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Table 2
SAR of 7,8-positions and 4-aryl group of 4-aryl-2-oxo-2H-chromenes in caspase activation assay
OMe
MeO
Br
R1
CN
O
CN
O
MeO
O
R1
O
R2
4a-4b
3a-3e
Entry
R1
R2
EC50
HCT116
(l
M)a
T47D
SNU398
3a
3b
3c
3d
3e
OMe
NH2
NMe2
Cl
H
H
H
H
0.042 0.003
0.82 0.09
0.28 0.05
6.9 0.5
0.041 0.003
0.99 0.16
0.40 0.06
9.4 0.9
0.026 0.002
0.49 0.03
0.26 0.07
5.5 0.2
CH@NCH@CH
CH@NCH@CH
3.0 0.6
4.8 0.9
2.5 0.5
MeO
OMe
4a
NAb
0.017 0.0001
0.053 0.003
0.018 0.0001
0.059 0.0005
0.015 0.0002
0.029 0.0009
OMe
4b
NA
a
Data are the mean of three or more experiments and are reported as mean standard error of the mean (SEM).
NA, not applied.
b
in T47D, HCT116 and SNU398 cells were run in a 96-well microti-
bition assay with a GI50 value of 0.7 nM in T47D cells.
ter plate as described previously.18 The GI50 are summarized in Ta-
ble 3. Compound 2a was found to be highly active with GI50 values
of 0.3–0.9 nM in the three cell lines tested. Similar to what was ob-
served in the caspase activation assay, compound 2b was found to
be less active than 2a in the GI50 assay. Compounds 3b and 3c,
which had low activity in the caspase activation assay, were also
found to have low activity in the GI50 assay.
In conclusion, we have explored the removal of the 4-position
chiral center in the 4-aryl-4H-chromenes and synthesized a ser-
ies of 4-aryl-2-oxo-2H-chromenes having modifications at the 4-
aryl, 7- and 8-positions. Converting the 2-amino group to a 2-
oxo group and removing the chiral center at the 4-position with
a 3,4 double bond led to a series of highly potent apoptosis
inducers. It was found that the 3-cyano-2-oxo-7-methyl-2H-pyr-
rolo[2,3-h]chromenes with 3,4,5-trisubstituted, 3,5-disubstituted
and 3-monosubstituted phenyl group at the 4-position all are
highly active. Similar to what had been found for 2-amino-3-cy-
ano-7-methyl-4H-pyrrolo[2,3-h]chromenes, 2a and 2g were
found to be the most potent analogues in the caspase activation
assay with EC50 values of 13 and 19 nM in T47D cells, respec-
tively. Compound 2a also was highly active in the growth inhi-
Differences in the SAR did arise however, when we looked at
substitutions at the 7-position. It was found that a 7-OMe group
was relatively well tolerated, while 7-NH2, 7-NMe2 and 7-Cl all
resulted in significant reduction of potency. With an OMe group
at the 7-position, modifications of the 4-phenyl group were well
tolerated and led to highly active analogues. The high activity of
4-aryl-2-oxo-2H-chromenes demonstrate that a chiral center at
the 4-position of 4-aryl-4H-chromenes is not essential for induc-
ing apoptosis and provides an alternative series of potent apop-
tosis inducers with a simpler structure compared to the 4-aryl-
4H-chromenes.
References and notes
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Pract. Oncol. 2006, 3, 388; (c) Mehlen, P.; Puisieux, A. Nat. Rev. Cancer 2006, 6,
449; (d) Reed, J. C. Nat. Rev. Drug Discov. 2002, 1, 111; (e) Reed, J. C.; Tomaselli,
K. J. Curr. Opin. Biotechnol. 2000, 11, 586.
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1998, 5, R97.
4. (a) Hunter, A. M.; LaCasse, E. C.; Korneluk, R. G. Apoptosis 2007, 12, 1543; (b)
Evan, G. I.; Vousden, K. H. Nature 2001, 411, 342; (c) Hanahan, D.; Weinberg, R.
A. Cell 2000, 100, 57; (d) Reed, J. C. J. Clin. Oncol. 1999, 17, 2941.
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A. H. Nature 2000, 407, 777.
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8. Cai, S. X.; Zhang, H. Z.; Guastella, J.; Drewe, J.; Yang, W.; Weber, E. Bioorg. Med.
Chem. Lett. 2001, 11, 39.
Table 3
Inhibition of Cell Growth of 4-Aryl-2-oxo-2H-chromenes
Entry
GI50
HCT116
(l
M)a
T47D
SNU398
9. Kasibhatla, S.; Gourdeau, H.; Meerovitch, K.; Drewe, J.; Reddy, S.; Qiu, L.; Zhang,
H.; Bergeron, F.; Bouffard, D.; Yang, Q.; Herich, J.; Lamothe, S.; Cai, S. X.; Tseng,
B. Mol. Cancer Ther. 2004, 3, 1365.
10. Gourdeau, H.; Leblond, L.; Hamelin, B.; Desputeau, C.; Dong, K.; Kianicka, I.;
Custeau, D.; Bourdeau, C.; Geerts, L.; Cai, S. X.; Drewe, J.; Labrecque, D.;
Kasibhatla, S.; Tseng, B. Mol. Cancer Ther. 2004, 3, 1375.
2a
2b
3b
3c
0.0007 0.0002
0.025 0.005
0.63 0.08
0.0009 0.0004
0.026 0.006
0.63 0.13
0.0003 0.0001
0.0079 0.0027
0.44 0.02
0.62 0.18
0.46 0.11
0.15 0.01
a
Data are the mean of three or more experiments and are reported as
mean standard error of the mean (SEM).
11. Kemnitzer, W.; Kasibhatla, S.; Jiang, S.; Zhang, H.; Wang, Y.; Zhao, J.; Jia, S.;
Herich, J.; Labreque, D.; Storer, R.; Meerovitch, K.; Bouffard, D.; Rej, R.; Denis,