Preparation of a series of novel bichalcones linked with a 1,4- dimethylenepiperazine moiety and examination of their cytotoxicity

Article abstract of DOI:10.1248/cpb.59.1549

The chalcone basic skeleton is a unique template which is associated with widespread biological activities. In the present study, a series of novel bichalcones linked with a 1,4-dimethylenepiperazine moiety was prepared through Mannich reaction and Clasie

Full text of DOI:10.1248/cpb.59.1549

December 2011
Note
Chem. Pharm. Bull. 59(12) 1549—1554 (2011)
1549
Preparation of a Series of Novel Bichalcones Linked with a 1,4-
Dimethylenepiperazine Moiety and Examination of Their Cytotoxicity
Mopuru Vijaya Bhaskar REDDY,a Shih-Shun CHEN,b Meng-Liang LIN,c Hsiu-Hui CHAN,f
d
,a,e
*
Ping-Chung KUO, and Tian-Shung WU
a Department of Chemistry, National Cheng Kung University; Tainan 70101, Taiwan, ROC: b Department of Medical
Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology; Taichung 40601, Taiwan,
ROC: c Department of Medical Laboratory Science and Biotechnology, China Medical University; Taichung 40402,
Taiwan, ROC: d Department of Biotechnology, National Formosa University; Yunlin 63201, Taiwan, ROC: e Department of
Pharmacy, China Medical University; and f Chinese Medicinal Research and Development Center, China Medical
University and Hospital; Taichung 40402, Taiwan, ROC.
Received August 11, 2011; accepted September 24, 2011; published online September 29, 2011
The chalcone basic skeleton is a unique template which is associated with widespread biological activities. In
the present study, a series of novel bichalcones linked with a 1,4-dimethylenepiperazine moiety was prepared
through Mannich reaction and Clasien–Schmidt condensation. The synthetic analogs 2—16 were subjected into
the cytotoxicity examinations using a panel of 25 human tumor cell lines. Among the tested compounds, 3 and 4
which possessed the 3-pyridyl and phenyl groups as the substructure, respectively, displayed significant cytotoxic-
ity against all the tumor cell lines. The results suggested that these bichalcones were potential to be the anti-
cancer lead drugs.
Key words bichalcone; 1,4-dimethylenepiperazine; cytotoxicity; human tumor cell line
Chalcones possess a 1,3-diphenyl-2-propen-1-one basic as lead drugs. Considering their pharmacological impor-
skeleton in which two aromatic rings are connected by a tance,28—30) a series of bichalcones linked with a 1,4-dimeth-
three carbon a,b-unsaturated carbonyl system. They are the ylenepiperazine moiety possessed different substituents in
intermediates in the biosynthesis of flavonoids which are the B-ring of the chalcone basic skeleton were synthesized in
substances widespread in plants and with an array of biologi- the present study. Furthermore, the synthesized analogs (2—
cal activities; however, their structure differs considerably 16) were tested for cytotoxicity against 25 human tumor cell
from the other members of the flavonoids family.1) Chalcones lines, including GBM-8401, M059K (human glioblastoma
are reported with diverse biological activities including anti- cell lines), FaDu (human pharyngeal squamous carcinoma
hyperglycemic,2) antibacterial,3) antiplatelet,4) antiulcerative,5) cell line), CE146T/VGH (human esophageal carcinoma cell
antimalarial,6) antiviral,7) antileishmanial,8) antioxidant,9) an- line), HSC-3 (human oral squamous carcinoma cell line),
titubercular,10) tyrosinase inhibiting,11) anti-inflammatory,12) CAL-27 and SAS (human tongue squamous carcinoma cell
and analgesic activities.13) In addition, chalcones exhibited lines), A549 and H-460 (human lung carcinoma cell lines),
various effects of inhibition on cell proliferation and demon- SK1—CP1, Huh7, HepG2 and Hep3B (human hepatoma cell
strated anticancer activities.14—19) The bichalcones are well lines), MDA-MB-231 and MCF-7 (human breast adenocarci-
represented in the Anacardiacea family.20) In general, natu- noma cell lines), A375 (human melanoma cell line), HeLa
rally occurring bichalcones carry either C–O–C or C–C link- (human cervical carcinoma cell line), MG-63 and U-2 OS
age between the two chalcone units. The Rhus genus is also a (human osteosarcoma cell lines), HT-29 and Colo 25 (human
rich source for bisflavonoids and bichalcones.21,22) For exam- colon carcinoma cell lines), NPC-039 and NPC-076 (human
ples, natural bichalcones from Rhus pyroides demonstrated nasopharyngeal carcinoma cell lines), and NT-2 and SH-
various degrees of cytotoxicity, however, they also showed SY5Y (human neuroblastoma cell lines), to construct the
more selectivity toward colon cancer cell lines, especially the preliminary biological profiles of bichalcones. These data
HT29 and HCT-116 cell lines.23) Thus for the development of could be provided as the bases for further design and devel-
anticancer lead drugs, the bichalcones were selected as the opment of bichalcones linked with the Mannich base group.
synthetic targets for preparation of cytotoxic agents.
The Mannich reaction is an important carbon–carbon Results and Discussion
bond-forming step in organic synthesis, and it has been
The template precursor 1a was prepared by the Mannich
widely utilized in the synthesis of nitrogen-containing com- reaction among piperazine, paraformaldehyde, and two
pounds, including natural products and biologically active equivalents of 4-hydroxy-3-methoxyacetophenone (1). The
principles.24,25) Mannich bases of chalcones and related com- reaction mixture in ethanol was stirred at 120 °C and moni-
pounds displayed significant cytotoxicity towards murine tored by TLC. After 20 h the reaction was completed and
P388 and L1210 leukemia cancer cell lines, as well as a acetophenone dimer linked with 1,4-dimethylpiperazine (1a)
number of other tumor cell lines.26) The Mannich base group was afforded in a good yield (Fig. 1a). In the 1H-NMR spec-
was accompanied by enhancing the bioactivity both in vitro trum of 1a, two singlets at d 7.46 (2H) and 7.28 (2H) were
and in vivo.27) Therefore, introducing a Mannich base group indicative of tetra-substituted aromatic basic skeleton. In the
into the bichalcone may enhance the bioactivity. In addition, upfield region, one methoxy singlet and one methylene sin-
the extra nitrogen atom may increase the hydrophilicity of glet were located at d 3.92 (6H) and 3.80 (4H), respectively.
the resulted compounds and thus improve their potentials In addition, one broad singlet at d 3.00—2.50 (8H, br s) and
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: tswu@mail.ncku.edu.tw

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3-pyridyl groups in the B-ring, respectively, displayed the
structure effect on the bioactivity. Compound 3 exhibited
more significant cytotoxicity against all tested tumor cell
lines with IC50 values ranging from 2.1ꢁ0.08 to 9.8ꢁ0.20
mM (Table 1), however 2 showed selective cytotoxic activity
on CAL-27 and FaDu cell lines with IC50 values 2.0ꢁ0.05
and 9.8ꢁ0.29 mM, respectively. These results indicate that 3-
pyridyl group as B-ring was responsible for potent cytotoxic-
ity in bichalcones linked with 1,4-dimethylenepiperazine.
Compound 4, which has phenyl group as B-ring, displayed
the most significant cytotoxicity towards all 25 human tumor
cell lines with IC50 values ranges from 2.0ꢁ0.05 to
9.9ꢁ0.10 mM. Introducing any substituents into the phenyl
ring would reduce the cytotoxicity. Insertion of hydroxyl
group at C-3 position of the phenyl moiety in B-ring as in 5,
would result in similar or some weaker cytotoxicity. Only for
A375 melanoma cells 5 would show more significant cyto-
toxicity than 4. If the C-3 hydroxyl group was protected with
methyl group as in 6, it would decrease the cytotoxicity
against all the tested cell lines. It indicated that the C-3 hy-
droxy group would be a factor on the cytotoxicity. Another
comparison of the structure–activity relationship was found
between 6 and 8, which have 3-methoxyphenyl and 4-
methoxyphenyl groups as B-ring, respectively. Compound
6 displayed significant cytotoxicity on NPC076 (IC50
9.9ꢁ0.12 mM), FaDu (IC50 9.9ꢁ0.15 mM), HSC-3 (IC50
9.7ꢁ0.10 mM), CAL-27 (IC50 8.0ꢁ0.08 mM), H-460 (IC50
8.0ꢁ0.05 mM), A375 (IC50 8.1ꢁ0.08 mM) and MG-63 (IC50
7.9ꢁ0.10 mM) tumor cell lines, however 8 did not show any
cytotoxicity at concentration of 10 mM. These results inferred
Fig. 1. (a) Synthesis of Precursor 1a; and (b) Target Compounds 2—16
one singlet resonated at d 2.53 (6H) indicated the presences that methoxy group at C-4 position in B-ring was responsible
of nitrogenated methylene groups and acetyl methyls, respec- for weaker cytotoxicity compared with that at C-3. It could
tively. The carbon signal at d 196.5 in its 13C-NMR spectrum be further confirmed through the weaker cytotoxicity of com-
also supported the appearance of acetyl group. On the basis pounds 7, 9, and 10 since 7 and 9 both possessed the di-
of the above spectroscopic evidences, the structure of this substitutions at C-3 and C-4 positions and 10 had similar
colorless solid was deduced as shown in Fig. 1a.
functional pattern as 8.
The structural characteristic of 1a was two acetyl methyl
Compounds 11 and 12 are positional isomers in B-ring,
groups on the benzene ring which was ready for the follow- while 11 showed moderate cytotoxicity on CAL-27, A375
ing Claisen–Schmidt condensation with the corresponding and MG-63 cell lines with IC50 values 6.2ꢁ0.10, 9.9ꢁ0.12,
aldehydes. In the basic methanol solution, different substi- and 8.1ꢁ0.12 mM, respectively, and 12 was potent on
tuted aromatic or heteroaromatic aldehydes were reacted NPC076, FaDu, CAL-27, MDA-MB-231, A375 and MG-63
with 1a to result in the formation of the target compounds cell lines with IC50 values 4.0ꢁ0.15, 6.0ꢁ0.06, 2.0ꢁ0.05,
2—16. In the 1H-NMR spectrum of 2, two doublets at d 8.05 6.1ꢁ0.10, 8.0ꢁ0.06, and 6.1ꢁ0.06 mM, respectively. From
(2H, Jꢀ15.0 Hz) and 7.70 (2H, Jꢀ15.0 Hz) were characteris- the results for 4—12, the structure–activity relationships
tic for the trans-double bond of the chalcone basic skeleton. could be generalized as follows. The phenyl group as B-ring
There were also a set of four mutually coupled signals at d in the bichalcones would be the most cytotoxic. Insertion of
8.62, 7.63, 7.39, and 7.21 characteristic of the four het- hydroxyl group in the C-3 position of the phenyl ring would
eroaromatic protons of the 2-pyridyl moiety. In addition, one decrease the cytotoxicity, however, protection of this hy-
singlet at d 7.55 (2H) and one multiplet at d 7.39 (2H) indi- droxyl group or shift of this substituent to C-4 would reduce
cated the presence of tetra-substituted aromatic ring. In the the cytotoxicity significantly. Similar results would be found
upfield region, two methoxys, two methylenes, and four ni- for the chloro substituent. Another heterocyclic five mem-
trogenated methylenes were located at d 3.89 (6H), 3.75 bered ring furan as B-ring in 13, showed significant cytotox-
(4H), and 2.46 (8H), respectively. According to the spectro- icity on NPC076, CAL-27, FaDu and A375 cell lines with
scopic data described above, the structure of this yellow solid IC50 values 4.0ꢁ0.06, 9.7ꢁ0.15, 6.1ꢁ0.12 and 5.9ꢁ0.10
was concluded as 2. With the similar procedures, the chemi- mM, respectively. As the B-ring furan group was replaced
cal structures of 3—16 were also identified as shown in Fig. with 5-methylfuran as in 14, no cytotoxicity would be ob-
1b.
served in 14. If the furan group was changed to thiophene as
The cytotoxicity data of 1a and 2—16 towards 25 human in 15, it displayed selectively cytotoxicity towards CAL-27
tumor cell lines were summarized in Table 1 and aloe- cell lines with IC50 value 2.1ꢁ0.10 mM. But no cytotoxicity
emodin was used as the reference compound.31,32) Compari- would be found if methyl group was introduced into the 3-
son of the cytotoxicity of 2 and 3, which have 2-pyridyl and position as in 16. Consequently, introducing heteroatoms into

December 2011
1551
m
m
m

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Vol. 59, No. 12
120 (11), 107 (22), 106 (11), 89 (21), 77 (14); HR-FAB-MS m/z 621.2711
[MꢄH]ꢄ (Calcd for C36H37O6N4 621.2713).
the B-ring would not enhance the cytotoxic bioactivity of the
bichalcones.
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-(pyridin-3-yl)prop-2-en-1-one) (3)
Compound 1a (1.105 g, 2.5 mmol) and 3-pyridinecarboxaldehyde (0.535 g,
5.0 mmol) were treated as described above and the title compound was iso-
lated as yellow solid in 87% yield. (3): mp 233—235 °C (80% benzene–ace-
tone); IR (neat) nmax: 2831, 1658, 1589, 1458, 1415, 1338, 1307, 1219,
In the present study, fifteen novel bichalcones linked with
1,4-dimethylenepiperazine 2—16 were synthesized through
Mannich reaction and Clasien–Schmidt condensation.
Among these synthetic compounds, 4 was highly active and
displayed the most significant cytotoxicity,33) with IC50 values
lower than 4.0 mM towards GBM-8401, MO59K, NPC 039,
NPC 076, FaDu, CAL-27, SAS, MDA-MB-231, A375, and
HeLa tumor cell lines. Comparison of the cytotoxicity of 4
with those reported in the previous research results published
by our group,34) the substituents on the aromatic ring signifi-
cantly reduced the anti-cancer potentials. However, these re-
sults still indicated that 4 could be a good candidate for the
development of anticancer lead drugs.
999 cmꢃ1 1H-NMR (300 MHz, CDCl3) d: 8.83 (2H, s), 8.58 (2H, d,
;
Jꢀ4.5 Hz), 7.92 (2H, d, Jꢀ6.0 Hz), 7.74 (2H, d, Jꢀ15.6 Hz), 7.62 (2H, d,
Jꢀ15.6 Hz), 7.54 (2H, s), 7.38 (2H, s), 7.33 (2H, m), 3.93 (6H, s), 3.82 (4H,
s), 2.71 (8H, br s); 13C-NMR (75 MHz, CDCl3) d: 187.3, 152.2, 150.7,
149.6, 148.2, 139.8, 134.4, 130.7, 129.1, 123.6, 123.2, 122.6, 119.8, 110.8,
60.5, 55.9, 52.0; FAB-MS m/z (rel. int. %): 621 ([MꢄH]ꢄ, 18), 391 (11),
354 (11), 352 (12), 307 (14), 269 (12), 268 (41), 155 (22), 154 (100), 149
(35), 139 (10), 138 (27), 137 (56), 136 (78), 132 (15), 120 (13), 107 (27), 89
(27), 77 (18); HR-FAB-MS m/z 621.2714 [MꢄH]ꢄ (Calcd for C36H37O6N4
621.2713).
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-phenylprop-2-en-1-one) (4) Compound
Experimental
General The chemicals were acquired from commercial sources and 1a (1.105 g, 2.5 mmol) and benzaldehyde (0.53 g, 5.0 mmol) were treated as
used without further purification unless stated otherwise. The melting points described above and the title compound was isolated as yellow solid in 74%
were determined by a Yanagimoto MP-S3 apparatus without correction. The yield. (4): mp 213—215 °C (95% benzene–acetone); IR (neat) nmax: 2827,
IR spectra were measured on a Shimadzu Fourier transform (FT)-IR Pres- 1654, 1597, 1489, 1338, 1265, 1161, 1087, 975, 937 cmꢃ1
;
1H-NMR
tige 21 spectrophotometer. 1H and 13C-NMR spectra were recorded on a
Bruker Avance-300 spectrometer, using tetramethylsilane (TMS) as internal
standard; all chemical shifts are reported in parts per million (ppm, d). FAB-
MS and high resolution (HR)-FAB-MS spectra were obtained on a JEOL
JMS-700 mass spectrometer. Column chromatography was performed on
silica gel (70—230 mesh, 230—400 mesh). TLC was conducted on pre-
coated Kieselgel 60 F254 plates (Merck), and the spots were visualized by
UV.
(300 MHz, CDCl3) d: 7.73 (2H, d, Jꢀ15.6 Hz), 7.57 (4H, m), 7.49 (2H, s),
7.45 (2H, d, Jꢀ15.6 Hz), 7.33 (8H, m), 3.88 (6H, s), 3.76 (4H, s), 2.46 (8H,
br s); 13C-NMR (75 MHz, CDCl3) d: 188.2, 151.9, 148.2, 143.8, 135.0,
130.3, 129.7, 128.8, 128.3, 122.5, 121.4, 119.8, 110.9, 60.7, 56.0, 52.1;
FAB-MS m/z (rel. int. %): 619 ([MꢄH]ꢄ, 35), 618 (18), 351 (15), 307 (15),
268 (13), 267 (50), 165 (12), 155 (23), 154 (100), 138 (27), 137 (54), 136
(78), 131 (25), 17 (25), 77 (18); HR-FAB-MS m/z 619.2806 [MꢄH]ꢄ (Calcd
for C38H39O6N2 619.2808).
Synthesis of 1a To a solution of 4-hydroxy-3-methoxyacetophenone (1)
(16.6 g, 100 mmol), paraformaldehyde (3.0 g, 100 mmol), and piperazine
(4.3 g, 50 mmol) were added in EtOH (75 ml) at room temperature as previ-
ously reported.25,35—38) Then the resulting mixture was heated to reflux for
20 h at 120 °C. After completion, the reaction mixture was concentrated
under reduced pressure and the crude product was purified by column chro-
matography to yield a 1,4-dimethylenepiperazine linked acetophenone dimer
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-(3-hydroxyphenyl)prop-2-en-1-one) (5)
Compound 1a (1.105 g, 2.5 mmol) and 3-hydroxybenzaldehyde (0.61 g,
5.0 mmol) were treated as described above and the title compound was iso-
lated as yellow solid in 39% yield. (5): mp 203—205 °C (80% benzene–ace-
tone); IR (neat) nmax: 2839, 1647, 1585, 1450, 1284, 1122, 1083, 995,
952 cmꢃ1; 1H-NMR (300 MHz, DMSO-d6) d: 8.24 (2H, d, Jꢀ15.6 Hz), 8.13
(1a, 86%). 1a: white solid, mp 246—248 °C (95% CHCl3–MeOH); IR (neat) (2H, s), 8.02 (2H, d, Jꢀ15.6 Hz), 7.98 (2H, s), 7.67 (6H, dd, Jꢀ9.0, 1.5 Hz),
n
max: 2830, 1654, 1581, 1450, 1408, 1354, 1211, 1180, 1080, 999, 948,
7.28 (2H, d, Jꢀ7.2 Hz), 4.28 (6H, s), 4.18 (4H, s), 2.91 (8H, s); 13C-NMR
1
894 cmꢃ1; H-NMR (300 MHz, CDCl3) d: 7.46 (2H, s), 7.28 (2H, s), 3.92 (75 MHz, DMSO-d6) d: 187.0, 157.6, 151.8, 147.6, 142.9, 129.8, 123.8,
(6H, s), 3.80 (4H, s), 3.00—2.50 (8H, br s), 2.53 (6H, s); 13C-NMR 122.0, 121.8, 119.7, 117.5, 115.0, 110.5, 58.0, 55.7, 51.9; FAB-MS m/z (rel.
(75 MHz, CDCl3) d: 196.5, 151.9, 147.9, 128.9, 122.6, 119.7, 110.4, 60.7, int. %): 651 ([MꢄH]ꢄ, 8), 393 (5), 391 (8), 349 (7), 307 (14), 289 (10), 283
55.9, 52.1, 26.1; FAB-MS m/z (rel. int. %): 443 ([MꢄH]ꢄ, 5), 307 (19), 289 (15), 176 (11), 155 (23), 154 (100), 149 (29), 139 (11), 138 (27), 137 (55),
(10), 155 (24), 154 (100), 149 (13), 138 (27), 137 (55), 136 (68), 120 (11),
136 (75), 120 (13), 107 (26), 89 (24), 77 (18); HR-FAB-MS m/z 651.2708
107 (20), 90 (12), 89 (19), 77 (12); HR-FAB-MS m/z 443.2182 [MꢄH]ꢄ [MꢄH]ꢄ (Calcd for C38H39O8N2 651.2706).
(Calcd for C24H31O6N2, 443.2182).
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
General Procedure for the Synthesis of 1,4-Dimethylenepiperazine 3-methoxy-5,1-phenylene))bis(3-(3-methoxyphenyl)prop-2-en-1-one) (6)
Linked Bichalcones The general synthetic strategy employed to prepare Compound 1a (1.105 g, 2.5 mmol) and 3-methoxybenzaldehyde (0.68 g,
the bichalcones linked with a 1,4-dimethylenepiperazine moiety was based 5.0 mmol) were treated as described above and the title compound was
on the Claisen–Schmidt condensation. As shown in Fig. 1b, a series of 15
isolated as pale yellow solid in 58% yield. (6): mp 197—199 °C (95%
derivatives were prepared by base-catalyzed condensation of 1a with appro- benzene–acetone); IR (neat) nmax: 2831, 1654, 1597, 1342, 1276, 1049,
priate aldehydes in MeOH. To a stirred reaction mixture at 0 °C was added a
30% solution of KOH (40 ml) drop wise over 30 min. The reaction mixture
was kept at room temperature for 24—36 h, then diluted with water and ex-
tracted with EtOAc. Pure target compounds were obtained by silica gel col-
umn chromatography (CC) of the residue eluting with various solvent mix-
tures as indicated below. The chemical structures of all the 15 bichalcones
756 cmꢃ1 1H-NMR (300 MHz, CDCl3) d: 7.76 (2H, d, Jꢀ15.6 Hz), 7.56
;
(2H, s), 7.50 (2H, d, Jꢀ15.6 Hz), 7.39 (2H, s), 7.32 (2H, d, Jꢀ8.4 Hz), 7.16
(2H, s), 6.96 (2H, d, Jꢀ7.8 Hz), 3.96 (6H, s), 3.85 (4H, s), 2.74 (8H, br s);
13C-NMR (75 MHz, CDCl3) d: 188.1, 159.8, 151.9, 148.2, 143.7, 136.4,
129.8, 129.6, 122.5, 121.8, 120.8, 119.8, 115.7, 113.5, 110.9, 60.7, 56.0,
55.3, 52.2; FAB-MS m/z (rel. int. %): 679 ([MꢄH]ꢄ, 22), 678 (12), 307
(18), 297 (32), 161 (16), 155 (22), 154 (100), 138 (25), 137 (51), 136 (74),
107 (24), 89 (25), 77 (22); HR-FAB-MS m/z 679.3019 [MꢄH]ꢄ (Calcd for
C40H43O8N2 679.3019).
1
were established on the basis of IR, H-, 13C-NMR, FAB-MS and HR-FAB-
MS analyses.
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-(pyridin-2-yl)prop-2-en-1-one) (2)
Compound 1a (1.105 g, 2.5 mmol) and 2-pyridinecarboxaldehyde (0.535 g,
5.0 mmol) were treated as described above and the title compound was iso-
lated as yellow solid in 77% yield. (2): mp 214—216 °C (90% benzene–ace-
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-(3,4-dimethoxyphenyl)prop-2-en-1-one)
(7) Compound 1a (1.105 g, 2.5 mmol) and 3,4-dimethoxybenzaldehyde
(0.83 g, 5.0 mmol) were treated as described above and the title compound
tone); IR (neat) nmax: 2823, 1654, 1577, 1462, 1342, 1311, 1288, 1230, was isolated as yellow solid in 60% yield. (7): mp 195—197 °C (95% ben-
1165, 1091, 1002, 752 cmꢃ1; 1H-NMR (300 MHz, CDCl3) d: 8.62 (2H, br s), zene–acetone); IR (neat) nmax: 2831, 1652, 1585, 1492, 1415, 1350, 1261,
1
8.05 (2H, d, Jꢀ15.0 Hz), 7.70 (2H, d, Jꢀ15.0 Hz), 7.63 (2H, br s), 7.55 (2H,
1138 cmꢃ1; H-NMR (300 MHz, CDCl3) d: 7.67 (2H, d, Jꢀ15.6 Hz), 7.47
s), 7.39 (4H, m), 7.21 (2H, d, Jꢀ4.8 Hz), 3.89 (6H, s), 3.75 (4H, s), 2.46 (2H, s), 7.35 (2H, d, Jꢀ15.6 Hz), 7.30 (2H, br s), 7.17 (2H, dd, Jꢀ9.0,
(8H, br s); 13C-NMR (75 MHz, CDCl3) d: 188.0, 153.2, 152.2, 149.9, 148.2,
3.0 Hz), 7.06 (2H, s), 6.80 (2H, d, Jꢀ9.0 Hz), 3.87 (6H, s), 3.86 (6H, s), 3.83
141.7, 136.8, 129.3, 125.4, 124.9, 124.2, 123.0, 119.8, 110.8, 60.5, 55.9, (6H, s), 3.75 (4H, s), 2.65 (8H, br s); 13C-NMR (75 MHz, CDCl3) d: 188.3,
52.0; FAB-MS m/z (rel. int. %): 621 ([MꢄH]ꢄ, 15), 307 (19), 289 (10), 269 151.7, 151.2, 149.1, 148.1, 144.1, 129.9, 128.0, 122.7, 122.4, 119.8, 119.4,
(9), 268 (25), 155 (23), 154 (100), 138 (26), 137 (52), 136 (71), 132 (12),
111.1, 111.0, 110.3, 60.7, 56.1, 56.0, 55.9, 52.1; FAB-MS m/z (rel. int. %):

December 2011
1553
739 ([MꢄH]ꢄ, 1), 391 (30), 307 (6), 279 (6), 179 (5), 167 (20), 155 (13),
Jꢀ6.0 Hz), 7.38 (6H, m), 3.98 (6H, s), 3.92 (4H, s), 2.77 (8H, s); 13C-NMR
265 (59), 150 (14), 149 (100), 138 (17), 137 (37), 136 (46), 113 (20), 107 (75 MHz, CDCl3) d: 188.2, 152.1, 148.0, 142.2, 136.6, 134.6, 130.4, 129.1,
(18), 91 (12), 90 (11), 77 (13), 71 (20); HR-FAB-MS m/z 739.3233 [MꢄH]ꢄ
(Calcd for C42H47O10N2 739.3231).
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-(4-methoxyphenyl)prop-2-en-1-one) (8)
Compound 1a (1.105 g, 2.5 mmol) and 4-methoxybenzaldehyde (0.68 g,
5.0 mmol) were treated as described above and the title compound was
isolated as yellow solid in 74% yield. (8): mp 235—237 °C (95% benzene–
127.5, 126.6, 122.8, 122.5, 119.9, 110.7, 60.2, 55.8, 51.9; FAB-MS m/z (rel.
int. %): 687 ([MꢄH]ꢄ, 6), 391 (17), 307 (14), 289 (10), 167 (13), 154 (100),
149 (58), 138 (28), 137 (56), 136 (76), 120 (12), 113 (12), 107 (26), 89 (27),
77 (20); HR-FAB-MS m/z 687.2028 [MꢄH]ꢄ (Calcd for C38H37O6N2Cl2
687.2029).
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-(furan-2-yl)prop-2-en-1-one) (13)
acetone); IR (neat) nmax: 2835, 1651, 1593, 1508, 1458, 1342, 1296, 1161, Compound 1a (1.105 g, 2.5 mmol) and 2-furaldehyde (0.48 g, 5.0 mmol)
1056, 999, 979, 825 cmꢃ1
;
1H-NMR (300 MHz, CDCl3) d: 7.70 (2H, d, were treated as described above and the title compound was isolated as yel-
Jꢀ15.6 Hz), 7.52 (4H, d, Jꢀ9.0 Hz), 7.49 (2H, s), 7.34 (2H, d, Jꢀ15.6 Hz), low solid in 77% yield. (13): mp 230—232 °C (95% benzene–aetone); IR
7.29 (2H, s), 6.85 (4H, d, Jꢀ9.0 Hz), 3.84 (6H, s), 3.76 (10H, s), 2.46 (8H, (neat) nmax: 2832, 1651, 1593, 1458, 1323, 1207, 1083, 960, 748 cmꢃ1; H-
1
br s); 13C-NMR (75 MHz, CDCl3) d: 188.2, 161.4, 151.7, 148.1, 143.7,
NMR (300 MHz, CDCl3) d: 7.51 (2H, d, Jꢀ15.3 Hz), 7.48 (2H, m), 7.46
130.0, 129.9, 127.7, 122.3, 119.8, 119.1, 114.3, 110.9, 60.7, 56.0, 55.3, (2H, s), 7.37 (2H, d, Jꢀ15.3 Hz), 7.26 (2H, s), 6.61 (2H, d, Jꢀ3.3 Hz), 6.42
52.1; FAB-MS m/z (rel. int. %): 679 ([MꢄH]ꢄ, 6), 308 (4), 307 (19), 289 (2H, dd, Jꢀ3.3, 3.0 Hz), 3.87 (6H, s), 3.75 (4H, s), 2.68 (8H, br s); 13C-NMR
(11), 155 (23), 154 (100), 138 (26), 137 (52), 136 (70), 120 (11), 107 (21),
(75 MHz, CDCl3) d: 187.5, 151.9, 151.7, 148.1, 144.5, 129.8, 129.6, 122.4,
89 (20), 77 (13); HR-FAB-MS m/z 679.3019 [MꢄH]ꢄ (Calcd for 119.8, 118.7, 115.7, 112.5, 110.8, 60.7, 56.0, 52.1; FAB-MS m/z (rel. int.
C40H43O8N2 679.3019).
%): 599 ([MꢄH]ꢄ, 12), 307 (17), 289 (10), 257 (12), 155 (22), 154 (100),
139 (10), 138 (27), 136 (73), 121 (10), 107 (23), 90 (15), 89 (23), 77 (15);
HR-FAB-MS m/z 599.2394 [MꢄH]ꢄ (Calcd for C34H35O8N2 599.2393).
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-(5-methylfuran-2-yl)prop-2-en-1-one)
(14) Compound 1a (1.105 g, 2.5 mmol) and 5-methyl-2-furaldehyde
(0.55 g, 5.0 mmol) were treated as described above and the title compound
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-
one) (9) Compound 1a (1.105 g, 2.5 mmol) and 3,4-methylenedioxybenz-
aldehyde (0.75 g, 5.0 mmol) were treated as described above and the title
compound was isolated as yellow solid in 61% yield. (9): mp 246—248 °C
(90% benzene–acetone); IR (neat) nmax: 2821, 1652, 1462, 1280, 1230 cmꢃ1
;
1H-NMR (300 MHz, CDCl3) d: 7.74 (2H, d, Jꢀ15.3 Hz), 7.57 (2H, s), 7.39 was isolated as yellow solid in 63% yield. (14): mp 174—176 °C (90% ben-
(2H, br s), 7.36 (2H, d, Jꢀ15.3 Hz), 7.19 (2H, s), 7.14 (2H, d, Jꢀ8.1 Hz), zene–acetone); IR (neat) nmax: 2831, 1651, 1570, 1450, 1346, 1157, 1083,
6.86 (2H, d, Jꢀ8.1 Hz), 6.04 (4H, s), 3.97 (6H, s), 3.86 (4H, s), 2.75 (8H, 995, 952, 779 cmꢃ1; H-NMR (300 MHz, CDCl3) d: 7.42 (8H, m, including
1
br s); 13C-NMR (75 MHz, CDCl3) d: 188.2, 151.9, 149.7, 148.4, 148.2, trans coupled protons), 6.52 (2H, s), 6.03 (2H, s), 3.87 (6H, s), 3.74 (4H, s),
143.8, 129.9, 129.5, 125.0, 122.4, 119.9, 119.5, 111.0, 108.6, 106.6, 101.6, 2.31 (8H, br s), 2.27 (6H, s); 13C-NMR (75 MHz, CDCl3) d: 187.6, 155.4,
60.8, 56.1, 52.2; FAB-MS m/z (rel. int. %): 707 ([MꢄH]ꢄ, 3), 391 (21), 307
151.6, 150.3, 148.0, 129.9, 129.8, 122.3, 119.7, 117.7, 116.9, 110.7, 109.1,
(15), 289 (10), 167 (12), 155 (23), 154 (100), 149 (55), 138 (27), 137 (54),
60.6, 55.9, 52.0, 13.9; FAB-MS m/z (rel. int. %): 627 ([MꢄH]ꢄ, 38), 355
136 (74), 120 (12), 113 (11), 107 (25), 91 (14), 90 (17), 89 (25), 77 (19), 71 (15), 307 (14), 271 (35), 154 (100), 149 (21), 137 (53), 136 (81), 120 (13),
(12); HR-FAB-MS m/z 707.2603 [MꢄH]ꢄ (Calcd for C40H39O10N2
707.2605).
107 (30), 89 (28), 77 (21); HR-FAB-MS m/z 627.2706 [MꢄH]ꢄ (Calcd for
C36H39O8N2 627.2706).
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-(4-(3-methylbut-2-enyloxy)phenyl)prop-
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-(thiophen-2-yl)prop-2-en-1-one) (15)
2-en-1-one) (10) Compound 1a (1.105 g, 2.5 mmol) and 4-O-prenylbenz- Compound 1a (1.105 g, 2.5 mmol) and thiophene-2-carboxaldehyde (0.56 g,
aldehyde (0.95 g, 5.0 mmol) were treated as described above and the title 5.0 mmol) were treated as described above and the title compound was iso-
compound was isolated as pale yellow solid in 50% yield. (10): mp 196— lated as pale yellow solid in 90% yield. (15): mp 213—215 °C (90% ben-
198 °C (95% benzene–acetone); IR (neat) nmax: 2835, 1647, 1585, 1454, zene–acetone); IR (neat) nmax: 2829, 1647, 1589, 1458, 1365, 1288, 1199,
1161, 1087, 941, 752 cmꢃ1
;
1H-NMR (300 MHz, CDCl3) d: 7.70 (2H, d,
752 cmꢃ1 1H-NMR (300 MHz, CDCl3) d: 7.84 (2H, d, Jꢀ15.3 Hz), 7.47
;
Jꢀ15.6 Hz), 7.51 (2H, d, Jꢀ15.6 Hz), 7.50 (4H, s), 7.33 (4H, d, Jꢀ9.0 Hz),
6.86 (4H, d, Jꢀ9.0 Hz), 5.41 (2H, t, Jꢀ6.3 Hz), 4.48 (4H, d, Jꢀ6.3 Hz), 3.88
(6H, s), 3.76 (4H, s), 2.62 (8H, br s), 1.72 (6H, s), 1.68 (6H, s); 13C-NMR
(2H, s), 7.32 (2H, d, Jꢀ5.1 Hz), 7.28 (2H, br s), 7.24 (2H, d, Jꢀ15.3 Hz),
7.19 (2H, d, Jꢀ5.1 Hz), 7.00 (2H, t, Jꢀ4.2 Hz), 3.87 (6H, s), 3.77 (4H, s),
2.45 (8H, br s); 13C-NMR (75 MHz, CDCl3) d: 187.6, 151.9, 148.1, 140.4,
(75 MHz, CDCl3) d: 188.3, 160.8, 151.7, 148.1, 143.8, 138.7, 130.0, 127.6, 136.3, 131.7, 129.6, 128.3, 128.2, 122.4, 120.2, 119.8, 110.8, 60.7, 56.0,
122.3, 119.8, 119.1, 119.0, 115.0, 111.0, 64.9, 60.8, 56.0, 52.2, 25.8, 18.2; 52.1; FAB-MS m/z (rel. int. %): 631 ([MꢄH]ꢄ, 14), 307 (16), 273 (19), 154
FAB-MS m/z (rel. int. %): 707 ([MꢄH]ꢄ, 42), 435 (21), 351 (29), 283 (57), (100), 149 (15), 137 (58), 136 (73), 120 (12), 107 (23), 89 (23), 77 (15);
163 (25), 154 (100), 152 (16), 137 (56), 136 (88), 121 (17), 107 (42), 90 HR-FAB-MS m/z 631.1938 [MꢄH]ꢄ (Calcd for C34H35O6N2S2 631.1937).
(26), 89 (39), 85 (44), 77 (39); HR-FAB-MS m/z 787.3961 [MꢄH]ꢄ (Calcd
for C48H55O8N2 787.3958).
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-(3-methylthiophen-2-yl)prop-2-en-1-
one) (16) Compound 1a (1.105 g, 2.5 mmol) and 3-methyl-2-thiophenecar-
3-methoxy-5,1-phenylene))bis(3-(2-chlorophenyl)prop-2-en-1-one) (11) boxaldehyde (0.63 g, 5.0 mmol) were treated as described above and the title
Compound 1a (1.105 g, 2.5 mmol) and 2-chlorobenzaldehyde (0.7 g, 5.0 compound was isolated as yellow solid in 72% yield. (16): mp 216—218 °C
mmol) were treated as described above and the title compound was isolated (95% benzene–acetone); IR (neat) nmax: 2827, 1647, 1585, 1492, 1458,
as yellow solid in 70% yield. (11): mp 228—230 °C (95% benzene–ace-
1292, 1161, 1056, 833, 713 cmꢃ1; 1H-NMR (300 MHz, CDCl3) d: 8.01 (2H,
tone); IR (neat) nmax: 2837, 1647, 1585, 1450, 1346, 1284, 1122, 1083, 995, d, Jꢀ15.0 Hz), 7.56 (2H), 7.36 (2H, d, Jꢀ6.0 Hz), 7.28 (4H, m), 6.90 (2H, d,
952 cmꢃ1
;
1H-NMR (300 MHz, CDCl3) d: 8.06 (2H, d, Jꢀ15.6 Hz), 7.67
Jꢀ6.0 Hz), 3.96 (6H, s), 3.85 (4H, s), 2.69 (8H, br s), 2.39 (6H, s); 13C-NMR
(75 MHz, CDCl3) d: 187.6, 151.8, 148.1, 142.3, 134.7, 134.6, 131.3, 129.8,
126.8, 122.3, 119.8, 119.3, 110.9, 60.7, 56.0, 52.1, 14.2; FAB-MS m/z (rel.
(2H, dd, Jꢀ9.0, 3.0 Hz), 7.48 (2H, s), 7.39 (2H, d, Jꢀ15.6 Hz), 7.38 (4H,
m), 7.24 (4H, m), 3.84 (6H, s), 3.76 (4H, s), 2.46 (8H, br s); 13C-NMR
(75 MHz, CDCl3) d: 188.3, 152.0, 148.2, 139.7, 135.3, 133.4, 130.9, 130.2, int. %): 659 ([MꢄH]ꢄ, 10), 307 (18), 289 (12), 287 (11), 155(23), 154
129.4, 127.7, 127.0, 124.5, 122.7, 119.8, 111.1, 60.7, 56.0, 52.1; FAB-MS (100), 138 (27), 137 (53), 136 (77), 120 (12), 107 (24), 90 (17), 89 (25), 77
m/z (rel. int. %): 687 ([MꢄH]ꢄ, 3), 307 (19), 289 (11), 155 (23), 154 (100), (21); HR-FAB-MS m/z 659.2248 [MꢄH]ꢄ (Calcd for C36H39O6N2S2
139 (9), 138 (26), 137 (52), 136 (69), 120 (11), 107 (21), 91 (10), 89 (20),
77 (13); HR-FAB-MS m/z 687.2031 [MꢄH]ꢄ (Calcd for C38H37O6N2Cl2
687.2029).
(2E,2ꢀE)-1,1ꢀ-(5,5ꢀ-(Piperazine-1,4-diylbis(methylene))bis(4-hydroxy-
3-methoxy-5,1-phenylene))bis(3-(3-chlorophenyl)prop-2-en-1-one) (12)
Compound 1a (1.105 g, 2.5 mmol) and 3-chlorobenzaldehyde (0.7 g, 5.0
mmol) were treated as described above and the title compound was isolated
as yellow solid in 63% yield. (12): mp 248—250 °C (90% benzene–ace-
659.2250).
Cell Culture The human glioblastoma cell lines (GBM-8401 and
M059K), human pharyngeal squamous carcinoma cell line (FaDu), human
esophageal carcinoma cell line (CE146T/VGH), human oral squamous car-
cinoma cell line (HSC-3), human tongue squamous carcinoma cell lines
(CAL-27 and SAS), human lung carcinoma cell lines (A549 and H-460),
human hepatoma cell lines (SK1—CP1, Huh7, HepG2 and Hep3B), human
breast adenocarcinoma cell lines (MDA-MB-231 and MCF7), human
tone); IR (neat) nmax: 2830, 1647, 1597, 1458, 1311, 1276, 1083, 1056, 960, melanoma cell line (A375), human cervical carcinoma cell line (HeLa),
837 cmꢃ1 1H-NMR (300 MHz, CDCl3) d: 7.74 (2H, d, Jꢀ15.6 Hz), 7.66
human osteosarcoma cell lines (MG-63 and U-2 OS), and the human colon
(2H, s), 7.58 (2H, d, Jꢀ1.0 Hz), 7.53 (2H, d, Jꢀ15.6 Hz), 7.49 (2H, d, carcinoma cell lines (HT-29 and Colo 25) were obtained from the Food In-
;

1554
Vol. 59, No. 12
dustry Research and Development Institute (Hsinchu, Taiwan). The human
nasopharyngeal carcinoma cell lines (NPC-TW 039 and NPC-TW 076) were
provided by Dr. C. Y. Yang (Institute of Molecular Biology, National Chung
Hsing University, Taichung, Taiwan). The human neuroblastoma cell line
(NT-2) was kindly provided by Dr. C. L. Liao (Department of Microbiology
and Immunology, National Defense Medical Center, Taichung, Taiwan). The
human neuroblastoma cell line (SH-SY5Y) was provided by J. G. Chung
(Department of Biological Science and Technology, China Medical Univer-
sity, Taichung, Taiwan). The CAL-27, FaDu, Huh7, HeLa, and MCF-7 cell
lines were cultured in MEM supplemented with 5% fetal bovine serum
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Acknowledgements This work was supported by a Grant of National
Science Council, Taiwan, Republic of China, and Grant (No. OUA 95-3-2-
021) from the National Cheng Kung University, Tainan, Taiwan R.O.C.
awarded to T. S. Wu. This study is supported in part by Taiwan Department
of Health Clinical Trial and Research Center of Excellence (DOH100-TD-
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