Y. Jahng et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2559–2562
2561
Table 1. COX-1, COX-2 and 5-LOX inhibitory activities of prepared
compounds
Gastroenterology 1989, 96, 647–655; (c) Fosslien, E. Ann.
Clin. Lab. Sci. 1998, 28, 67–81; (d) Huang, H.-C.; Li, J. J.;
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S. A.; Anderson, G. D.; Veenhuizen, A. W.; Zhang, Y.;
Perkins, W. E.; Burton, E. G.; Cogburn, J. N.; Isakson, P.
C.; Reitz, D. B. J. Med. Chem. 1996, 39, 253–266.
Compounds
IC50 (lM)
COX-1
COX-2
5-LOX
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
1
32.5
23.6
23.6
10.6
13.0
59.7
21.0
13.0
22.1
46.2
9.01
59.9
60.7
80.7
65.3
40.1
57.4
28.7
7.44
12.0
9.01
5.22
12.0
7.92
18.4
11.2
9.02
3.40
26.7
13.7
29.0
1.89
23.4
14.1
8.13
13.5
13.8
10.0
7.60
12.0
13.4
10.0
12.2
9.50
4.80
5.90
14.0
12.8
0.37
6.51
7.52
0.032
2
3
3. (a) Hoffman, C. Curr. Med. Chem. 2000, 7, 1113–1120; (b)
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272–277; (d) Bertolini, A.; Ottani, A.; Sandrini, M.
Pharmacol. Res. 2001, 44, 437–450.
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Parente, L. J. Rheumatol. 2001, 28, 2375–2382; (d)
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5. Parente, L.; Perretti, M. Biochem. Pharmcol. 2003, 63,
153–159.
6. (a) Charlier, C.; Michaux, C. Eur. J. Med. Chem. 2003, 38,
645–659; (b) Ulbich, H.; Fiebich, B.; Dannhardt, G. Eur.
J. Med. Chem. 2002, 37, 953–959; (c) Kirchner, T.;
Argentieri, D. C.; Barbone, A. G.; Singer, M.; Steber,
M.; Ansell, J.; Beers, S. A.; Wachter, M. P.; Wu, W.;
Malloy, E.; Stewart, A.; Ritchie, D. M. J. Pharmacol. Exp.
Ther. 1997, 282, 1094–1101; (d) Skelly, M. M.; Hawkey, C.
J. Int. J. Clin. Pract. 2003, 57, 301–304; (e) Pasqualini, M.
E.; Mohn, C. E.; Petiti, J. P.; Manzo, P.; Eynard, A. R.
Prostaglandins Leukot. Essent. Fatty Acids 2000, 63, 377–
4
5
6
7
8
9
10
11
12
13
14
15
16
17
a
AA861
NS398
b
1.67
<0.002
a
10
Positive control for 5-LOX.
Positive control for COX-1 and COX-2.
b
11
inflammatory process. This result will be published
elsewhere. The structure–activity relationship study of
the prepared compounds for COX-1, COX-2 and
5
5
-LOX inhibitory activities showed that C15 containing
-membered ring at C1 position and six-membered ring
3
83; (f) De Gaetano, G.; Donati, M. B.; Cerletti, C. Trends
Pharmacol. Sci. 2003, 24, 245–252; (g) Kuhn, C.; Bekeme-
ier, H.; Hirschelmann, R.; Giessler, A. J. Biomed. Biochim.
Acta 1988, 47, S320–S323.
at C3 position showed 10–40 times more active for
-LOX than other compounds.
5
7
. (a) Radmark, O. P. Am. J. Respir. Crit. Care Med. Part 2
2
Res. 2001, 43, 429–436; (c) Nickerson-Nutter, C. L.;
Medvedeff, E. D. Arthritis Rheum. 1996, 39, 515–521; (d)
Dyer, R. D.; Connor, D. T. Curr. Pharm. Des. 1997, 3,
In conclusion, we prepared the 17 aromatic compounds
containing propenone moiety and evaluated their COX/
000, 161, S11–S15; (b) Celotti, F.; Laufer, S. Pharmacol.
5
-LOX inhibitory activities. This was the first report of
the dual COX/5-LOX inhibitory activities of simple
propenone derivatives. The results of this study may
provide valuable information to researchers who are
working on the development of safer anti-inflammatory
agents. Further studies are in progress to elaborate the
structure–activity relationship.
4
63–472.
8
. Bone marrow cells from male Balb/cJ mice were cultured
for up to 10 weeks in 50% enriched medium (RPMI 1640
containing 2 mM L-glutamine, 0.1 mM nonessential amino
acids, antibiotics and 10% foetal calf serum) and 50%
WEHI-3 cell conditioned medium as a source of IL-3.
After 3 weeks, >98% of the cells were found to be BMMC
checked by the previously described procedure (13,15).
For measuring inhibitory activity on COX-2 by prepared
compounds, cells suspended at
5
a
cell density of
Acknowledgements
5
· 10 cells/mL in an enriched medium were preincubated
with aspirin (10 lg/mL) for 2 h in order to irreversibly
inactivate the preexisting COX-1. After washing, BMMC
were activated with KL (100 ng/mL), IL-10 (100 l/mL)
and LPS (100 ng/mL) at 37 ꢁC for 8 h in the presence or
absence of the prepared compounds previously dissolved
in dimethylsulfoxide (DMSO). For measuring COX-1
activity, cells without aspirin pretreatment were incubated
at 37 ꢁC for 2 h with activators. All reactions were stopped
by centrifugation at 120g at 4 ꢁC for 5 min. The superna-
tant and cell pellet were immediately frozen in liquid N
and stored at )80 ꢁC for further analysis.
This work was supported by a grant (KRF-2002-005-
E00019) from the Korea Research Foundation, ROK.
References and notes
1
2
. (a) Vane, J. R. Nature (New Biol.) 1971, 231, 232–235; (b)
Laneuville, O.; Breuer, D. K.; De Witt, D. L.; Hla, T.;
Funk, C. D.; Smith, W. L. J. Pharmacol. Exp. 1994, 271,
927–934; (c) Fiorucci, S.; Meri, R.; Buch, M.; Cirino, G.
Biochem. Pharmacol. 2001, 62, 1433–1438.
. (a) De Witt, D. L.; Meade, E. A.; Smith, W. L. Am. J.
Med. 1993, 95, 40S–44S; (b) Fries, J. F.; Miller, S. R.;
Spitz, B. W.; Williams, C. A.; Hubert, H. B.; Broch, D. A.
2
LTC determination: BMMC suspended in an enriched
4
6
medium at a cell density of 1 · 10 cells/mL were pretreated
with prepared compounds for 30 min at 37 ꢁC and stimu-
lated with stem cell factor (SCF; 100 ng/mL). After 20 min
of stimulation, the supernatants were isolated for further