Synthesis, anticancer activity and cytotoxicity of novel double Schiff-base condensed α,β-unsaturated keto derivatives

Article abstract of DOI:10.3184/174751916X14652218083379

Five double Schiff-base condensed α,β-unsaturated keto derivatives, as curcumin analogues, were synthesised in three steps. Cyclohexanone, or N-methyl-4-pyridone, and 3-nitrobenzaldehyde (2 equiv.) were subjected to Claisen-Schmidt condensation under acid

Full text of DOI:10.3184/174751916X14652218083379

400 RESEARCH PAPER
VOL. 40 JULY, 400–403
JOURNAL OF CHEMICAL RESEARCH 2016
Synthesis, anticancer activity and cytotoxicity of novel double Schiff-base
condensed α,β-unsaturated keto derivatives
Qin Chen, Yun Hou, Guige Hou*, Ning Li, Wei Cong, Feng Zhao, Hongjuan Li, Chunhua Wang and
Jufeng Sun
The Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University,
Yantai, 264003, P.R. China
Five double Schiff-base condensed α,β-unsaturated keto derivatives, as curcumin analogues, were synthesised in three steps.
Cyclohexanone, or N-methyl-4-pyridone, and 3-nitrobenzaldehyde (2 equiv.) were subjected to Claisen–Schmidt condensation under acid
conditions to yield tricyclic dinitro compounds which were reduced to the corresponding diamines and then derivatised at their amino
groups with 1-aryl(alkyl)-butan-1,3-diones (MeCOCH COR). Anticancer activities of the five compounds against four human carcinoma
cell lines and their cytotoxicities for LO2 cell lines were2evaluated by the MTT method. All compounds showed moderate anticancer activity
and low cytotoxicity. The single N-methyl-4-piperidinone-derived compound that was synthesised displayed the highest anticancer
activity toward THP-1 and the lowest cytotoxicity.
Keywords: α,β-unsaturated keto, 4-piperidone, cyclohexanone, Schiff-base, anticancer activity, cytotoxicity
Curcumin, the active principle of turmeric,1,2 has been reported
to possess anti-inflammatory, anticoagulant, antibacterial,
agents.16–20 The results show interesting structure–property
relationship between structures and anticancer activities.
However, structure–activity relationships of these derivatives
need to be further improved. With this aim in mind, in this
study, starting from a 2,6-bis(arylidene)cyclohexanone and a
3,5-bis(arylidene)-4-piperidone, five novel curcumin analogues
have been synthesised and their anticancer activities against
human cell lines HePG2, HeLa, K562, THP-1 and their
cytotoxicities for LO2 cell lines have been evaluated by the
MTT method.
antifungal,
anticarcinogenic,
antitumour,
anti-HIV,
antimutagenic, antiproliferative, antioxidant, antiprotozoal and
antivenom activities.3–6 Curcumin and its analogues containing
the pharmacophore of α,β-unsaturated keto, can interact
at the primary binding site of bio-thiols from susceptible
neoplasms. Since, these compounds have some problems in
their clinical application, such as poor aqueous solubility,
relatively low bioavailability, intense staining colour and so
on,7 some improved curcumin analogues have been reported,
such as demethoxycurcumin, bisdemethoxycurcumin and
cyclocurcumin.8–13
2,6-Bis(arylidene)cyclohexanone and 3,5-bis(arylidene)-
4-piperidone derivatives,14,15 as curcumin analogues, were
reported and their bioactivity evaluated. Like curcumin, these
compounds incorporate two α,β-unsaturated keto groups, which
could combine with sensitive parts of the tumour cells twice.
More importantly, these analogues have lower toxicity toward
normal cells. In other words, these compounds can more easily
attack malignant cells than normal cells. For example, 3,5-bis(2-
fluorobenzylidene)-1-methyl-4-piperidone (EF24, Fig. 1) was
first reported to possess very good anti-proliferative activity in
2004.14 Subsequently in 2010, 4-[3,5-bis(2-chlorobenzylidene-
4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] (CLEFMA,
Fig. 1) was reported which showed better antiproliferative
activity against H441 cells than EF24.15 Recently, our group has
also reported some novel N-substituted or bispyridyl-substituted
3,5-bis(arylidene)-4-piperidone derivatives as anticancer
Results and discussion
Our synthetic route to the target compounds is shown in
Scheme 1. Cyclohexanone, or N-methyl-4-pyridone, and
3-nitrobenzaldehyde (2 equiv.) was subjected to Claisen–
Schmidt condensation under acid conditions to yield tricyclic
dinitro compounds 1a and 1b, respectively, which were reduced
with SnCl2/HCl to the corresponding diamines 2a and 2b.
Formic acid-catalysed reaction of 2a with three 1-aryl(alkyl)-
butan-1,3-diones effected derivatisation at their amino groups
with α,β-unsaturated ketone residues to give triketones 3a–d.
Compound 3e was synthesised in a similar way starting from
2b and 1-phenyl-butan-1,3-dione. Compounds 3a–e were
characterised by their 1H NMR, 13C NMR, and IR spectra and
by their HRMS. Some selected spectral data are discussed
below.
1
In the H NMR spectra of compounds 3a–e, the chemical
shifts of the two NH protons appear as a broad singlet at 12.53–
13.22 ppm. Two singlets at 8.5–9.0 ppm are attributed to the
Cl
O
N
Cl
O
O
F
O
F
HO
OH
OCH3
N
H
O
O
OCH3
OH
CLEFMA
Curcumin
EF24
Fig. 1 Structures of curcumin, EF24 and CLEFMA.
* Correspondent. E-mail: guigehou@163.com

JOURNAL OF CHEMICAL RESEARCH 2016 401
O
O
CHO
O
ꢑꢉ ꢔnꢃlꢅꢕꢄꢃl
ꢓꢐꢏ ꢄꢃl
ꢄꢗꢘ
ꢑꢑꢉ ꢆaꢖꢄ
R1
R1
NO2
R1
NH2
NH2
NO2
NO2
1a ꢀꢁ ꢂ ꢃꢄꢅ, 1b ꢂ ꢆꢇꢈ
2a ꢀꢁ ꢂ ꢃꢄꢅ, 2b ꢂ ꢆꢇꢈ
O
O
O
3aꢉ ꢀꢁ ꢂ ꢃꢄꢅ, ꢀꢅ ꢂ ꢇꢈ
3bꢉ ꢀꢁ ꢂ ꢃꢄꢅ, ꢀꢅ ꢂ ꢊꢋ
3cꢉ ꢀꢁ ꢂ ꢃꢄꢅ, ꢀꢅ ꢂ ꢌꢍꢎꢏꢐꢑdꢏl
3dꢉ ꢀꢁ ꢂ ꢃꢄꢅ, ꢀꢅ ꢂ ꢒꢍꢎꢏꢐꢑdꢏl
3eꢉ ꢀꢁ ꢂ ꢆꢇꢈ, ꢀꢅ ꢂ ꢊꢋ
R1
R2
ꢄꢃꢖꢖꢄꢕꢇꢈꢖꢄ
NH
O
HN
O
R2
R2
Scheme 1
Table 1 Anticancer activity and cytotoxicity of 3a–e and DOX
IC50*/μM
K562
Compounds
Hepg2
>10
Hela
7.67 0.08
9.13 0.11
>10
8.25 0.03
>10
THP-1
LO2
3a
3b
3c
3d
3e
DOX
2.2 0.05
4.06 0.09
3.13 0.03
2.37 0.02
4.80 0.23
1.42 0.04
3.20 0.08
1.44 0.03
1.68 0.06
1.78 0.07
1.17 0.08
0.3 0.02
8.54 0.07
6.98 0.05
7.65 0.04
7.05 0.03
13.13 1.05
6.93 0.32
5.54 0.03
2.54 0.02
3.14 0.02
5.52 0.27
0.57 0.07
2.02 0.02
*IC50 is the concentration of compounds required to inhibit the growth of the cells by 50%.
two aryidene protons (C=CHAr). The signal at ca 5.9 ppm
can be assigned to the two olefinic protons of the two side-
chains (COCH=CN). The chemical shifts of the methylene
groups of 3a–d appear at 1.7–3.0 ppm, while compound 3e
characteristically shows the chemical shifts of the N-methyl and
methylene groups at δ 3.8 and 2.52 ppm.
In the FTIR spectra, the characteristic bands at around
1670–1665 cm–1 are attributed to the -C=O group in the
cyclohexanone or piperidone rings. The strong bands at around
1569–1564 cm–1 are attributed to -C=C bonds of an α,β-
unsaturated ketone and the -C=N bonds of Schiff-base groups.
13C NMR and MS further confirmed the correctness of their
structures.
The anticancer activities against human carcinoma cell
lines HePG2, HeLa, K562 and THP-1 were evaluated by the
MTT method. In order to evaluate the cytotoxicity of target
compounds, the LO2 cell line was selected as the experimental
cells. Doxorubicin (DOX) was selected as positive control. The
results of the biological activity evaluation are shown in Table 1.
The results suggested that about 60% of the IC50 values of the
compounds against HeLa, HePG2, K562 and THP-1 were lower
than 5 μM.
As shown in Table 1, their anticancer activities against Hepg2
and Hela are very poor, with high IC50 values (> 2.5 μM). The
activities of all compounds 3a–e against the THP-1 cell line
were better than that against others. The IC50 values of 3b–e
against THP-1 cells were 2.0 μM. Compound 3e displays the
highest anticancer activity toward THP-1 cells with an IC50
value of 1.17 μM. Moreover, the cytotoxicity of 3b–e is very
small (6.98–13.13 μM) which was lower than that of DOX
(6.93 μM). The cytotoxicity of 3e is the lowest (13.13 μM). In
summary, 3e displays the best anticancer activity toward THP-1
and the lowest cytotoxicity toward LO2 cell lines. Structure
analysis shows that the N-methyl-4-piperidinone group is
better for improved anticancer activity toward THP-1 and lower
cytotoxicity toward LO2 than the cyclohexanone group.
Experimental
Cyclohexanone, N-methyl-4-piperidinone,
3-nitrobenzaldehyde,
tetrabutyl ammonium bromide (TBAB), stannous chloride and
all diacetone materials were purchased from Sinopharm Chemical
Reagent Co. Ltd (Shanghai, P.R. China) and were used as obtained
without further purification. NMR spectra were obtained on a Bruker
Avance 400 MHz spectrometer (1H NMR at 400 Hz, 13C NMR at 100
Hz) in CDCl3 using TMS as an internal standard. Chemical shifts
(δ) are given in ppm and coupling constants (J) in Hz. HRMS were
determined on an Agilent 6210 TOF LC/MS. Infrared (IR) spectra
were obtained in the 400–4000 cm–1 range using a Perkin-Elmer
Frontier Mid-IR FTIR spectrometer. All melting points were measured
on a digital melting point apparatus and were uncorrected.
Synthesis of (2E,6E)-2,6-bis(3-aminobenzylidene)cyclohexanone (2a)
Cyclohexanone (0.98 g, 0.01 mol) and 3-nitrobenzaldehyde (3.32 g,
0.022 mol) were mixed with glacial acetic acid (40 mL), stirring on a
magnetic stirrer at room temperature for about 30 min, during which
time a clear solution was obtained. Dry hydrogen chloride gas was
bubbled into this mixture for 2 h, a large precipitate appeared, and
stirring was continued at room temperature for 24 h (monitored by
TLC). After filtering, the residue as 1a was dried under vacuum. 1a
was then dissolved in a solution of trichloromethane (10 mL), water
(20 mL) and methanol (16 mL) with TBAB (0.32 g, 0.001 mol). In
addition, stannous chloride (6.75 g, 0.03 mol) dissolved in concentrated
hydrochloric acid (12 mL), was slowly added to the reaction system.
The mixture was stirred at 40 °C for 8 h. After cooled to temperature,
the mixture was adjusted to pH 12 by 40% NaOH. The precipitate
was collected and dried under the vacuum to get a yellow powder 2a.

402 JOURNAL OF CHEMICAL RESEARCH 2016
Yield 57%; m.p. 70–72 °C. IR (cm–1): 3408, 3299, 2985, 2872, 1647,
1592, 1549, 1486, 1456, 1381, 1315, 1262, 1162, 1135, 1062, 986, 881,
783. 1H NMR: δ 7.71 (s, 2H), 7.22 (t, J = 8.0 Hz, 2H), 6.89 (d, J = 7.6
Hz, 2H), 6.78 (s, 2H), 6.69 (d, J = 7.6 Hz, 2H), 3.73 (s, 4H), 2.92 (t,
J = 8.0 Hz, 4H), 1.85–1.75 (m, 2H). HRMS for C20H21N2O [M + H+]
calcd 305.1654; found: 305.1650.
(3E,5E)-3,5-Bis(3-((Z)-4-oxo-4-phenylbut-2-en-2-ylamino)
benzylidene)-1-methylpiperidin-4-one (3e): Yellow powder; yield
68.3%; m.p. 152–154 °C; IR (KBr, cm–1): v 1667, 1564, 1510, 1430,
1353, 1316, 1270, 1161, 1020, 976, 930, 869, 795, 740, 691. 1H NMR: δ
13.16 (s, 2H), 7.95 (d, J = 6.6 Hz, 4H), 7.82 (s, 2H), 7.54–7.40 (m, 8H),
7.28 (s, 2H), 7.21 (s, 4H), 5.96 (s, 2H), 3.80 (s, 4H), 2.52 (s, 3H), 2.20 (s,
6H). 13C NMR: δ 188.6, 161.3, 139.3, 138.6, 135.8, 135.4, 135.3, 133.1,
130.6, 129.0, 127.9, 127.2, 126.6, 125.7, 124.9, 94.3, 56.5, 45.4, 20.1.
HRMS for C40H38N3O3 [M + H+] calcd 608.2913; found: 608.2908.
Synthesis of (3E,5E)-3,5-bis(3-aminobenzylidene)-1-methyl-piperidin-
4-one (2b)
N-methyl-4-piperidinone (1.13 g, 0.01 mol) and 3-nitrobenzaldehyde
(3.32 g, 0.022 mol) was mixed with 40 mL glacial acetic acid.
Dry hydrogen chloride gas was bubbled into this mixture for 2 h.
During this time, much precipitate appears and the viscosity of the
mixture increases. The mixture is allowed to continue stirring at
room temperature for 24 hours (monitored by TLC). The precipitate
was collected and dried under the vacuum to get 1b which was then
dissolved in a solution of water (20 mL) and methanol (16 mL) with
TBAB (0.32 g, 0.001 mol). Stannous chloride (6.75 g, 0.03 mol)
dissolved in concentrated hydrochloric acid (12 mL), was slowly added
to the reaction system. The mixture was stirred at 40 °C for 8 h. After
cooled to temperature, the precipitate was collected and washed with
5% sodium hydroxide solution, and dried under the vacuum to get a
yellow powder 2b. Yield 52%; m.p. 101–103 °C. IR (cm–1): 3355, 3347,
3222, 1670, 1600, 1583, 1452, 1316, 1259, 1171, 1095, 1051, 991, 915,
862, 780, 688. 1H NMR: δ 7.74 (s, 2H), 7.31–7.17 (m, 2H), 6.81 (d, J =
7.7 Hz, 2H), 6.78–6.66 (m, 4H), 3.76 (s, 4H), 2.47 (s, 3H). 13C NMR: δ
187.0, 146.4, 136.8, 136.3, 132.9, 129.4, 120.7, 116.7, 115.8, 57.1, 45.7.
HRMS for C20H21N3O [M+] calcd 319.1685; found: 319.1681.
Anticancer testing by the MTT method
Compounds 3a–e were screened against four human neoplastic
cell lines, human cervical carcinoma cells (HeLa), human liver
hepatocellular carcinoma cell line (HePG2), human chronic
myelogenous leukaemia cell line (K562), human acute mononuclear
granulocyte leukaemia (THP-1), and human normal hepatical cell line
(LO2) by MTT assay (3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-
H-tetrazolium bromide, MTT, Dojindo Laboratories, Tokyo, Japan).
The cells were seeded in a 96-well plate with 200 μL medium per well
at a density of 1 × 104 cells/well for 24 h. The cells were treated with
serial concentrations of compounds 3a–e and incubated for 24 h.
Cells with only culture media were used as control. After the media
was removed and 20 μL of MTT (5 mg mL–1) added, the plates were
incubated for 4 h at 37 °C. The MTT containing media were removed
and then 150 μL of DMSO was added to dissolve the dark-blue formazan
crystals. The optical density (OD) was measured by a multi-well plate
reader (TECAN, Mӓnnedorf, Switzerland) at 540 nm. The results
are expressed as a decrease in the cell viability (%) in comparison to
untreated controls. The concentration of each compound was examined
in triplicate, and the IC50 values are shown in Table 1. The concentrations
of the compounds were 10, 8, 5, 3, 2, 1, 0.5, 0.1, 0.05 and 0.01 μg mL–1.
Doxorubicin (DOX) was used as a positive control. The concentrations
of DOX were 1.5, 1.2, 1.0, 0.8, 0.5, 0.3, 0.1, 0.05 and 0.01 μg mL–1.
Synthesis of compound 3: general procedure
2a (0.30 g, 0.001 mol) or 2b (0.32 g, 0.001 mol) and diacetone materials
(0.002 mol) were dissolved in methanol (5 mL). Two drops of formic
acid were added and the mixture was stirred for 3–8 h at ambient
temperature (monitored by TLC). The precipitate was collected and
recrystallised from methanol to afford 3a–e.
(2E,6E)-2,6-Bis(3-((Z)-4-oxopent-2-en-2-ylamino)benzylidene)
cyclohexanone (3a): Yellow powder; yield 78.2%; m.p. 58–60 °C; IR
(KBr, cm–1): v 1667, 1564, 1510, 1430, 1353, 1316, 1270, 1161, 1020,
976, 930, 869, 795, 740, 691. 1H NMR: δ 12.53 (s, 2H), 7.75 (s, 2H),
7.39 (t, J = 7.8 Hz, 2H), 7.29 (d, J = 9.4 Hz, 2H), 7.20 (s, 2H), 7.10 (d,
J = 7.6 Hz, 2H), 5.23 (s, 2H), 2.99–2.85 (m, 4H), 2.13 (s, 6H), 2.03 (s,
6H), 1.83 (m, 2H). 13C NMR: δ 196.0, 189.5, 159.4, 138.4, 136.5, 136.2,
135.7, 128.7, 127.1, 125.6, 124.4, 97.6, 28.8, 28.0, 22.3, 19.5. HRMS for
C30H33N2O3 [M + H+] calcd 469.2491; found: 469.2496.
This work was supported by the National Natural Science
Foundation of China (no. 21402010), the Foundation of
Shandong province (nos. ZR2013BM022, ZR2014HP006,
ZR2014BL008, 2014CGZH1316 and 2015GGX102013), the
Foundation of Yantai (no. 2013ZH095) and the Foundation of
Shandong Provincial Key Laboratory of Clean Production of
Fine Chemicals (no. ZDSYS-KF201505). Qin Chen and Yun
Hou contributed equally to this work.
Received 11 March 2016; accepted 22 April 2016
Paper 1603977 doi: 10.3184/174751916X14652218083379
Published online: 15 June 2016
(2E,6E)-2,6-Bis(3-((Z)-4-oxo-4-phenylbut-2-en-2-ylamino)
benzylidene)cyclohexanone (3b): Yellow powder; yield 72.5%; m.p.
158–160 °C; IR (KBr, cm–1): v 1670, 1569, 1435, 1316, 1281, 1169, 1089,
1023, 925, 801, 741, 693. 1H NMR: δ 13.13 (s, 2H), 7.91 (d, J = 7.0 Hz,
4H), 7.61 (s, 2H), 7.50–7.40 (m, 14H), 6.09 (s, 2H), 2.90 (s, 4H), 2.18
(s, 6H), 1.71 (s, 2H). HRMS for C40H37N2O3 [M + H+] calcd 593.2804;
found: 593.2810.
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