5068
P.-C. Hong et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5065–5068
Table 3
IC50 value of subnanomolar range possess the most potent inhibi-
tory activities against the CHK1 enzyme. Amidation of either the
C40- or C50-carboxylic acid on the selenophene ring results in not
only increase in CHK1 enzyme potency, also provides a handle
for introducing water soluble groups to improve the pharmaceuti-
cal properties of the indol-2-ones. Our continued efforts to further
study and improve the overall biological and pharmaceutical pro-
file will be reported in future.
Inhibition data for 3-hydroxyphenyl analogs 22 and 44–48
O
R3
CH3
Se
O
N
H
Acknowledgment
OH
Compd
R3
IC50 (nM)
a
The authors thank the Ministry of Economy Affairs of ROC (Tai-
wan) for financially supporting this research.
22
44
45
46
47
48
OH
NH(CH2)2N(CH3)2
NH(CH2)2N(CH2CH3)2
NH(CH2)2N(CH2CH2)2
NH(CH2)2N(CH2CH2)2O
NH(CH2)3-1H-imidazole
>100
33.0
78.9
74.3
>100
64.9
References and notes
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1607.
a
Values are means of two or more experiments.
2. (a) Sancar, A.; Lindsey-Boltz, L. A.; Unsal-Kacmaz, K.; Linn, S. Annu. Rev.
Biochem. 2004, 73, 39; (b) Kastan, M. B.; Bartek, J. Nature 2004, 432, 316.
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Table 4
Inhibition data for 2-hydroxyphenyl analogs 23 and 49–53
O
4. Zhou, B.-B.; Bartek, J. Nat. Rev. Cancer 2004, 4, 216.
R3
5. For recent reviews on CHK1 inhibitors, see: (a) Tao, Z.-F.; Lin, N.-H. Anti-Cancer
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CH3
Se
O
7. Jiang, X.; Zhao, B.; Britton, R.; Lim, L. Y.; Leong, D.; Sanghera, J. S.; Zhou, B.-B. S.;
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N
H
OH
Compd
R3
IC50 (nM)
a
23
49
50
51
52
53
OH
>100
>100
>100
>100
>100
>100
NH(CH2)2N(CH3)2
NH(CH2)2N(CH2CH3)2
NH(CH2)2N(CH2CH2)2
NH(CH2)2N(CH2CH2)2O
NH(CH2)3-1H-imidazole
a
Values are means of two or more experiments.
13. Ni, Z.-J.; Barsanti, P.; Brammeier, N.; Diebes, A.; Poon, D. J.; Ng, S.; Pecchi, S.;
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shows a 55-fold decrease in potency compared with the corre-
sponding 4-hydroxyphenyl compound 39. This trend was also ob-
served on compounds 45–48 a more than 125-fold decrease in
potency compared with corresponding 4-hydroxyphenyl com-
pounds 40–43. Table 4 also reveals that replacing the 4-hydroxy-
phenyl group in 39–43 by 2-hydroxyphenyl (49–53) greatly
reduce their activity. These SAR studies clearly indicate that the
3-methoxy-4-hydroxyphenyl analogues 29–33 and the 4-hydroxy-
phenyl analogues 39–43 with IC50 values of subnanomolar range
provide the most potent compounds and are far more potent than
the other 3-hydroxyphenyl and 2-hydroxyphenyl analogues in this
investigation.
In summary, we have demonstrated selenophene derivatives
29–33 and 39–43 are potent CHK1 inhibitors. Variation of the sub-
stituent on the C40 or C50-position of selenophene ring and the hy-
droxyl group position on C-6 phenolic ring of oxindole are critical
for CHK1 inhibitory. In general, 3-methoxy-4-hydroxyphenyl ana-
logues 29–33 and the 4-hydroxyphenyl analogues 39–43 with an
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20. All of the new compounds were characterized. The 1H NMR spectrum of
compounds 14 and 15 are described herein. Compound 14: 1H NMR (500 MHz,
DMSO-d6) d 10.70 (s, 1H), 9.17 (s, 1H), 8.57 (d, 1H), 8.23 (s, 1H), 7.96 (d, 1H),
7.73 (d, 1H), 7.47 (m, 1H), 7.27 (d, 1H), 7.18 (s, 1H), 7.07 (m, 2H), 6.85 (d, 1H),
3.86 (s, 3H). Compound 15: 1H NMR (500 MHz, DMSO-d6) d 10.67 (s, 1H), 9.18
(s, 1H), 8.11 (s, 1H), 7.76 (d, 1H), 7.68 (d, 1H), 7.26 (m, 1H), 7.17 (d, 1H), 7.12
(m, 1H), 7.05 (m, 2H), 6.85 (d, 1H), 3.85 (s, 3H), 2.60 (s, 3H).
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