Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5 2317
Figure 4. Docking model of Bcl-XL with (A) 6 and docking model of Mcl-1 with (B) 6 and (C) 7. Residues from mutation studies are colored
according to the degree of the corresponding chemical shift perturbation observed: yellow (þþþþþ, þþþþ) = strong shift; orange (þþþ) =
moderate shift; red (þþ) = weak shift. The labeled residues indicate areas of potential steric clashes that prevent the isomers from occupying
the same pocket.
repulsed. Similarly, the aryl ring of 7 lies within a small pocket
atthe BH3 binding site. Thearylring is inproximityto a bulky
H233 residue which may prevent an ortho-substituted com-
pound such as 6 from binding at this position. The structural
features in the antagonists that subtly control the orientation
of binding could perhaps be exploited in the design of new and
more potent inhibitors of Mcl-1. For example, each orienta-
tion may provide new possible sites for interactions with
appropriately placed functionalities in the ligands.
An important opportunity that has arisen from the findings
reported here is the scope for rational and selective drug
design for inhibitors of Bcl-XL and Mcl-1. To the best of
our knowledge, this is the first report where molecular deter-
minants governing the specificity of ligand binding to Bcl-XL
and Mcl-1 have been compared and delineated. This opens up
new challenges and provides new directions in selective drug
design for the Bcl-2 family of proteins.
Acknowledgment. We thank the Agency for Science, Tech-
nology and Research (A*STAR), Singapore, for the funding
for this project. This work was also supported by Grant
BMRC 04/1/21/19/320 (to H.Y.K.M.) from the Biomedical
Research Council of Singapore.
Supporting Information Available: Full experimental details
and 1H and 13C NMR spectra and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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Experimental Section
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The procedures for the synthesis of 6 and 7 are described in
detail in the Supporting Information. Purities of compounds
(>95%) are determined via elemental analysis.
6. Yellow solid, 54% yield. Mp 160-162 ꢀC. 1H NMR
(CDCl3): δ 3.64 (d, J = 7 Hz, 2H), 3.70 (s, 3H, OCH3), 3.92
(s, 3H, OCH3), 6.00 (br s, 1H, NCH), 7.03 (d, J = 8 Hz, 1H), 7.20
(m, 6H), 7.40 (d, J=8 Hz, 1H), 7.74 (s, 1H), 7.81 (d, J=8 Hz, 1H),
8.04 (d, J=8 Hz, 1H), 8.88 (s, 1H). 13C NMR (CDCl3): δ 33.9,
56.0, 58.2, 61.2, 113.9, 122.6, 124.2, 124.6, 125.6, 127.1, 127.8,
128.5, 128.9, 129.2, 132.1, 135.9, 136.7, 147.4, 151.4, 153.1, 156.5,
166.9, 170.9, 191.6. FTIR (KBr, cm-1) 3410 (br), 2920, 1723,
1609, 1263, 1174, 1031, 831, 739, 670. HRMS (ESI-): calcd
505.0897 for C26H21N2O5S2 [M - H]-. Found: 505.0873. Anal.
(C26H22N2O5S2) C, H, N.
7. Obtained as the HCl salt, orange solid, 86% yield. Mp
1
202-203 ꢀC. H NMR (DMSO-d6): δ 3.53 (d, J = 4 Hz, 2H,
PhCH2), 3.83 (s, 3H, CH3), 3.86 (s, 3H, CH3), 5.86 (br s, 1H,
NCH), 7.09 (d, J=8 Hz, 1H), 7.15-7.23 (m, 5H), 7.77 (m, 2H),
7.86 (s, 1H), 7.98 (dd, J=2 and 9 Hz, 1H), 8.13 (d, J=9 Hz, 1H),
8.90 (d, J=2 Hz, 1H). 13C NMR(CDCl3 þ CD3OD): δ 33.6, 55.8,
58.2, 109.8, 111.0, 120.0, 120.1, 123.0, 126.8, 127.0, 128.3, 128.95,
129.0, 130.5, 136.0, 137.0, 149.2, 150.8, 151.8, 157.8, 166.9, 169.5,
191.8. FTIR (KBr, cm-1) 3476 (br), 2907, 2360, 1719, 1584, 1263,
1229, 1023, 836, 738, 698. HRMS (ESI-): calcd 505.0897 for
C26H21N2O5S2 [M - H]-. Found: 505.0873. Anal. (C26H23ClN2-
O5S2) C, H, N.