Synthesis of novel curcumin mimics with asymmetrical units and their anti-angiogenic activity

Article abstract of DOI:10.1016/j.bmcl.2005.05.064

Novel curcumin mimics with asymmetrical units phenyl group with alkyl amide, chloro-substituted benzamide, or heteroaromatic amide moieties were synthesized and their anti-angiogenic activity was evaluated with the proliferation and tube formation inhibit

Full text of DOI:10.1016/j.bmcl.2005.05.064

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3782–3786
Synthesis of novel curcumin mimics with asymmetrical units
and their anti-angiogenic activity
Ho Bum Woo,a Woon-Seob Shin,c Seokjoon Leed and Chan Mug Ahna,b,
*
aDepartment of Basic Sciences, Wonju College of Medicine, Yonsei University, Wonju 220-701, Republic of Korea
bInstitute of Basic Medical Science, Wonju College of Medicine, Yonsei University, Wonju 220-701, Republic of Korea
cDepartment of Microbiology, Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea
dDepartment of Basic Science, Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea
Received 28 February 2005; revised 4 May 2005; accepted 16 May 2005
Available online 1 July 2005
Abstract—Novel curcumin mimics with asymmetrical units phenyl group with alkyl amide, chloro-substituted benzamide, or
heteroaromatic amide moieties were synthesized and their anti-angiogenic activity was evaluated with the proliferation and tube
formation inhibitory activity on the human umbilical vein endothelial cells. Compounds 5, 14, 17, and 18 showed potent growth
inhibitory activity and tube formation inhibitory activity.
Ó 2005 Elsevier Ltd. All rights reserved.
Curcumin (Diferuloyl methane, 1) is a chemopreventive
and chemotherapeutic natural product that is isolated
from the root of Curcuma longa L., which shows sup-
pression, retardation, or inversion of carcinogenesis.1
Furthermore, it also exhibits anti-inflammatory, antiox-
idant, antiviral, and anti-infectious activities and wound
healing properties.2
ing lead compound for structural modification to dis-
cover novel anticancer agents.
But the commonality of reported novel analogs of cur-
cumin is that they have a symmetrical a,b-unsaturated
ketone with limited substituents on the aromatic rings.8
To search for useful drug candidates in the development
of chemotherapeutic agents, it is necessary to bring
about substantial chemical modification of the curcumin
structure. Therefore, to achieve our objective, we report
a novel method for the preparation of asymmetrical
curcumin derivatives having a phenyl group with alkyl
amide, chloro-substituted benzamide, or heteroaromatic
amide moieties (2) (Fig. 1).
In particular, there are many reports on the anti-angio-
genesis of curcumin (1). Arbiser et al.3, Kwon and co-
5
workers4, and Bowen and co-workers also reported
that curcumin (1) and its derivatives have a potent
anti-angiogenic activity. Based on our assumption that
rigidity of symmetrical aromatic moieties on a curcumin
structure plays an important role in enhancing anti-an-
giogenic activity, we synthesized symmetrical bis-aro-
matic alkynyl pyridine and thiophene derivatives and
bis-aromatic alkyl pyridine and thiophene derivatives,
and reported on their biological activity.6 In 2004, two
groups have also reported on the novel curcumin ana-
logs as anticancer and anti-angiogenesis agents.7
Although structure–anti-angiogenic activity of curcumin
(1) is not completely understood, curcumin is a promis-
Keywords: Curcumin; Anti-angiogenic activity; Heteroaromatic
amides.
*
Corresponding author. Tel.: +82 33 741 0371; fax: +82 33 745
2170; e-mail: ahn0707@wonju.yonsei.ac.kr
Figure 1.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.05.064

H. B. Woo et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3782–3786
3783
The anti-angiogenic activities of those synthetic com-
pounds were evaluated with the proliferation9 and tube
formation inhibitory activities10 on the human umbilical
vein endothelial cells (HUVEC).
products (11–18) gave a quantitative yield. 1H, 13C
NMR spectrum and GC/MS spectrum of synthetic
intermediate (5) and various curcumin mimics (6–18)
were identified to study the relationship between struc-
tural modification and anti-angiogenic activity.13
The target compounds were prepared, as shown in
Scheme 1. Commercially available 4-hydroxy-3-meth-
oxybenzaldehyde (3) was reacted with 3-acetylaniline
(4) in the presence of basic catalyst (40% KOH) in eth-
anol at room temperature for 10 h.11 The crude product
was chromatographed (CHCl3/CH3OH 97/3) on silica
gel to afford 1-(3-aminophenyl)-3-(4-hydroxy-3-meth-
oxyphenyl)propenone (5). This amine (5) was dissolved
in a 1:1 mixture solution of dioxane and H2O and then
cooled to 0 °C (ice bath). Acetic anhydride or one of a
variety of acyl chlorides was slowly added to the reac-
tion mixture and then stirred at 0 °C for 5–7 h.12 The
solvent was removed in vacuo. The residues were chro-
matographed (CHCl3/MeOH 95/5) on silica gel to give
amides (6–18). Synthetic curcumin mimics with an alkyl
amide group (7–10) were of slightly low yield, except for
acetamide compound (6). Other aromatic amide
The biological result of synthetic molecules is shown in
Table 1. As we had expected, all compounds showed a
strong inhibitory activity against HUVEC growth.
Compounds with an aromatic amide moiety (11–18)
showed a activity higher than those of alkyl amide
groups (6–10). In particular, benzamide (11), furan
amide (17), and thiophene amide (18) exhibited the high-
est activity. When considering HUVEC growth inhibi-
tion activity in our screening set, presence of various
amide groups in asymmetric units, especially aromatic
amide moieties, was shown to be important for activity.
The introduction of mono-chloro or di-chloro substitu-
tion in benzamide has no effect of increasing activity.
In the tube formation assay using HUVEC on the
Matrigel to conform to the anti-angiogenic activity of
Scheme 1. Synthesis of novel curcumin mimics with asymmetrical units including alkyl amide, chloro-substituted benzamide, or heteroaromatic
amide moieties. Yield for 5, 45%; 6, 97%; 7, 21%; 8, 24%; 9, 26%; 10, 25%; 11, 98%; 12, 94%; 13, 85%; 14, 91%; 15, 88%; 16, 70%; 17, 85%; 18, 87%.
Table 1. Inhibitory activity of curcumin mimics on HUVEC growth and tube formation
Entry
Cytotoxic activity against cancer cell
lines IC50 (lg/mL)a
aHUVEC growth inhibition IC50 (lg/mL)
HUVEC tube formation inhibition
percentage (%)b
B16
Vero
U87
7.71
>50
5.56
8.31
>50
SiHa
12.33
2.5 lg/mL
5 lg/mL
10 lg/mL
5
11.48
3.62
1.43
1.09
7.03
4.41
0.82
0.59
12.81
1.58
3.88
4.83
5.46
6.93
—
6.02
2.87
7.06
1.27
1.44
13.3
1.50
0.37
0.76
0.40
0.46
2.97
0.75
0.38
0.38
10.84
20
—
40
11
—
—
—
—
29
53
—
15
61
71
—
50
15
57
51
45
20
48
42
51
88
5
90
32
87
56
66
43
69
66
70
99
45
58
100
90
—
6
14.48
2.04
3.47
15.75
3.94
5.96
7
8
9
10
>50
>50
3.55
3.47
12.24
8.82
7.71
4.57
11
12
3.82
27.22
2.48
>50
>50
17.81
29.46
>50
2.30
34.43
3.56
13
14
15
16
>50
>50
3.11
3.98
25.28
17.67
0.76
51
82
80
—
17
18
6.65
14.69
6.57
Curcumin
—
—
—
a IC50 was calculated from the nonlinear regression by Graphpad Prism software.
b Values expressed in percentage of HUVEC total tube length/field as compared to untreated control. Total tube length was measured using Image-
pro plus version 3.0 (Media Cybernetics, MD, USA).

3784
H. B. Woo et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3782–3786
6. Ahn, C. M.; Shin, W.-S.; Woo, H. B.; Lee, S.; Lee, H.-W.
Bioorg. Med. Chem. Lett. 2004, 14, 3893.
synthetic curcumin mimics, all compounds strongly
inhibited the tube of HUVEC at a concentration of
10 lg/mL. Interestingly, compound 5 with a free amine
group, synthetic intermediate for target molecules,
shows 90% inhibition activity. Among the alkyl amide
groups (6–10), only propyl amide compound 7 showed
a good activity as 87% at the same concentration. Ex-
cept 15, the promising molecules (11–14, 16–18) possess-
ing aromatic amide groups exhibited a generally strong
inhibitory activity against the tube formation. Especial-
ly, compounds (14, 17, and 18) showed the strongest
activity at a concentration of 5.0 lg/mL. Even at a con-
centration of 2.5 lg/mL, compound 18 inhibited about
71%.
7. (a) Adams, B. K.; Ferstl, E. M.; Davis, M. C.; Herold, M.;
Kurtkaya, S.; Camalier, R. F.; Hollingshead, M. G.;
Kaur, G.; Sausville, E. A.; Rickles, F. R.; Snyder, J. P.;
Lioota, D. C.; Shoji, M. Bioorg. Med. Chem. 2004, 12,
3871; (b) Hahm, E.-R.; Gho, Y. S.; Park, S.; Park, C.;
Kim, K.-W.; Yang, C.-H. Biochem. Biophys. Res. Com-
mun. 2004, 321, 337.
8. (a) Nurfina, A. N.; Reksohadiprodjo, M. S.; Timmerman,
H.; Jenie, U. A.; Sugiyanto, D.; van der Goot, H. Eur. J.
Med. Chem. 1997, 32, 321; (b) Hahm, E.-R.; Cheon, G.;
Lee, J.; Kim, B.; Park, C.; Yang, C.-H. Cancer Lett.
2002, 184, 89; (c) Youssef, K. M.; El-Sherbeny, M. A.;
El-Shafie, F. S.; Farag, H. A.; Al-Deeb, O. A.; Awadalla,
S. A. A. Arch. Pharm. Pharm. Med. Chem. 2004, 337, 42;
´ ´
(d) Ligeret, H.; Barthelemy, S.; Doulakas, G. B.; Carrupt,
To compare the selectivity between HUVEC and tumor
cell lines, four types of tumor cells, such as B16, Vero,
U87, and SiHa, were used for the MTT assay. All tested
molecules have a specific inhibition activity against HU-
VEC growth, as shown in Table 1. Three compounds
(14, 17, and 18) with higher growth inhibition and
tube-forming inhibition activity show a good selectivity
on HUVEC. Interestingly, compound 13 inhibits mod-
erately tube formation, but shows the highest selectivity
among the tested molecules.
P.-A.; Tillement, J.-P.; Labidalle, S.; Morin, D. FEBS
Lett. 2004, 569, 37.
9. Mosmann, T. J. Immunol. Methods 1983, 65, 55.
10. Aoki, K.; Watanabe, K.; Sato, M.; Ikekita, M.; Haka-
matsuka, T.; Oikawa, T. Eur. J. Pharmacol. 2003, 459,
131.
11. Maitra, S.; Singh, R.; Sinha, A.; Lahiri, S. Synth.
Commun. 1989, 19, 2363.
12. Park, C. H.; Givens, R. S. J. Am. Chem. Soc. 1997, 119,
2453.
13. Analytical data for 5: yield 45%; mp 154–155 °C; TLC
(methylene chloride/methanol 94/6) Rf = 0.39; 1H NMR
(CDCl3): d 3.82 (2H, s, NH2), 3.97 (3H, s, OCH3), 5.89
(1H, s, OH), 6.88–6.90 (1H, m, NH2C6H4), 6.96 (1H, d,
J = 8.21 Hz, CH3OC6H3), 7.13 (1H, d, J = 1.76 Hz,
CH3OC6H3), 7.21 (1H, dd, J = 8.21 and 1.80 Hz,
CH3OC6H3), 7.28–7.39 (3H, m, NH2C6H4), 7.33 (1H, d,
J = 15.63 Hz, CH@CHAr), 7.73 (1H, d, J = 15.63 Hz,
CH@CHAr) ppm. 13C NMR (CDCl3): d 56.0, 110.2,
114.4, 115.1, 118.7, 119.2, 119.9, 123.4, 127.3, 129.4, 139.6,
145.0, 146.9, 147.1, 148.6, 190.9. GC/MSD (m/z) 269 (M+);
for 6: yield 97%; mp 119–120 °C; TLC (methylene
In conclusion, we have readily synthesized various
curcumin mimics with asymmetric units possessing al-
kyl amide, chloro-substituted benzamide, or heteroaro-
matic amide moieties. Those synthetic molecules
showed a stronger anti-angiogenic activity than the
mother molecule, curcumin, without exhibiting any
cytotoxic activity against HUVEC. In particular, com-
pounds (14, 17, and 18) need to be studied further in
the screening of other cancer cell lines, in vivo study,
and toxicology. Substantial structural modifications of
curcumin have an important potential for further drug
development as antitumor and anti-angiogenesis
agents.
chloride/methanol
94/6)
Rf = 0.33;
1H
NMR
(CDCl3 + DMSO-d6): d 2.20 (3H, s, CH3), 3.97 (3H, s,
OCH3), 6.64 (1H, s, OH), 6.96 (1H, d, J = 8.18 Hz,
CH3OC6H3), 7.15 (1H, d, J = 1.58 Hz, CH3OC6H3), 7.21
(1H, dd, J = 8.19 and 1.65 Hz, CH3OC6H3), 7.36 (1H, d,
J = 15.67 Hz, CH@CHAr), 7.41–7.47 (1H, m, NHC6H4),
7.72 (1H, m, NHC6H4), 7.75 (1H, d, J = 15.67 Hz,
CH@CHAr), 7.96 (1H, d, J = 7.52 Hz, NHC6H4), 8.04
(1H, s, NHC6H4), 8.31 (1H, br s, NH) ppm.13C NMR
(CDCl3 + DMSO-d6): d 24.5, 56.1, 110.3, 115.1, 119.5,
119.6, 123.5, 123.9, 124.0, 127.3, 129.2, 138.8, 139.1, 145.5,
147.1, 148.7, 168.9, 190.3. GC/MSD (m/z) 311 (M+); for 7:
Acknowledgment
This work was supported by Yonsei University
Research Fund of 2004.
1
yield 21%; TLC (ethyl acetate/n-hexane 1/1) Rf = 0.20; H
d
References and notes
NMR (CDCl3):
1.01 (3H, t, J = 14.76 Hz,
CH2CH2CH3), 1.75–1.80 (2H, m, CH2CH2CH3), 2.38
(2H, t, J = 14.87 Hz, CH2CH2CH3), 3.94 (3H, s, OCH3),
6.10 (1H, s, OH), 6.94 (1H, d, J = 8.17 Hz, CH3OC6H3),
7.11 (1H, d, J = 1.68 Hz, CH3OC6H3), 7.20 (1H, dd,
J = 8.22 and 1.70 Hz, CH3OC6H3), 7.34 (1H, d,
J = 15.59 Hz, CH@CHAr), 7.44 (1H, t, J = 15.8 Hz,
NHC6H4), 7.71 (1H, br s, NH), 7.71–7.72 (1H, m,
NHC6H4), 7.74 (1H, d, J = 15.59 Hz, CH@CHAr), 7.96
(1H, d, J = 7.7 Hz, NHC6H4), 8.03 (1H, s, NHC6H4) ppm.
13C NMR (CDCl3): d 13.8, 19.0, 29.8, 39.6, 56.1, 110.2,
114.9, 119.5, 119.6, 123.5, 124.1, 127.3, 129.3, 138.6, 139.1,
145.7, 146.9, 148.5, 171.8, 190.4. GC/MSD (m/z) 339 (M+);
for 8: yield 24%; TLC (ethyl acetate/n-hexane 1/1)
1. Duvoix, A.; Blasius, R.; Delhalle, S.; Schnekenburger, M.;
Morceau, F.; Henry, E.; Dicato, M.; Diederich, M. ; Cancer
Lett. 2004, 223, 181.
2. Joe, B.; Vijaykumar, M.; Lokesh, B. R. Crit. Rev. Food
Sci. Nutr. 2004, 44, 97.
3. Arbiser, J. L.; Klauber, N.; Rohan, R.; van Leeuwen, R.;
Huang, M. T.; Fisher, C.; Flynn, E.; Byers, H. R. Mol.
Med. 1998, 4, 376.
4. Shim, J. S.; Kim, D. H.; Jung, H. J.; Kim, J. H.; Lim, D.;
Lee, S. K.; Kim, K.-W.; Ahn, J. W.; Yoo, J.-S.; Rho,
J.-R.; Shin, J.; Kwon, H. J. Bioorg. Med. Chem. 2002, 10,
2987.
1
5. Robinson, T. P.; Ehlers, T.; Hubbard, R. B., IV; Bai, X.;
Arbiser, J. L.; Goldsmith, D. J.; Bowen, J. P. Bioorg. Med.
Chem. Lett. 2003, 13, 115.
Rf = 0.23; H NMR (CDCl3): d 1.28 (6H, d, J = 6.87 Hz,
CH3), 2.55–2.58 (1H, m, CH), 3.96 (3H, s, OCH3), 5.99
(1H, br s, OH), 6.95 (1H, d, J = 8.23 Hz, CH3OC6H3),

H. B. Woo et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3782–3786
3785
7.13 (1H, d, J = 1.64 Hz, CH3OC6H3), 7.22 (1H, dd,
J = 8.22 and 1.71 Hz, CH3OC6H3), 7.36 (1H, d,
J = 15.59 Hz, CH@CHAr), 7.46 (1H, t, J = 15.85 Hz,
NHC6H4), 7.49 (1H, br s, NH), 7.72 (1H, s, NHC6H4),
7.76 (1H, d, J = 15.59 Hz, CH@CHAr), 7.87 (1H, d,
J = 7.52 Hz, NHC6H4), 8.04 (1H, s, NHC6H4) ppm.13C
NMR (CDCl3): d 19.6, 36.7, 56.0, 110.2, 114.9, 119.5,
119.6, 123.5, 124.0, 124.1, 127.3, 129.3, 138.7, 139.1, 145.7,
146.9, 148.5, 175.8, 190.4. GC/MSD (m/z) 339 (M+); for 9:
yield 26%; TLC (chloroform/methanol 95/5) Rf = 0.35; 1H
NMR (CDCl3): d 1.07 (3H, t, J = 14.11 Hz, CH2CH3),
3.97 (3H, s, OCH3), 4.45 (2H, q, J = 7.09 Hz, CH2CH3),
5.98 (1H, s, OH), 6.96 (1H, d, J = 8.14 Hz, CH3OC6H3),
7.14 (1H, s, CH3OC6H3), 7.25 (1H, t, J = 15.73 Hz,
CH3OC6H3), 7.36 (1H, d, J = 15.59 Hz, CH@CHAr),
7.53(1H, t, J = 15.82 Hz, NHC6H4), 7.78 (1H, d,
J = 15.59 Hz, CH@CHAr), 7.84 (1H, d, J = 7.73 Hz,
NHC6H4), 7.99 (1H, d, J = 7.96 Hz, NHC6H4), 8.19
(1H, s, NHC6H4), 9.04 (1H, s, NH) ppm. 13C NMR
(CDCl3): d 14.0, 56.1, 64.0, 110.1, 114.9, 119.2, 119.7,
123.6, 123.7, 125.4, 127.3, 129.6, 136.8, 139.4, 145.9, 146.8,
148.5, 154.2, 160.7, 189.7. GC/MSD (m/z) 369 (M+); for
10: yield 25%; TLC (chloroform/methanol 97/3) Rf = 0.11;
1H NMR (CDCl3 + DMSO-d6): d 2.23 (3H, s, CH3), 3.95
(3H, s, OCH3), 4.72 (2H, s CH2), 6.94 (1H, d, J = 8.07 Hz,
CH3OC6H3), 7.16 (1H, d, J = 1.56 Hz, CH3OC6H3), 7.18
(1H, dd, J = 8.20 and 1.68 Hz, CH3OC6H3), 7.36 (1H, d,
J = 15.58 Hz, CH@CHAr), 7.46 (1H, t, J = 15.78 Hz,
NHC6H4), 7.74 (1H, d, J = 15.58 Hz, CH@CHAr), 7.75
(1H, d, J = 7.96 Hz, NHC6H4), 8.00 (1H, d, J = 7.96 Hz,
NHC6H4), 8.12 (1H, s, NHC6H4), 8,12 (1H, s, OH), 9.38
(1H, s, NH) ppm.13C NMR (CDCl3 + DMSO-d6): d 20.8,
56.0, 63.0, 110.7, 115.5, 119.1, 119.8, 123.5, 124.1, 124.2,
126.8, 129.2, 138.2, 139.1, 145.7, 147.7, 149.4, 165.9, 170.1,
190.2. GC/MSD (m/z) 369 (M+); for 11: yield 98%; mp 80–
82 °C; TLC (chloroform/methanol 95/5) Rf = 0.33; 1H
NMR (CDCl3 + DMSO-d6): d 3.93 (3H, s, OCH3), 6.93
(1H, d, J = 8.04 Hz, CH3OC6H3), 7.15–7.18 (2H, m,
CH3OC6H3), 7.39 (1H, d, J = 16.00 Hz, CH@CHAr),
7.45–7.49 (3H, m, benzoyl-H), 7.52 (1H, t, J = 14.48 Hz,
NHC6H4), 7.74 (1H, d, J = 16.00 Hz, CH@CHAr), 7.75
(1H, m, NHC6H4), 8.00 (2H, d, J = 7.26 Hz, benzoyl-H),
8.16 (1H, d, J = 8.24 Hz, NHC6H4), 8.19 (1H, s, OH), 8.35
(1H, s, NHC6H4),9.69 (1H, s, NH) ppm. 13C NMR
(CDCl3 + DMSO-d6): d 56.0, 110.8, 115.5, 119.3, 120.5,
123.4, 123.9, 124.7, 126.8, 127.7, 128.4, 129.0, 131.7, 135.0,
139.0, 139.3, 145.5, 147.6, 149.3, 166.5, 190.4. GC/MSD
(m/z) 373 (M+); for 12: yield 94%; mp 212–215 °C; TLC
(chloroform/methanol 95/5) Rf = 0.31; 1H NMR
(CDCl3 + DMSO-d6): d 4.04 (3H, s, OCH3), 6.87 (1H, d,
J = 7.77 Hz, CH3OC6H3), 7.11–7.13 (2H, m, CH3OC6H3),
7.31–7.40 (2H, m, 4-chlorobenzoyl-H), 7.43 (1H, t,
J = 17.2 Hz, NHC6H4), 7.39 (1H, d, J = 16.00 Hz,
CH@CHAr), 7.68 (1H, d, J = 16.00 Hz, CH@CHAr),
7.69 (1H, m, NHC6H4), 7.94 (2H, d, J = 8.45 Hz, 4-
chlorobenzoyl-H), 8.10 (1H, d, J = 7.60 Hz, NHC6H4),
8.26 (1H, s, NHC6H4), 8.40 (1H, s, OH), 9.89 (1H, s, NH)
ppm. 13C NMR (CDCl3 + DMSO-d6): d 56.3, 111.2,
116.0, 119.5, 120.9, 123.8, 124.3, 125.1, 127.1, 128.8,
129.3, 129.7, 133.7, 138.0, 139.3, 139.7, 145.9, 148.1, 149.8,
165.7, 190.6. GC/MSD (m/z) 407 (M+); for 13: yield 85%;
mp 170–172 °C; TLC (chloroform/methanol 95/5)
7.67 (1H, d, J = 8.27 Hz, 2,4-dichlorobenzoyl-H), 7.76
(1H, d, J = 15.00 Hz, CH@CHAr), 7.76–7.80 (1H, m,
NHC6H4), 8.08 (1H, d, J = 7.25 Hz, NHC6H4), 8.22 (1H,
s, NHC6H4), 9.08 (1H, s, NH) ppm.13C NMR
(CDCl3 + DMSO-d6): d 56.1, 110.4, 115.2, 119.4, 120.0,
123.5, 124.2, 124.6, 127.2, 127.5, 129.3, 130.0, 131.0, 131.9,
134.2,136.9, 138.4, 139.3, 145.8, 147.2, 148.9, 164.2, 190.2.
GC/MSD (m/z) 442 (M+); for 14: yield 91%; mp 157–
160 °C; TLC (chloroform/methanol 95/5) Rf = 0.29; 1H
NMR (CDCl3 + DMSO-d6):d 3.96 (3H, s, OCH3), 6.87
(1H, s, OH), 6.95 (1H, d, J = 8.17 Hz, CH3OC6H3), 7.16
(1H, d, J = 1.48 Hz, CH3OC6H3), 7.22 (1H, dd, J = 8.12
and 1.51 Hz, CH3OC6H3), 7.29–7.39 (3H, m, 2,6-dic-
hlorobenzoyl-H), 7.39 (1H, d, J = 16.00 Hz, CH@CHAr),
7.52 (1H, t, J = 15.74 Hz, NHC6H4), 7.76 (1H, d,
J = 16.00 Hz, CH@CHAr), 7.79 (1H, m, NHC6H4), 8.10
(1H, d, J = 7.93 Hz, NHC6H4), 8.25 (1H, s, NHC6H4),
9.24 (1H, s, NH) ppm.13C NMR (CDCl3 + DMSO-d6): d
56.1, 110.4, 115.2, 119.6, 120.0, 123.5, 124.3, 124.6, 127.2,
128.0, 129.3, 130.7, 132.5, 136.3, 138.4, 139.3, 145.6, 147.2,
148.8, 162.9, 190.2. GC/MSD (m/z) 442 (M+); for 15: yield
88%; mp 208–210 °C; TLC (chloroform/methanol 95/5)
Rf = 0.32; 1H NMR (DMSO-d6): d 3.87 (3H, s, OCH3),
6.85 (1H, d, J = 8.00 Hz, CH3OC6H3), 7.30 (1H, d,
J = 7.94 Hz, CH3OC6H3), 7.51 (1H, s, CH3OC6H3), 7.59
(1H, t, J = 7.55 Hz, NHC6H4), 7.71 (2H, s, 3,4-dic-
hlorobenzoyl-H), 7.85 (1H, d, J = 8.25 Hz, CH@CHAr),
7.96–8.00 (1H, m, NHC6H4), 7.99 (1H, d, J = 8.25 Hz,
CH@CHAr), 8.11 (1H, d, J = 7.73 Hz, NHC6H4), 8.28
(1H, s, 3,4-dichlorobenzoyl-H), 8.38 (1H, s, NHC6H4),
9.73 (1H, br s, OH), 10.60 (1H, s, NH) ppm. 13C NMR
(DMSO-d6): d 56.2, 112.2, 116.0, 119.0, 120.3, 124.4,
124.6, 125.0, 126.5, 128.5, 129.5, 130.0, 131.2, 131.7, 134.9,
135.2, 138.9, 139.5, 145.6, 148.3, 150.2, 163.7, 189.2. GC/
MSD (m/z) 442 (M+); for 16: yield 70%; mp 202–206 °C;
TLC (chloroform/methanol 95/5) Rf = 0.36; 1H NMR
(CDCl3 + DMSO-d6): d 3.95 (3H, s, OCH3), 6.93 (1H, d,
J = 8.26 Hz, CH3OC6H3), 7.17–7.19 (2H, m, CH3OC6H3),
7.40 (1H, d, J = 15.57 Hz, CH@CHAr), 7.50 (1H, t,
J = 15.97 Hz, NHC6H4), 7.52 (1H, s, 3,5-dichlorobenzoyl-
H), 7.74 (1H, d, J = 15.57 Hz, CH@CHAr), 7.77 (1H, m,
NHC6H4), 8.02 (2H, d, J = 1.47 Hz, 3,5-dichlorobenzoyl-
H), 8.18 (1H, d, J = 8.04 Hz, NHC6H4), 8.35 (1H, s,
NHC6H4), 8.88 (1H, s, OH), 10.32 (1H, s, NH) ppm.13C
NMR (CDCl3 + DMSO-d6): d 56.3, 111.2, 116.0, 119.3,
120.8, 123.7, 124.3, 124.9, 126.9, 129.3, 131.4, 134.2, 135.2,
138.0, 139.2, 139.4, 145.8, 148.2, 150.0, 163.8, 190.3. GC/
MSD (m/z) 442 (M+); for 17: yield 85%; mp 82–84 °C;
TLC (chloroform/methanol 95/5) Rf = 0.30; 1H NMR
(CDCl3): d 3.96 (3H, s, OCH3), 6.01 (1H, s, OH), 6.58–
6.59 (1H, m, furan-H), 6.96 (1H, d, J = 8.15 Hz, furan-H),
7.14 (1H, s, CH3OC6H3), 7.23 (1H, d, J = 8.32 Hz,
CH3OC6H3), 7.27 (1H, t, J = 7.13 Hz, CH3OC6H3), 7.37
(1H, d, J = 15.67 Hz, CH@CHAr), 7.51 (1H, t,
J = 15.91 Hz, NHC6H4), 7.54 (1H, d, J = 0.72 Hz, furan-
H), 7.78 (1H, d, J = 15.67 Hz, CH@CHAr), 8.05 (1H, d,
J = 7.69 Hz, NHC6H4), 8.16 (1H, s, NHC6H4), 8.26 (1H,
s, NH) ppm.13C NMR (CDCl3): d 56.1, 110.2, 112.7,
114.9, 115.7, 119.5, 119.7, 123.6, 124.1, 124.4, 127.4, 129.4,
137.9, 139.3, 144.5, 145.7, 146.9, 147.5, 148.5, 156.3, 190.2.
GC/MSD (m/z) 363 (M+); for 18: yield 87%; mp 193–
195 °C; TLC (chloroform/methanol 95/5) Rf = 0.28; 1H
NMR (CDCl3 + DMSO-d6): d 3.97 (3H, s, OCH3), 6.79
(1H, s, OH), 6.95 (1H, d, J = 8.27 Hz, CH3OC6H3), 7.13–
7.15 (2H, m, CH3OC6H3), 7.21–7.23 (1H, m, thiophene-
H), 7.39 (1H, d, J = 15.68 Hz, CH@CHAr), 7.48–7.52
(1H, t, J = 7.80 Hz, NHC6H4), 7.57 (1H, d, J = 4.97 Hz,
thiophene-H), 7.75–7.79 (1H, m, NHC6H4), 7.77 (1H, d,
J = 15.68 Hz, CH@CHAr), 7.83 (1H, d, J = 3.71 Hz,
1
Rf = 0.34; H NMR (CDCl3 + DMSO-d6): d 3.96 (3H, s,
OCH3), 6.94 (1H, d, J = 7.96 Hz, CH3OC6H3), 6.95 (1H, s,
OH), 7.15 (1H, d, J = 1.66 Hz, CH3OC6H3), 7.22 (1H, dd,
J = 8.21 and 1.65 Hz, CH3OC6H3), 7.36–7.40 (1H, m,
2,4-dichlorobenzoyl-H), 7.38 (1H, d, J = 15.00 Hz,
CH@CHAr), 7.49 (1H, d, J = 1.67 Hz, 2,4-dic-
hlorobenzoyl-H), 7.52 (1H, t, J = 15.88 Hz, NHC6H4),

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H. B. Woo et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3782–3786
thiophene-H), 8.13 (1H, d, J = 7.76 Hz, NHC6H4), 8.20
(1H, s, NHC6H4), 8.90 (1H, s, NH) ppm. 13C NMR
(CDCl3 + DMSO-d6): d 56.1, 110.4, 115.1, 119.5, 120.1,
123.5, 124.1, 124.5, 127.2, 127.8, 128.8, 129.3, 131.1, 138.7,
139.1, 139.6, 145.6, 147.1, 148.8, 160.5, 190.3. GC/MSD
(m/z) 379 (M+).