N-(substituted benzyl)-3,5-bis(benzylidene)-4-piperidones: Synthesis and preliminary anti-leukemia activity (I)

Article abstract of DOI:10.1002/cjoc.201180365

A series of novel N-(substituted benzyl)-3,5-bis(benzylidene)-4-piperidones 5a-5o were synthesized with substituted benzylamines as raw materials via a series of Michael addition, Dieckmann condensation, hydrolysis decarboxylation and aldol condensation.

Full text of DOI:10.1002/cjoc.201180365

FULL PAPER
N-(Substituted benzyl)-3,5-bis(benzylidene)-4-piperidones:
Synthesis and Preliminary Anti-leukemia Activity (I)
Wang, Jing(王静)
Meng, Wen(孟雯)
Ni, Zhenjie(倪振杰)
Xue, Sijia*(薛思佳)
Department of Chemistry, College of Life and Environmental Science, Shanghai Normal University, Shanghai
200234, China
A series of novel N-(substituted benzyl)-3,5-bis(benzylidene)-4-piperidones 5a—5o were synthesized with sub-
stituted benzylamines as raw materials via a series of Michael addition, Dieckmann condensation, hydrolysis de-
carboxylation and aldol condensation. The structures were confirmed by 1H NMR, IR, MS techniques and elemental
analysis. Assay-based antiproliferative activity study using leukemic cell lines K562 revealed that most of the title
compounds have high effectiveness in inhibiting leukemia K562 cells proliferation, among which the compounds
5g (IC50＝7.81 µg•mL－ 1), 5k (IC50＝6.35 µg•mL－ 1), 5l (IC50＝7.20 µg•mL－ 1), and 5o (IC50＝5.79 µg•mL－ 1) have
better inhibition activities than standard 5-fluorouracil (IC50＝8.56 µg•mL－ 1).
Keywords 4-piperidone, synthesis, inhibition, leukemia K562 cell, MTT
Introduction
by 1H NMR, IR, MS techiniques and elemental analysis.
The preliminary anti-leukemia activity tests indicate that
most of the novel compounds have good effect on the
antiproliferative activity against leukemia K562 cells.
Chronic myelogenous leukemia (CML) is regarded
as a growing public health threat, killing people faster
than other diseases. It is caused by clonal expansion of
pluripotent hematopoietic stem cells retaining their dif-
ferentiation potential.1 Some studies have showed that
CML cell line K562 is considerably more resistant to
apoptosis than a number of other human hematopoietic
cell lines.2-3 Thus, the development of novel, more ef-
fective leukemia drugs for CML K562 is urgently
needed.
－
1
Compounds 5g (IC50＝7.81 µg•mL ), 5k (IC50＝6.35
－
－
1
1
µg•mL ), 5l (IC50＝7.20 µg•mL ) and 5o (IC50＝5.79
－
1
µg•mL ) have better inhibition activities than standard
－
1
5-fluorouracil (IC50＝8.56 µg•mL ).
Experimental
Materials and apparatus
During last decade different series of compounds
have been designed based on the 1,5-diaryl-3-oxo-
1,4-pentadienyl pharmacophore,4-7 which lead to the
discovery of a number of potent cytotoxic8,9 and antitu-
bercular10 activities. The cytotoxic properties of
3,5-bis(benzylidene)-4-piperidones reported by Dim-
mock et al.,6,7,11 revealed that molecular modification at
the nitrogen atom, e.g. N-acylation, affects the capacity
of transportation of this biologically active molecules
via the cellular membrane and therefore resulted in the
significantly higher level of anticancer activity.
N-(4-Substituted benzyl)piperidone derivatives were
reported to have certain anti-leukemia activitives in our
previous researches.12-14 In order to find some potent
anti-leukemia activity lead compounds, we suggested
combination of the 1,5-diaryl-3-oxo-1,4-pentadienyl
pharmacophore and N-(4-substituted benzyl)piperidones
to obtain a series of novel N-(4-substituted ben-
zyl)-3,5-bis(benzylidene)-4-piperidones 5a — 5o. The
structures of all new compounds have been confirmed
All the chemical reagents purchased were of ana-
lytical grade and used without further purification, ex-
cept for the toluene, which was dried by refluxing in the
1
presence of sodium and distilled prior to use. H NMR
spectra were recorded on a Bruker Avance 400 (400
MHz) spectrometer, using CDCl3 or DMSO-d6 as sol-
vents and tetramethylsilane (TMS) as internal standard.
Melting points were determined by an RK1 microscopic
melting apparatus (uncorrected). Elemental analysis was
performed with a Perkin-Elmer 2400 instrument. MS
spectra were recorded on a Trace DSQ mass spectro-
graph. IR spectra were obtained on a Nicolet 5DX
FT-IR spectrophotometer in the region 4000—400 cm－
1
using KBr discs.
General procedure for the synthesis of N-(4-substi-
tuted benzyl)-4-piperidone derivatives 4I— 4IV
The intermediates of N-(4-methylbenzyl)-4-piperid-
one (4I), N-(4-methoxybenzyl)-4-piperidone (4II), N-
* E-mail: sjxue@sohu.com
Received October 25, 2010; revised May 4, 2011; accepted June 15, 2011.
Project supported by the Key Laboratory of Rare Earth Functional Materials of Shanghai (No. 07dz22303) and the Key Scientific and Technological
Project of Shanghai Science and Technology Commission (No. 09391212100).
Chin. J. Chem. 2011, 29, 2109— 2113
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
2109

Wang et al.
FULL PAPER
(4-bromobenzyl)-4-piperidone (4III) and N-(4-fluoro-
benzyl)-4-piperidone (4IV) were synthesized in our
laboratory according to the literature.14
＋
－1
813 cm ; MS (ESI) m/z: 408 ([M＋H] ). Anal. calcd
for C29H29NO: C 85.30, H 7.64, N 3.69; found C 85.47,
H 7.17, N 3.44.
N-(4-Methylbenzyl)-4-piperidone (4I): Yellow oil,
yield 74%; 1H NMR (CDCl3, 400 MHz) δ: 2.32 (s, 3H),
2.46 (t, J＝6.0 Hz, 4H), 2.74 (t, J＝6.0 Hz, 4H), 3.59 (s,
2H), 7.16 (d, J＝8.0 Hz, 2H), 7.27 (d, J＝8.0 Hz, 2H);
N-(4-Methylbenzyl)-3,5-bis(4-methoxybenzylidene)-
4-piperidone (5c): Yield 79%, yellow solid, m.p. 172—
1
174 ℃; H NMR (CDCl3, 400 MHz) δ: 2.28 (s, 3H),
3.66 (s, 2H), 3.84 (s, 4H), 3.91 (s, 6H), 7.04 (d, J＝7.8
Hz, 2H), 7.13 (d, J＝7.9 Hz, 2H), 7.25 (d, J＝8.3 Hz,
4H), 7.42 (d, J＝8.4 Hz, 4H), 7.80 (s, 2H); IR (KBr) ν:
2934, 2835, 1664, 1600, 1510, 1303, 1255, 1171, 1033,
－1
IR (KBr) ν: 1718, 1514, 795 cm ; MS (EI) m/z: 203.
Anal. calcd for C13H17NO: C 76.81, H 8.43, N 6.89;
found C 76.68, H 8.38, N 6.93.
＋
－1
N-(4-Methoxybenzyl)-4-piperidone (4II): Yellow oil,
827 cm ; MS (ESI) m/z: 440 ([M＋H] ). Anal. calcd
for C29H29NO3: C 79.30, H 6.64, N 3.49; found C 79.24,
H 6.65, N 3.19.
1
yield 78%; H NMR (CDCl3, 400 MHz) δ: 2.37 (t, J＝
6.0 Hz, 4H), 2.65 (t, J＝6.0 Hz, 4H), 3.48 (s, 2H), 3.73
(s, 3H), 6.79 (d, J＝8.4 Hz, 2H), 7.18 (d, J＝8.4 Hz,
N-(4-Methoxybenzyl)-3,5-bis(benzylidene)-4-piperi-
done (5d): Yield 71%, yellow solid, m.p. 129—130 ℃;
1H NMR (CDCl3, 400 MHz) δ: 3.64 (s, 2H), 3.74 (s,
3H), 3.84 (s, 4H), 6.75 (d, J＝8.7 Hz, 2H), 7.15 (d, J＝
8.6 Hz, 2H), 7.31—7.40 (m, 10H), 7.80 (s, 2H); IR
(KBr) ν: 2990, 2828, 1671, 1615, 1587, 1508, 1446,
－1
2H); IR (KBr) ν: 1716, 1511, 834 cm ; MS (EI) m/z:
219. Anal. calcd for C13H17NO2: C 71.21, H 7.81, N
6.39; found C 71.33, H 7.78, N 6.44.
N-(4-Bromobenzyl)-4-piperidone (4III): Yellow oil,
1
yield 68%; H NMR (CDCl3, 400 MHz) δ: 2.48 (t, J＝
＋
－1
6.2 Hz, 4H), 2.78 (t, J＝6.2 Hz, 4H), 3.60 (s, 2H), 7.36
(d, J＝8.1 Hz, 2H), 7－.47 (d, J＝8.0 Hz, 2H); IR (KBr) ν:
1284, 939, 768 cm ; MS (ESI) m/z: 396 ([M＋H] ).
Anal. calcd for C27H25NO2: C 82.12, H 6.34, N 3.55;
found C 82.00, H 6.37, N 3.54.
1
1719, 1510, 791 cm ; MS (EI) m/z: 267. Anal. calcd
for C12H14BrNO: C 53.71, H 5.23, N 5.29; found C
53.75, H 5.26, N 5.22.
N-(4-Methoxybenzyl)-3,5-bis(4-methylbenzylidene)-
4-piperidone (5e): Yield 89%, yellow solid, m.p. 145—
1
N-(4-Fluorobenzyl)-4-piperidone (4IV): Yellow oil,
yield 71%; 1H NMR (CDCl3) δ: 2.45 (t, J＝6.1 Hz, 4H),
2.73 (t, J＝6.1 Hz, 4H), 3.58 (s, 2H), 7.02 (t, J＝8.7 Hz,
2H－), 7.29—7.34 (m, 2H); IR (KBr) ν: 1715, 1507, 760
146 ℃; H NMR (CDCl3, 400 MHz) δ: 2.36 (s, 6H),
3.68 (s, 2H), 3.78 (s, 3H), 3.90 (s, 4H), 6.90 (d, J＝8.7
Hz, 2H), 7.08 (d, J＝8.7 Hz, 2H), 7.18 (d, J＝8.0 Hz,
4H), 7.25 (d, J＝8.0 Hz, 4H), 7.84 (s, 2H); IR (KBr) ν:
2996, 2－833, 1672, 1615, 1511, 1248, 1180, 1036, 936,
1
cm ; MS (EI) m/z: 207. Anal. calcd for C12H14FNO: C
＋
1
69.52, H 6.86, N 6.71; found C 69.55, H 6.81, N 6.76.
814 cm ; MS (ESI) m/z: 424 ([M＋H] ). Anal. calcd
for C29H29NO2: C 82.20, H 6.95, N 3.30; found C 82.24,
H 6.90, N 3.31.
General procedure for the synthesis of N-(4-substi-
tuted benzyl)-3,5-bis(benzylidene)-4-piperidone de-
rivatives 5a— 5o
N-(4-Methylbenzyl)-3,5-bis(4-methoxybenzylidene)-
4-piperidone (5f): Yield 79%, yellow solid, m.p. 172—
1
To a stirred solution of intermediates 4I—4IV (5
mmol) and the appropriate aldehyde (10 mmol) in 15
mL of absolute ethanol, was added 1 mL of 10%
NaOH.15 The reaction mixture was maintained under
room temperature for 0.5—2 h. After this, the separated
solid was filtered off and recrystallized from ethanol to
obtain title compounds 5a — 5o in 68.2% — 92.6%
yields.
174 ℃; H NMR (CDCl3, 400 MHz) δ: 2.28 (s, 3H),
3.66 (s, 2H), 3.84 (s, 4H), 3.91 (s, 6H), 7.04 (d, J＝7.8
Hz, 2H), 7.13 (d, J＝7.9 Hz, 2H), 7.25 (d, J＝8.3 Hz,
4H), 7.42 (d, J＝8.4 Hz, 4H), 7.80 (s, 2H); IR (KBr) ν:
2934, 2835, 1664, 1600, 1510, 1303, 1255, 1171, 1033,
＋
－1
827 cm ; MS (ESI) m/z: 456 ([M＋H] ). Anal. calcd
for C29H29NO3: C 79.30, H 6.64, N 3.49; found C 79.24,
H 6.65, N 3.19.
N-(4-Methylbenzyl)-3,5-bis(benzylidene)-4-piperi-
done (5a): Yield 92%, yellow solid, m.p. 168—170 ℃;
1H NMR (CDCl3, 400 MHz) δ: 2.22 (s, 3H), 4.43 (s,
2H), 4.56 (s, 4H), 7.09 (d, J＝8.4 Hz, 2H), 7.41 (d, J＝
7.8 Hz, 2H), 7.46—7.50 (m, 10H), 7.92 (s, 2H); IR
(KBr) ν: 3055, 2139, 1600, 1569, 1436, 1265, 1181, 990,
N-(4-Methoxybenzyl)-3,5-bis(4-chlorobenzylidene)-
4-piperidone (5g): Yield 90%, yellow solid, m.p. 206—
1
208 ℃; H NMR (CDCl3, 400 MHz) δ: 3.64 (s, 2H),
3.74 (s, 3H), 3.94 (s, 4H), 6.80 (d, J＝8.6 Hz, 2H), 7.10
(d, J＝8.7 Hz, 2H), 7.24 (d, J＝8.0 Hz, 4H), 7.36 (d,
J＝8.1 Hz, 4H), 7.78 (s, 2H); IR (KBr) ν: 3028, 2980,
＋
－1
－1
818, 763 cm ; MS (ESI) m/z: 379 ([M＋H] ). Anal.
calcd for C27H25NO: C 85.45, H 6.64, N 3.69; found C
85.22, H 6.76, N 3.50.
1610, 1516, 1491, 1260, 1183, 1094, 1004, 829 cm ;
MS (ESI) m/z: 464 ([M ＋ H] ＋ ). Anal. calcd for
C27H23Cl2NO2: C 69.80, H 4.98, N 3.03; found C 69.83,
H 4.99, N 3.02.
N-(4-Methylbenzyl)-3,5-bis(4-methylbenzylidene)-
4-piperidone (5b): Yield 77%, yellow solid, m.p. 170—
N-(4-Fluorobenzyl)-3,5-bis(benzylidene)-4-piperi-
done (5h): Yield 68%, yellow solid, m.p. 146—148 ℃;
1H NMR (CDCl3, 400 MHz) δ: 3.66 (s, 2H), 3.85 (s,
4H), 7.05—7.12 (m, 2H), 7.18—7.21 (m, 2H), 7.33—
7.41 (m, 10H), 7.83 (s, 2H); IR (KBr) ν: 3128, 2993,
1
171 ℃; H NMR (CDCl3, 400 MHz) δ: 2.28 (s, 3H),
2.36 (s, 6H), 3.66 (s, 2H), 3.83 (s, 4H), 7.04 (d, J＝7.8
Hz, 2H), 7.13 (d, J＝7.9 Hz, 2H), 7.17 (d, J＝8.0 Hz,
4H), 7.25 (d, J＝8.1 Hz, 4H), 7.76 (s, 2H); IR (KBr) ν:
2916, 2745, 1670, 1613, 1578, 1558, 1264, 1180, 1072,
－1
1669, 1615, 1508, 1268, 1222, 1193, 998, 765 cm ;
2110
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 2109— 2113

N-(Substituted benzyl)-3,5-bis(benzylidene)-4-piperidones: Synthesis and Anti-leukemia Activity
MS (ESI) m/z: 384 ([M ＋ H] ＋ ). Anal. calcd for
C26H22FNO: C 81.30, H 5.64, N 3.53; found C 81.44, H
5.78, N 3.65.
C26H20BrCl2NO: C 66.70, H 5.23, N 2.73; found C
66.67, H 5.20, N 2.78.
N-(4-Bromobenzyl)-3,5-bis(4-chlorobenzylidene)-4-
piperidone (5o): Yield 77%, yellow solid, m.p. 186—
N-(4-Fluorobenzyl)-3,5-bis(4-methylbenzylidene)-4-
piperidone (5i): Yield 90%, yellow solid, m.p. 165—
1
188 ℃; H NMR (CDCl3, 400 MHz) δ: 3.65 (s, 2H),
1
167 ℃; H NMR (CDCl3, 400 MHz) δ: 2.36 (s, 6H),
3.79 (s, 4H), 7.12 (d, J＝8.4 Hz, 2H),7.23—7.24 (m,
2H), 7.26—7.37 (m, 8H), 7.74 (s, 2H); IR (KBr) ν: 2822,
1605, 1489, 1456, 1264, 1264, 1180, 1095, 1003, 817
3.68 (s, 2H), 3.90 (s, 4H), 7.08 (t, J＝8.3 Hz, 2H), 7.20
(dd, J＝8.7, 5.8 Hz, 2H), 7.22 (d, J＝8.0 Hz, 4H), 7.38
(d, J＝8.0 Hz, 4H), 7.84 (s, 2H); IR (KBr) ν: 3031, 27－96,
＋
－1
cm ; MS (ESI) m/z: 512 ([M＋H] ). Anal. calcd for
C26H20BrCl2NO: C 60.80, H 3.93, N 2.83; found C
60.84, H 3.93, N 2.73.
1
1602, 1507, 1269, 1219, 1181, 1071, 1006, 812 cm ;
MS (ESI) m/z: 412 ([M ＋ H] ＋ ). Anal. calcd for
C28H26FNO: C 81.70, H 6.40, N 3.42; found C 81.72, H
6.37, N 3.40.
Inhibiting leukemia K562 cells proliferation test
N-(4-Fluorobenzyl)-3,5-bis(4-methoxybenzylidene)-
4-piperidone (5j): Yield 92%, yellow solid, m.p. 163—
The growth inhibition activities of the title com-
pounds and 5-fluorouracil (5-FU) against K562 cells
were determined by the MTT assay according to the
standard bioactivity test procedures of the
Zooblast-molecular Biology Laboratory of Shanghai
Normal University of China.16 Specific methods were
the same as the previous research.14 Equation of growth
inhibition of cells was shown as follows.
1
164 ℃; H NMR (CDCl3, 400 MHz) δ: 3.62 (s, 2H),
3.79 (s, 4H), 3.91 (s, 6H), 7.04 (d, J＝7.8 Hz, 2H), 7.12
(d, J＝8.2 Hz, 4H), 7.26 (d, J＝8.3 Hz, 4H), 7.35 (dd,
J＝8.0, 5.1 Hz, 2H), 7.80 (s, 2H); IR (KBr) ν: 2833,
1663, 1597, 1561, 1513, 1258, 1173, 1032, 1011, 828
＋
－1
cm ; MS (ESI) m/z: 444 ([M＋H] ). Anal. calcd for
C28H26FNO3: C 75.85, H 5.97, N 3.20; found C 75.83,
H 5.91, N 3.16.
Inhibition [1 A(experiment)/A(control)] 100%
＝ －
×
N-(4-Fluorobenzyl)-3,5-bis(4-chlorobenzylidene)-4-
piperidone (5k): Yield 88%, yellow solid, m.p. 167—
Results and discussion
1
169 ℃; H NMR (CDCl3, 400 MHz) δ: 3.66 (s, 2H),
Synthesis of N-(substituted benzyl)-3,5-bis(benzyli-
dene)-4-piperidones 5a— 5o
3.79 (s, 4H), 7.08—7.15 (m, 2H), 7.25 (d, J＝8.3 Hz,
4H), 7.28—7.32 (m, 2H), 7.38 (d, J＝8.5 Hz, 4H), 7.74
(s, 2H); IR (KBr) ν: 2792,－1607, 1508, 1491, 1268, 1222,
A five-step synthetic strategy was adopted for the
synthesis of N-(substituted benzyl)-3,5-bis(ben-zyl-
idene)-4-piperidones 5a—5o. The general schematic
representation describing the routes of syntheses is fur-
nished in Scheme 1. N,N-Bis[2-(methoxy carbonyl)ethyl]
substituted amines 2I—2IV were obtained by the Mi-
chael addition of substituted amine and methyl acrylate,
in 1 ∶ 4 molar ratio. The N,N-bis[2-(methoxy car-
bonyl)ethyl]substituted amines 2I — 2IV afforded
N-substituted-4-piperidones 4I—4IV upon reflux with
sodium methoxide in the presence of absolute toluene
and the fllowed mixture was extracted with 25% HCl,
then directly reacted. For the formation of the N-
(substituted benzyl)-3,5-bis(benzylidene)-4-piperidones
5a—5o, according to the literature,15 N-substituted-
4-piperidones 4I—4IV were reacted with appropriate
1
1198, 1006, 926, 817 cm ; MS (ESI) m/z: 452 ([M＋
H]＋). Anal. calcd for C26H20Cl2FNO: C 69.05, H 4.47,
N 3.10; found C 69.04, H 4.46, N 3.10.
N-(4-Bromobenzyl)-3,5-bis(benzylidene)-4-piperi-
done (5l): Yield 79%, yellow solid, m.p. 132—134 ℃;
1H NMR (CDCl3, 400 MHz) δ: 3.68 (s, 2H), 3.85 (s,
4H), 6.87—6.92 (m, 2H), 7.18—7.21 (m, 2H), 7.33—
7.41 (m, 10H), 7.88 (s, 2H); IR (KBr) ν: 3056, 2750,
－1
1665, 1604, 1569, 1267, 1192, 1183, 764, 687 cm ;
MS (ESI) m/z: 444 ([M ＋ H] ＋ ). Anal. calcd for
C26H22BrNO: C 70.25, H 4.97, N 3.10; found C 70.28,
H 4.99, N 3.15.
N-(4-Bromobenzyl)-3,5-bis(4-methylbenzylidene)-
4-piperidone (5m): Yield 81%, yellow solid, m.p. 186—
1
187 ℃; H NMR (CDCl3, 400 MHz) δ: 2.36 (s, 6H),
3.36 (s, 2H), 3.83 (s, 4H), 7.02 (d, J＝7.8 Hz, 2H),
7.10—7.25 (m, 8H), 7.36 (d, J＝8.0 Hz, 2H), 7.80 (s,
2H); IR (KBr) ν: 2817, 2－748, 1669, 1609, 1577, 1508,
－1
aldehyde, using 0.1 g•mL NaOH as catalyst, anhy-
drous ethyl alcohol as solvent, stirred under room tem-
perature to obtain the title compounds.
1
1264, 1179, 999, 814 cm ; MS (ESI) m/z: 472 ([M＋
H]＋). Anal. calcd for C28H26BrNO: C 71.20, H 5.53, N
2.93; found C 71.19, H 5.55, N 2.96.
Inhibitory effects of compounds 5a— 5o on the pro-
liferation of leukemia K562 cells
N-(4-Bromobenzyl)-3,5-bis(4-methoxybenzylidene)-
4-piperidone (5n): Yield 89%, yellow solid, m.p. 167—
The growth inhibition activities of the title com-
pounds and 5-fluorouracil (5-FU) against leukemia
K562 cells were determined by the MTT assay accord-
ing to the standard bioactivity test procedures. As indi-
cated in Figure 1, most of our designed compounds ex-
hibited significant inhibition activities against leukemia
K562 cells proliferation and had ＞80% inhibition at
1
170 ℃; H NMR (CDCl3, 400 MHz) δ: 3.62 (s, 2H),
3.79 (s, 4H), 3.91 (s, 6H), 7.04 (d, J＝7.8 Hz, 2H), 7.12
(d, J＝8.2 Hz, 4H), 7.26 (d, J＝8.3 Hz, 4H), 7.35 (d,
J＝8.0 Hz, 2H), 7.80 (s, 2H); IR (KBr) ν: 2833,－ 1663,
1
1597, 1561, 513, 258, 1173, 1032, 1011, 828 cm ; MS
＋
(ESI) m/z: 504 ([M ＋ H] ). Anal. calcd for
Chin. J. Chem. 2011, 29, 2109— 2113
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Wang et al.
FULL PAPER
Scheme 1
O
C
O
C
CH2 CH2
OCH3
OCH3
b
R1
CH2NH2
1I — 1IV
+
a
R1
CH2 CH
OCH3
CH2N
CH2 CH2
C
O
2I — 2IV
O
COOCH3
O
N
N
R2
N
R2
c, d
e
R1
R1
O
3I — 3IV
4I — 4IV
R1
5a — 5o
1I— 4I: R1 = Me, 1II— 4II: R1 = OMe, 1III— 4III: R1 = Br, 1IV— 4IV: R1 = F
5a: R1 = Me, R2 = H; 5b: R1 = Me, R2 = Me; 5c: R1 = Me, R2 = OMe
5d: R1 = OMe, R2 = H; 5e: R1 = OMe, R2 = Me; 5f: R1 = OMe, R2 = OMe
5g: R1 = OMe, R2 = Cl; 5h: R1 = F, R2 = H; 5i: R1 = F, R2 = Me
5j: R1 = F, R2 = OMe; 5k: R1 = F, R2 = Cl; 5l: R1 = Br, R2 = H
5m: R1 = Br, R2 = Me; 5n: R1 = Br, R2 = OMe; 5o: R1 = Br, R2 = Cl
Reagent and conditions: (a) absolute methanol, refluxing; (b) sodium/absolute methanol, toluene, refluxing; (c) 25% HCl, refluxing;(d) 35%
sodium hydroxide, r.t.; (e) the appropriate aldehyde, 10% sodium hydroxide, absolute ethanol, r.t.
100 µg/mL, which is higher than that of the anti-leuke-
mia drug of clinical practice 5-FU at the same
concentration. As described in Table 1, the title com-
pounds’ IC50 values are largely influenced by the dif-
ferent substituents on the 1,5-diaryl-3-oxo-1,4-pen-
tadienyl pharmacophore. Electron withdrawing groups
on aryl showed excellent inhibition percentage than
electron donor groups. Taking 5d— 5g for example,
when R1＝ OCH3, the inhibition activities of the corre-
sponding analogues decreased in the order R2＝ Br (5g)
＞ R2＝ H (5d)＞ R2＝ CH3 (5e)＞ R2＝ OCH3 (5f). On the
other hand, the differences of the N-(4-substituted ben-
zyl) of piperidine rings also influence the compounds’
inhibition percentage, the introduction of 4-bromo-
benzyl at the N-position of piperidine rings showed bet-
ter inhibitory activities than other substituents. On the
basis of above discussions, 5o is deserved as the most
Figure 1 Inhibition of K562 cells proliferation treated with
compounds 5a— 5o. Cells were seeded in 96-well plates at the
density of 6250/cm2. Cells were treated with the compounds at
concentrations of 1, 10, and 100 µg/mL for 48 h. The cell viabil-
ity was determined by MTT assay.
Table 1 Growth inhibitory properties IC50 values for the com-
pounds 5a— 5o and 5-FU at 48 h
potent compound in this series, having an IC50 value of
5.79 µg/mL in suppressing leukemia K562 cells.
Compd.
5a
5b
5c
5d
5e
5f
5g
5h
R1
Me
Me
Me
OMe
OMe
OMe
OMe
F
R2
H
IC50/(µg•mL－
9.17
)
1
Conclusions
Me
OMe
H
Me
OMe
Cl
21.13
22.52
9.28
24.41
51.58
7.81
In summary, we have described a facile approach to
prepare N-(substituted benzyl)-3,5-bis(benzylidene)-4-
piperidones 5a— 5o. These compounds were character-
1
ized by IR, H NMR, MS techniques and elemental
analysis. Most of the title compounds have high effec-
tiveness in inhibiting leukemia K562 cells proliferation,
H
8.66
5i
5j
5k
F
F
F
Me
OMe
Cl
32.17
30.20
6.35
－
1
among which compounds 5g (IC50＝ 7.81 µg•mL ), 5k
－
－
1
1
(IC50＝ 6.35 µg•mL ), 5l (IC50＝ 7.20 µg•mL ), and 5o
－
1
(IC50＝ 5.79 µg•mL ) have better inhibition activities
than standard 5-fluorouracil (IC50 ＝ 8.56 µg•mL－ 1).
Further research work will be needed to find piperidine
derivatives with more potential anti-leukemia bioactivi-
ties.
5l
5m
5n
5o
5-Fu
Br
Br
Br
Br
H
7.20
Me
OMe
Cl
17.18
21.75
5.79
8.56
2112
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 2109— 2113

N-(Substituted benzyl)-3,5-bis(benzylidene)-4-piperidones: Synthesis and Anti-leukemia Activity
K. N.; Zello, G. A. Bioorg. Med. Chem. 2007, 15, 5854.
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www.cjc.wiley-vch.de
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