Brief Articles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 333
azaLeu-OBz (10a, R ) R1 ) CH2CH(CH3)2, R2 ) H). To a
stirred solution of 4a (1.8 g, 5 mmol) in diethyl ether (5 mL)
was added dropwise 2-formylbenzenzeboronic acid (0.8 g, 5.5
mmol) in a solution of diethyl ether (5 mL). A white precipitate
appeared. After stirring for 1 h, the precipitate was filtered
and washed with diethyl ether to give 10a (1.70 g, 82%): mp
142 °C.1H NMR (CDCl3) δ 0.91 (d, J ) 6.0 Hz, 6H, CH3), 1.12
(d, J ) 6.2 Hz, 6H, CH3), 1.86 (m, 1H, CH), 2.15 (m, 1H, CH),
3.31 (br, 2H, CH2), 3.81 (br, 2H, CH2), 4.50 (br, 2H, CH2), 5.40
(s, 2H, CH2), 7.01 (t, J ) 7.0 Hz, 1H, CH), 7.52 (m, 5H, C6H5),
8.21 (d, J ) 7.5 Hz, 1H, CH), 9.30 (s, 1H, NH), 11.26 (s, 2H,
OH). Anal. (C25H35N4O5B) C, H, N.
activity was decreased in a dose-dependent manner in
B16 cells treated with 11b, a hydrazino-azapeptoid with
in vitro proteasome inhibitory activity. In addition, a
linear correlation (r ) 0.975) was observed between cell
growth and endogenous proteasome activity inhibitions
(see insert of Figure 3).
As expected, ALLN-treated B16 cells also displayed
a reduced proteasome activity. In contrast, 6h, a com-
pound with an antiproliferative activity similar to 11b
but devoid of any in vitro proteasome inhibitory activity,
did not induce any decrease in endogenous proteasome
activity even at a dose equivalent to 2 times its IC50.
These results suggest that the proteasome inhibitor 11b
may promote cell growth inhibition through inhibition
of endogenous proteasome.
m-B(OH)2PhCH)-aza-â3-Phe-N-azaLeu-OBz (11b R )
CH2C6H5, R1 ) CH2CH(CH3)2, R2 ) H). To a stirred solution
of 4b (1.92 g, 5 mmol) in diethyl ether (5 mL) was added
dropwise 3-formylbenzenzeboronic acid (0.8 g, 5.5 mmol) in a
solution of diethyl ether (5 mL). A white precipitate appeared.
After stirring for 1 h, the precipitate was filtered and washed
1
with diethyl ether to give 11b (2.11 g, 82%): mp 157 °C; H
Conclusion
NMR (DMSO-d6 δ 0.92 (m, 6H, CH3), 1.92 (m, 1H, CH), 3.35
(br, 2H, CH2), 4.23 (br, 2H, CH2), 4.69 (s, 2H, CH2), 5.23 (s,
2H, CH2), 7.23 (s, 1H, CH), 7.40 (m, 12H, C6H5), 7.64 (t, J )
6.0 Hz, 1H, CH), 7.70 (d, J ) 7.1 Hz, 1H, CH), 7.85 (s, 1H,
CH), 8.13 (s, 2H, NH + OH), 10.1 (s, 1H, OH); Anal.
(C28H33N4O5B) C, H, N, B.
The present study is, to our knowledge, the first
attempt to synthesize and evaluate the biological activ-
ity of peptidomimetics of known proteasome inhibitors.
The more active compounds were boronic acid deriva-
tives (e.g. 11b) that displayed both in vitro and in vivo
proteasome inhibitory activity. Despite a high selectivity
and specificity, their proteasome inhibitory activity is
very low compared to PS-341, the reference boronic acid
inhibitor which is active in the nanomolar range. In the
present hydrazino-azapeptoid series, the boronic acid is
attached to a phenyl group. This structural feature
likely causes a steric hindrance which could impair the
binding of the compound into the active site and could
be responsible for their low affinity for the proteasome.
These observations will be taken into consideration in
the design of more active peptidomimetics.
Acknowledgment. This work was supported by the
“Ligue Nationale Contre le Cancer” (LNCC), the “As-
sociation pour la Recherche sur le Cancer” (ARC) and
the “Conseil Re´gional de Bretagne”.
Supporting Information Available: Synthesis and
analytical data for 1-14 and biological techniques. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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Experimental Section
General Procedure for Synthesis of Bromo Analogues
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1
tography: (1.18 g, 50%); H NMR (CDCl3) δ 0.80 (m, 2 × 6H,
CH3), 1.56 (m, 1H, CH), 1.81 (m, 1H, CH), 2.46 (d, J ) 5.5 Hz,
2H, CH2), 3.29-3.61 (br, 3 × 2H, CH2), 5.09 (s, 2H, CH2), 7.27
(m, 5H, C6H5), 8.19 (s br, 1H, NH), 8.42 (s br, 1H, NH); Anal.
(C20H31N4O4Br) C, H, N, Br.
m-BrBn-aza-â3-Phe-N-azaLeu-OBz (6b R ) CH2C6H5,
R1 ) CH2CH(CH3)2, R2 ) H). To a stirred solution of 4b
(0.77 g, 2 mmol) in ethanol (5 mL) was added dropwise
3-bromobenzaldehyde (0.38 g, 2.1 mmol) in a solution of
ethanol (2 mL). After 1 h of stirring, NaBH3CN (1.90 g, 30
mmol) was added in small portions at pH 4 (by addition of 2
N HCl), and the reaction mixture was stirred for 1 h. Then, 2
N HCl was added to the solution until pH 1, followed by the
addition of NaHCO3 until pH 4. Finally, the solution was
extracted twice by CH2Cl2 (20 mL). The organic layers were
combined and dried with anhydrous Na2SO4, filtered, and
evaporated under reduced pressure to afford 6b as an oil which
crystallized slowly upon the addition of diethyl ether (4.48 g,
1
82%): mp 82 °C; H NMR (CDCl3) δ 0.94 (d, J ) 6.5 Hz, 6H,
CH3), 1.90 (m, 1H, CH), 3.40 (d, J ) 6.7 Hz, 2H, CH2), 3.84 (s,
2H, CH2), 4.00 (s, 2H, CH2), 4.70 (s, 2H, CH2), 5.13 (s, 2H,
CH2), 7.25-7.45 (m, 15H, C6H5 + NH), 7.56 (s, 1H, NH).
General Procedure for Synthesis of Boronic Acid
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