4094
G. H. Jin et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4092–4094
Table 1
To further understand the mechanism of the action of 8d, we
investigated the effect of 8d on the expression of iNOS protein in
LPS-activated BV-2 cells by Western blot analysis. As shown in Fig-
ure 4, compound 8d strongly inhibited expression of iNOS in dose-
dependent manners. These results suggested that the inhibition of
LPS-induced NO production by compound 8d occurred mainly
through inhibition of iNOS expression.
Inhibitory activities of azaisoflavones on the NO production in LPS-activated microglia
R3
R1
O
R2
N
R4
In summary, we synthesized azaisoflavone derivatives and eval-
uated their inhibitory activities of NO production in LPS-activated
microglia. Among the prepared compounds, N-ethyltrihydroxy
azaisoflavone 8d was the most potent. Compound 8d inhibited
NO production through the suppression of iNOS expression. Fur-
ther study of the structural modification, underlying mechanism
and biological activity in vivo are underway. Our result implies
the prepared azaisoflavones can act as good leads for the develop-
ment of useful therapeutic agents to modulate inflammatory dam-
age caused by activated microglia.
Compound
R1
R2
R3
R4
Inh.a (%)
IC50 (lM)
5a
5b
5c
6a
6b
7a
7b
7c
8a
8b
8c
8d
H
OMe
H
H
OH
H
H
OMe
H
H
OH
OH
H
OMe
OMe
OMe
OH
H
H
H
H
nab
23.2
na
—
20.5
—
OMe
OMe
H
OH
H
H
OMe
H
29.5
45.0
31.9
14.9
27.3
47.4
27.0
39.3
58.1
15.6
10.9
18.8
25.8
17.6
9.91
18.5
13.3
7.83
OH
H
OMe
OMe
OMe
OH
OH
OH
Me
Et
Et
Me
Et
Me
Et
H
OH
OH
OH
Acknowledgments
a
Values mean the inhibition of NO production relative to the LPS control at
This work was supported by Grant (R01-2006-000-10515-0)
from the Basic Research Program of the Korea Science & Engineer-
ing Foundation and Seoul R&BD Program (10541).
10
l
M concentration of compounds (n = 3).
b
Not active but only toxic.
50
40
30
20
10
0
Supplementary data
Supplementary data associated with this article can be found, in
**
***
***
References and notes
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hydroxy substituents on the azaisoflavone ring, did not show any
meaningful effect on the activity and even decreased the activity.