Synthesis and anticancer evaluation of thiazolyl-chalcones

Article abstract of DOI:10.1016/j.bmcl.2010.09.041

Thirty-seven (E)-1-(4-methyl-2-arylaminothiazol-5-yl)-3-arylprop-2-en-1- ones were synthesized via Claisen-Schmidt condensation of 1-(4-methyl-2- (arylamino)thiazol-5-yl)ethanone with the corresponding arylaldehydes. All these thiazolyl-chalcones were cha

Full text of DOI:10.1016/j.bmcl.2010.09.041

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6555–6559
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and anticancer evaluation of thiazolyl–chalcones
Hai-Bo Shi a,b, Shi-Jie Zhang a, Qiu-Fu Ge c, Dian-Wu Guo c, Chao-Ming Cai b, Wei-Xiao Hu a,
⇑
a College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, PR China
b Zhejiang Pharmaceutical College, Ningbo 315100, PR China
c Hangzhou Minsheng Pharmaceutical Group Co. Ltd, Hangzhou 310011, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2010
Revised 4 September 2010
Accepted 8 September 2010
Available online 21 September 2010
Thirty-seven (E)-1-(4-methyl-2-arylaminothiazol-5-yl)-3-arylprop-2-en-1-ones were synthesized via
Claisen-Schmidt condensation of 1-(4-methyl-2-(arylamino)thiazol-5-yl)ethanone with the correspond-
ing arylaldehydes. All these thiazolyl–chalcones were characterized and evaluated by MTT assay on
human cancer cell lines BGC-823, PC-3, NCI-H460, BEL-7402 in vitro. Compounds 5, 8, 26, 37 and 41
are effective against cancer cell lines with IC50s below 10 lM. The antitumor activity in ICR mice bearing
sarcoma 180 tumors indicates compounds 10 and 41 have moderate in vivo activity with 22–25% tumor-
weight inhibition.
Keywords:
Thiazole
Chalcone
Ó 2010 Elsevier Ltd. All rights reserved.
Claisen-Schmidt condensation
Anticancer
Molecules that possess sulfur atoms are universal and crucial in
living organisms.1 Thiazoles are an important kind of compounds
containing one sulfur atom.2 These heterocyclic moieties are existed
in many natural products and syntheticdrugs with a broad spectrum
of pharmacological activities, including antibacterial sulfathiaz-
ole,3,4 anticonvulsivant riluzole,5 antiparkinsonian talipexole,6 anti-
viral ritonavir,7 and anticancer dasatinib.8 Chalcones are also an
important kind of compounds that are present in edible plants. They
are the precursors of flavonoids and essential secondary metabolites
in many plants and bacteria.9 Chalcones exhibit a diversity of bioac-
tivities, such as antioxidant, anticancer and anti-inflammatory
activities.10–12 Liu found that many piperidinyl chalcones have
promising antiproliferative activities (IC50 65 l
M).10 To date, there
were some thiazolyl–chalcones being reported. Patil studied syn-
thesis of arylacrylothiazoles and their antifungal activity, but found
none of them active.13 However, there appears to be little in litera-
ture concerning such thiazolyl–chalcones with their anticancer
activities. We attempted to investigate that whether introduction
of thiazole groups into chalcones could enhance their anticancer
activities or not.
In order to find novel thiazolyl–chalcones with high anticancer
activities, we designed and synthesized a series of (E)-1-(4-methyl-
2-arylaminothiazol-5-yl)-3-arylprop-2-en-1-ones 5–41, outlined
in Scheme 1. N-Aryl thioureas 1a–h were prepared by known
R2
O
O
O
S
R2
H
N
O
NH2
2
Cl
a
4
S
NH
R1
NH
b
R1
N
O
1a-h
S
3a-h
NH
R1 = H, 2-CH3, 3-CH3, 4-CH3, 3-Cl, 4-Cl, 3,4-Cl, 3-Cl-4-F;
R2 = H, 2-Cl, 4-Cl, 3-OCH3, 3,4-methylenedioxy, 3,4,5-OCH3
R1
5-41
Scheme 1. Synthesis of thiazolyl–chalcones. Reagents and conditions: (a) methanol, reflux, 54.2–77.5%; (b) KOH, THF, reflux, 11.8–81.3%.
⇑
Corresponding author. Tel./fax: +86 571 88320557.
E-mail address: huyang@mail.hz.zj.cn (W.-X. Hu).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.041

Table 1
Synthesis of thiazolyl–chalcones 5–41
Compds
Substituents
Yield (%)
Mp (°C)
1H NMR (CDCl3)
HRMS/elemental analysisa
R1
R2
C
H
N
5
6
7
8
9
3,4-Cl
H
49.6
42.5
64.4
52.5
45.0
213–215
230–232
215–217
214–215
237–239
7.79 (d, J = 15.2 Hz, 1H, @CH), 7.63–7.19 (m, 8H, Ar–H), 7.16 (d, J =15.2 Hz, 1H, @CH), 2.75 (s, 3H, CH3)
M+H 389.0280
(389.0282)
M+H 422.9885
(422.9892)
M+H 419.0385
(419.0388)
M+H 419.0392
(419.0388)
b
3,4-Cl
3,4-Cl
3,4-Cl
3,4-Cl
4-Cl
7.72 (d, J = 16 Hz, 1H, @CH), 7.60 (d, J = 2.8 Hz, 1H, Ar–H), 7.41 (d, J = 8.0 Hz, 2H, Ar–H), 7.48–7.43 (m, 2H, Ar–H),
7.39 (d, J = 8.0 Hz, 2H, Ar–H), 7.12 (d, J = 15.2 Hz, 1H, @CH), 2.74 (s, 3H, CH3)
7.76 (d, J = 15.2 Hz, 1H, @CH), 7.58 (d, J = 2.4 Hz, 1H, Ar–H), 7.44 (d, J = 8.8 Hz, 2H, Ar–H), 7.29–7.24 (m, 2H, Ar–H),
7.05 (d, J = 15.2 Hz, 1H, @CH), 6.94 (d, J = 8.8 Hz, 2H, Ar–H), 3.85 (s, 3H, OCH3), 2.70 (s, 3H, CH3)
7.75 (d, J = 16 Hz, 1H, @CH), 7.60 (s, 1H, Ar–H), 7.49–7.21 (m, 4H, Ar–H), 7.18 (d, J = 15.2 Hz, 1H, @CH), 7.12 (mc,
1H, Ar–H), 6.98 (d, J = 7.6 Hz, 1H, Ar–H), 3.87(s, 3H, OCH3), 2.75(s, 3H, CH3)
7.69 (d, J = 16 Hz, 1H, @CH), 7.59 (d, J = 2.5 Hz, 1H, Ar–H), 7.47 (d, J = 9 Hz, 1H, Ar–H), 7.28 (d, J = 3.0 Hz, 1H, Ar–H),
7.12–7.10 (m, 2H, Ar–H), 6.98 (d, J = 15.5 Hz, 1H, @CH), 6.85 (d, J = 8.5 Hz, 1H, Ar–H), 6.04 (s, 2H, CH2), 2.72 (s, 3H,
CH3)
4-OCH3
3-OCH3
3,4-methylenedioxy
10
11
3,4-Cl
4-CH3
3,4,5-OCH3
32.4
27.8
232–234
228–230
7.67(d, J = 15.6 Hz, 1H, @CH), 7.63 (d, J = 2.8 Hz, 1H, Ar–H), 7.46 (d, J = 9.2 Hz, 1H, Ar–H), 7.31 (dd, J1 = 2.4 Hz,
J2 = 2.8 Hz, 1H, Ar–H), 7.02 (d, J = 15.2 Hz, 1H, @CH), 6.82 (s, 2H, Ar–H), 3.92 (s, 6H, 2ÂOCH3), 3.90 (s, 3H, OCH3),
2.72 (s, 3H, CH3)
7.65 (d, J = 15.5 Hz, 1H, @CH), 7.27–7.23 (m, 4H, Ar–H), 7.09 (d, J = 2.0 Hz, 1H, Ar–H), 7.07 (dd, J1 = 1.5 Hz,
J2 = 1.5 Hz, 1H, Ar–H), 6.96 (d, J = 15.5 Hz, 1H, @CH), 6.82 (d, J = 8.5 Hz, 1H, Ar–H), 6.02 (s, 2H, CH2), 2.66 (s, 3H,
CH3), 2.38 (s, 3H, CH3)
55.27
(55.12)
4.11
(4.21)
5.69
(5.84)
3,4-methylenedioxy
66.89
(66.65)
4.57
(4.79)
7.53
(7.40)
12
13
14
4-CH3
4-CH3
4-CH3
H
20.0
79.2
47.0
183–185
213–215
174–176
7.75 (d, J = 15.6 Hz, 1H, @CH), 7.60–7.58 (m, 2H, Ar–H), 7.40–7.39 (m, 3H, Ar–H), 7.25–7.19 (m, 4H, Ar–H), 7.15 (d,
J = 15.2 Hz, 1H, @CH), 2.71 (s, 3H, CH3), 2.40 (s, 3H, CH3)
7.68 (d, J = 15.6 Hz, 1H, @CH), 7.52 (d, J = 8.8 Hz, 2H, Ar–H), 7.37 (d, J = 8.4 Hz, 2H, Ar–H), 7.25–7.20 (m, 4H, Ar–H),
7.09 (d, J = 15.6 Hz, 1H, @CH), 2.68 (s, 3H, CH3), 2.38 (s, 3H, CH3)
7.69 (d, J = 15.2 Hz, 1H, @CH), 7.31 (t, J = 8.0 Hz, 1H, Ar–H), 7.24–7.18 (m, 5H, Ar–H), 6.94 (dd, J1 = 2.0 Hz,
J2 = 1.6 Hz, 1H, Ar–H), 7.11 (d, J = 15.2 Hz, 1H, @CH), 7.09 (mc, 1H, Ar–H), 3.85 (s, 3H, OCH3), 2.68 (s, 3H, CH3), 2.37
(s, 3H, CH3)
b
b
4-Cl
3-OCH3
68.98
(69.20)
5.61
(5.53)
7.74
(7.69)
15
4-CH3
2-Cl
27.5
205–206
8.12 (d, J = 15.6 Hz, 1H, @CH), 7.66 (dd, J1 = 2.0 Hz, J2 = 1.6 Hz, 1H, Ar–H), 7.43 (dd, J1 = 1.6 Hz, J2 = 1.6 Hz, 1H, Ar–
H), 7.33–7.28 (m, 2H, Ar–H), 7.24–7.18 (m, 4H, Ar–H), 7.11 (d, J = 15.2 Hz, 1H, @CH), 2.69 (s, 3H, CH3), 2.37 (s, 3H,
CH3)
b
16
17
4-CH3
H
3,4,5-OCH3
3-OCH3
44.4
15.1
203–205
170–172
7.66 (d, J = 15.6 Hz, 1H, @CH), 7.24 (d, J = 3.2 Hz, 4H, Ar–H), 7.00 (d, J = 15.2 Hz, 1H, @CH), 6.80 (s, 2H, Ar–H), 3.91
(s, 6H, 2ÂOCH3), 3.90 (s, 3H, OCH3), 2.70 (s, 3H, CH3), 2.37 (s, 3H, CH3)
65.32
(65.07)
68.60
5.66
(5.70)
5.27
6.74
(6.60)
7.81
7.72 (d, J = 15.6 Hz, 1H, @CH), 7.44 (t, J = 7.8 Hz, 2H, Ar–H), 7.38–7.30 (m, 3H, Ar–H), 7.20 (t, J = 6.8 Hz, 2H, Ar–H),
7.13 (d, J = 15.2 Hz, 1H, @CH), 7.11 (mc, 1H, Ar–H), 6.95 (dd, J1 = 1.6 Hz, J2 = 2.0 Hz, 1H, Ar–H), 3.85 (s, 3H, OCH3),
2.70 (s, 3H, CH3)
(68.55)
(5.18)
(7.99)
18
19
20
21
22
H
H
31.3
13.0
35.3
22.4
19.0
196–197
174–176
200–202
250–252
204–206
7.75 (d, J = 15.2 Hz, 1H, @CH), 7.60 (dd, J1 = 3.2 Hz, J2 = 2.0 Hz, 2H, Ar–H), 7.45–7.36 (m, 7H, Ar–H), 7.21 (d,
J = 7.6 Hz, 1H, Ar–H), 7.16 (d, J = 15.2 Hz, 1H, @CH), 2.71 (s, 3H, CH3)
b
b
b
H
2-Cl
8.13 (d, J = 15.6 Hz, 1H, @CH), 7.68 (dd, J1 = 2.0 Hz, J2 = 2.0 Hz, 1H, Ar–H), 7.46–7.42 (m, 3H, Ar–H), 7.37–7.29 (m,
4H, Ar–H), 7.21 (t, J = 7.4 Hz, 1H, Ar–H), 7.13 (d, J = 16 Hz, 1H, @CH), 2.71 (s, 3H, CH3)
7.69 (d, J = 15.2 Hz, 1H, @CH), 7.52 (d, J = 8.4 Hz, 2H, Ar–H), 7.44 (t, J = 7.8 Hz, 2H, Ar–H), 7.37 (d, J = 8.0 Hz, 4H, Ar–
H), 7.21 (t, J = 7.4 Hz, 1H, Ar–H), 7.11 (d, J = 15.6 Hz, 1H, @CH), 2.69 (s, 3H, CH3)
7.67 (d, J = 15.2 Hz, 1H, @CH), 7.44 (t, J = 8.0 Hz, 2H, Ar–H), 7.37 (d, J = 7.6 Hz, 2H, Ar–H), 7.21 (t, J = 7.4 Hz, 1H, Ar–
H), 7.02 (d, J = 15.2 Hz, 1H, @CH), 6.81 (s, 2H, Ar–H), 3.92 (s, 6H, 2ÂOCH3), 3.90 (s, 3H, OCH3), 2.72 (s, 3H, CH3)
7.67 (d, J = 15.2 Hz, 1H, @CH), 7.54–7.52 (m, 1H, Ar–H), 7.50 (d, J = 8.0 Hz, 2H, Ar–H), 7.36 (d, J = 8.4 Hz, 2H, Ar–H),
7.31 (d, J = 7.6 Hz, 2H, Ar–H), 7.24–7.20 (m, 1H, Ar–H), 7.05 (d, J = 15.6 Hz, 1H, @CH), 2.70 (s, 3H, CH3),
2.35 (s, 3H, CH3)
H
4-Cl
H
3,4,5-OCH3
4-Cl
64.51
(64.37)
65.25
5.49
(5.40)
4.79
6.93
(6.82)
7.50
2-CH3
(65.12)
(4.65)
(7.59)

23
24
2-CH3
2-CH3
2-Cl
51.6
16.5
181–183
173–176
8.11 (d, J = 15.6 Hz, 1H, @CH), 7.64 (dd, J1 = 2.4 Hz, J2 = 2.4 Hz, 1H, Ar–H), 7.53 (d, J = 8.8 Hz, 1H, Ar–H), 7.42 (dd,
J1 = 2.0 Hz, J2 = 0.8 Hz, 1H, Ar–H), 7.33–7.27 (m, 4H, Ar–H), 7.23–7.20 (m, 1H, Ar–H), 7.07 (d, J = 15.2 Hz, 1H, @CH),
2.69 (s, 3H, CH3), 2.35 (s, 1H, CH3)
7.69 (d, J = 15.6 Hz, 1H, @CH), 7.54 (d, J = 8.0 Hz, 1H, Ar–H), 7.34–7.29 (m, 3H, Ar–H), 7.23–7.16 (m, 2H, Ar–H),
7.09 (d, J = 15.6 Hz, 1H, @CH), 7.08 (mc, 1H, Ar–H), 6.94 (dd, J1 = 2.0 Hz, J2 = 2.8 Hz, 1H, Ar–H), 3.84 (s, 3H, OCH3),
2.70 (s, 3H, CH3), 2.35 (s, 3H, CH3)
65.20
(65.12)
4.73
(4.65)
7.45
(7.59)
3-OCH3
69.25
(69.20)
5.71
(5.53)
7.56
(7.69)
25
26
2-CH3
2-CH3
H
28.8
28.0
194–196
146–148
7.72 (d, J = 15.6 Hz, 1H, @CH), 7.58–7.53 (m, 3H, Ar–H), 7.38 (t, J = 3.2 Hz, 3H, Ar–H), 7.32 (t, J = 7.2 Hz, 2H, Ar–H),
7.23–7.19 (m, 1H, Ar–H), 7.10 (d, J = 15.6 Hz, 1H, @CH), 2.68 (s, 3H, CH3), 2.35 (s, 3H, CH3)
7.63 (d, J = 15.6 Hz, 1H, @CH), 7.54 (d, J = 7.6 Hz, 1H, Ar–H), 7.34–7.31 (m, 2H, Ar–H), 7.22 (t, J = 7.6 Hz, 1H, Ar–H),
6.95 (d, J = 15.2 Hz, 1H, @CH), 6.78 (s, 2H, Ar–H), 3.90 (s, 6H, OCH3), 3.88 (s, 3H, OCH3), 2.66 (s, 3H, CH3), 2.35 (s,
3H, CH3)
71.67
(71.83)
65.23
5.69
(5.42)
5.81
8.51
(8.38)
6.75
3,4,5-OCH3
(65.07)
(5.70)
(6.60)
27
3-CH3
3-OCH3
30.8
164–166
7.70 (d, J = 15.6 Hz, 1H, @CH), 7.32 (t, J = 7.4 Hz, 2H, Ar–H), 7.18 (t, J = 7.0 Hz, 2H, Ar–H), 7.14–7.10 (mc, 2H, Ar–H),
7.13 (d, J = 15.6 Hz, 1H, @CH), 7.02 (d, J = 7.6 Hz, 1H, Ar–H), 6.94 (dd, J1 = 2.0 Hz, J2 = 2.4 Hz, 1H, Ar–H), 3.85 (s, 3H,
OCH3), 2.70 (s, 3H, CH3), 2.40 (s, 3H, CH3)
69.25
(69.20)
5.68
(5.53)
7.77
(7.69)
28
29
3-CH3
3-CH3
H
33.8
29.3
173–175
196–198
7.76 (d, J = 15.2 Hz, 1H, @CH), 7.60 (dd, J1 = 3.6 Hz, J2 = 2.0 Hz, 2H, Ar–H), 7.41 (t, J = 3.2 Hz, 3H, Ar–H), 7.34–7.28
(m, 2H, Ar–H), 7.16 (d, J = 15.6 Hz, 1H, @CH), 7.16 (mc, 2H, Ar–H), 2.72 (s, 3H, CH3), 2.41 (s, 3H, CH3)
7.69 (d, J = 15.6 Hz, 1H, @CH), 7.52 (d, J = 8.8 Hz, 2H, Ar–H), 7.37 (d, J = 8.4 Hz, 2H, Ar–H), 7.31 (t, J = 8.0 Hz, 1H, Ar–
H), 7.17 (d, J = 8.4 Hz, 1H, Ar–H), 7.14 (mc, 2H, Ar–H), 7.11 (d, J = 15.6 Hz, 1H, @CH), 2.70 (s, 3H, CH3), 2.40 (s, 3H,
CH3)
71.75
(71.83)
65.28
5.60
(5.42)
4.73
8.57
(8.38)
7.48
4-Cl
(65.12)
(4.65)
(7.59)
30
3-CH3
3,4,5-OCH3
11.8
190–192
7.66 (d, J = 15.2 Hz, 1H, @CH), 7.31 (t, J = 7.6 Hz, 1H, Ar–H), 7.18 (d, J = 8.8 Hz, 1H, Ar–H), 7.14 (s, 1H, Ar–H), 7.03
(mc, 1H, Ar–H), 7.02 (d, J = 14.8 Hz, 1H, @CH), 6.81 (s, 2H, Ar–H), 3.91 (s, 6H, 2ÂOCH3), 3.90 (s, 3H, OCH3), 2.70 (s,
3H, CH3), 2.40 (s, 3H, CH3)
65.19
(65.07)
5.87
(5.70)
6.71
(6.60)
31
32
33
34
35
36
37
3-CH3
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
3-Cl
2-Cl
45.8
38.8
48.8
40.9
41.9
27.0
19.5
174–176
199–202
190–192
242–244
233–235
211–212
188–190
8.12 (d, J = 15.6 Hz, 1H, @CH), 7.68–7.66 (m, 1H, Ar–H), 7.44–7.42 (m, 1H, Ar–H), 7.33–7.29 (m, 3H, Ar–H), 7.18–
7.16 (mc, 2H, Ar–H), 7.13 (d, J = 15.2 Hz, 1H, @CH), 7.01 (d, J = 7.2 Hz, 1H, Ar–H), 2.69 (s, 3H, CH3), 2.40 (s, 3H, CH3)
7.76 (d, J = 15.2 Hz, 1H, @CH), 7.60 (dd, J1 = 3.6 Hz, J2 = 2.4 Hz, 2H, Ar–H), 7.41(dd, J1 = 4.0 Hz, J2 = 3.2 Hz, 4H, Ar–
H), 7.38–7.33 (m, 3H, Ar–H), 7.15 (d, J = 15.2 Hz, 1H, @CH), 2.71 (s, 3H, CH3)
7.71 (d, J = 15.2 Hz, 1H, @CH), 7.40–7.31 (m, 5H, Ar–H), 7.19 (d, J = 7.6 Hz, 1H, Ar–H), 7.12 (d, J = 15.2 Hz, 1H,
@CH), 7.10 (mc, 1H, Ar–H), 6.96 (dd, J1 = 2.0 Hz, J2 = 2.4 Hz, 1H, Ar–H), 3.85 (s, 3H, OCH3), 2.70 (s, 3H, CH3)
7.70 (d, J = 15.6 Hz, 1H, @CH), 7.53 (d, J = 8.4 Hz, 2H, Ar–H), 7.41–7.33 (m, 6H, Ar–H), 7.10 (d, J = 15.2 Hz, 1H,
@CH), 2.70 (s, 3H, CH3)
65.30
(65.12)
b
4.53
(4.65)
7.44
(7.59)
H
3-OCH3
4-Cl
62.60
(62.41)
b
4.82
(4.45)
7.45
(7.28)
3,4,5-OCH3
4-OCH3
3-OCH3
7.67 (d, J = 15.6 Hz, 1H, @CH), 7.36 (dd, J1 = 8.8 Hz, J2 = 8.4 Hz, 4H, Ar–H), 7.01 (d, J = 15.6 Hz, 1H, @CH), 6.81 (s, 2H,
Ar–H), 3.92 (s, 6H, 2ÂOCH3), 3.90 (s, 3H, OCH3), 2.71 (s, 3H, CH3)
59.25
(59.39)
b
4.79
(4.76)
6.43
(6.30)
7.72 (d, J = 15.2 Hz, 1H, @CH), 7.55 (d, J = 8.4 Hz, 2H, Ar–H), 7.36 (dd, J1 = 9.2 Hz, J2 = 7.2 Hz, 4H, Ar–H), 7.02 (d,
J = 15.2 Hz, 1H, @CH), 6.92 (d, J = 8.4 Hz, 2H, Ar–H), 3.85 (s, 3H, OCH3), 2.70 (s, 3H, CH3)
7.72 (d, J = 15.2 Hz, 1H, @CH), 7.43 (t, J = 2.0 Hz, 1H, Ar–H), 7.36–7.28 (m, 3H, Ar–H), 7.20 (d, J = 8.0 Hz, 1H, Ar–H),
7.15–7.10 (mc, 2H, Ar–H), 7.14 (d, J = 15.6 Hz, 1H, @CH), 6.95 (dd, J1 = 2.4 Hz, J2 = 2.4 Hz, 1H, Ar–H), 3.86 (s, 3H,
OCH3), 2.71 (s, 3H, CH3)
62.34
(62.41)
4.62
(4.45)
7.53
(7.28)
38
39
40
41
3-Cl
H
26.4
13.5
24.7
81.3
210–212
207–209
215–217
241–243
7.76 (d, J = 15.2 Hz, 1H, @CH), 7.62–7.59 (m, 2H, Ar–H), 7.43–7.40 (m, 4H, Ar–H), 7.36–7.28 (m, 2H, Ar–H), 7.16 (d,
64.49
(64.31)
58.45
(58.62)
59.47
(59.39)
57.26
4.41
(4.26)
3.74
(3.62)
4.91
(4.76)
4.64
7.73
(7.89)
7.39
(7.20)
6.53
(6.30)
6.24
J = 15.2 Hz, 1H, @CH), 7.15–7.13 (mc, 1H, Ar–H), 2.72 (s, 3H, CH3)
3-Cl
4-Cl
7.70 (d, J = 15.6 Hz, 1H, @CH), 7.53 (d, J = 8.4 Hz, 2H, Ar–H), 7.43 (t, J = 2.0 Hz, 1H, Ar–H), 7.39–7.27 (m, 4H, Ar–H),
7.16 (mc, 1H, Ar–H), 7.12 (d, J = 15.2 Hz, 1H, @CH), 2.71 (s, 3H, CH3)
7.67 (d, J = 15.2 Hz, 1H, @CH), 7.44 (t, J = 2.0 Hz, 1H, Ar–H), 7.33–7.28 (m, 2H, Ar–H), 7.14 (d, J = 7.6 Hz, 1H, Ar–H),
7.03 (d, J = 15.2 Hz, 1H, @CH), 6.81 (s, 2H, Ar–H), 3.92 (s, 6H, 2ÂOCH3), 3.90 (s, 3H, OCH3), 2.71 (s, 3H, CH3)
7.72 (d, J = 15.6 Hz, 1H, @CH), 7.59–7.05 (m, 5H, Ar–H), 7.02 (d, J = 15.2 Hz, 1H, @CH), 3.99 (s, 6H, 2ÂOCH3), 3.96
(s, 3H, OCH3), 2.79 (s, 3H, CH3)
3-Cl
3,4,5-OCH3
3,4,5-OCH3
3-Cl,4-F
(57.08)
(4.35)
(6.05)
a
b
c
The data are experimental found by HRMS (APCI) or elemental analysis, and the data in the parentheses are calculated.
Known compounds, see Ref. 13.
Overlapped with @CH signals.

6558
H.-B. Shi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6555–6559
Table 2
Table 3
Anticancer activities against BGC-823, PC-3, NCI-460, BEL-7402 cell lines in vitroa
Antitumor efficacy of selected compounds 10 and 41 against S180 xenograft in micea
No. animalsb
TW (g)c
TWI (%)d
Compds
Cancer cell inhibition, IC50 (lM)
Groups
Dose (mg/kg)
Ad.
BGC-823
PC-3
NCI-H460
BEL-7402
Control
CTX
10
—
100
25
50
25
Ip
Ip
Ip
Ip
Ip
Ip
10
8
8
8
8
2.52 0.80
0.21 0.05*
2.64 0.70
1.89 0.37
1.94 0.74
1.95 0.37
—
91.68
—
25.15
22.97
22.61
5
6
7
8
9
10.64
22.69
>25
8.35
>25
>25
>25
>25
>25
>25
>25
>25
14.29
19.53
22.76
>25
>25
>25
>25
>25
>25
5.40
>25
13.62
>25
17.22
24.15
>25
>25
>25
>25
>25
nt
>25
>25
7.99
>25
>25
10.10
>25
19.33
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
11.68
>25
>25
22.17
24.60
>25
>25
>25
>25
>25
>25
>25
>25
nt
22.67
>25
>25
20.07
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
6.32
>25
21.83
>25
19.83
>25
>25
>25
>25
22.00
>25
>25
>25
>25
>25
6.31
2.57
21.54
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
10.28
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
13.97
nt
10
41
41
50
8
*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
DDP
p <0.01, compared to control.
Values presented are means SD. Statistical analysis: student t-test.
Number of mice tested in the group.
Average tumor-weight after drug treatment.
Percentage of tumor-weight inhibition versus control group.
a
b
c
d
stituent (R1 = 3,4-Cl) but different R2, it could be found that com-
pounds 5 (R2 = H) and 8 (R2 = 3-OCH3) have better anticancer
activities. Moreover, compound 26 (R2 = 3,4,5-OCH3) has better
activities among compounds 22–26 (R1 = 2-CH3), and 28 (R2 = H)
has better activities among 27–31 (R1 = 3-CH3), and 37 (R2 = 3-
OCH3) have better activities among 37–40 (R1 = 3-Cl). Therefore,
substituents R2 like H, 3-OCH3, 3,4,5-OCH3 may be positive to
enhance the activities. On the other hand, comparing the activities
of compounds 10, 16, 21, 26, 30, 35, 40 and 41, they have the same
R2 (R2 = 3,4,5-OCH3) but different R1. For prostate carcinoma PC-3
cell lines, compound 10 (R1 = 3,4-Cl) has better activity, and for
NCI-H460, BGC-823 and BEL-7402, compound 26 (R1 = 2-CH3) has
better activities. Comparing the activities of compounds 8, 14, 17,
24, 27, 33 and 37, which have the same R2 (R2 = 3-OCH3), it could
be found that compound 8 (R1 = 3,4-Cl) has better activities. Also,
comparing the activities of compounds 5, 12, 18, 25, 28, 32 and
38 with the same R2 (R2 = H), compounds 5 (R1 = 3,4-Cl) and 28
(R1 = 3-CH3) have better activities. So the better substituent R1
may be 3,4-Cl, 2-CH3 or 3-CH3 moieties.
Compounds 10 and 41 were also selected to evaluate their anti-
tumor activity in vivo in ICR mice bearing sarcoma 180 cells. Cyto-
phosphane (CTX) was used as a positive control and physiological
saline as a blank control. The results presented in Table 3 showed
that compound 10 through intraperitoneal injection (ip) adminis-
tration at dose of 50 mg/kg, exhibited moderate experimental ther-
apeutic efficacy by 25%, but no tumor inhibition was observed
when the dose was decreased to 25 mg/kg. And compound 41
exhibited equivalent antitumor activity by about 23% at doses of
50 or 25 mg/kg. Anatomical observation found that compound 41
11.59
9.70
21.43
19.06
17.90
a
Values presented are means of three experiments; nt = not tested.
methods in high yields.14,15 3-Chloropentane-2,4-dione 2 was pre-
pared by acetylacetone and NCS (N-chlorosuccinimide) refluxing in
carbon tetrachloride. The aminothiazoles 3a–h were prepared by
thioureas 1a–h and 2 refluxing in methanol with 54.2–77.5%
yields.16 The desired thiazolyl–chalcones 5–41 were obtained by
aminothiazoles 3a–h condensed with the corresponding arylalde-
hydes 4 catalyzed by potassium hydroxide in refluxing THF.17
The structures of compounds 5–41 were confirmed by IR, 1H
NMR, MS, HRMS or elemental analysis, and the results were sum-
marized in Table 1. The configuration of compounds 5–41 is of the
trans form, as the coupling constant of two protons on vinyl bond is
above 15.0 Hz. For example, in 1H NMR spectrum of compound 5,
there are two doublet peaks at 7.79 and 7.16 ppm with coupling
constant J = 15.2 Hz.
All thiazolyl–chalcones 5–41 were evaluated by MTT assay on
growth of human gastric cancer BGC-823, human prostate carci-
noma PC-3, human lung carcinoma NCI-H460, hepatocellular carci-
noma BEL-7402 cell lines. Cisplatin (DDP) was introduced as a
positive control in the assay. The results were summarized in
Table 2.
When testing in high concentration at 100 lg/mL, many thiaz-
olyl–chalcones with low solubility were precipitated out partially
that influenced the precision of MTT assay and the inhibition rates
for most compounds exceeded 80% observed by microscope. From
Table 2, some preliminary structure–activity relationships
concerning the effect of substituents R1 and R2 could be drawn.
Comparing the results of compounds 5–10 with the same R1 sub-
Figure 1. Anatomical observation indicating precipitation of compound 41 and
intestinal obstruction in mouse.

H.-B. Shi et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6555–6559
6559
7. Bell, F. W.; Cantrell, A. S.; Hogberg, M.; Jaskunas, S. R.; Johansson, N. G.; Jordan,
C. L.; Kinnick, M. D.; Lind, P.; Morin, J. M.; Noreen, R.; Oberg, B.; Palkowitz, J. A.;
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precipitated partially in body and led to intestinal obstruction as
shown in Figure 1.
In conclusion, we synthesized a series of thiazolyl–chalcones
(E)-1-(4-methyl-2-arylaminothiazol-5-yl)-3-arylprop-2-en-1-ones
and evaluated their activities against several cancer cell lines in vi-
tro, and compounds 10 and 41 were tested antitumor activity
in vivo against S180 xenograft in mice. Results showed the idea
is true that introduction of thiazole groups into chalcones can im-
prove their anticancer activities and some compounds exhibited
potential anticancer activities. Further studies including the modi-
fication with solubility-enhancing groups are undertaken.
13. Patil, V. H.; Mane, R. A.; Ingle, D. B. Indian J. Chem. 1978, 16B, 1114.
14. Liu, B.; Gao, H. Q.; Zhou, X. J. Chemistry (Hua Xue Tong Bao) 1994, 57,
42.
Acknowledgments
15. Lin, Y.-F.; Hu, W.-X.; Yang, Z.-Y.; Wang, L.-G. J. Zhejiang Univ. Technol. 2007, 35,
27.
16. General procedure for preparation of compounds 3a–h: To a stirred solution of 1-
(3,4-dichlorophenyl)thiourea 1a (11.05 g, 50 mmol) in methanol (100 mL)
We are grateful for Hangzhou Minsheng Pharmaceutical Group
Co. Ltd for drug screening and the Natural Science Foundation of
Ningbo City (Grant No. 2009A610185) for financial support.
below 25 °C, was added
a solution of 3-chloropentane-2,4-dione (6.73 g,
50 mmol) in methanol (15 mL). After addition, the reaction was kept at
refluxing to reach completion. After cooling in ice, white solid was precipitated
and treated with 5% K2CO3 to adjust pH to 7–8. Compound 3a was filtered and
crystallized from ethyl acetate, pale yellow crystals, 11.66 g (yield 77.5%), mp:
220–221 °C; IR mmax (KBr)/cmÀ1: 3270, 3070, 1604, 1587, 1546, 1472, 1362,
1318; 1H NMR (500 MHz, CDCl3, TMS) d: 7.56 (d, J = 2.0 Hz, 1H, Ar–H), 7.47 (d,
J = 8.5 Hz, 1H, Ar–H), 7.24 (dd, J1 = 2.0 Hz, J2 = 8.5 Hz, 1H, Ar–H), 2.65 (s, 3H,
CH3), 2.50 (s, 3H, CH3CO); EIMS m/z (%): 300 (M+, 80), 285 (100), 257 (12), 218
(7), 186 (6), 172 (7), 86 (13), 71 (9). Compounds 3b–h was synthesized in the
same manner by reaction of the corresponding N-substituted thioureas 1b–h
with 3-chloro-acetylaceton 2, respectively.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.09.041.
References and notes
17. General procedure for preparation of compounds 5–41: To a cooled mixture of 1-
(2-(3,4-dichlorophenylamino)-4-methylthiazol-5-yl)ethanone 3a (3.01 g,
10 mmol), benzaldehyde (1.27 g, 12 mmol) and tetrahydrofuran (40 mL) in ice
at about 5 °C, was added dropwise 40% aq potassium hydroxide (5.5 mL) and
then the reaction mixture was allowed to reflux until completion (EtOAc/
toluene = 2:1, monitored by TLC). It was then poured into icy water containing
acetic acid (30 mL) and stood overnight in refrigerator. The precipitated was
filtered and washed with H2O, recrystallized from THF/EtOAc to get pure 5,
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yellow-brown solid, 1.93 g (yield 49.6%), mp: 213–215 °C; IR m :
max (KBr)/cmÀ1
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7.79 (d, J = 15.2 Hz, 1H, @CH), 7.63–7.19 (m, 8H, Ar–H), 7.16 (d, J = 15.2 Hz, 1H,
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