2438
J.Simpson et al./ Bioorg.Med.Chem.Lett.13 (2003) 2435–2439
Figure 2. Compound 13 compared with luteolin, fisetin and baicalein (common features emphasised).
Table 3. Effect of test compounds on the metabolism of arachidonic
acid through the 5-, 12- and 15-LOX pathways
terminal phenol are both blocked in the former but
exposed in the latter. Further work is required to eluci-
date the mechanism of this effect. Compound 3 was a
more effective inhibitor of all three LOX pathways than
CV-6504, and it did not appear to have any specificity for
a particular pathway. Thus the effect of these agents on
the LOX pathways mirrors their effect on cell-growth
inhibition. As in previous studies the catechol moiety
appeared to be essential for inhibition of LOX.
Compd
Eicosanoid production (pmole/2h)
5-HETE
12-HETE
15-HETE
None (control)
CV6504
3
9
33.5
13.3
4.7
33.6
15.0
7.8
67.5
22.2
5.3
91.5
78.0
110.0
the compounds were potent inhibitors of the enzyme
over a relatively narrow range, IC50 1–2 mM. The activ-
ity appears to be insensitive to the length of the chain
connecting the catechol to the rest of the molecule and
even to the functionality within the chain (amide, a,b-
unsaturated amide, urea and thiourea). In addition, the
precise location of the salicylamide connection to the
central aromatic ring appears not to matter (compare 2,
a 1,4-connection and 3, a 1,3-connection). This toler-
ance in the non-catechol part of the molecules invites
comparison between the catechols in this report and
other 15-LOX inhibiting catechols from different clas-
ses. For example, a recent study by Sadik et al.18 pro-
vides the 15-LOX inhibitory structure–activity data for
a set of flavonoid compounds wherein the best inhibi-
tory activity is found in cases where an aromatic 1,2-
dihydroxy system is present. The most potent was luteolin
(IC50 0.6 mM) followed by baicalein (1 mM) and fisetin
(1.5 mM). See Figure 2 for a comparison of the features
common to luteolin, fisetin, baicalein and compound 13.
In contrast, flavone, a non-catechol, was some 300-fold
less active.
Acknowledgements
We thank Aston Molecules (OSI Pharmaceuticals) and
EPSRC for a studentship to J.S.
References and Notes
1. Rioux, N.; Castonguay, A. Carcinogenesis 1998, 19, 1393.
2. Bandyopadhyay, G. K.; Imagawa, N.; Wallace, D. R.;
Nandi, S. J.Biol.Chem. 1988, 263, 7567.
3. Honn, K. V.; Tang, D. G.; Gao, X.; Butovich, I. A.; Liu, B.;
Timar, J.; Hagmann, W. Cancer Metastasis Rev. 1994, 13, 365.
4. Liu, B.; Maler, R. J.; Hannun, Y. A.; Porter, A. T.; Honn,
K. V. J.Natl.Cancer Inst. 1994, 86, 1145.
5. Honn, K. V.; Tang, D. G.; Duniec, Z. M.; Grossi, I. M.;
Timar, J.; Renaud, C.; Leithauser, M.; Blair, I.; Diglio, C. A.;
Kimler, V. A.; Taylor, J. D.; Marnett, L. J. Cancer Res. 1994,
54, 565.
6. Lysz, T. W.; Arora, J. K.; Lin, C.; Zelenka, P. S. Cell
Growth Differ. 1994, 5, 1069.
7. Tang, D. G.; Gunn, K.-L.; Li, L.; Honn, K. V.; Chen,
Y. Q.; Rice, R. L.; Taylor, J. D.; Porter, A. T. Int.J.Cancer
1997, 72, 1078.
In order to measure the effect of our compounds on the
flux of arachidonic acid through the LOX pathways,
cells were pulsed with [3H] arachidonic acid19 for 2h
after 24-h incubation with 50 mM CV-6504, 3 and 9.
Formation of 5-, 12- and 15-HETE during this time
interval is shown in Table 3. No effect upon cell survival
or growth was observed for 3 or 9 on the timescale of
the experiment. Both 3 and CV-6054 effectively inhib-
ited 5-, 12- and 15-HETE formation. In contrast, 9
promoted their formation by a mechanism as yet
unknown. All that can be said at this point is that 9
differs from 3 in that the catechol function and the
8. Ding, X.-Z.; Kuszynski, C. A.; El-Metivally, T. H.; Adrian,
T. E. Biochem.Biophys.Res.Commun. 1999, 266, 392.
9. Hussey, H. J.; Tisdale, M. J. Br.J.Cancer 1996, 74, 683.
10. Hussey, H. J.; Bibby, M. C.; Tisdale, M. J. Br.J.Cancer
1996, 73, 1187.
11. Hussey, H. J.; Tisdale, M. J. Br.J.Cancer 1997, 75, 845.
12. Hussey, H. J.; Tisdale, M. J. Br.J.Cancer 1996, 74, 1349.
13. Cho, H.; Ueda, M.; Tamaoka, M.; Hamaguchi, M.;
Aisaka, K.; Kiso, Y.; Inoue, T.; Ogino, R.; Tatsuoka, T.;
Ishihara, T. J.Med.Chem. 1991, 34, 1503.
14. Tait, B. D.; Dyer, R. D.; Auerbach, B. J.; Bornemeier, D.;
Guilds-Zamarka, L.; Oxender, M.; Roth, B. D.; Trevedi, B. K.;
Cornicelli, J. A. Bioorg.Med.Chem.Lett. 1996, 6, 93.