
1-(4-(2-(Pyrrolidine-1-carbonyl)pyridin-4-ylthio)-
phenyl)-3-(4-(trifluoromethoxy)phenyl)thiourea (9r)
Off-white solid, yield 71.7%, m.p. 169—170 ℃; 1H
NMR (400 MHz, DMSO-d6) δ: 1.81 (t, J＝6.6, 4H,
CH2CH2), 3.44 (t, J＝6.6 Hz, 2H, N-CH2), 3.54 (t, J＝
6.6 Hz, 2H, N-CH2), 7.16 (dd, J＝5.4, 2.0 Hz, 1H, pyri-
dine-H), 7.24 (d, J＝1.8 Hz, 1H, pyridine-H), 7.36 (d,
J＝8.4 Hz, 2H, Ph-H), 7.60 (d, J＝8.4 Hz, 2H, Ph-H),
7.62 (d, J＝8.4 Hz, 2H, Ph-H), 7.72 (d, J＝8.4 Hz, 2H,
Ph-H), 8.38 (d, J＝5.4 Hz, 1H, pyridine-H), 10.15 (s,
1H, NH), 10.20 (s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6) δ: 23.4, 26.0, 46.3, 48.4, 119.1, 121.0, 121.2,
1-(3,5-Bis(trifluoromethyl)phenyl)-3-(4-(2-(pyrroli-
dine-1-carbonyl)pyridin-4-ylthio)phenyl)thiourea
(9o)
Off-white solid, yield 79.1 %, m.p. 171—172 ℃; 1H
NMR (600 MHz, DMSO-d6) δ: 1.79—1.83 (m, 4H,
2426
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2423—2430

Design, Synthesis and Antiproliferative Activities of Diaryl Thiourea Derivatives as Anticancer Agents
MTT assay
Preliminary cytotoxic activity of these sorafenib de-
122.2, 124.1, 125.2, 135.6, 138.5, 141.4, 144.7, 148.0,
151.0, 154.4, 164.9, 179.6; HRMS (AP-ESI) m/z: calcd
＋
for C24H22F3N4O2S2 [M ＋ H]
519.1131, found
rivatives (9a—9t) on PC-3, HCT116 and MDA-MB-
231 cell lines was investigated in vitro. PC-3, HCT116,
MDA-MB-231 cell lines were plated on 96-well plates
at a density of 5000 per well and incubated overnight.
The cells were treated with 9a—9t and sorafenib at final
concentrations ranging from 0.5 to 200 μmol/L, while
control cells were treated with equal volume DMSO.
After 48 h treatment, 0.5% MTT (Amresco, USA) solu-
tion was added to each well, and further incubated for 4
h, then cells were centrifuged at 2500 r/min for 15 min,
the culture medium was removed, and 150 μL DMSO
was added to dissolve the formazan. After mixing for
5min, optical density was detected at 570 nm on a mi-
croplate reader (Thermo, USA).
519.1131.
1-(4-(2-(Pyrrolidine-1-carbonyl)pyridin-4-ylthio)-
phenyl)-3-m-tolylthiourea (9s)
Light-yellow solid, yield 64.9%, m.p. 149—151 ℃;
1H NMR (600 MHz, DMSO-d6) δ: 1.80—1.82 (m, 4H,
CH2CH2), 2.30 (s, 3H, Ph-CH3), 3.44 (t, J＝6.6 Hz, 2H,
N-CH2), 3.55 (t, J＝6.6 Hz, 2H, N-CH2), 6.98 (d, J＝
7.2 Hz, 1H, Ph-H), 7.13—7.14 (m, 1H, pyridine-H),
7.22—7.28 (m, 4H, aryl-H), 7.56 (d, J＝9.0 Hz, 2H,
Ph-H), 7.72 (d, J＝8.4 Hz, 2H, Ph-H), 8.38 (d, J＝5.4
Hz, 1H, pyridine-H), 9.99 (s, 1H, NH), 10.04 (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6) δ: 22.0, 24.4, 27.0,
47.3, 49.4, 120.0, 121.8, 122.8, 125.0, 125.1, 126.4,
129.3, 136.6, 138.8, 140.0, 142.6, 149.0, 152.0, 155.3,
165.9, 180.3; HRMS (AP-ESI) m/z: calcd for
C24H25N4OS2 [M＋H]＋ 449.1465, found 449.1468.
Results and Discussion
Chemistry
The synthetic routes to the library compounds were
illustrated as outlined in Scheme 1.
1-(4-(2-(Pyrrolidine-1-carbonyl)pyridin-4-ylthio)-
phenyl)-3-p-tolylthiourea (9t)
The diaryl ether compound, 5a, and the diaryl thio-
ether compound, 5b, were prepared in a four-step se-
quence. Reaction of 2-picolinic acid 1 with hot thionyl
chloride gave 4-chloropicolinoyl chloride 2, which was
treated with methanol to produce methyl 4-chloropico-
linate 3. Subsequent displacement of compound 3 with
pyrrolidine provided compound 4, which was then
treated with 4-aminophenol or 4-aminobenzenethiol to
afford 5a or 5b in the total yields of 56.5% and 62.5%
respectively. Various isothiocyanates (8a—8j) were ob-
tained from substituted anilines (2,4-dichloroaniline,
3,4-difluoroaniline, 4-fluoroaniline, 3-(trifluoromethyl)-
aniline, 3,5-bis(trifluoromethyl)aniline, 4-chloro-3-
(trifluoromethyl)aniline, 4-methoxyaniline, 4-(trifluoro-
Light-yellow solid, yield 64.1%, m.p. 156—158 ℃;
1H NMR (600 MHz, DMSO-d6) δ: 1.80—1.82 (m, 4H,
CH2CH2), 2.289 (s, 3H, Ph-CH3), 3.43 (t, J＝6.6 Hz, 2H,
N-CH2), 3.54 (t, J＝6.6 Hz, 2H, N-CH2), 7.14—7.17 (m,
3H, aryl-H), 7.24 (d, J＝1.8 Hz, 1H, pyridine-H), 7.35
(d, J＝7.8 Hz, 2H, Ph-H), 7.56 (d, J＝9.0 Hz, 2H,
Ph-H), 7.72 (d, J＝8.4 Hz, 2H, Ph-H), 8.38 (d, J＝5.4
Hz, 1H, pyridine-H), 9.96 (s, 1H, NH), 9.99 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d6) δ: 21.5, 24.4, 27.0, 47.3,
49.4, 120.0, 121.9, 122.7, 124.8, 125.0, 130.0, 134.9,
137.0, 137.5, 142.7, 149.0, 152.1, 155.3, 165.9, 180.3;
HRMS (AP-ESI) m/z: calcd for C24H25N4OS2 [M＋H]＋
449.1465, found 449.1470.
Scheme 1
Cl
Cl
b
a
N
1
COOH
N
COCl
N
COOCH3
2
3
Cl
O
X
c
d
N
N
N
N
H2N
R
H
H
O
4
N
N
g
N
5a, 5b
S
N
X
R
R
O
R
S
e
f
H
9a - 9t
X = O, S
N C SH
NCS
NH2
6a - 6j
7a - 7j
8a - 8j
Reagents and conditions: (a) SOCl2; (b) CH3OH; (c) pyrrolidine, THF; (d) 4-aminophenol or 4-aminobenzenethiol, DMF, t-BuOK; (e)
Dabco, CS2, toluene; (f) BTC, DCM; (g) DCM
Chin. J. Chem. 2012, 30, 2423—2430
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2427

Yao et al.
FULL PAPER
methoxy)aniline), m-toluidine or p-toluidine (6a—6j),
which reacted with CS2 to afford 7a—7j, and then
treated with triphosgene (BTC) to give 8a—8j. Finally,
these isothiocyanates were reacted with 5a and 5b in
DCM to give target compounds (9a—9t) in 35.4%—
50.9% total yields. The final products were purified by
column chromatography and their structures were char-
acterized by 1H NMR, 13C NMR and HRMS.
compounds 9e, 9f, 9o and 9p exhibited inhibitory ac-
tivities against all three cell lines. Notably, compared
with sorafenib, the antiproliferative activity of the newly
synthesized derivatives to MDA-MB-231 cells is
weaker. Only the compounds (9e, 9f, 9o and 9p) con-
taining 3-CF3, 4-Cl-disubstituted or 3,5-CF3-disubstitu-
ted phenyl ring could inhibit the growth of MDA-MB-
231 cells, while the other compounds just showed anti-
proliferative activity against PC-3 or HCT116 cells.
Furthermore, series B is more potent than series A,
which suggests that the thioether moiety is optimal for
the antiproliferative activity of thiourea derivatives.
The effect of the terminal substituents on the tail
phenyl ring was also investigated. The electron-donating
group may decrease the inhibitory activity of the com-
pounds. For example, compounds 9g and 9q having
—OCH3 substituted on 4-position of phenyl ring,
showed no activity against HCT116 cells. Compounds
In vitro cell cytotoxicity assay
In vitro cell cytotoxicity of these derivatives was ini-
tially evaluated against PC-3, HCT116 and MDA-MB-
231 cells by MTT assay using sorafenib as a positive
control. As listed in Table 1, all 20 compounds generally
showed antiproliferative activity to PC-3 cells with IC50
＝5.2—99.0 μmol/L, most of the analogs except for 9g,
9h and 9q demonstrated potent antiproliferative activity
to HCT116 cells with IC50＝5.9—128.1 μmol/L, and
Table 1 The structures and IC50 values of the target compounds
IC50a/(μmol•L－
)
1
Comp.
Substituent Ar
PC-3
HCT116
MDA-MB-231
Cl
9a
43.5±0.9
29.1±1.1
＞200
Cl
F
9b
9c
9d
21.4±1.9
46.0±3.1
62.0±4.0
11.6±0.9
40.7±2.1
16.5±1.2
＞200
＞200
＞200
F
F
CF3
CF3
CF3
H
H
N
N
Ar
N
9e
9f
16.8±1.9
22.0±1.8
21.2±1.0
11.2±0.9
38.8±1.5
50.1±2.2
S
N
O
O
Series A
CF3
Cl
OCF3
>200
>200
>200
9g
9h
59.5±3.0
24.0±1.9
OCF3
CH3
＞200
9i
9j
99.0±3.8
67.6±0.9
52.1±2.1
51.4±3.2
＞200
＞200
CH3
2428
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2423—2430

Design, Synthesis and Antiproliferative Activities of Diaryl Thiourea Derivatives as Anticancer Agents
Continued
IC50a/(μmol•L－
)
1
Comp.
Substituent Ar
PC-3
HCT116
MDA-MB-231
Cl
9k
27.8±1.9
33.2±1.1
＞200
Cl
F
9l
29.2±2.1
29.2±1.4
35.1±1.5
28.1±1.4
29.0±2.0
29.5±2.4
＞200
＞200
＞200
F
F
9m
9n
CF3
CF3
CF3
H
H
N
N
Ar
N
9o
9p
5.2±0.8
7.3±0.4
8.3±1.0
5.9±0.6
20.2±1.8
80.8±3.0
S
N
S
O
Series B
CF3
Cl
OCF3
9q
9r
77.0±3.2
30.1±1.6
＞200
＞200
＞200
OCF3
CH3
8.0±0.2
9s
9t
52.1±1.9
128.1±3.2
＞200
CH3
22.5±2.0
6.8±0.9
94.1±2.1
7.8±1.1
＞200
Sorafenib
—
36.6±2.1
a Mean value of three experiments and standard deviation are given.
9i, 9j, 9s and 9t with methyl group, the weaker elec-
tron-donating group, produced diminished activities
against HCT116 cells (IC50 ＝51.4—128.1 μmol/L),
comparative with other compounds containing elec-
tron-withdrawing groups. The most potent compounds
(9e, 9f, 9o and 9p) all contained two electron-with-
drawing groups (3-CF3, 4-Cl-disubstituted or
3,5-CF3-disubstituted) on the phenyl ring which were
mentioned above. The effects of the substituents on the
phenyl ring are similar between series A and series B,
except for the 4-OCF3 substituted compounds (9h and
9r). Compound 9r demonstrated potent antiproliferative
activity against HCT116 cells (IC50＝8.0 μmol/L), while
compound 9h showed a IC50 value＞200 μmol/L. Fur-
thermore, the analysis of the charge distribution regard-
ing distal phenyl ring is still required and currently be-
ing pursued.
Conclusions
In summary, two new series of sorafenib derivatives
were designed and synthesized based on our previous
literature studies. All compounds generally showed an-
tiproliferative activity against PC-3 cells, and most of
the 20 analogs except 9g, 9h and 9q demonstrated po-
tent antiproliferative activity to HCT116 cells. Com-
pounds 9e, 9f, 9o and 9p demonstrated competitive an-
tiproliferative activities to sorafenib. Series B is more
potent than series A, and electronic effect of the sub-
stituents on terminal phenyl ring is also related to the
cytotoxicity of the compounds. Further modifications of
these derivatives are still required in order to improve
Chin. J. Chem. 2012, 30, 2423—2430
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2429

Yao et al.
FULL PAPER
Chem. 2010, 45, 2299.
their potency and are in progress in our laboratory.
[11] Dai, Y.; Hartandi, K.; Ji, Z.; Ahmed, A. A.; Albert, D. H.; Bauch, J.
L.; Bouska, J. J.; Bousquet, P. F.; Cunha, G. A.; Glaser, K. B.; Harris,
C. M.; Hickman, D.; Guo, J.; Li, J.; Marcotte, P. A.; Marsh, K. C.;
Moskey, M. D.; Martin, R. L.; Olson, A. M.; Osterling, D. J.; Pease,
L. J.; Soni, N. B.; Stewart, K. D.; Stoll, V. S.; Tapang, P.; Reuter, D.
R.; Davidsen, S. K.; Michaelides, M. R. J. Med. Chem. 2007, 50,
1584.
Acknowledgement
This work was supported by the National Science
and Technology Major Project (No. 2009-ZX09103-118)
and Ph.D. Programs Foundation of Ministry of Educa-
tion of China (No. 20110131110037).
[12] Ménard, D.; Niculescu-Duvaz, I.; Dijkstra, H. P.; Niculescu-Duvaz,
D.; Suijkerbuijk, B. M.; Zambon, A.; Nourry, A.; Roman, E.; Davies,
L.; Manne, H. A.; Friedlos, F.; Kirk, R.; Whittaker, S.; Gill, A.;
Taylor, R. D.; Marais, R.; Springer, C. J. J. Med. Chem. 2009, 52,
3881.
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