Tuan-Ahn. N. Pham et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2534–2535
2535
OCH3
R
HO
O
O
HO
O
O
HO
O
HO
R
O
O
H3CO
OH
OH
OH
O
OH
wogonin
chrysin
oroxylin A
6,8-disubstituted chrysin
Figure 1. Structures of chrysin, oroxylin A, wogonin and 6,8-disubstituted chrysin analogs.
MeO
MeO
OH
I2, DMSO,
100ºC
KOH, MeOH,
rt or
MeO
MeO
OH
+
R
R
OHC
KOH, MeOH/
THF, 40ºC
OMe O
OMe O
1
R
R
R :
HO
O
MeO
MeO
O
HBr (48%)
AcOH
(a) 4-H (b) 4-NO2 (c) 4-F
(d) 3-F (e) 2-F (f) 3-Br
(g) 2,4-F2 (h) 3,4-Cl2
(i) 3-OMe, 4-OH
MeO
reflux
OH
O
OMe O
3
2
Scheme 1. Synthesis of oroxylin A and its analogs.
In conclusion, structural modification of oroxylin A provided
synthetic oroxylin A analogs possessing strong inhibitory activities
against iNOS-mediated NO production from LPS-stimulated BV2
cells. Strong inhibitory activity was observed from the analogs
with mono-substitution at 30 or 40 position of oroxylin A regardless
of atoms or functional groups. Further SAR study with a large num-
ber of analogs possessing diverse functional groups with different
electronic and physical parameters is under progress.
Table 1
Inhibition of NO production from LPS-stimulated BV2 cells by oroxylin A analogs at
10
Ma,b,c
l
No
% of Inhibition (IC50
,
lM)
No
% of Inhibition (IC50, lM)
3a
3b
3c
3d
3e
26.0
3f
45.2 (10.84)
10.6
13.1
8.2
40.0 (7.80)
45.7 (4.73)
40.8 (8.58)
39.9 (11.42)
14.2
3g
3h
3i
wgn
Acknowledgments
a
All compounds were treated at 10
NO production from the basal level.
lM. Treatment of LPS to BV2 cells increased
b
This work was supported by the grant (2009-0072124: Synthe-
sis of Biologically Active Flavonoids Analogs) from the Korea Sci-
ence & Engineering Foundation. The authors thank to Pharmacal
Research Institute and Central Laboratory of Kangwon National
University for the use of analytical instruments and bioassay
facilities.
% inhibition = 100 ꢁ [1 ꢂ (NO of LPS with the analogs treated group ꢂ NO of the
basal)/(NO of LPS stimulated group ꢂ NO of the basal)].
c
Wogonin (wgn) was used as the reference compound.
As demonstrated in Table 1, synthetic oroxylin A (3a) exhibited
less potent inhibitory activity against iNOS-mediated NO produc-
tion from LPS-stimulated BV2 cells compared to that of wogonin.
However, several analogs (3b, 3c, 3d, 3f) showed equivalent to
more potent inhibitory activities than that of wogonin. Mono-
substitutions at 40 (3b, 3c), or 30 (3d, 3f) position increased the
bioactivities, while mono-substitution at 20 position exhibited sig-
nificantly reduced bioactivity (3e) compared to those of analogs at
30 (3d) and 40 (3c) positions. Moreover, di-substitutions at 20/40 (3g)
and 30/40 (3h, 3i) positions resulted in significantly decreased bio-
activities regardless of atoms or functional group. Our present re-
References and notes
1. Hui, K. M.; Michael, S. Y.; Huen, H. Y. W.; Zheng, H.; Sigel, E.; Bauer, R.; Ren, H.;
Li, Z. W.; Wong, J. T. F.; Xue, H. Biochem. Pharmacol. 2002, 64, 1415.
2. Lin, C.; Shied, D. E. Am. J. Chin. Med. 1996, 24, 31.
3. Jeong, J. O.; An, N. Y.; Park, S. H.; Oh, J. G.; Oh, H. L.; Lee, B. G.; Om, A. S.; Kim, B.
S.; Kim, D. H.; Ryu, J. H. J. Pharmacogn. 2004, 35, 22.
4. Hui, K. M.; Wang, X. H.; Xue, H. Planta Med. 2000, 66, 91.
5. Yoon, S. Y.; Chun, M. S.; Lee, Y. S.; Park, H.; Shin, C. Y.; Ryu, J. H.; Cheong, J. H.
Biomol. Ther. 2008, 16, 343.
6. Chi, Y. S.; Cheon, B. S.; Kim, H. P. Biochem. Pharmacol. 2001, 61, 1195.
7. Park, H.; Tran, T. D.; Kim, H. P. Eur. J. Med. Chem. 2005, 40, 943.
8. Gurung, S. K.; Kim, H. P.; Park, H. Arch. Pharm. Res. 2009, 32, 1503.
9. Che, H.; Lim, H.; Kim, H. P.; Park, H. Eur. J. Med. Chem. 2011, 46, 4657.
10. Huang, W. H.; Chien, P. Y.; Yang, C. H.; Lee, A. R. Chem. Pharm. Bull. 2003, 51,
339.
sults imply that anti-inflammatory activity of oroxylin
A is
largely dependent on structural modification of B ring. Also the
methoxyl group of oroxylin A is essential for strong inhibitory
activity since deletion of the methoxyl group resulted in signifi-
cantly reduced bioactivity as shown in the previous results.8,9