Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26 7909
N,N′-Bis(3-hydroxybenzylidene)benzene-1,4-diamine (3c). 3-Hy-
droxybenzaldehyde (2.0 equiv), room temperature for 3 days (80%).
1H NMR: δ ) 6.92-6.94 (m, 2 H), 7.30-7.38 (m, 10 H), 8.58 (s,
2 H), 9.66 (s, 2 OH). 13C NMR: δ ) 114.18, 118.62, 120.20,
121.88, 129.70, 137.39, 149.18, 157.62, 159.89. ESI-MS (m/z): 317
[M + H]+. Anal. (C20H16N2O2‚0.2H2O) C, H, N.
hydrogen bonds have an effect on the NMR spectra of 3b, giving
a more downfield chemical shift of the hydroxyl groups (in
DMSO-d6). The same chemical shift cannot be observed for
N,N′-bis(2-hydroxybenzyl)benzene-1,4-diamine (4b) but can
again be observed for N,N′-bis(2-hydroxybenzylidene)naphtha-
lene-1,4-diamine (5b).
To elucidate the binding possibilities of the SIRT2 inhibitors,
compounds 3b, 5c, 5d, sirtinol, 1, and 2 were docked to the
crystal structure of SIRT2.22 Compounds 3b, 5c, and 5d were
able to adopt binding modes that shared similarities with the
best ranked binding conformation of sirtinol. Compound 2 was
also able to bind in the same area of the cavity. However, a
similar binding pose for 1 could not be found in these dockings.
N,N′-Bis(4-hydroxybenzylidene)benzene-1,4-diamine (3d). 4-Hy-
1
droxybenzaldehyde (2.0 equiv), reflux for 3.0 h (56%). H NMR:
δ ) 6.89 (d, 3J ) 8.5 Hz, 4 H), 7.26 (s, 4 H), 7.78 (d, 3J ) 8.5 Hz,
4 H), 8.51 (s, 2 H), 10.08 (s, 2 OH). 13C NMR: δ ) 115.56, 121.66,
127.56, 130.50, 149.22, 158.98, 160.48. ESI-MS (m/z): 317 [M +
H]+. Anal. (C20H16N2O2‚0.5H2O) C, H, N.
N,N′-Bis(3,4-dihydroxybenzylidene)benzene-1,4-diamine (3e).
3,4-Dihydroxybenzaldehyde (2.1 equiv), room temperature over-
night (63%). 1H NMR (DMSO-d6/CD3OD): δ ) 6.87 (d, 3J ) 8.1
Hz, 2 H), 7.21 (dd, 3J ) 8.1 Hz, 4J ) 1.8 Hz, 2 H), 7.25 (s, 4 H),
7.44-7.45 (m, 2 H), 8.42 (s, 2 H). 13C NMR (DMSO-d6/CD3OD):
δ ) 114.33, 115.63, 121.94, 122.88, 128.50, 145.76, 149.34, 149.56,
159.51. ESI-MS (m/z): 349 [M + H]+. Anal. (C20H16N2O4‚0.3H2O)
C, H, N.
Conclusions
A series of N,N′-bisbenzylidenebenzene-1,4-diamine and
N,N′-bisbenzylidenenaphthalene-1,4-diamine derivatives were
synthesized and tested in vitro against SIRT2. The most potent
compounds were 3b, 5c, and 5d with IC50 of 58.4, 195.9, and
137.4 µM, respectively. Compound 3b was equipotent with the
well-known SIRT2 inhibitor sirtinol. These compounds have a
new type of backbone for SIRT2 inhibitors. The new compounds
were able to adopt binding modes that shared similarities with
the best ranked binding conformation of sirtinol. The synthesized
compounds are symmetrical, but there is no requirement of
symmetry in the binding site of the SIRT2 inhibitor, and
therefore, the next study will involve the synthesis of unsym-
metrical compounds.
N,N′-Bis(2-methoxybenzylidene)benzene-1,4-diamine (3f).
2-Methoxybenzaldehyde (2.0 equiv), room temperature for 2 h
1
(95%). H NMR: δ ) 3.92 (s, 6 H), 7.03-7.06 (m, 2 H), 7.08-
7.10 (m, 2 H), 7.26 (s, 4 H), 7.46-7.50 (m, 2 H), 8.06-8.08 (m,
2 H), 8.92 (s, 2 H). 13C NMR: δ ) 55.57, 111.53, 120.51, 121.73,
124.12, 126.86, 132.78, 149.93, 154.75, 159.23. ESI-MS (m/z): 345
[M + H]+. Anal. (C22H20N2O2‚0.1H2O) C, H, N.
N,N′-Bis(3-methoxybenzylidene)benzene-1,4-diamine (3g).
1
3-Methoxybenzaldehyde (2.5 equiv), reflux 2 h (65%). H NMR:
δ ) 3.84 (s, 6H), 7.10-7.12 (m, 2 H), 7.36 (s, 4 H), 7.43-7.46
(m, 2 H), 7.52-7.53 (m, 4 H), 8.66 (s, 2 H). 13C NMR: δ ) 55.14,
112.48, 117.58, 121.54, 121.94, 129.80, 137.47, 149.16, 159.49,
159.82. ESI-MS (m/z): 345 [M + H]+. Anal. (C22H20N2O2‚0.1H2O)
C, H, N.
Experimental Section
General. NMR spectra (Bruker Avance 500, Bruker Biospin,
Switzerland; 500.1 MHz for 1H and 125.8 MHz for 13C) were
measured in DMSO-d6 if not otherwise noted, and chemical shifts
are expressed in ppm relative to tetramethylsilane as an internal
standard. Positive ion mass spectra (ESI-MS) were acquired with
a LCQ quadrupole ion trap mass spectrometer (Finnigan MAT, San
Jose, CA) equipped with an electrospray ionization source. Com-
bustion analyses for CHN were measured on Thermo Quest CE
Instruments EA 1110 CHNS-O elemental analyzer. Flash chroma-
tography was performed on silica gel. The reactions were performed
in 1-7 mmol scale.
General Method for Synthesis of Imines 3a-h and 5a-g. The
appropriate aldehyde (2.0-2.5 equiv) was added to a solution 1,4-
phenylenediamine (1.0 equiv) in anhydrous ethanol (20 mL) or
naphthalene-1,4-diamine (1.0 equiv) in anhydrous tetrahydrofuran
(except 5c in anhydrous acetonitrile) (20 mL). The reaction was
performed under an argon or nitrogen atmosphere and protected
from light. Benzene-1,4-diamine reactions were stirred at room
temperature or refluxed if necessary. The product precipitated out
of the reaction mixture. Naphthalene-1,4-diamine reactions were
stirred overnight at room temperature. Afterward, the solvent was
evaporated and the residue was washed with methanol.
N,N′-Bis(4-methoxybenzylidene)benzene-1,4-diamine (3h).
4-Methoxybenzaldehyde (3.7 equiv), room temperature for 3 h
1
3
(97%). H NMR: δ ) 3.89 (s, 6 H), 7.00 (d, J ) 8.5 Hz, 4 H),
7.25 (s, 4 H), 7.86 (d, 3J ) 8.5 Hz, 4 H), 8.47 (s, 2 H). 13C NMR:
δ ) 55.69, 114.72, 122.32, 129.97, 130.92, 150.20, 159.32, 162.70.
ESI-MS (m/z): 345 [M + H]+. Anal. (C22H20N2O2‚0.1H2O) C, H,
N.
N,N′-Bisbenzylidenenaphthalene-1,4-diamine (5a). Benzalde-
hyde (2.1 equiv), room temperature overnight (64%). 1H NMR: δ
) 7.31 (s, 2 H), 7.57-7.62 (m, 8 H), 8.08-8.10 (m, 4 H), 8.37-
8.39 (m, 2 H), 8.76 (s, 2 H). 13C NMR: δ ) 113.18, 123.45, 126.21,
128.76, 128.76, 128.92, 131.42, 136.21, 146.18, 159.97. ESI-MS
(m/z): 335 [M + H]+. Anal. (C24H18N2‚0.2H2O) C, H, N.
N,N′-Bis(2-hydroxybenzylidene)naphthalene-1,4-diamine (5b).
2-Hydroxybenzaldehyde (2.1 equiv), room temperature overnight
1
(51%). H NMR: δ ) 7.03-7.06 (m, 4 H), 7.46-7.50 (s, 2 H),
7.55 (s, 2 H), 7.70-7.72 (m, 2 H), 7.77-7.79 (m, 2 H), 8.25-
8.27 (m, 2 H), 9.07 (s, 2 H), 13.06 (s, 2 OH). 13C NMR: δ )
114.73, 116.57, 119.24, 119.73, 122.79, 127.14, 128.23, 132.37,
133.47, 144.16, 160.22, 163.46. ESI-MS (m/z): 367 [M + H]+.
Anal. (C24H18N2O2) C, H, N.
N,N′-Bis(3-hydroxybenzylidene)naphthalene-1,4-diamine (5c).
3-Hydroxybenzaldehyde (2.5 equiv), room temperature for 2.5 h
(27%). 1H NMR: δ ) 6.98-6.99 (m, 2 H), 7.26-7.62 (m, 10 H),
8.36 (m, 2 H), 8.68 (s, 2 H), 9.76 (s, 2 OH). 13C NMR: δ )113.32,
114.41, 118.87, 120.46, 123.48, 126.30, 128.96, 129.90, 137.62,
146.16, 157.79, 160.15. ESI-MS (m/z): 367 [M + H]+. Anal.
(C24H18N2O2‚1.1H2O) C, H, N.
N,N′-Bisbenzylidenebenzene-1,4-diamine (3a). Benzaldehyde
(2.1 equiv), room temperature for 1 h (77%). 1H NMR: δ ) 7.33
(s, 4 H), 7.48-7.51 (m, 6 H), 7.93-7.95 (m, 4 H), 8.63 (s, 2H).
13C NMR: δ ) 121.62, 128.39, 128.42, 131.00, 135.91, 149.16,
159.39. ESI-MS (m/z): 285 [M + H]+. Anal. (C20H16N2) C, H, N.
N,N′-Bis(2-hydroxybenzylidene)benzene-1,4-diamine (3b). 2-Hy-
1
droxybenzaldehyde (2.0 equiv), reflux for 3.5 h (99%). The H
NMR parameters were solved precisely with the PERCHit iterator23
N,N′-Bis(4-hydroxybenzylidene)naphthalene-1,4-diamine (5d).
4-Hydroxybenzaldehyde (2.1 equiv), room temperature for 3 days
3
using PERCH software.24 1H NMR: δ ) 6.977 (d, J ) 8.28 Hz,
1
3
4J ) 1.06 Hz, 2 H), 6.995 (t, 3J ) 7.70, 7.27 Hz, 4J ) 1.06 Hz, 2
H), 7.426 (td, 3J ) 8.28, 7.27 Hz, 4J ) 1.72 Hz, 2 H), 7.545 (s, 4
(47%). H NMR: δ ) 6.94 (d, J ) 8.2 Hz, 4 H), 7.21 (s, 2 H),
3
7.56-7.58 (m, 2 H), 7.92 (d, J ) 8.2 Hz, 4 H), 8.35-8.37 (m, 2
3
4
H), 7.673 (dd, J ) 7.70 Hz, J ) 1.72 Hz, 2 H), 9.030 (s, 2 H),
13.068 (s, 2 OH). 13C NMR: δ ) 116.51, 119.08, 119.27, 122.44,
132.47, 133.22, 146.58, 160.23, 163.05. ESI-MS (m/z): 317 [M +
H]+. Anal. (C20H16N2O2) C, H, N.
H), 8.60 (s, 2 H), 10.16 (s, 2 OH). 13C NMR: δ ) 113.10, 115.74,
123.57, 126.03, 127.87, 129.08, 130.83, 146.23, 159.25, 160.72.
ESI-MS (m/z): 367 [M + H]+. Anal. (C24H18N2O2‚1.7CH3OH) C,
H, N. CH3OH was observed in the NMR spectra.