Brief Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 4 1105
a nanomolar Ki with Mcl-1 and a nanomolar IC50 against
SMMC7721 cells, similar to the initial compound 3. Excit-
ingly, 6h is much more effective, with a 10-fold lower IC50 than 3.
It not only enhanced the affinity to Mcl-1 but also main-
tained the affinity toBcl-2. The improvedaffinity of6hinvitro
also translated to enhanced intracellular disruption of the
heterodimerization of Mcl-1/Bak, which induced more cas-
pase 3 activation in a dose-dependent manner. These studies
strongly suggested that 6h exhibited antitumor properties
through inhibition of Bcl-2/Mcl-1 and was much more effi-
cient than 3. Extensive studies are in progress to ascertain its
therapeutic potential.
In addition, the binding orientation and positioning of 3
and its derivatives were examined using solution-based bind-
ing studies, docking studies, and SAR studies. The carbonyl
substitution of 3 binds near R146 of Bcl-2 and R263 of Mcl-1
through hydrogen bonds, whereas the 3-position substituent
extends into the p2 pocket. More importantly, our working
hypothesis for accessing a deep p2 pocket of Mcl-1 was
confirmed throughout this study. Enhanced affinity could
be achieved using a proper 3-position group, mimicking the
Bim BH3 peptide, together with the creation of additional
hydrogen bonds. The geometry and bulk of an isopropyl group
are appropriate to hit the p2 pocket of Bcl-2 and Mcl-1. Atert-
amyl group, however, is more suitable for Bcl-2 than Mcl-1.
This illustrated the difference between the p2 pocket of Bcl-2
and Mcl-1.
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Taken together, our data indicated that 3 and its derivates
represent attractive templates for a future “dirty drug” that
functions to kill tumor cells by a canonical machine-based
model of action.
Experimental Section
The synthesis of 6h and 6i is shown in Supporting Information
Scheme 2. 6h. Yield: 0.05 g, 33%. 1H NMR (400 MHz, CDCl3): δ
8.86 (d, J=8.0 Hz, 1H), 8.82 (d, J=8.0 Hz, 1H), 8.02 (d, J=8.4
Hz, 1H), 7.95 (t, J=8.0 Hz, 1H), 7.48 (d, J=8.48 Hz, 2H), 7.05 (d,
J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 1H), 3.42(br, 2H). TOF MS
(EIþ): C21H11N3OS, calcd for 353.0623, found 353.0625. HPLC
system 2: purity=98.43%, tR=20.99 min.
(15) Wang, G.; Nikolovska-Coleska, Z.; Yang, C.; Wang, R.; Tang, G.;
Guo, J.; Shangary, S.; Qiu, S.; Gao, W.; Yang, D.; Meagher, J.;
Stuckey, J.; Krajewski, K.; Jiang, S.; Roller, P. P.; Abaan, H. O.;
Tomita, Y.; Wang, S. Structure-based design of potent small-
molecule inhibitors of anti-apoptotic Bcl-2 proteins. J. Med. Chem.
2006, 49, 6139–6142.
6i. Yield: 0.07 g, 35%. 1H NMR (400 MHz, CDCl3): δ 8.86 (d,
J=8.4 Hz, 1H), 8.81 (d, J=8.4 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H),
7.96 (t, J=8.0Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8Hz,
2H), 7.00 (d, J =8.0 Hz, 1H). TOF MS (EIþ): C21H9N2OSBr,
calcd for 415.9619, found 415.9628. HPLC system 2: purity=
98.5%, tR=15.88 min.
~
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Shangary, S.; Wang, R.; Guo, J.; Gao, W.; Meagher, J.; Stuckey, J.;
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Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (Grant 30772622)
and partly supported bythe Fundamental Research Fundsfor
the Central Universities.
Supporting Information Available: Full experimental details,
1H NMR and HRMS spectra, and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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