J. J. Marugan et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3115–3120
3119
Table 2. Comparison of the activity of compounds inhibiting growth
of wt-p53 tumor cells (MCF7) versus mutant p53 tumor cells (MDA-
MB-231)
nists. Structure-base predictions have provided reli-
able guidance in exploring this class of molecules.
Increased potency was obtained by the introduction
of an amine functional group in the ortho position
of the benzylic ring, leading to the formation of an
additional hydrogen bond with Val93. We have also
shown that the replacement of the valeric acid side
chain with different solubilizing groups has major im-
pact on the cellular potency of this class of mole-
cules. Additionally, these series of compounds
induce PIG3 production in cell-based assays, and dis-
play selectivity towards wild-type p53 tumor cells.
The caspase induction shown with compounds 12i,
12e, and 12b indicates that benzodiazepinediones are
capable to activate an apoptotic response in cell-
based assay.
O
R2
R4
N
Cl
N
O
R1
R1
R2
R4
BrdU IC50
(lM)
MCF
MDA
Cl
O
O
12a
12e
12i
I
I
I
16
80
10
57
10
8
OH
Cl
Cl
Cl
Cl
N
O
1.3
NH
NH
NH
2
2
2
2
References and notes
1. Oren, M. J. Biol. Chem. 1999, 274, 36031.
1.1
1.7
0.8
O
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O
12j
N
N
12k
I
N
NH
5. (a) Garcia-Echeverria, C.; Chene, P.; Blommers, M. J. J.;
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Caspase 3/7 Induction
3
2
1
l2i
6. (a) Grasberger, B. L.; Lu, T.; Schubert, C.; Parks, D. J.;
Carver, T. E.; Koblish, H. K.; Cummings, M. D.;
LaFrance, L. V.; Milkiewicz, K. L.; Calvo, R. R.;
Maguire, D.; Lattanze, J.; Franks, C. F.; Zhao, S.;
Ramachandren, K.; Bylebyl, G. R.; Zhang, M.; Manthey,
C. L.; Petrella, E. C.; Pantoliano, M. W.; Deckman, I.
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l2e
l2b
DMSO
0
50 μm
25 μm
10 μm
Treatment
Figure 5. Caspase induction in JAR cells, 48-h exposure.
cells treated with some of our best antagonists.8 At 25
and 50 lM, the rate of caspase-3 and -7 production is
substantially increased compared to that observed for
cells treated with DMSO control. These data clearly
indicate that inhibition of the Hdm2 interaction with
p53 leads to activation of an apoptotic response in
JAR cells.
7. CCDC 601389 contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
In summary, we have reported herein the synthesis of
enantiomerically pure 1,4-benzodiazepine-2,5-diones as
Hdm2 antagonists 12a–m as potent Hdm2 antago-