Synthesis and anti-cancer activity of chalcone linked imidazolones

Article abstract of DOI:10.1016/j.bmcl.2010.06.097

A series of novel chalcone linked imidazolones were prepared and evaluated for their anti-cancer activity against a panel of 53 human tumour cell lines derived from nine different cancer types: leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast. Some of these hybrids (6, 7 and 8) showed good anti-cancer activity with GI₅₀ values ranging from 1.26 to 13.9 μM. When breast carcinoma cells (MCF-7) were treated with 10 μM concentration of compounds TMAC, CA-4, 6 and 8 cell cycle arrest was observed in G2/M phase. Surprisingly, the increased concentration of the same compound to 30 μM caused accumulation of cells in G0/G1 phase of the cell cycle.

Full text of DOI:10.1016/j.bmcl.2010.06.097

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4865–4869
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and anti-cancer activity of chalcone linked imidazolones
*
Ahmed Kamal , G. Ramakrishna, P. Raju, A. Viswanath, M. Janaki Ramaiah, G. Balakishan,
*
Manika Pal-Bhadra
Chemical Biology Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel chalcone linked imidazolones were prepared and evaluated for their anti-cancer activity
against a panel of 53 human tumour cell lines derived from nine different cancer types: leukemia, lung,
colon, CNS, melanoma, ovarian, renal, prostate and breast. Some of these hybrids (6, 7 and 8) showed
Received 24 March 2010
Revised 28 May 2010
Accepted 16 June 2010
Available online 25 June 2010
good anti-cancer activity with GI50 values ranging from 1.26 to 13.9
(MCF-7) were treated with 10 M concentration of compounds TMAC, CA-4, 6 and 8 cell cycle arrest
was observed in G2/M phase. Surprisingly, the increased concentration of the same compound to
30 M caused accumulation of cells in G0/G1 phase of the cell cycle.
lM. When breast carcinoma cells
l
Keywords:
l
Chalcone linked imidazolones
Anti-cancer activity
Cell cycle arrest
G2/M
Ó 2010 Elsevier Ltd. All rights reserved.
G0/G1
Petitt et al. isolated combretastatin A-4 (CA-4) in 1982 from the
bark of Combretum caffrum, having strong antitubulin activity.1 CA-
4 binds to colchicine binding site and exhibits strong anti-cancer
activity against wide variety of human cancer cell lines including
MDR cancer cell lines.2 CA-4 exhibit strong anti-cancer activity
in vitro against a number of cancer cell lines whereas it shows poor
antitumour activity in animal models due to low water solubility. A
potent prodrug, CA-4 phosphate (CA-4P), has been developed to
overcome the problem of water solubility.3,4 It is observed that
on long standing cis CA-4 is converted to trans CA-4 and further
the trans form of these compounds exhibit reduction in antitubulin
and antitumour activity. Thus many attempts have been made to
retain the cis-olefinic bond by introducing five membered hetero
cycle.5 Structurally, in CA-4, two phenyl rings are spaced by two
carbon atoms. Similarly many of the combretastatin analogues
are separated by two atom bridge. However, CA-4 analogues pos-
sessing spacers of three carbon atoms are very few and the present
study is focused on it. Combretastatin A-4 is thus attractive as a
lead compound for the development of new anti-cancer
compounds.
cer activity were found to prevent tubulin polymerization by bind-
ing with colchicine binding site.10–12
The compounds containing imidazolone (B) chromophore are
known to have a wide range of biological activities like anti-cancer,
anti-inflammatory, cardioactivity and angiotensin II receptor
antagonistic activity.13 A trisubstituted imidazolone (MZ3) induced
high degree of apoptosis in human leukemia cells and also have
prominent cytotoxicity.14 The compounds having imidazolone
scaffold are known to inhibit hdm 2 E3 ligase activity, which ubiq-
uitinates oncoprotein p53. It is well established in the literature
that imidazolones exhibit selective blocking of hdm 2 mediated
ubiquitation of p53 thus promoting apoptosis.15 Chalcones (A),
O
CH3
N
N
MeO
MeO
OH
OMe
MeO
MeO
O
NH2
OMe
CA-4
A-105972
MeO
Chalcones (A) are an important class of anti-cancer agents that
are present in edible plants. They exhibit a broad spectrum of bio-
logical activities, including anti-inflammatory,6,7 anti-invasive8,9
and antibacterial properties. Chalcones exhibiting potent anti-can-
O
O
NH
MeO
MeO
MeO
N
R
R1
MeO
MeO
OMe
B
A
* Corresponding authors. Tel.: +91 40 27193157; fax: +91 40 27193189 (A.K.);
tel.: +91 40 27193236 (M.P.-B.).
E-mail addresses: ahmedkamal@iict.res.in (A. Kamal), manika@iict.res.in (M. Pal-
Bhadra).
Figure 1. Chemical structures of combretastatin (CA-4), A-105972, chalcones (A)
and imidazolones (B).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.097

4866
A. Kamal et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4865–4869
O
H
O
NH2
O
NH2
a
O
Br
R1
R
R
4
3
2
1
O
NH
O
R1
O
O
N
H
N
c
b
R1
R
6-15
R
5
6: R = 4-OH-3-OMe; R1 = Phenyl
7: R = 4-OH-3-OMe; R1 = 4 -methoxy phenyl
8: R = 4-OH-3-OMe; R1 = 4 -chloro phenyl
9: R = 3-OH; R1 = phenyl
10: R = 3-OH; R1 = 4 -chloro phenyl
11: R = 3,4,5-(MeO)3; R1 = phenyl
12: R = 3,4,5-(MeO)3; R1 = 4 -methoxy phenyl
13: R = 3,4,5-(MeO)3; R1 = 3,4,5 -trimethoxy phenyl
14: R = 3,4,5-(MeO)3; R1 = 4 chloro phenyl
15: R = 3-OH; R1 = naphthyl
Scheme 1. Reagents and conditions: (a) 40% KOH, ethanol, 0 °C to rt, 10 h; (b) NaHCO3, ethanol, 25 °C, 16 h; (c) KOCN, AcOH, 60–70 °C, 2 h.
Table 1
Table 1 (continued)
Anti-cancer activities of chalcono linked imidazolones against the NCI human
tumours cell linesa
Cancer panel/cell line
GI50
(lM)
6
7
8
9
10 11 12 13 14 17
Cancer panel/cell line
GI50
(lM)
Ovarian
6
7
8
9
10 11 12 13 14 17
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
2.29 2.70 1.56 3.08 1.56 1.23 1.78 1.48 2.40 1.33
5.19 6.08 4.64 5.30 2.21 1.88 3.57 3.77 11.4 1.68
2.04 3.38 2.00 5.44 2.19 1.88 2.64 4.38 3.11 1.89
4.11 4.97 4.18 2.80 0.99 1.62 2.53 2.32 3.85 2.33
2.92 2.56 2.28 3.73 2.20 1.10 1.70 2.10 2.36 1.55
3.76 4.77 3.19 11.1 4.21 3.27 4.60 5.12 31.4 2.15
Leukemia
RPMI-8226
K-562
1.67 1.35 1.33 2.15 1.55 0.62 0.92 0.23 3.92 1.67
2.04 2.35 1.42 3.35 0.40 0.50 1.27 0.59 3.69 1.43
Non-small cell lung
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
3.85 4.14 6.78 3.89 3.55 4.03 11.8 3.03 na 3.38
3.90 13.4 9.61 15.6 2.40 2.30 4.20 9.47 na 2.64
1.48 5.15 2.84 6.93 2.36 4.12 5.91 3.08 na 2.26
Breast
MCF7
1.55 3.18 2.30 2.47 1.27 0.31 0.44 0.47 1.74 0.47
2.27 2.96 1.26 5.04 1.6 10.8 14.9 nt
na 0.51
MDA-MB-231/ATCC 3.36 5.25 3.87 3.86 3.35 2.17 5.48 4.19 13.8 1.66
2.60 4.10 2.77 24.8 2.31 14.6 35.2 14.4 na 2.43
2.02 2.85 3.18 3.35 2.78 1.43 1.63 2.00 3.56 1.52
3.39 8.20 4.58 10.6 2.52 2.02 2.66 3.61 12.9 1.66
1.95 3.23 3.90 2.49 2.41 1.4 1.56 1.73 3.74 1.67
HS 578T
BT-549
TD-47D
4.16 4.25 4.67 6.14 4.00 3.41 3.39 na 5.96 2.01
2.78 4.57 2.52 9.32 1.45 1.93 2.59 1.52 12.3 1.89
2.7 3.60 3.09 4.24 1.92 2.19 3.84 3.08 6.65 1.11
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
2.36 3.48 2.36 nt
1.65 0.95 1.85 1.05 4.10 1.29
1.88 2.44 1.63 1.85 1.57 0.48 0.72 1.23 1.72 0.85
2.67 4.42 3.06 6.21 1.83 1.31 1.79 1.80 18.1 2.08
2.61 5.14 2.86 4.53 2.01 1.35 1.85 2.12 4.36 1.49
2.14 3.35 2.25 3.12 2.06 1.20 1.86 2.11 3.63 1.71
3.65 5.54 3.66 8.26 2.07 2.06 2.63 3.02 3.44 2.31
1.85 2.03 2.06 5.63 3.64 1.74 2.03 1.61 10.9 3.79
1.59 2.63 1.80 3.18 1.53 1.40 2.03 2.76 8.70 1.16
6.81 13.3 8.69 7.68 4.07 1.52 3.04 2.22 17.4 4.13
2.01 3.96 2.74 3.65 1.85 1.52 2.06 1.87 8.88 1.80
Colon
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
2.21 6.61 3.40 2.01 2.29 1.51 1.84 1.52 7.38 2.09
1.51 2.32 1.85 4.09 13.7 1.26 1.64 1.92 2.46 2.13
1.40 1.93 1.46 3.02 1.23 0.33 0.37 0.74 1.39 0.40
2.73 3.15 1.80 3.10 2.33 1.13 1.38 1.89 3.85 1.56
3.77 3.84 2.97 3.33 1.90 0.66 1.28 1.70 2.00 1.54
1.61 1.77 1.48 1.83 1.34 1.37 1.42 1.12 5.45 1.21
2.29 2.50 2.00 2.41 1.62 0.39 0.45 1.03 1.75 0.22
KM12
SW-620
CNS
a
Values are reported as GI50, the concentration of the compound required to
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
2.07 3.40 2.50 4.53 1.78 1.92 3.21 2.20 5.07 1.73
3.04 13.9 10.5 18.2 1.79 1.90 4.95 4.96 24.3 1.44
1.91 2.25 1.78 1.98 1.68 1.68 2.00 3.12 3.49 1.55
2.96 5.84 3.17 10.9 1.92 2.35 4.38 4.07 16.1 1.32
3.90 4.73 2.75 12.1 1.46 4.47 4.59 5.13 nac 1.88
2.11 3.45 2.23 1.61 0.58 0.63 0.88 1.23 2.12 1.09
cause 50% inhibition of cell growth.
b
nt = not tested.
na = not active.
c
Renal
A498
imidazolones (B) and A-105972 are the derivatives of CA-4, where-
in the two aryl rings are bridged through three atoms as illustrated
in Figure 1.16
1.68 3.72 2.82 14.3 3.71 2.65 4.21 20.3 30.2 nt
1.35 4.53 2.07 2.98 1.57 1.38 1.61 1.59 2.14 1.74
2.50 3.40 2.19 2.76 1.84 1.60 1.82 1.74 7.17 1.57
2.19 4.99 2.64 13.3 1.72 1.75 3.05 2.89 na 1.45
2.27 5.85 6.40 1.89 1.51 1.71 1.92 1.62 3.22 1.41
3.31 4.11 2.87 3.14 1.95 2.09 3.50 2.75 5.14 1.44
5.29 6.08 4.67 ntb 2.83 3.02 3.04 3.00 6.46 3.45
2.18 5.19 1.67 2.16 0.55 1.51 1.91 0.96 7.03 1.26
786-0
ACHN
CAKI-1
RXF 393
SN12C
TK-10
UO-31
In the present study we have linked the chalcone pharmaco-
phore with imidazolones as outlined in Scheme 1.17,18 Initially,
amino chalcone intermediates (3) have been synthesized from
the easily available starting materials, like aldehydes and 3-amino
acetophenone. Further, these on reactions with phenacyl bromides
in ethanol in the presence of sodium bicarbonate gives intermedi-
ates 5. Finally, these intermediates are reacted with KCNO in acetic
acid at 60 °C to provide the chalcone linked imidazolones.19
Prostate
PC3
2.52 3.05 1.95 2.82 nt
3.26 6.22 2.63 na 1.85

A. Kamal et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4865–4869
4867
Figure 2. FACS analysis of cell cycle distribution of MCF-7 cells after treatment with chalcone imidazolones compounds TMAC, CA-4, 6 and 8 at 10 lM and at 30 lM
concentration for 24 h. TMAC is the starting material. CA-4 was used as the positive control. Control is DMSO.
Compounds 6–15, which passed the preliminary screening on
the tumour cell lines were tested for five dose studies in the frame-
work of the in vitro Anticancer Screen Program of the National
Cancer Institute (Bethesda, USA) on a panel of 53 human tumour
cell lines derived from nine different cancer types: leukemia, lung,
colon, CNS, melanoma, ovarian, renal, prostate and breast. The GI50
values for the test compounds are illustrated in Table 1.
Amongst all the compounds tested for five dose studies, three
compounds that is, 6, 7, 8 have showed reproducible results. The
antitumour activity (GI50) of these compounds 6, 7 and 8 are in
phenyl)-2-propen-1-ne(TMAC), the starting material has shown
23.57% of G2/M cell cycle arrest. The positive control CA-4, com-
pounds 6 and 8 have shown 68.8% 48.85% and 31.65% of G2/M ar-
rest, respectively as seen in (Figs. 2 and 3a).
This data clearly showed that these compounds arrest the cell
cycle at G2/M phase. Moreover this data further revealed that com-
pound 6 is the most potent one amongst the two investigated. Sur-
prisingly, the increased concentrations of these compounds to
30 lM have shown enhanced accumulation of cells at G0 phase
and drastic reduction of cells at G2/M phase. The increased cells
in G0 phase indicated the extent of apoptosis, as it is obvious that
increased concentration after certain threshold leads to apoptosis.
the range of 1.35–6.81, 1.35–13.9 and 1.26–10.5
From the cell cycle analysis in FACS studies,20 it is observed that
compounds 6 and 8 exhibited significant cell cycle arrest. At 10
lM, respectively.
lM
At 30 lM concentration the control cells showed 1.44% and TMAC,
concentration we have tested these compounds for the possible
regulatory role on cell cycle. The control cells have shown 1.44%,
72.99%, 13.53% and 12.04% of G0, G1, S and G2/M phase of the cell
cycle, respectively. (E)-1-(3-Aminophenyl)-3-(3,4,5-trimethoxy-
CA-4, 6 and 8 showed 22.58%, 11.64%, 40.05% and 32.89% of G0
phase cells (Fig. 3b). The increase of G0 cells concomitantly de-
creased the G2/M phase cells that is, 15.8%, 23.69%, 7.63% and
10.35% of TMAC, CA-4, compounds 6 and 8. This data obtained

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A. Kamal et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4865–4869
G0
G1
S
80
70
60
50
40
30
20
10
0
G2/M
Figure 4. Effect of chalcone linked imidazolones (TMAC, CA-4, 6 and 8) on the
expression of apoptotic proteins (ProCaspase-7) and cleavage PARP. Here MCF7
cells treated with 30 M concentration of compounds. CA-4 was used as positive
l
control. Cell lysates were collected and western blot analysis was carried out with
the above mentioned antibodies and b-actin was used as loading control.
24 h cell lysates were extracted and subjected to Western blot
analysis using antibodies procaspase-7 and cleavage specific PARP.
It was observed that there is a decrease in the level of procaspase-7
and cleaved PARP (87 kDa) in compounds 6 and 8, and there is no
significant difference in case of CA-4 and TMAC. Thus indicating
that in compounds 6 and 8 apoptotic cell death takes place in a cas-
pase dependent pathway as shown in Figure 4.
1
2
3
4
5
6
8
Compounds
Figure 3a. Histogram depicting the different phases of cell cycle in MCF-7 cells
In conclusion, in the present study, a series of novel chalcone
linked imidazolones were prepared and evaluated for their anti-
cancer activity against a panel of 53 human tumour cell lines de-
rived from nine different cancer types. Some of these hybrids like
6 and 8 showed good anti-cancer activity with GI50 values ranging
exposed to chalcone imidazolone hybrid compounds (6 and 8) at 10
indicated are mean of three experiments).
l
M (values
G0
G1
S
from 1.26 to 10.5 lM. The FACS analysis data clearly showed that
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
these compounds (6 and 8) arrest the cell cycle at G2/M phase.
Some of the compounds like 6 and 8 from this series have shown
promising activity and useful in the design and development of
new molecules based on these leads.
G2/M
Acknowledgements
We thank the National Cancer Institute, Bethesda, for anti-can-
cer assay in human cell lines. The authors (G.R.K., P.R. and A.V.)
thank to CSIR and UGC, New Delhi for financial assistance.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.06.097.
0
References and notes
1
2
3
4
5
6
8
1. Petitt, G. R.; Gragg, G. M.; Herald, D. L.; Schmidt, J. M.; Lohavanijaya, P. Can. J.
Chem. 1982, 60, 1374.
2. Mc Gown, A. T.; Fox, B. W. Cancer Chemother. Pharmacol. 1990, 26, 79.
3. Young, S. L.; Chaplin, D. J. Expert Opin. Invest. Drugs 2004, 13, 1171.
4. Petitt, G. R.; Temple, C., Jr.; Narayanan, V. L.; Varma, R.; Simpson, M. J. Anti-
cancer Drug Des. 1995, 10, 299.
5. (a) Petitt, G. R.; Rhodes, M. R.; Herald, D. L.; Chaplin, D. J.; Stratford, M. R. L.;
Hamel, E.; Petitt, R. K.; Chapuis, J.; Oliva, D. Anti-cancer Drug Des. 1998, 13, 981;
(b) Nam, N. H.; Kim, Y.; You, Y.-J.; Hong, D.-H.; Ki, H.-M.; Ahn, B.-Z. Bioorg. Med.
Chem. Lett. 2001, 11, 3073.
Compounds
Figure 3b. Histogram depicting the different phases of cell cycle in MCF-7 cells
exposed to chalcone imidazolone hybrid compounds (6 and 8) at 30 M concen-
tration. CA-4 was used as a positive control. TMAC was the starting material for the
chalcone imidazolone compounds (values indicated are mean of three
experiments).
l
6. Won, S. J.; Liu, C.-T.; Tsao, L.-T.; Weng, J.-R.; Ko, H.-H.; Wang, J.-P.; Lin, C.-N. Eur.
J. Med. Chem. 2005, 40, 103.
7. Hsieh, H.-K.; Tsao, L.-T.; Wang, J.-P.; Lin, C.-N. J. Pharm. Pharm. 2000, 52, 163.
8. Mukerjee, S.; Kumar, V.; Prasad, A. K.; Raj, H. G.; Bracke, M. E.; Olsen, C. E.; Jain,
S. C.; Parmar, V. S. Bioorg. Med. Chem. 2001, 9, 337.
9. Parmar, V. S.; Jain, S. C.; Bisht, K. S.; Sharma, N. K.; Himanshu Gupta, S.; Prasad,
A. K.; Jha, A.; Poonam Malhotra, S.; Sharma, S. K.; Brache, M. E.; Errington, W.;
Olsen, C. E.; Wengel, J. Indian J. Chem., Sect. B 1998, 37, 628.
10. Nielsen, S. F.; Boesen, T.; Larsen, M.; Schonnig, K.; Kromann, H. Bioorg. Med.
Chem. 2004, 12, 3047.
11. Ducki, S.; Forrest, R.; Hadfield, J. A.; Kendall, A.; Lawrence, N. J.; Mc Gown, A. T.;
Rennison, D. Bioorg. Med. Chem. Lett. 1998, 8, 1051.
12. Lawrence, N. J.; Mc Gown, A. T.; Ducki, S.; Hadfield, J. A. Anti-cancer Drug Des.
2000, 15, 135.
13. Siamaki, A. R.; Black, D. A.; Arndtsen, B. A. J. Org. Chem. 2008, 73, 1135.
14. Fang, L.; He, Q.; Hu, Y.; Yang, B. Cancer Chemother. Pharmacol. 2007, 59, 397.
from these studies clearly revealed the G2/M arrest caused by
these compounds. The concentration of 10 lM concentration was
found to be optimum by our in vitro cytotoxic studies.
Previous studies by Twiddy et al. have discovered that caspase-
7 and PARP play an important role in causing apoptosis in human
breast cancer cells.21 Mooney and coworkers have also reported
that activation of the caspase cascade leads to cleavage of DNA re-
pair enzyme poly-ADP-ribose polymerase (PARP) in Staurosporine
induced apoptosis in breast cancer cells.22 Therefore, in the present
investigation human breast cancer cells (MCF-7) were treated with
30 lM concentration of compounds CA-4, 6, 8 and TMAC. After

A. Kamal et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4865–4869
4869
15. Lai, Z.; Yang, T.; Kim, Y. B.; Sielecki, T. M.; Diamond, M. A.; Strack, P.; Rolfe, M.;
Caligiuri, M.; Benfield, P. A.; Auger, K. R.; Copleland, R. A. PNAS 2002, 99, 14734.
16. Wu-Wong, J. R.; Alder, J. D.; Alder, L.; Burns, D. J.; Han, E. K-H.; Credo, B.; Tahir,
S. K.; Dayton, B. D.; Ewing, P. J.; Chiou, W. J. Cancer Res. 2001, 61, 1486.
17. Congiu, C.; Cocco, M. T.; Onnis, V. Bioorg. Med. Chem. Lett. 2008, 18, 989.
18. (a) Kumar, S. K.; Hager, E.; Petitt, C.; Gurulingappa, H.; Davidson, N. E.; Khan, S.
R. J. Med. Chem. 2003, 46, 2813; (b) Dhar, D. N.; Lal, J. B. J. Org. Chem. 1958, 23,
1159.
111.9, 106.7, 55.76; MS (ESI): m/z 413 [M+H]+; purity 98%, C18 column,
acetonitrile–water (mobile phase), wavelength 289 nm; yellow solid. 4-(4-
Chlorophenyl)-1-3-[(E)-3-(4-hydroxy-3-methoxyphenyl)-2-
propenoyl]phenyl-2,3-dihydro-1H-2-imidazolone (8): mp 217–221 °C; IR:
3356, 1710, 1657, 1580 cmÀ1 1H NMR (400 MHz, CDCl3): d 11.23 (1H, br s),
;
9.74 (1H, s), 8.4 (1H, s), 8.05 (2H, m), 7.84 (1H, br d), 7.71 (4H, m), 7.5 (3H, m),
7.31 (1H, d, J = 15.92 Hz), 6.82 (1H, d, J = 15.92 Hz), 3.86 (3H, s); 13C NMR
(75 MHz, CDCl3): d 188.6, 152.2, 149.7, 147.8, 145.3, 138.9, 137.3, 131.3, 129.3,
128.6, 127.8, 126.1, 125, 124.9, 124.6, 123.9, 121.4., 119.9, 118.6, 115.5, 111.9,
107.5, 55.70; MS (ESI): m/z 447 [M+H]+; purity 95%, C18 column, acetonitrile–
water (mobile phase), wavelength 289 nm; yellow solid.
19. The spectral data of final compounds 6 and 8 are given below 1-3-[(E)-3-(4-
hydroxy-3-methoxyphenyl)-2-propenoyl]phenyl-4-phenyl-2,3-dihydro-1H-2-
imidazolone (6): mp 141–151 °C; IR 3283, 1689, 1659, 1580 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d 10.67 (1H, br s), 8.01 (1H, s), 7.81 (1H, d, J = 7.30 Hz), 7.64
(1H, d, J = 7.28 Hz), 7.52 (1H, s), 7.36 (1H, d, J = 16.02 Hz), 7.32 (2H, m), 7.16
(2H, m), 7.03 (1H, d, J = 16.02 Hz), 6.95 (3H, m), 6.73 (2H, m), 3.73 (3H, s); 13C
NMR (75 MHz, CDCl3): d 188.6, 152.3, 149.8, 147.8, 145.3, 138.9, 137.5, 129.4,
128.9, 128.7, 127, 126.1, 125, 124.6, 124, 123.3, 122.5, 119.9, 118.6, 115.5,
20. Luo, P.; He, Q.; He, X.; Hu, Y.; Lu, W.; Cheng, Y.; Yang, B. Mol. Cancer Ther. 2006,
5, 962.
21. Twiddy, D.; Cohen, G. M.; MacFarlane, M.; Cain, K. J. Biol. Chem. 2006, 281, 3876.
22. Mooney, L. M.; Al-Sakkaf, K.; Brown, B. L.; Dobson, P. R. M. Br. J. Cancer 2002, 87,
907.