G.-X. Zhong et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4399–4402
4401
Table 1
IC50 to inhibition growth of cancer cells for compounds (5–8)
Compound
R1
R2
R3
In vitro inhibition (IC50
,
l
mol Lꢀ1
)
Selectivitya
A549
Ishikawa
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
8a
8b
8c
H
H
H
H
CH3
CH2CH3
CH3
CH2CH3
4-Methylpiperazin-1-yl
4-Ethylpiperazin-1-yl
Imidazol-1-yl
CH3
>360
>360
47.39
16.22
2.45
27.60
97.75
70.65
0.94
81.18
4.74
203.27
6.11
142.35
12.54
0.35
>250
0.47
114.57
130.15
122.48
14.72
142.46
37.46
2.00
56.94
7.50
1.87
17.39
11.88
18.32
4.05
0.13
0.69
63.03
103.47
>230
3.79
/
159.96
229.91
75.18
120.76
178.59
130.70
20.49
42.64
86.21
61.33
111.12
109.08
124.71
101.12
>250
30.70
191.95
192.92
178.80
103.01
132.00
11.85
22.41
78.16
57.08
58.72
86.57
94.01
53.21
56.14
8.36
3.38
14.2
30.6
4.37
1.83
1.85
21.9
1.90
18.2
3.31
18.2
1.31
9.94
290
/
63.9
1.68
1.48
1.46
7.00
1.08
3.16
11.2
1.37
7.61
31.3
5.04
7.91
2.90
13.8
64.7
248
2.12
/
H
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
COC6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
CH2CH3
Cyclohexyl
CH2C6H5
C6H5
o-C6H4CH3
m-C6H4CH3
p-C6H4CH3
2,5-(CH3)2C6H3
o-C6H4Cl
m-C6H4Cl
p-C6H4Cl
Morpholine-4-yl
CH3
H
H
H
CH3
CH2CH3
CH2CH2CH3
CH3
CH2CH3
Cyclohexyl
CH2C6H5
CH2CH3
H
H
H
H
H
H
H
H
H
H
H
C6H5
o-C6H4CH3
m-C6H4CH3
p-C6H4CH3
2,5-(CH3)2C6H3
o-C6H4Cl
m-C6H4Cl
p-C6H4Cl
171.06
29.67
>230
>230
9.01
24.59
31.43
20.50
8.73
p-C6H4OCH3
4-Methylpiperazin-1-yl
Morpholine-4-yl
4-NO2-3-CF3C6H3
4-NO2-3-CF3C6H3
4-NO2-3-CF3C6H3
4-NO2-3-CF3C6H3
/
H
H
H
H
/
2.38
8.14
348
52.34
/
COCH3
COC6H5
p-NO2C6H5CO
/
3.02
0.09
0.39
12.20
8d
Cisplation
a
Selectivity is equal to IC50,max/IC50,min for the both tested cells.
12. Hung, D. Y.; Mellick, G. D.; Anissimov, Y. G.; Weiss, M.; Roberts, M. S. J. Pharm.
Sci. 1998, 87, 943.
Acknowledgments
13. Zhong, G. X.; Hu, J. Q.; Zhao, K.; Chen, L. L.; Hu, W. X.; Qiu, M. Y. Bioorg. Med.
Chem. Lett. 2009, 19, 516.
14. Zhong, G. X.; Chen, L. L.; Li, J.; Hu, W. X.; Qi, M. Y. Chin. Chem. Lett. 2008, 19,
1419.
The authors thank the Opening Foundation of The Biochemical
Engineering Key Discipline (20050105), Zhejiang, China, for finan-
cial support and the Nantong Center for Disease Control and Pre-
vention, Nantong, China, for evaluation of anti-tumor activity.
15. Zhong, G. X.; Li, J.; Hu, H. D. CN Patent 101,250,132A, 2008.
16. The 1H NMR, MS and EA of compound 8.
Compound 8a: 83%, white solid, mp 175–176 °C (butanone); 1H NMR (500 MHz,
CDCl3, d ppm): 6.96 (t, 1H, J = 8.5 Hz, 30-H), 6.99 (t, 1H, J = 8.5 Hz, 50-H), 7.16 (d,
1H, J = 8.5 Hz, 5-H), 7.40 (q, 1H, J = 8.5 Hz, 60-H), 7.63 (d, 1H, J = 8.0 Hz, 6-H),
7.68 (s, 1H, 2-H), 8.05 (d, 1H, J = 8.0 Hz, 500-H), 8.09 (s, 1H, 200-H), 8.11 (d, 1H,
J = 8.0 Hz, 600-H, 8.29 (s, 1H, –NH), 11.30 (s, 1H, –OH); EIMS: m/z (%) = 438(M+,
12.93), 233(100), 232 (89.69), 204 (18.02), 177 (28.11), 151 (25.23), 63 (4.45),
53 (16.24); Anal. Calcd for C20H11F5N2O4: C, 54.81; H, 2.53; N, 6.39. Found: C,
54.69; H, 2.48; N, 6.30.
References and notes
1. Yasumoto, M.; Yamawaki, I.; Marunaka, T.; Hashimoto, S. J. Med. Chem. 1978,
21, 738.
2. Unemi, N.; Takeda, S.; Kitasato, K.; Kajihara, M.; Fujii, S. Chemotherapy (Tokyo)
1978, 26, 2000.
3. Ahlin, G.; Karlsson, J.; Pedersen, J. M.; Gustavsson, L.; Larsson, R.; Matsson, P.;
Norinder, U.; Bergstroem, C. A. S.; Artursson, P. J. Med. Chem. 2008, 51, 5932.
4. Lu, S.; Wang, A.; Lu, S.; Dong, Z. Mol. Cancer Ther. 2007, 6, 2057.
5. Cherkasov, A.; Hilpert, K.; Jenssen, H.; Fjell, C. D.; Waldbrook, M.; Mullaly, S. C.;
Volkmer, R.; Hancock, R. E. W. ACS Chem. Biol. 2009, 4, 65.
6. Gaudreau, C.; Girouard, Y.; Gilbert, H.; Gagnon, J.; Bekal, S. Antimicrob. Agents
Chemother. 2008, 52, 4475.
7. Green, N. S.; Palaninathan, S. K.; Sacchettini, J. C.; Kelly, J. W. J. Am. Chem. Soc.
2003, 125, 13404.
8. Adamski-werner, S. L.; Palaninathan, S. K.; Sacchettini, J. C.; Kelly, J. W. J. Med.
Chem. 2004, 47, 355.
9. Funk, L. A.; Mary, M. C.; Kung, P. P.; Meng, J. J.; Zhou, J. Z. WO Patent
2006,117,669, 2006.
10. Yu, C. X.; Xu, L. WO Patent 2008,012,603, 2008.
11. Kucukguzel, G.; Kocatepe, A.; Clercq, E. D.; Sahin, F.; Gulluce, M. Eur. J. Med.
Chem. 2006, 41, 353.
Compound 8b: 67%, white solid, mp 171–173 °C (butanone); 1H NMR
(500 MHz, CDCl3, d ppm): 2.40 (s, 3H, –CH3), 6.97 (t, 1H, J = 8.0 Hz, 30-H),
7.01 (t, 1H, J = 8.0 Hz, 50-H), 7.30 (d, 1H, J = 7.5 Hz, 5-H), 7.44 (q, 1H, J = 8.5 Hz,
60-H), 7.73 (d, 1H, J = 8.0 Hz, 6-H), 7.98 (s, 1H, 2-H), 8.04 (d, 1H, J = 8.0 Hz, 500-
H), 8.07 (d, 1H, J = 8.0 Hz, 600-H), 8.08 (s, 1H, 200-H), 8.47 (s, 1H, –NH); EIMS: m/z
(%) = 480 (M+, 0.90), 438 (24.85), 233 (95.36), 232 (100.00), 204 (16.55), 175
(21.00), 151 (13.30), 53 (8.11); Anal. Calcd for C22H13F5N2O5: C, 55.01; H, 2.73;
N, 5.83. Found: C, 54.92; H, 2.63; N, 5.75.
Compound 8c: 73%, white solid, mp 197–199 °C (butanone); 1H NMR (400 MHz,
CDCl3, d ppm): 6.97 (t, 1H, J = 8.4 Hz, 30-H), 7.02 (t, 1H, J = 8.0 Hz, 50-H), 7.41 (d,
1H, J = 8.4 Hz, 5-H), 7.48 (q, 1H, J = 8.4 Hz, 60-H), 7.60 (t, 2H, J = 8.0 Hz, 3000,5000
-
H), 7.71 (s, 1H, 2-H), 7.75 (t, 1H, J = 8.0 Hz, 4000-H), 7.78 (d, 1H, J = 8.0 Hz, 6-H),
7.92 (d, 1H, J = 8.0 Hz, 500-H), 8.02 (d, 1H, J = 8.0 Hz, 600-H), 8.15 (s, 1H, 200-H),
8.24 (d, 2H, J = 8.0 Hz, 2000,6000-H), 8.85 (s, 1H, –NH); EIMS: m/z (%) = 542 (M+,
5.13), 391 (3.92), 337 (18.54), 232 (73.34), 204 (68.72), 176 (65.61), 175