5242
W. Huang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5239–5243
Table 3
SAR study for R2 position*
Scaffold
Entry
Compd
Scaffold
R2
1% O2 IC50 (lM)
1
2
3
20
21
22
A
A
A
4-F
2-tBu
2-NO2
Inactive
Inactive
Inactive
4
5
6
7
8
1
23
A
A
2-EtO
H
2-Cl
2-Me
2-Benzyloxy
2-F
0.43
Inactive
O
R2
24
25
26
27
28
A
A
A
A
A
Inactive
Inactive
Inactive
Inactive
Inactive
N
N
9
10
N
N
2-PhO
O
O
Scaffold A
O
11
12
29
30
A
A
2-MeO
2-MeO, 5-CF3
3.3
Inactive
R2
13
14
15
16
17
31
32
42
33
34
B
B
B
B
B
2-MeO, 5-NO2
2-EtNH
2-Benzyloxy
2-Benzyloxy
2-isobutoxy
0.2
4.2
4.1
22.9
6.2
N
N
N
N
H
Scaffold B
18
19
20
35
36
16
B
B
B
2-EtS
4-MeO
2-EtO
3.5
Inactive
0.09
*
Values of IC50 are the mean of three independent experiments.
try. This research was supported by the Molecular Libraries
Initiative of the National Institutes of Health Roadmap for Medical
Research, National Institutes of Health.
16 16 18 18
Compounds
-
-
-
1
+
10
+
1
+
10
+
µM
+
1% O2
Supplementary data
HIF-1a
Supplementary data associated with this article can be found, in
ß-Actin
References and notes
Figure 2. Effect of compounds 16 and 18 on the accumulation of the HIF-1a protein
under hypoxia conditions.
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However, compound 18 at 10 lM also inhibited HIF-1a protein
accumulation. Stockwell and co-workers reported that these
quinazolin-4-ones caused rapid death of human tumor cells
(BJ-TERT/LT/ST/RASV12 cells) via RAS-RAF-MEK dependent signal-
ing.9 Because Ras, a well known oncogene, has been shown to
stimulate HIF-1
possible that the activity of these quinazolin-4-ones against HIF-
a
expression via the Raf/Mek/ERK pathway,10 it is
1a
accumulation is via the RAS signaling pathway.
In conclusion, we have identified a series of novel quinazolin-4-
one HIF-1
analogue 16 as the new lead, which was almost 5-fold more potent
than the hit from the primary screen (1). The inhibition of HIF-1
a inhibitors. A library synthesis and SAR studies revealed
a
was further confirmed in Western blot analyses. Detailed mecha-
nistic studies and evaluation of these compounds as anti-cancer
agents in rare types of cancer are currently under way and will
be reported in due course.
3. Xia, M.; Bi, K.; Huang, R.; Cho, M.-H.; Sakamuru, S.; Miller, S. C.; Li, H.; Sun, Y.;
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Acknowledgments
4. Becklin, R. R.; Chepanoske, C. L.; Pelter, J. M.; Qi, L.; Robbins, P. B.;
Sahasrabudhe, S. R.; Selliah, R.; Simmons, K.; Stockwell, B. R.; Venkat, R. G.;
Von Rechenberg, M.; Zhen, E. PCT Int. Appl., WO2006081331, 2006.
We thank Paul Shinn and Danielle Van Leer for compound man-
agement, William Leister and Jeremy Smith for analytical chemis-