Thiourea and thioether derivatives of sorafenib: Synthesis, crystal structure, and antiproliferative activity

Article abstract of DOI:10.1007/s00044-012-0400-8

A series of novel sorafenib derivatives containing diaryl thiourea and thioether, 9a-u, was designed and synthesized, and their antiproliferative activities against HCT116 and MDA-MB-231 cell lines were also evaluated and described. Most compounds exhibited potent antiproliferative activity against HCT116 cells with IC₅₀ = 1.8-80.4 μM. Compounds 9p, 9r, and 9s demonstrated competitive antiproliferative activities to sorafenib, against all two cancer cell lines. The structures of all the newly synthesized compounds were determined by ¹H NMR, ¹³C NMR, and HRMS, and compound 9n was characterized by single-crystal X-ray diffraction. Primary structure-activity relationships (SAR) have also been established.

Full text of DOI:10.1007/s00044-012-0400-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3959–3968
DOI 10.1007/s00044-012-0400-8
ORIGINAL RESEARCH
Thiourea and thioether derivatives of sorafenib: synthesis, crystal
structure, and antiproliferative activity
•
Jianwen Yao Jing Chen Zuopeng He Wei Sun
•
•
•
•
Hao Fang Wenfang Xu
Received: 28 June 2012 / Accepted: 6 December 2012 / Published online: 18 December 2012
Ó Springer Science+Business Media New York 2012
Abstract A series of novel sorafenib derivatives containing
diaryl thiourea and thioether, 9a–u, was designed and syn-
thesized, and their antiproliferative activities against HCT116
and MDA-MB-231 cell lines were also evaluated and
described. Most compounds exhibited potent antiproliferative
activity against HCT116 cells with IC50 = 1.8–80.4 lM.
Compounds 9p, 9r, and 9s demonstrated competitive anti-
proliferative activities to sorafenib, against all two cancer cell
lines. The structures of all the newly synthesized compounds
receptor (VEGFR), platelet-derived growth factor receptor
(PDGFR), Fms-like tyrosine kinase-3 (Flit-3), and stem-cell
growth factor (c-KIT) (Liu et al., 2006; Wilhelm et al., 2006;
Guida et al., 2007; Wilhelm et al., 2008). The multi-mecha-
nisms provide sorafenib with broad-spectrum anticancer
potency and well-tolerated results in combination trials, and
more and more attentions are given to the optimization of
sorafenib (Dai et al., 2007; Potashman et al., 2007; Ramurthy
´
et al., 2008; Menard et al., 2009; Sun et al., 2010).
1
were determined by H NMR, 13C NMR, and HRMS, and
Based on the bioisosteric theory, we have previously
described a series of diaryl thiourea derivatives (Yao et al.,
2012). In the present paper, a series of sorafenib derivatives
(9a–u) containing both diaryl thiourea and thioether were
designed and synthesized (Fig. 1). The crystal structure of
9n was also obtained. The antiproliferative activities of 21
compounds against human colorectal carcinoma cell line
(HCT116) and human breast cancer cell line (MDA-
MB-231) were evaluated. Apparent growth inhibition
against HCT116 cells was observed for most of the com-
pounds, and 9h, 9p, 9q, 9r, and 9s demonstrating potent
activities against both cancer cells.
compound 9n was characterized by single-crystal X-ray dif-
fraction. Primary structure–activity relationships (SAR) have
also been established.
Keywords Sorafenib analogs ꢀ Antiproliferative activity ꢀ
Synthesis ꢀ Crystal structure
Introduction
Sorafenib, a multiple targeted antitumor agent containing a
diaryl urea and a diaryl ether skeleton, can not only inhibit Raf
to block Raf/MEK/ERK signaling pathway (Liu et al., 2006),
but also inhibit other kinases involved in tumor proliferation
and angiogenesis, such as vascular endothelial growth factor
Results and discussion
Chemistry
J. Yao ꢀ J. Chen ꢀ Z. He
The synthetic routes to the library compounds were illus-
trated as outlined in Scheme 1.
Department of Medicinal Chemistry, School of Pharmacy,
Yantai University, 30 Qingquan Road, Yantai 264005,
Shandong, People’s Republic of China
The substituted diaryl thioethers, 5a–e, were prepared
from 2-picolinic acid 1, which was treated with SOCl2 to
generate 4-chloropicolinoyl chloride 2. Then methyl
4-chloropicolinate 3 was obtained by treating 2 with
methanol, which was treated with corresponding amine (methyl-
amine, ethylamine, phenylmethanamine, cyclopropanamine, and
J. Yao ꢀ W. Sun ꢀ H. Fang ꢀ W. Xu (&)
Department of Medicinal Chemistry, School of Pharmaceutical
Sciences, Shandong University, 44 West Culture Road,
Jinan 250012, Shandong, People’s Republic of China
e-mail: wfxu@yahoo.cn; xuwenf@sdu.edu.cn
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Med Chem Res (2013) 22:3959–3968
Fig. 1 Structures of sorafenib
and its derivatives
H
N
H
N
Ar
N
H
N
S
O
R
O
H
H
previously reported diaryl-thiourea derivatives
F3C
Cl
N
N
N
O
NH
O
CH3
O
H
H
N
N
sorafenib
Ar
N
H
N
S
S
R
O
compounds 9a-9u
Cl
Cl
b
a
N
1
COOH
N
COCl
N
3
COOCH3
2
Cl
N
O
S
R1
c
d
N
H
H
N
N
R1
H2N
R2
H
N
H
N
O
4a-4e
g
N
5a-5e
S
NH R1
R2
S
R2
O
R2
S
e
f
H
N
9a-9u
C
SH
NCS
NH2
6a-6h
8a-8h
7a-7h
Scheme 1 Reagents and conditions: (a) SOCl2 (b) CH3OH (c) R1NH2, THF (d) 4-aminobenzenethiol, DMF, t-BuOK (e) Dabco, CS2, toluene
(f) BTC, DCM (g) DCM
Fig. 2 The crystal structure of
compound 9n. Disorderd atoms,
F10, F20, and F30, were omitted
as clarity
cyclohexanamine) to form 4a–e. Subsequently, they were
treated with 4-aminobenzenethiol to afford corresponding
diaromatic thioethers (5a–e) in the total yields of
40.5–56.4 %. On the other hand, virous isothiocyanates
(8a–h) were obtained from substituted anilines (2,4-dichloro-
aniline, 4-chloroaniline, 3,4-difluoroaniline, 4-fluoroaniline,
3-(trifluoromethyl)aniline, 3,5-bis(trifluoromethyl)aniline, 4-
chloro-3-(trifluoromethyl) aniline, or 4-(trifluoromethoxy)ani-
line), 6a–h, which reacted with CS2 to generate 7a–h, and then
treated with BTC to produce various isothiocyanates 8a–
h. Finally, these isothiocyanates were reacted with different
substituted diaryl thioethers (5a–e) in DCM to give target
compounds (9a–u) in 26.9–44.8 % total yields. The final
products were purified by column chromatography and their
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Med Chem Res (2013) 22:3959–3968
3961
Fig. 3 A view showing the
ribbon extending along the b-
axis, formed by N–H_O
hydrogen bonds (dashed lines).
H atoms not involved in
hydrogen bonding have been
omitted for clarity. [Symmetry
codes: (i) 3/2 - x, 1/2 ? y,
1 - z; (ii) 3/2 - x, y - 1/2,
1 - z]
1
structures were characterized by H NMR, 13C NMR, and
the steric hindrance of S atom. The distance between S1
˚
and H2 in 9n is 2.76 A, which is shorter than the sum
HRMS.
˚
(2.95 A) of van der Waals Radius of S and H atom (Pauling
Crystal structure of 9n
and Pauling, 1975).
Although there many structure differences between
sorafenib and 9n mentioned above, the conformational
flexibility of the urea and ether linkages in the molecules
allow the terminal groups adopting the appropriate orien-
tations to bind the target. On the other hand, the size of the
total molecule between two structures is similar. The dis-
As shown in Fig. 2, the molecular structure of 9n con-
taining three six-membered aromatic rings and one cyclo-
propane ring adopts an extended conformation. The atoms
F1, F2, and F3 appeared to be disordered, and were refined
as two parts. Each molecular was connected by two clas-
sical hydrogen bond N1—H10_O1i and N2—H2_O1i
(i = 3/2 - x, 1/2 ? y, 1 - z) to form an extended chain
along the b axis (Fig. 3).
˚
tance between N1 and N4 in 9n is 13.576 A which is a
˚
little longer than that (13.477 A) of sorafenib. Considering
that 9n lack a Cl atom on 4-position of phenyl group
compared with sorafenib, we anticipate that the compound
9s have more similar structure with sorafenib, and the
antiproliferative activities of 9s are also comparative with
those of sorafenib (Table 1).
The plane of amide group (C18, C20, N4, and O1) forms
the diangle of 9.8° with pyridine plane (C15, C16, C17, N3,
C18, and C19). This value is much smaller than that of
sorafenib (18.3°) (Ravikumar et al., 2011). The pyridine
ring connects a phenyl ring (C9, C10, C11, C12, C13, and
C14) by an S atom. The angle of C12–S2–C15 is
103.85(17)°, which is much smaller than that of sorafenib
(118.48°), that induces the dihedral angle between them
(74.6°) to be similar with that angle of 78.4° in sorafenib.
Another obvious difference between 9n and sorafenib is
that 9n use thiourea to displace the urea in sorafenib. The
dihedral angles between the thiourea group (N1, C8, N2,
and S1) and the terminal phenyl planes is 35.6°. This value
is much larger than that between the urea group and the
phenyl plane in sorafenib (9.9°), which is perhaps due to
Cell inhibition
In vitro cell cytotoxicity of the 21 new sorafenib deriva-
tives was evaluated against HCT116 and MDA-MB-231
cells by MTT assay using sorafenib as a positive control.
As shown in Table 1, compounds 9h, 9p, 9q, 9r, and 9s
showed significant inhibitory activities against both cell
lines, and most compounds (except 9a, 9b, 9e and 9g, 9m)
exhibited potent antiproliferative activities to HCT116
cells with IC50 = 1.8–78.0 lM. Notably, compared with
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Med Chem Res (2013) 22:3959–3968
Table 1 The structures and IC50 values of the target compounds
H
N
H
N
Ar
N
S
NH R
S
O
Comp. no. Substituents
Ar
IC50 (lM)a
Comp. no. Substituents
Ar
IC50 (lM)a
R
HCT116
MDA-MB-231
R
HCT116
MDA-MB-231
9a
[200
[200
9l
46.8 2.0 [200
Cl
CF3
Me
Me
Cl
9b
[200
[200
9m
[200
[200
Cl
CF3
Cl
9c
14.5 0.7 [200
9n
50.5 3.5 [200
2.94 0.3 [200
29.1 0.8 38.2 1.1
CF3
Me
Cl
9d
15.8 1.7 [200
9o
CF3
Cl
9e
[200
[200
9p
CF3
Me
Me
Cl
CF3
9f
78.0 1.2 [200
9q
12.0
2
84.0 4.2
F
CF3
Me
F
Cl
9g
[200
[200
9r
9s
9t
8.8 .2
53.6 3.7
F
CF3
Cl
F
9h
34.5 2.1 94.1 5.7
38.5 3.5 [200
3.3 0.14 [200
22.0 2.8 50.8 2.8
F
CF3
Cl
F
9i
1.8 0.7
[200
F
CF3
Cl
F
9j
9u
11.5 1.7 [200
F
OCF3
Me
F
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Med Chem Res (2013) 22:3959–3968
3963
Table 1 continued
Comp. no. Substituents
IC50 (lM)a
Comp. no. Substituents
Ar
IC50 (lM)a
Ar
R
HCT116
MDA-MB-231
R
–
HCT116
MDA-MB-231
9k
47.0 1.6 [200
Sorafenib
–
7.75 1.1 36.6 2.1
Me
F
a
Mean value of three experiments and standard deviation are given
sorafenib, some compounds showed good inhibitory
selectivity on HCT116 cells. For example, compounds 9j,
9o, and 9t which contains cyclohexyl substitute showed
more potent inhibitory activities (IC50 = 1.8–3.3 lM)
against HCT116 cells, while they have no inhibitory
activities against MDA-MB-231 cell line. This trait was
also found in the previously reported diaryl thiourea
9e, 9g, and 9m) exhibited potent antiproliferative activities to
HCT116 cells with IC50 = 1.8–78.0 lM. Compounds 9h, 9p,
9q, 9r, and 9s showed significant inhibitory activities against
both HCT116 and MDA-MB-231cell lines. Notably, com-
pared with sorafenib, most of the derivatives showed excellent
selectivity toward HCT-116 over MDA-MB-231 cells, espe-
cially the compounds 9j, 9o, and 9t which contains cyclohexyl
substitute showed no inhibitory activities against MDA-
MB-231 cells, but demonstrated more potent inhibitory
activities against HCT116 cells (IC50 = 1.8–3.3 lM) than
those of sorafenib and previously reported diarylthiourea
derivatives. Further modifications of these derivatives are still
required in order to improve their potency and are in progress
in our laboratory.
derivatives (Yao et al., 2012), but the activities (IC50
=
9.15–26.15 lM) of them are weaker than those of 9j, 9o,
and 9t. Comparing the test data, we obtained some basic
structure–activity relationships (SAR) as the following: (1)
The size and shape of R on the terminal amide: a. Too large
substitutes may diminish the cytotoxicity of the com-
pounds. For example, all compounds (9b, 9e, 9g, and 9m)
whose R substitutes are benzyl group have no antiprolif-
erative activity to both cells. b. The cytotoxicity of the
compounds with methyl, ethyl, and cyclopropyl substitutes
have no significant differences. c. As mentioned above,
cyclohexyl substitute may contribute to the selectivity on
the HCT116 cells. (2) The substitutes on the terminal
phenyl ring: a. 3-CF3, 4-Cl-disubstitution on the phenyl
ring may be conducive to the antiproliferative activity
against MDA-MB-231 cells. All 3-CF3, 4-Cl-disubstituted
compounds (except 9t whose R is cyclohexyl ring) showed
potent cytotoxicity against MDA-MB-231 cells; the other
compound having the cytotoxicity against MDA-MB-231
cells is 3,5-CF3-disubstituted on the phenyl ring (9p). b. 2-,
4-disubstituted on phenyl group may be disadvantageous to
the inhibitory activity of compounds. For example, 9a with
chloro substituted at 2-, 4-position of phenyl has no activity
against both cells, while other compounds (9c, 9l, 9k, 9f,
9p, 9q, and 9u) having the same R group with 9a showed
potent activity against HCT116 cells.
Experimental
General
All the materials we used were purchased from commercial
suppliers and used without further purification. Solvents
were distilled prior to use and flash chromatography was
˚
performed using silica gel (60 A, 200–300 mesh). Com-
pounds 3, 4a–e and 8a–h were synthesized according to the
literature method (Yao et al., 2012). All reactions were
monitored by thin-layer chromatography on 0.25 mm silica
gel plates (60F-254, Merk) and visualized with UV light, or
chloride ferric. Melting points were determined on an
electrothermal melting point apparatus, and the thermom-
1
eter was uncorrected. H, 13C NMR spectra were deter-
mined on a Brucker Avance 600/300 spectrometer using
TMS as an internal standard in DMSO-d6 or CDCl3 solu-
tions. Chemical shifts are reported in delta (d) units, parts
per million (ppm) 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 intensity).
Conclusion
In summary, we report here thesynthesis, crystal structure, and
biological evaluation of a series of new sorafenib derivativesas
potential antitumor agents. Most compounds (except 9a, 9b,
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Med Chem Res (2013) 22:3959–3968
General procedure for synthesis of compounds 5a–e
(d, J = 1.8 Hz, 1H), 7.99 (br d, 1H), 8.18 (d, J = 5.3 Hz,
1H). ESI-MS m/z 286.1 [M ? H]?.
4-Aminobenzenethiol (24.8 mmol) and potassium tert-
butoxide (25.0 mmol) were first dissolved in 40 mL
anhydrous DMF. After stirring the resulting mixture at
room temperature for 2 h, a solution of 4a–e (24.8 mmol)
and K2CO3 (14.9 mmol) in DMF (20 mL) was added, and
the mixture was stirred at 75–80 °C for 8 h. After the
temperature was back to room temperature, the mixture
was diluted with water and the aqueous layer was extracted
with EtOAc (3 9 80 mL). The combined ethyl acetate
extracts were washed with brine (2 9 60 mL) and then
dried with anhydrous sodium sulfate. The solvent was
evaporated and the resulting crude material was purified by
column chromatography to afford the pure compounds.
General procedure for synthesis of 9a–u
To a 10 mL DCM solution of compound 5a–e (4.5 mmol),
a DCM solution of 8a–h (4.5 mmol) was added slowly
under 0–5 °C. The mixture was stirred for 2 h in ice bath
and then stirred for another 20 h at room temperature.
60 mL petroleum ether was poured into the mixture. The
resulting precipitates were collected by filtration and
washed with methanol to give compounds.
4-(4-(3-(2,4-Dichlorophenyl)thioureido)phenylthio)-
N-methylpicolinamide (9a) Light yellow solid (yield
69.2 %), mp 158–160 °C; 1H NMR (600 MHz, DMSO-d6)
d 2.77 (d, J = 5.4 Hz, 3H), 7.25 (dd, J = 5.4, 1.8 Hz, 1H),
7.46 (dd, J = 6.4, 2.4 Hz, 1H), 7.59–7.62 (m, 4H), 7.71 (d,
J = 2.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 8.42 (d,
J = 4.8 Hz, 1H), 8.74 (d, J = 5.4 Hz, 1H), 9.71 (s, 1H),
10.22 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d 26.92,
118.76, 123.38, 123.42, 125.20, 128.41, 129.98, 131.97,
132.16, 132.42, 136.44, 136.62, 142.22, 149.31, 151.04,
152.87, 164.33, 181.26; HRMS(AP-ESI) m/z: calcd for
C20H17Cl2N4OS2 [M ? H]? 463.0216, found 463.0211.
4-(4-Aminophenylthio)-N-methylpicolinamide (5a) Yield
1
69.5 %, mp 123–124 °C;. H NMR (400 MHz, CDCl3) d
2.98 (d, J = 5.2 Hz, 3H), 4.09 (br s, 2H), 6.74 (d,
J = 8.5 Hz, 2H), 6.97 (dd, J = 5.2, 1.9 Hz, 1H), 7.32 (d,
J = 8.5 Hz, 2H),7.84 (d, J = 1.7 Hz, 1H), 8.75 (br s, 1H),
8.20 (d, J = 5.2 Hz, 1H); ESI-MS m/z 260.2 [M ? H]?.
4-(4-Aminophenylthio)-N-ethylpicolinamide (5b) Yield
70.6 %, mp 138–140 °C; 1H NMR (400 MHz, CDCl3)
d.1.24 (t, J = 7.3, 3H), 3.43–3.50 (m, 2H), 3.98 (br s, 2H),
6.73 (d, J = 8.4 Hz, 2H), 6.97 (dd, J = 5.3, 1.9 Hz, 1H),
7.32 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 1.6 Hz, 1H), 7.96
(br s, 1H), 8.21 (d, J = 5.2 Hz, 1H). ESI-MS m/z 274.1
[M ? H]?.
N-benzyl-4-(4-(3-(2,4-dichlorophenyl)thioureido)phenylthio)
picolinamide (9b) Off-white solid (yield 66.4 %),
mp = 126–130 °C; 1H NMR (600 MHz, DMSO-d6) d 4.44
(d, J = 6.0 Hz, 2H), 7.22 (m, 1H), 7.28 (s, 5H), 7.45 (d,
J = 8.4 Hz, 1H), 7.61 (m, 4H), 7.10 (d, J = 1.8 Hz, 1H),
7.79 (d, J = 8.4 Hz, 2H), 8.44 (d, J = 4.8 Hz, 1H), 9.32 (d,
J = 6.0 Hz, 1H), 9.71 (s, 1H), 10.21 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) d 43.39, 118.77, 123.35, 123.43,
125.21, 127.71, 128.30, 128.42, 129.18, 129.96, 131.99,
132.12, 132.39, 136.46, 136.63, 140.34, 142.22, 149.32,
151.05, 152.87, 164.34, 181.20. HRMS(AP-ESI) m/z: calcd
for C28H21F6N4OS2 [M ? H]? 607.1056, found 607.1051.
4-(4-Aminophenylthio)-N-benzylpicolinamide (5c) Yield
1
66.5 %, mp 122–124 °C; H NMR (400 MHz, CDCl3) d
3.98 (br s, 2H), 4.62 (d, J = 6.1 Hz, 2H), 6.73 (d,
J = 8.5 Hz, 2H), 6.98 (dd, J = 5.3, 1.9 Hz, 1H), 7.29–7.34
(m, 7H), 7.85 (d, J = 1.8 Hz, 1H), 8.19 (d, J = 5.3 Hz,
1H), 8.38 (br d, 1H). ESI-MS m/z 336.3 [M ? H]?.
4-(4-Aminophenylthio)-N-cyclohexylpicolinamide
(5d)
Yield 72.8 %, mp 177–179 °C; 1H NMR (400 MHz,
CDCl3) d 1.25–1.46 (m, 5H), 1.61–1.66 (m, 1H), 1.72–1.77
(m, 2H), 1.95–1.99 (m, 2H), 3.86–3.96 (m, 3H), 6.73 (d,
J = 11.0 Hz, 2H), 6.96 (dd, J = 5.3, 1.8 Hz, 1H), 7.32 (d,
J = 11.0 Hz, 2H), 7.83 (d, J = 1.8 Hz, 1H), 7.88 (br d,
1H), 8.20 (d, J = 5.3 Hz, 1H). ESI-MS m/z 328.2
[M ? H]?.
4-(4-(3-(4-Chlorophenyl)thioureido)phenylthio)-N-methyl-
picolinamide (9c) Off-white solid (yield 68.3 %),
mp = 174–176 °C; 1H NMR (600 MHz, DMSO-d6) d 2.77
(d, J = 5.4 Hz, 3H), 7.26 (dd, J = 5.4, 1.8 Hz, 1H), 7.42
(d, J = 6.6 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.58 (m,
3H), 7.73 (d, J = 8.4 Hz, 2H), 8.42–8.44 (m, 2H), 10.14 (s,
1H), 10.20 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d
26.92, 118.70, 123.08, 123.34, 125.10, 126.24, 129.38,
129.47, 136.57, 139.19, 142.44, 149.65, 151.11, 152.47,
164.75, 180.48; HRMS(AP-ESI) m/z: calcd for
C20H18ClN4OS2 [M ? H]? 429.0605, found 429.0611.
4-(4-Aminophenylthio)-N-cyclopropylpicolinamide
(5e)
Yield 75.7 %, mp 167–169 °C; 1H NMR (400 MHz,
CDCl3) d 0.63–0.69 (m, 2H), 0.78–0.88 (m, 2H), 2.86–2.92
(m, 1H), 4.12 (br d, 2H), 6.74 (d, J = 11.0 Hz, 2H), 6.96
(dd, J = 5.3, 1.9 Hz, 1H), 7.32 (d, J = 11.0 Hz, 2H), 7.82
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Med Chem Res (2013) 22:3959–3968
3965
4-(4-(3-(4-Chlorophenyl)thioureido)phenylthio)-N-cyclo-
hexylpicolinamide (9d) White solid (yield 71.1 %),
mp = 161–164 °C; 1H NMR (600 MHz, DMSO-d6) d
1.09–1.15 (m, 1H), 1.25–1.32 (m, 2H), 1.34–1.41 (m, 2H),
1.58 (d, J = 12.0 Hz, 1H), 1.68–1.70 (m, 2H), 1.73–1.75
(m, 2H), 3.72 (m, 1H), 7.27 (dd, J = 5.4, 1.8 Hz, 1H), 7.41
(d, J = 6.6 Hz, 2H), 7.53 (d, J = 7.2 Hz, 2H), 7.58 (m,
3H), 7.73 (d, J = 8.4 Hz, 2H), 8.42–8.43 (m, 2H), 10.12 (s,
1H), 10.17 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d
25.70, 26.01, 33.03, 48.95, 118.68, 123.07, 123.30, 125.06,
126.24, 129.36, 129.46, 136.53, 139.18, 142.41, 149.71,
151.16, 152.86, 163.12, 180.42; HRMS(AP-ESI) m/z: calcd
for C25H26ClN4OS2 [M ? H]? 497.1231, found 497.1227.
4-(4-(3-(3,4-Difluorophenyl)thioureido)phenylthio)-N-eth-
ylpicolinamide (9h) Light yellow solid (yield 76.5 %),
mp = 138–140 °C; 1H NMR (600 MHz, DMSO-d6) d 1.09
(t, J = 7.8 Hz, 3H), 3.27 (m, 2H), 7.26 (m, 2H), 7.43 (m,
1H), 7.58 (m, 3H), 7.67–7.73 (m, 3H), 8.42 (d, J = 4.8 Hz,
1H), 8.75 (d, J = 4.8 Hz, 1H), 10.10 (s, 1H), 10.18 (s, 1H);
13C NMR (75 MHz, DMSO-d6) d 15.71, 34.66, 114.04,
114.31, 117.90, 118.13, 118.67, 121.48 (q, J = 12 Hz),
123.29, 123.38, 125.24, 136.52, 137.17 (dd, J = 36,
12 Hz), 142.26, 149.20, 151.26, 152.70, 163.97, 180.67;
HRMS(AP-ESI) m/z: calcd for C21H19F2N4OS2 [M ? H]?
445.0963, found 445.0970.
N-cyclopropyl-4-(4-(3-(3,4-difluorophenyl)thioureido)
phenylthio)picolinamide (9i) Off-white solid (yield
66.9 %), mp = 154–156 °C; 1H NMR (600 MHz, DMSO-
d6) d 0.62-0.68 (m, 4H), 0.83-0.87 (m, 1H), 7.26 (m, 2H),
7.43 (m, 1H), 7.58–7.73 (m, 6H), 8.43 (d, J = 4.8 Hz, 1H),
N-benzyl-4-(4-(3-(4-chlorophenyl)thioureido)phenylthio)
picolinamide (9e) Light yellow solid (yield 75.6 %),
mp = 100–104 °C; 1H NMR (600 MHz, DMSO-d6) d 4.43
(d, J = 6.6, 2H), 7.21–7.31 (m, 6H), 7.41 (d, J = 9.0 Hz,
2H), 7.54 (d, J = 8.4 Hz, 2H), 7.59 (m, 3H), 7.74 (d,
J = 9.0 Hz, 2H), 8.44 (d, J = 6.0 Hz, 1H), 9.33 (t,
J = 6.0 Hz, 2H), 10.19 (s, 1H), 10.25 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) d 43.37, 118.71, 123.04, 123.30,
125.05, 126.25, 127.70, 128.31, 129.18, 129.39, 129.50,
136.58, 139.18, 140.34, 142.40, 149.71, 151.16, 152.87,
164.32, 180.45; HRMS (AP-ESI) m/z: calcd for
C26H22ClN4OS2 [M ? H]? 505.0918, found 505.0923.
8.76 (d, J = 4.8 Hz, 1H), 10.11 (s, 1H), 10.19 (s, 1H); 13
C
NMR (75 MHz, DMSO-d6) d 6.63, 23.82, 114.01, 114.32,
117.91, 118.14, 118.69, 121.49 (q, J = 12 Hz), 123.26,
123.34, 125.26, 136.50, 137.14 (dd, J = 33, 12 Hz),
142.23, 149.21, 151.23, 152.64, 165.57, 180.63;
HRMS(AP-ESI) m/z: calcd for C22H19F2N4OS2 [M ? H]?
457.0963, found 457.0960.
N-cyclohexyl-4-(4-(3-(3,4-difluorophenyl)thioureido)phen-
ylthio)picolinamide (9j) Off-white solid (yield 69.7 %),
mp = 154–157 °C; 1H NMR (600 MHz, DMSO-d6) d
1.09–1.15 (m, 1H), 1.25–1.32 (m, 2H), 1.34–1.40 (m, 2H),
1.57 (d, J = 11.4 Hz, 1H), 1.68–1.70 (m, 2H), 1.73–1.75
(m, 2H), 3.71 (m, 1H), 7.25 (m, 2H), 7.42 (m, 1H), 7.59 (m,
3H), 7.68–7.73 (m, 3H), 8.42 (d, J = 4.8 Hz, 1H), 8.75 (d,
J = 4.8 Hz, 1H), 10.10 (s, 1H), 10.18 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) d 25.71, 26.00, 33.03, 48.94, 114.02,
114.33, 117.92, 118.12, 118.61, 121.47 (q, J = 12 Hz),
123.30, 123.39, 125.25, 136.55, 137.19 (dd, J = 36,
12 Hz), 142.25, 149.19, 151.26, 152.83, 163.17, 180.63;
HRMS(AP-ESI) m/z: calcd for C25H25F2N4OS2 [M ? H]?
499.1435, found 499.1428.
4-(4-(3-(3,4-Difluorophenyl)thioureido)phenylthio)-N-meth
ylpicolinamide (9f) Light gray solid (yield 78.0 %),
mp = 142–144 °C; 1H NMR (600 MHz, DMSO-d6) d 2.77
(d, J = 4.8 Hz, 3H), 7.25 (m, 2H), 7.43 (m, 1H), 7.58–7.73
(m, 6H), 8.42 (d, J = 4.8 Hz, 1H), 8.75 (d, J = 4.8 Hz,
1H), 10.11 (s, 1H), 10.18 (s, 1H); 13C NMR (75 MHz,
DMSO-d6) d 26.92, 114.02, 114.30, 117.87, 118.16,
118.56, 121.45 (q, J = 12 Hz), 123.30, 123.37, 125.22,
136.51, 137.16 (dd, J = 36, 12 Hz), 142.28, 149.21,
151.27, 152.84, 164.28, 180.69; HRMS(AP-ESI) m/z: calcd
for C20H17F2N4OS2 [M ? H]? 431.0807, found 431.0811.
N-benzyl-4-(4-(3-(3,4-difluorophenyl)thioureido)phenyl-
thio)picolinamide (9g) Beige solid (yield 68.0 %),
mp = 138–140 °C; 1H NMR (600 MHz, DMSO-d6) d 4.43
(d, J = 6.6 Hz, 2H), 7.21–7.31 (m, 7H), 7.41 (m, 1H),
7.59, (m, 3H), 7.69–7.73 (m, 3H), 8.44 (d, J = 2.4 Hz,
1H), 9.33 (t, J = 6.6 Hz, 1H), 10.14 (s, 1H), 10.22 (s, 1H);
13C NMR (75 MHz, DMSO-d6) d 43.40, 114.00, 114.26,
117.90, 118.14, 118.80, 121.43 (q, J = 12 Hz), 123.26,
123.44, 125.20, 127.71, 128.30, 129.18, 136.58, 137.18
(dd, J = 33, 12 Hz), 140.34, 142.31, 149.31, 151.07,
152.86, 164.35, 180.62; HRMS(AP-ESI) m/z: calcd for
C26H21F2N4OS2 [M ? H]? 507.1119, found 507.1110.
4-(4-(3-(4-Fluorophenyl)thioureido)phenylthio)-N-methyl-
picolinamide (9k) Light yellow solid (yield 82.3 %),
mp = 154–157 °C; 1H NMR (600 MHz, DMSO-d6) d 2.77
(s, 3H), 7.20 (t, J = 8.4 Hz, 2H), 7.24 (m, 1H), 7.48 (m,
2H), 7.58 (m, 3H), 7.73 (d, J = 8.4 Hz, 2H), 8.42 (d,
J = 5.4 Hz, 1H), 8.75 (d, J = 4.8 Hz, 1H), 10.01 (s, 1H),
10.09 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d 26.92,
115.87, 116.19, 118.76, 123.28, 123.43, 125.20, 127.25 (d,
J = 33 Hz), 136.52, 136.65 (d, J = 12 Hz), 142.24,
149.31, 151.20, 152.85, 164.30, 181.11; HRMS (AP-ESI)
123

3966
Med Chem Res (2013) 22:3959–3968
m/z: calcd for C20H18FN4OS2 [M ? H]? 413.0901, found
by the direct method followed by Fourier syntheses. Structure
refinement was performed by full-matrix least-squares pro-
cedures using SHELXL-97 on F2 (Sheldrick, 1997). All H
atoms were placed in calculated positions, with C–H distance
413.0898.
N-methyl-4-(4-(3-(3-(trifluoromethyl)phenyl)thioure-
ido)phenylthio)picolinamide (9l) Off-white solid (yield
75.3 %), mp = 99–103 °C; 1H NMR (DMSO-d6) 2.78
(d, J = 4.8 Hz, 3H), 7.18 (dd, J = 5.6, 2.4 Hz, 1H), 7.23
(d, J = 6.6 Hz, 2H), 7.42 (d, J = 2.4 Hz, 1H), 7.47 (d,
J = 7.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.58 (d, J =
6.6 Hz, 2H), 7.77 (m, 1H), 7.97 (s, 1H), 8.45 (d,
J = 5.4 Hz, 1H), 8.78 (d, J = 4.8 Hz, 1H), 10.26 (s, 1H),
10.31 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d 26.92,
118.81, 120.72 (q), 121.83 (d, J = 15 Hz), 123.37 (m),
125.17, 126.82, 129.81, 130.22, 130.59, 136.60, 141.21,
142.20, 149.30, 151.04, 152.85, 164.31, 180.67; HRMS
(AP-ESI) m/z: calcd for C21H18F3N4OS2 [M ? H]?
463.0869, found 463.0861.
´
˚
of 0.93(aromatic), 0.97 (methylene), 0.98 A (methine), and
´
˚
with N–H distance of 0.86 A, and refined as riding, with Uiso
(H) = 1.2Ueq (C, N). F1, F2, and F3 appeared to be disor-
dered, and were refined as two groups. Crystallographic data
have been deposited with the Cambridge Crystallographic
Data Centre as CCDC No. 869085. Copies of the data can be
obtained on application to the Director, CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: ?44 1223 336 033;
email: deposit@ccdc.cam.ac.uk or www: http://www.ccdc.
cam.ac.uk).
N-cyclohexyl-4-(4-(3-(3-(trifluoromethyl)phenyl)thiourei-
do)phenylthio)picolinamide (9o) White solid (yield
73.5 %), mp = 152–154 °C; 1H NMR (600 MHz, DMSO-
d6) d1.09–1.16 (m, 1H), 1.25–1.31 (m, 2H), 1.34–1.41 (m,
2H), 1.58 (d, J = 12.0 Hz, 1H), 1.68–1.71 (m, 2H),
1.73–1.76 (m, 2H), 3.72 (m, 1H), 7.26 (dd, J = 5.4,
1.8 Hz, 1H), 7.497 (d, J = 8.4 Hz, 1H), 7.57–7.61 (m, 4H),
7.74 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.97 (s,
1H), 8.41 (d, J = 5.4 Hz, 1H), 8.72 (d, J = 4.8 Hz, 1H),
10.26 (s, 1H), 10.32 (s, 1H); 13C NMR (75 MHz, DMSO-
d6) d 25.71, 26.03, 33.04, 48.93, 118.83, 120.71 (q), 121.87
(d, J = 15 Hz), 123.32 (m), 125.15, 126.82, 129.82,
130.23, 130.58, 136.60, 141.19, 142.19, 149.31, 151.03,
152.88, 163.15,180.66; HRMS (AP-ESI) m/z: calcd for
C26H26F3N4OS2 [M ? H]? 531.1495, found 531.1501.
N-benzyl-4-(4-(3-(3-(trifluoromethyl)phenyl)thioureido)
phenylthio)picolinamide (9m) Beige solid (yield
76.3 %), mp = 117–120 °C; 1H NMR (600 MHz, DMSO-
d6) d 4.44 (d, J = 6.0 Hz, 2H), 7.21–7.31 (m, 6H), 7.49 (d,
J = 7.8 Hz, 1H), 7.57–7.61 (m, 4H), 7.73 (d, J = 9.0 Hz,
2H), 7.77 (d, J = 7.8 Hz, 1H), 7.96 (s, 1H), 8.45 (d,
J = 5.4 Hz, 1H), 9.33 (t, J = 6.0 Hz, 1H), 10.27 (s, 1H),
10.32 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d 43.4,
118.84, 120.74 (q), 121.80 (d, J = 15 Hz), 123.34 (m),
125.17, 126.81, 127.11, 128.30, 129.18, 129.82, 130.23,
130.56, 136.62, 140.34, 141.19, 142.22, 149.32, 151.08,
152.81, 164.35, 180.61; HRMS (AP-ESI) m/z: calcd for
C27H22F3N4OS2 [M ? H]? 539.1182, found 539.1177.
4-(4-(3-(3,5-Bis(trifluoromethyl)phenyl)thioureido)phenyl-
thio)-N-methylpicolinamide (9p) Light yellow solid
(yield 70.8 %), mp = 154–156 °C; HPLC purity =
N-cyclopropyl-4-(4-(3-(3-(trifluoromethyl)phenyl)thiourei-
1
do)phenylthio)picolinamide (9n) Off-white solid (yield
1
60.8 %), mp = 160–163 °C; H NMR (600 MHz, DMSO-
98.9 %. H NMR (600 MHz, DMSO-d6) d 2.77 (d, J =
4.2 Hz, 3H), 7.27 (d, J = 5.4 Hz, 1H), 7.61 (m, 3H), 7.71
(d, J = 8.4 Hz, 2H), 7.84 (s, 1H), 8.26 (s, 2H), 8.43 (d,
J = 5.4 Hz, 1H), 8.75 (d, J = 5.4 Hz, 1H), 10.45 (s, 1H),
10.54 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d 26.92,
118.71, 123.36, 124.15, 124.58, 125.58, 130.87, 131.31,
136.62, 141.71, 142.58, 149.30, 151.23, 152.45, 164.75,
180.78; HRMS (AP-ESI) m/z: calcd for C22H17F6N4OS2
[M ? H]? 531.0743, found 531.0750.
d6) d 0.623–0.681 (m, 4H), 0.82-0.87 (m, 1H), 7.26 (dd,
J = 5.4, 1.8 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.58-7.60 (m,
4H), 7.73 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.96
(s, 1H), 8.40 (d, J = 5.4 Hz, 1H), 8.72 (d, J = 4.8 Hz, 1H),
10.26 (s, 1H), 10.32 (s, 1H);13C NMR (75 MHz, DMSO-d6) d
6.64, 23.81, 118.82, 120.75 (q), 121.85 (d, J = 12 Hz),
123.36 (m), 125.16, 126.83, 129.81, 130.24, 130.58, 136.61,
141.20, 142.18, 149.31, 151.04, 152.63, 165.54, 180.63;
HRMS (AP-ESI) m/z: calcd for C23H20F3N4OS2 [M ? H]?
489.1025, found 489.1022. Crystal data for 9n: C23H19
F3N4OS2, FW = 488.56, monoclinic, space group P21/a,
4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)thioure-
ido)phenylthio)-N-methylpicolinamide
(9q) Off-white
a = 10.494(14) A, b = 10.538(14) A, c = 21.69(3)A, a =
solid (yield 74.6 %), mp = 158–160 °C; 1H NMR
(600 MHz, DMSO-d6) d 2.77 (d, J = 5.4 Hz, 3H), 7.26
(dd, J = 5.4, 1.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 3H), 7.71
(t, J = 8.4 Hz, 3H), 7.82 (dd, J = 8.4, 2.4 Hz, 1H), 8.09
(d, J = 2.4 Hz, 1H), 8.42 (d, J = 5.4 Hz, 1H), 8.75 (d,
J = 4.8 Hz, 1H), 10.31 (s, 1H), 10.38 (s, 1H); 13C NMR
˚
˚
˚
3
˚
c = 90°, b = 93.92(2)°, V = 2393(6) A , Z = 4, dcalc
=
1.356 g/cm3, R = 0.1006, wR2 = 0.3274. The crystal struc-
ture analyses were carried out on a Bruker APEX area-
detector diffractometer with graphite monochromated Mo Ka
´
˚
radiation (k = 0.71073 A). The crystal structure was solved
123

Med Chem Res (2013) 22:3959–3968
3967
N-methyl-4-(4-(3-(4-(trifluoromethoxy)phenyl)thioureido)
phenylthio)picolinamide (9u) White solid (yield 72.7 %),
mp = 163–165 °C; 1H NMR (600 MHz, DMSO-d6) d 2.77
(d, J = 4.8 Hz, 3H), 7.26 (dd, J = 5.4, 1.8 Hz, 1H), 7.36 (d,
J = 9.0 Hz, 2H), 7.58–7.62 (m, 5H), 7.74 (d, J = 8.4 Hz,
2H), 8.42 (d, J = 5.4 Hz, 1H), 8.75 (d, J = 5.4 Hz, 1H),
10.15 (s, 1H), 10.21 (s, 1H); 13C NMR (75 MHz, DMSO-d6)
d 26.92, 118.55, 122.23, 123.14, 123.21, 125.09, 126.19,
136.55, 139.45, 142.38, 145.66 (d, J = 12 Hz), 149.26,
151.18, 152.74, 164.76, 180.59. HRMS (AP-ESI) m/z: calcd
for C21H18F3N4O2S2 [M ? H]? 479.0818, found 479.0818.
(75 MHz, DMSO-d6) d 26.91, 118.55, 121.85, 123.41 (m),
123.67, 125.35, 126.34 (d, J = 6 Hz), 127.05, 127.47,
129.51, 132.65, 136.63, 139.94, 142.02, 149.23, 151.08,
152.89, 164.34, 180.65; HRMS (AP-ESI) m/z: calcd for
C21H17ClF3N4OS2 [M ? H]? 497.0479, found 497.0473.
4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)thioureido)
phenylthio)-N-ethylpicolinamide (9r) Off-white solid
1
(yield 63.5 %), mp = 154–156 °C; H NMR (600 MHz,
DMSO-d6) d 1.08 (t, J = 7.2, 3H), 3.27 (m, 2H), 7.28 (dd,
J = 4.8, 1.8 Hz, 1 H), 7.59 (m, 3H), 7.71 (m, 3H), 7.82
(dd, J = 8.4, 1.8 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 8.42
(d, J = 5.4 Hz, 1H), 8.79 (t, J = 6.0 Hz, 1H), 10.31 (s,
1H), 10.38 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d
15.70, 34.66, 118.58, 121.83, 123.37 (m), 123.67, 125.35,
126.36 (d, J = 6 Hz), 127.06, 127.46, 129.48, 132.60,
136.58, 139.93, 142.01, 149.18, 151.07, 152.72, 163.97,
180.62; HRMS(AP-ESI) m/z: calcd for C22H17ClF3N4OS2
[M ? H]? 511.0635, found 511.0638.
Biological evaluation
Preliminary cytotoxic activity of these sorafenib deriva-
tives (9a–u) on HCT116 and MDA-MB-231 cell lines was
investigated in vitro. HCT116, MDA-MB-231 cell lines
were plated on 96-well plates at a density of 5,000 per well
and incubated overnight. The cells were treated with 9a–u
and sorafenib at final concentrations ranging from 0.5 to
200 lM, while control cells were treated with equal vol-
ume of DMSO (0.1 %). After 48 h treatment, 0.5 % MTT
(Amresco, USA) solution was added to each well, and
further incubated for 4 h, then cells were centrifuged at
2,500 rpm for 15 min, the culture medium was removed,
and 150 lL DMSO was added to dissolve the formazan.
After mixing for 5 min, optical density was detected at
570 nm on a microplate reader (Thermo, USA).
4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)thioureido)
phenylthio)-N-cyclopropylpicolinamide (9s) Light yel-
low solid (yield 69.1 %), mp = 150–154 °C; 1H NMR
(600 MHz, DMSO-d6) d 0.63-0.69 (m, 4H), 0.83–0.87 (m,
1H), 7.27 (dd, J = 5.4, 1.8 Hz, 1H), 7.61 (d, J = 8.4 Hz,
3H), 7.70 (m, 3H), 7.82 (dd, J = 8.4, 2.4 Hz, 1H), 8.09 (d,
J = 2.4 Hz, 1H), 8.43 (d, J = 5.4 Hz, 1H), 8.76 (d,
J = 5.4 Hz, 1H), 10.32 (s, 1H), 10.39 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) d 6.64, 23.81, 118.57, 121.83, 123.39
(m), 123.66, 125.34, 126.33 (d, J = 6 Hz), 127.06, 127.47,
129.50, 132.61, 136.60, 139.93, 142.02, 149.19, 151.08,
152.62, 165.52, 180.60; HRMS(AP-ESI) m/z: calcd for
C23H20ClF3N4OS2 [M ? H]? 523.0636, found 523.0630.
Acknowledgments This study was supported by National Science
and Technology Major Project (Grant No. 2009-ZX09103-118) and
Ph.D. Programs Foundation of Ministry of Education of China (No.
20110131110037).
References
4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)thioureido)
phenylthio)-N-cyclohexylpicolinamide (9t) Off-white
solid (yield 71.7 %), mp = 174–175 °C; 1H NMR
(600 MHz, DMSO-d6) d 1.22 * 1.45 (m, 6H), 1.72 (m,
4H), 3.71 (m, 1H), 7.28 (dd, J = 5.4, 2.0 Hz, 1H), 7.59 (d,
J = 1.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.71 (d,
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