K. Wang et al. / Chinese Chemical Letters 25 (2014) 702–704
703
J = 5.6 Hz, Ar-H), 8.12 (s, 1H, Ar-H), 7.61 (m, 4H, Ar-H), 7.32 (m, 5H,
Ar-H), 7.20 (m, 4H, Ar-H), 3.52 (s, 2H, –CH2–). HRMS (ESI) (m/z):
Calcd. for C28H22O4N5ClF3 584.1307 [M+H]+, found 584.1305.
Compound 5b: Yield: 82%; white solid. Mp 182–184 8C 1H NMR
(300 MHz, DMSO-d6): d 10.52 (s, 1H, –CO–NH–), 10.29 (s, 1H, –CO–
NH–), 9.25 (s, 1H, –CONH–), 9.03 (s, 1H, –CONH–), 8.54 (d, 1H,
J = 5.7 Hz, Ar-H), 8.12 (d, 1H, J = 8.7 Hz, Ar-H), 7.64 (m, 4H, Ar-H),
7.35 (m, 4H, Ar-H), 7.17 (m, 3H, Ar-H), 3.52 (s, 2H, –CO–CH2–).
HRMS (ESI) (m/z): Calcd. for C28H21O4N5Cl2F3 618.0917 [M+H]+,
found 618.0907.
Fig. 1. The structure of sorafenib.
44.00 mmol) in dry N,N-dimethylformamide (DMF) (75 mL) was
treated with potassium tert-butoxide (5.15 g, 45.85 mmol) and the
reddish-brown mixture was stirred at room temperature for 2 h.
The contents were treated with methyl 4-chloropicolinate (1,
7.50 g, 44.00 mmol) and potassium carbonate (3.25 g, 23.52 mmol)
and then heated to 80 8C under argon. After 8 h, the mixture was
cooled to room temperature and poured into ethyl acetate
(250 mL) and brine (250 mL). The layers were separated, and
the aqueous phase was back-extracted with ethyl acetate
(150 mL). The combined organic phase were washed with brine
(3Â 500 mL), dried over sodium sulfate, filtered and concentrated
to afford 2 (9.52 g, 89%) as a brown solid after vacuum-drying at
40 8C for 5 h.
3. Results and discussion
Cytotoxicity of these derivatives was evaluated against three
human cancer cell lines by the MTT assay. These three cell lines
are: non-small cell lung carcinoma (A549), human kidney
adenocarcinoma cell line (ACHN) and human breast cancer cell
line (MDA-MB-231). The results of cytotoxicity studies were
summarized in Table 1.
As shown in Table 1, most of compounds exhibited potent
antiproliferative activity against all three cell lines with IC50 = 1–
20
mmol/L; 12 compounds demonstrated significant inhibitory
The suspension of 2 (3.35 g, 13.77 mmol) in CH2Cl2 (10 mL) was
treated with dropwise addition of 4-chloro-3-(trifluoromethyl)-
phenyl isothiocyanate (3.10 g, 14.01 mmol) in CH2Cl2 (15 mL) 0 8C
under argon. The mixture was stirred at room temperature, and a
yellow solid precipitated after 15 min. The mixture was stirred for
24 h and then filtered. The solid was washed with CH2Cl2 and dried
under vacuum for 12 h at 40 8C to afford 3 (6.07 g, 95%) as white
solid [19].
activities against all three cell lines. Compound 5a with
unsubstituted aryl ring exhibited no cytotoxicity against all the
tumor cell lines tested (IC50 > 20
mmol/L). Compound 5c with 3-
chlorophenyl moiety was more potent than 5b and 5d with 2-
chlorophenyl and 4-chlorophenyl moiety. Compound 5g and 5h
with 3-fluorophenyl moiety and 4-fluorophenyl moiety showed
potent inhibitory activity against all three cell lines, with IC50
values of 1.29, 1.99, 3.11
mmol/L and 7.14, 4.47, 3.04 mmol/L,
The suspension of
3 (4.37 g, 9.40 mmol) and hydrazine
respectively. These results indicated that halogen substituent at
the 3-position of phenyl ring is favorable for activity. Compound 5e
and 5f with 3-trifluoromethylphenyl moiety and 4-trifluoro-
methylphenyl moiety showed the most potent inhibitory activity
against MDA-MB-231 cell line with the inhibitory concentration
monohydrate (5.00 g) in methanol (50 mL) was heated to reflux
for 10 h. After cooling at room temperature, the precipitate formed
was filtered and washed with water, to afford 4 (4.0 g, 91%) as
white solid.
Added compound 4 (1 equiv.), appropriate acids (1.2 equiv.), 2-
(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexa-
fluorophosphate (HATU) (1.2 equiv.), Et3N (1.5 equiv.) to anhy-
drous DMF (5 mL) and stirred the solution at room temperature for
12 h. The reaction mixture was poured into H2O (100 mL). The
precipitates were collected by filtration and washed with water to
give the target compound 5a–r in a reasonable yield. Selected
spectral data are listed below and the others were given in
Supporting information.
(IC50) values of 2.39 and 2.61
mmol/L, respectively. Compounds 5i,
5j and 5k, with 3,5-dichlorophenyl moiety, 3-fluoro-4-bromophe-
nyl moiety and 2,3-difluorophenyl moiety showed similar activity
against tested all three cell lines to 5c. Compound 5j exhibited the
most potent inhibitory activity against ACHN cell line with
IC50 = 0.89
m
mol/L. Compound 5l with 3-chloro-4-hydroxylphenyl
mol/L).
moiety was inactive to all tested cell lines (IC50 > 20
m
Bearing one or two methoxyl group on the aromatic derivatives,
Compounds 5m and 5n with 2-methoxylphenyl moiety and 3,4-
dimethoxylphenyl moiety only exhibited cytotoxicity against
Compound 5a: Yield: 93%; white solid. Mp 203–205 8C. 1H NMR
(400 MHz, DMSO-d6):
d 10.50 (s, 1H, –CONH–), 10.29 (s, 1H, –
ACHN, with IC50 values of 9.88 and 10.48
mmol/L. Compound 5o
CONH–), 9.21 (s, 1H, –CONH–), 9.00 (s, 1H, –CONH–), 8.54 (d, 1H,
with 4-ethoxylphenyl moiety only exhibited cytotoxicity against
O
CF3
O
O
O
Cl
Cl
Cl
O
O
O
a
O
O
O
O
O
b
N
N
N
N
N
H
N
H
H2N
1
2
3
CF3
CF3
O
H
N
Cl
O
NH2
O
N
H
O
N
H
d
c
N
N
H
N
H
N
H
N
R
H
5a-r
4
Scheme 1. Synthetic route for the preparation of title compounds 5a–5r. Reagents and conditions: (a) DMF, t-BuOK, 4-aminophenol, K2CO3, 89%, (b) 4-chloro-3-
(trifluoromethyl)phenyl isothiocyanate, DCM, 0 8C to r.t., 95%, (c) NH2NH2, MeOH, reflux, 12 h, 91%, (d) HATU, Et3N, DMF, 73%-93%.
Wang, Ke
