Synthesis of sulfonyl curcumin mimics exerting a vasodilatation effect on the basilar artery of rabbits

Article abstract of DOI:10.1016/j.bmcl.2009.01.019

In order to discover novel small vasodilatory molecules for potential use in the treatment of vascular disease, we tested the vasodilatation effect of two types of synthetic curcumin mimics, amide type (3) and sulfonyl amide type (4), upon the basilar art

Full text of DOI:10.1016/j.bmcl.2009.01.019

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1481–1483
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of sulfonyl curcumin mimics exerting a vasodilatation effect
on the basilar artery of rabbits
e,
Chan Mug Ahn a, , Byong-Gon Park b, , Ho Bum Woo a, Jungyeob Ham c, Woon-Seob Shin d, , Seokjoon Lee
*
*
a Department of Basic Sciences and Institute of Basic Medical Science, Wonju College of Medicine, Yonsei University, Wonju 220-701, Republic of Korea
b Department of Physiology, Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea
c Korea Institute of Science and Technology, Gangneung Institute, Gangneung 210-340, Republic of Korea
d Department of Microbiology, Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea
e Department of Basic Science, Kwandong University College of Medicine, Gangneung 210-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to discover novel small vasodilatory molecules for potential use in the treatment of vascular dis-
ease, we tested the vasodilatation effect of two types of synthetic curcumin mimics, amide type (3) and
sulfonyl amide type (4), upon the basilar artery of rabbits. In general, the sulfonyl amide type mimic (4) is
more potent than the amide type (3). Curcumin (1) and compounds 12 and 20 effectively dilated the bas-
ilar artery of white rabbits.
Received 15 October 2008
Revised 5 January 2009
Accepted 8 January 2009
Available online 11 January 2009
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Keywords:
Organic synthesis
Curcumin
Sulfonyl curcumin mimics
Vasodilatation
Basilar artery
Curcumin, a chemopreventive and chemotherapeutic natural
product (diferuloyl methane, 1), isolated from the root of Curcuma
longa L., suppresses, retards, or reverses carcinogenesis.1 Curcumin
also has antiinflammatory, antioxidant, antiviral, and anti-infec-
tious activities and wound-healing properties.2
a negative effect on the brain’s blood supply and blood pressure
in physiological and pathophysiological conditions.9 Therefore, it
is important to develop vasodilatory molecules with low toxicity
profiles for clinical use.10
During our search for vasoactive molecules from a natural prod-
uct with a low toxicity, we reported, for the first time, that the sar-
gahydroquinoic acid purified from the brown alga Sargassum
micracanthum, shows a selective 10-fold greater vasodilatation ef-
fect on the basilar artery than on the carotid artery of white rab-
bits.11 Moreover, previous reports have stated that our promising
lead compound, curcumin (1), showed a relaxant effect on porcine
coronary arterial ring segments12 and isolated rat aorta.13
We have previously reported that pyridine- and thiophene-
linked symmetrical bis-alkynyl curcumin derivatives (2) effectively
inhibit the proliferation and tube formation of human umbilical
vein endothelial cells (HUVECs).3 We have also found that various
curcumin mimics (3) with asymmetric units possessing the alkyl
amide and the aryl amide functional groups have an antiangiogen-
esis effect4 and a multidrug resistance (MDR) reversal activity.5,6
The results of our researches on curcumin mimics to discover the
diverse biological activities of curcumin indicate that it is a poten-
tial leading natural product for potential use in drugs (Fig. 1).
Recently, vascular diseases, including hypertension, stroke, sub-
arachnoid hemorrhage, and Alzheimer’s disease, have become pub-
lic health challenges; hence, there is a very urgent need to develop
modulators that control vascular tone in order to treat these dis-
eases.7,8 In particular, vasoconstriction of the basilar artery exerts
OCH3
OCH3
OH
HO
O
O
H3CO
HO
OCH3
OH
1
: heteroaromatic linker
2
O
O
H
N
H
N
H3CO
HO
R
H3CO
HO
R
O2
* Corresponding authors. Tel.: +82 33 649 7454; fax: +82 33 641 1074 (W.-S.S.
and S.L.).
S
O
3
E-mail addresses: shinws@kwandong.ac.kr (W.-S. Shin), sjlee@kwandong.ac.kr
4
(S. Lee).
These authors contributed equally to this work.
Figure 1.
0960-894X/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.01.019

1482
C. M. Ahn et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1481–1483
O
O
O
O
H
N
NH2
RSO2Cl
H3CO
HO
R
H3CO
HO
40% KOH H3CO
NH2
H3C
S
H
+
O2
dioxane/water
=1:1
EtOH
HO
6
8 - 22
5
7
CH3
CH3
CH3 (8),
(10),
CH2CH2CH3 (9),
Cl (12),
CF3
(17),
(11),
R:
(16),
(13),
(18),
CF3
F
OCH3
Cl
OCF3 (15),
(20),
(14),
Cl
Cl
Cl
Cl
Cl
S
(19),
(21),
Cl
(22)
Cl
Scheme 1. Synthesis of novel curcumin mimics with the sulfonyl units including the various alkyl and aryl groups. Yield for 7, 45%; 8, 20%; 9, 19%; 10, 15%; 11, 66%; 12, 74%;
13, 76%; 14, 55%; 15, 67%; 16, 67%; 17, 68%; 18, 66%; 19, 80%; 20, 60%; 21, 50%; 22, 40%.
We assumed that the search for natural lead molecules using a
specific screening system and the preparation of a synthetic library
of such molecules are very effective methods for drug develop-
ment. Hence, we tested the vasodilatation effect of previously de-
scribed asymmetric alkyl or aryl amide curcumin mimics (3)4 and
newly synthesized sulfonyl curcumin mimics (4) upon the basilar
artery of rabbits. We discovered that some asymmetric alkyl or aryl
amide curcumin derivatives (3) show a vasodilatation effect, and
that a novel type of curcumin mimics with various sulfonyl groups
(4) dilate the basilar arteries of rabbits more effectively. In this re-
port, we describe the method for synthesizing effective sulfonyl
curcumin mimics and their vasodilatation effects.
In order to evaluate the vasodilatation effect on the basilar
arteries of rabbits, we tested synthetic curcumin mimics in the
organ bath system.17–20 To begin with, to examine whether cur-
cumin and our curcumin mimics exert a dilatation effect on the
basilar arteries of white rabbits, we used a single concentration
of 10 lM of the candidate compounds; the results are summa-
rized in Table 1. When treated under high-K+ concentrations
(50 mM), the basilar arteries isometrically contracted by an in-
crease in intracellular Ca2+ concentration ([Ca2+]i), and a steady
state was reached within 20 min. First, when the natural lead
compound, that is, curcumin (1), was applied to the pre-con-
The curcumin mimics with a substituted sulfonyl group were
prepared as shown in Scheme 1. The reaction of 4-hydroxy-3-
methoxybenzaldehyde (5) with 3-acetylaniline (6) in the
presence of a basic catalyst (40% KOH) in ethanol at room
temperature for 10 h produced 1-(3-aminophenyl)-3-(4-hydro-
xy-3-methoxyphenyl) propenone (7) through flash column chro-
matography (CHCl3/CH3OH = 97/3) on silica gel.6,14 This amine
(7) was dissolved in a 1:1 mixture solution of dioxane and
H2O, cooled to 0 °C (ice bath), and reacted with each of a variety
of sulfonyl chlorides, with stirring, for 5–7 h at 0 °C. After the
solvent was removed under reduced pressure, chromatography
was performed (CHCl3/MeOH = 95/5) on silica gel to afford the
desired library of sulfonamides (8–22).15 The yields of synthetic
curcumin mimics with the alkyl sulfonyl group (8–10) were
slightly low, but those of aromatic amide products (11–22) were
moderate. The 1H, 13C NMR, and GC/MS spectra of all curcumin
mimics (8–22) were identified to study the relationship between
structural modification and the vasodilatation effect on the bas-
ilar arteries of the rabbits.16
Table 1
Vasodilatation potency of curcumin mimics, including types 3 and 4 on depolariza-
tion-induced constriction of rabbit basilar artery of the rabbit
Compound
Effective percentage
(%) at 10
Compound
Effective percentage
(%) at 10
lM
lM
1
7
8
58.4 ( 6.4)a
8.3 ( 2.2)
4.2 ( 2.8)
42.3 ( 4.7)
8.4 ( 3.6)
40.4 ( 5.7)
93.4 ( 3.8)
71.8 ( 6.4)
26.4 ( 4.4)
76.7 ( 5.2)
65.8 ( 5.3)
52.3 ( 4.5)
18
19
20
21
22
23
24
25
26
27
28
4.2 ( 2.2)
30.2 ( 4.8)
99.4 ( 0.4)
37.3 ( 6.4)
36.1 ( 3.3)
20.6 ( 3.7)
32.3 ( 4.2)
22.5 ( 4.6)
27.9 ( 2.7)
41.7 ( 5.2)
27.1 ( 4.6)
9
10
11
12
13
14
15
16
17
a
Values are means of three experiments; standard deviation is shown within
parentheses.
Figure 2. Vasodilatation effects of curcumin and synthetic curcumin mimics with an aromatic ring on depolarization-induced vasoconstriction of the rabbit basilar artery.
Representative normalized traces were acquired by a single application of curcumin 1 (A) and compounds 12 (B) and 20 (C) in log scale concentration (10À5.5, 10À5, 10À4.5 M)
for 40 min after pre-contraction with high K+ (50 mM), and the effect reached a stationary phase (20 min). The vasodilatation efficacy was plotted as a function of the log scale
concentration of curcumin (1) and the other compounds (12 and 20), and the curves were fitted using the Hill equation, E = (1 + EC50/[compound]n)À1 (D). The estimated EC50
values of curcumin (1) and the other compounds (12 and 20) are 7.48 0.28, 5.58 0.64, and 2.78 0.33 lM, respectively. Data are represented as mean SD (n = 4).

C. M. Ahn et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1481–1483
1483
tracted with high-K+ concentration (50 mM) of the basilar artery,
the curcumin slightly dilated the basilar artery at the concentra-
tion of 10 lM. Although the effect was not sufficiently strong to
9. Shaw, M. D.; Vermeulen, M.; Murray, G. D.; Pickard, J. D.; Bell, B. A.; Teasdale, G.
M. J. Neurosurg. 2000, 93, 992.
10. Kasuya, H.; Onda, H.; Takeshita, M.; Okada, Y.; Hori, T. Stroke 2002, 33, 1011.
11. Park, B. G.; Shin, W. S.; Um, Y.; Cho, S.; Park, G. M.; Yeon, D. S.; Kwon, S. C.;
Ham, J.; Choi, B. W.; Lee, S. Bioorg. Med. Chem. Lett. 2008, 18, 2624.
12. Xu, P.-H.; Long, Y.; Dai, F.; Liu, Z.-L. Vasc. Pharmacol. 2007, 47, 25.
13. Sasaki, Y.; Goto, H.; Tohda, C.; Hatanaka, F.; Shibahara, N.; Shimada, Y.;
Terasawa, K.; Komatsu, K. Biol. Pharm. Bull. 2003, 26, 1135.
consider the use of this compound as a vasodilatory drug, we
could confirm that it is very useful to use curcumin mimics as
the lead structure for the development of vasodilatative drugs.
In the case of asymmetric alkyl or aryl amide curcumin mimics,
the result was unsatisfactory, that is, only six compounds dilated
the basilar artery slightly, by about 30%.20 Finally, using the or-
gan bath system, we discovered that some molecules of the cur-
cumin mimics with various sulfonyl groups exhibited a strong
vasodilatation effect on the basilar arteries of rabbits. In particu-
lar, compounds 12 and 20 caused efficient dilatation of the bas-
14. Maitra, S.; Singh, R.; Sinha, A.; Lahiri, S. Synth. Commun. 1989, 19, 2363.
15. Park, C. H.; Givens, R. S. J. Am. Chem. Soc. 1997, 119, 2453.
16. Selected instrumental data for highly active compounds. Compound 12: mp
162–164 °C; TLC (ethyl acetate/n-hexane = 1/1) Rf = 0.31; 1H NMR (CDCl3): d
3.97 (3H, s, OCH3), 5.92 (1H, s, OH), 6.97 (1H, d, J = 8.21 Hz, CH3OC6H3), 7.00
(1H, s, NH), 7.15 (1H, d, J = 1.64 Hz, CH3OC6H3), 7.24 (2H, dd, J = 10.12 and
1.72 Hz, CH3OC6H3), 7.30 (1H, d, J = 15.61 Hz, CH@CHAr), 7.41 (2H, d,
J = 8.65 Hz, 4-chlorobenzenesulfonyl-H), 7.41–7.44 (2H, m, NHC6H4), 7.72
(2H, d, J = 8.55 Hz, 4-chlorobenzenesulfonyl-H), 7.73 (1H, s, NHC6H4), 7.77–
7.80 (1H, m, NHC6H4), 7.82 (1H, d, J = 15.72 Hz, CH@CHAr) ppm. 13C NMR
(CDCl3 + DMSO-d6): d 56.0, 110.5, 115.4, 119.3, 120.8, 124.5, 124.7, 128.5,
128.6, 129.1, 129.2, 129.4, 137.9, 138.2, 139.1, 139.5, 145.7, 147.4, 149.2, 190.0.
MS (FAB+) (m/z) 443 (M+); Anal. Calcd for C22H18ClNO5S: C, 59.53; H, 4.09; N,
3.16; S, 7.22. Found: C, 59.29; H, 3.98; N, 3.09; S, 7.09; compound 13: mp 163–
165 °C; TLC (ethyl acetate/n-hexane = 1/1) Rf = 0.29; 1H NMR (CDCl3): d 3.97
(3H, s, OCH3), 5.92 (1H, s, OH), 6.93 (1H, s, NH), 6.97 (1H, d, J = 8.24 Hz,
CH3OC6H3), 7.10 (2H, d, J = 8.49 Hz, 4-fluorobenzenesulfonyl-H), 7.14 (1H, d,
J = 2.94 Hz, CH3OC6H3), 7.24 (1H, dd, J = 9.93 and 1.28 Hz, CH3OC6H3), 7.29 (1H,
d, J = 15.77 Hz, CH@CHAr), 7.42–7.43 (2H, m, NHC6H4), 7.71 (1H, s, NHC6H4),
7.80 (2H, d, J = 8.92 Hz, 4-fluorobenzenesulfonyl-H), 7.81 (1H, d, J = 10.73 Hz,
NHC6H4), 7.82 (1H, d, J = 15.71 Hz, CH@CHAr) ppm. 13C NMR (CDCl3 + DMSO-
d6): d 56.0, 110.5, 115.4, 116.1, 116.3, 119.3, 120.8, 123.5, 124.4, 124.7, 127.0,
129.4, 129.8, 129.9, 138.0, 139.5, 145.7, 147.4, 149.2, 190.0. MS (FAB+) (m/z)
427 (M+); Anal. Calcd for C22H18FNO5S: C, 61.82; H, 4.24; N, 3.28; S, 7.50.
Found: C, 59.98; H, 4.12; N, 3.22; S, 7.24; compound 20: mp 177–179 °C; TLC
(chloroform/methanol = 95/5) Rf = 0.50; 1H NMR (CDCl3 + DMSO-d6): d 3.95
(3H, s, OCH3), 6.94 (1H, d, J = 8.58 Hz, CH3OC6H3), 7.15 (1H, s, CH3OC6H3), 7.15–
7.16 (1H, m, CH3OC6H3), 7.30 (1H, d, J = 15.58 Hz, CH@CHAr), 7.31 (1H, d,
J = 6.83 Hz, 2,6-dichlorobenzenesulfonyl-H), 7.37 (1H, t, J = 7.86 Hz, NHC6H4),
7.41–7.42 (1H, m, NHC6H4), 7.41–7.42 (2H, m, 2,6-dichlorobenzenesulfonyl-H),
7.67 (1H, d, J = 7.54 Hz, NHC6H4), 7.70 (1H, d, J = 15.59 Hz, CH@CHAr), 7.87 (1H,
s, NHC6H4), 8.21 (1H, s, OH), 10.14 (1H, s, NH) ppm. 13C NMR (CDCl3 + DMSO-
d6): d 56.3, 111.0, 115.9, 119.2, 119.3, 123.4, 123.9, 124.3, 127.1, 129.9, 131.9,
133.2, 134.7, 135.9, 137.7, 139.8, 146.1, 148.0, 149.8, 190.2. MS (FAB+) (m/z)
477 (M+); Anal. Calcd for C22H17Cl2NO5S: C, 55.24; H, 3.58; N, 2.93; S, 6.70.
Found: C, 57.52; H, 3.73; N, 3.06; S, 6.96.
ilar artery by almost 100% at the concentration of 10 lM.
Although the structure–activity relationship revealed by the pre-
liminary results is more or less vague, curcumin mimics possess-
ing the chlorobenzene sulfonyl group, such as 12 and 20, have
shown a strong dilatation effect.
The serial application of curcumin (1) and compounds 12 and
20 induced vasodilatation of the basilar arteries in a concentra-
tion-dependent manner. As shown in Figure 2, the curve fittings
of the concentration–response relationship determined based on
the Hill equation confirmed that the concentration required for
half maximal dilatation (EC50) of curcumin (1) and compounds
12 and 20 for the basilar artery were 7.48 0.28, 5.58 0.64, and
2.78 0.33 lM (n = 4), respectively. These results indicated that
curcumin mimics, especially compounds 12 and 20, exerted a more
effective and rapid dilatation effect on the basilar artery than cur-
cumin at an equimolar concentration.
In conclusion, in order to discover efficient vasodilatory mole-
cules for the treatment of vascular diseases, including hyperten-
sion, stroke, subarachnoid hemorrhage, and Alzheimer’s disease,
we synthesized a library of curcumin mimics by a simple aldol
reaction and amide or sulfonyl amide addition, and then tested
the library. Curcumin (1), a natural product, was found to exert a
dilation effect on the basilar arteries of rabbits. In addition, curcu-
min mimics with various sulfonyl groups are more potent than
those possessing amide groups. In particular, compounds 12 and
20 were found to be strong vasodilatory molecules and are now
are being tested in an in vivo study for their potential use in the
treatment of strokes.
17. Komuro, T.; Miwa, S.; Zhang, X. F.; Minowa, T.; Enoki, T.; Kobayashi, S.;
Okamoto, Y.; Ninomiya, H.; Sawamura, T.; Kikuta, K.; Iwamuro, Y.; Furutani, H.;
Hasegawa, H.; Uemura, Y.; Kikuchi, H.; Masaki, T. J. Cardivasc. Pharmacol. 1997,
30, 504.
18. Zhang, X. F.; Iwamuro, Y.; Enoki, T.; Okazawa, M.; Lee, K.; Komuro, T.; Minowa,
T.; Okamoto, Y.; Hasegawa, H.; Furutani, H.; Miwa, S.; Masaki, T. Br. J.
Pharmacol. 1999, 127, 1388.
19. Experimental procedures: After anesthetizing 20 male white rabbits weighing
2–2.5 kg by enflurane inhalation, basilar arteries were isolated quickly under
sterile conditions and placed in
a physiological salt solution (PSS) that
contained 137 mM NaCl, 5.4 mM KCl, 1.5 mM CaCl2, 1 mM MgCl2, 23.8 mM
NaHCO3, and 5.5 mM glucose. Residual blood was rinsed from the lumen and
adherent connective tissue, fat, and adventitia were carefully removed. Basilar
arteries were cut into rings (3 mm) in a dissecting chamber filled with PSS
saturated with a mixture containing 95% O2 and 5% CO2. Basilar rings were
mounted using a pair of stainless steel hooks under a resting tension of 0.8 g in
an organ bath containing 15 ml of PSS, which was maintained at 37 °C and
aerated with a mixture containing 95% O2 and 5% CO2. One of the hooks was
connected to a force transducer (MLT050; ADInstruments, Colorado Springs,
CO, USA), and the vascular tone was recorded using a Powerlab/400 on a chart
5.0 (ADInstruments). After equilibration for 40 min, each ring specimen was
repeatedly exposed to the high-K+ solution (50 mM), which was prepared by
replacing NaCl with an equimolar concentration of KCl in PSS, until the
responses became stable.
Acknowledgments
This research was supported by a grant from the Marine Bio-
technology Program funded by the Ministry of Land, Transport
and Maritime Affairs, Republic of Korea.
References and notes
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. Ahn, C. M.; Shin, W.-S.; Woo, H. B.; Lee, S.; Lee, H.-W. Bioorg. Med. Chem. Lett.
2004, 14, 3893.
4. Woo, H. B.; Shin, W.-S.; Lee, S.; Ahn, C. M. Bioorg. Med. Chem. Lett. 2005, 15,
3782.
5. Kim, Y. K.; Song, Y. J.; Seo, D. W.; Kang, D. W.; Lee, H. Y.; Rhee, D. K.; Han, J. W.;
Ahn, C. M.; Lee, S.; Kim, S. N. Biochem. Biophys. Res. Commun. 2007, 355, 136.
6. Um, Y.; Cho, S.; Woo, H. B.; Kim, Y. K.; Kim, H.; Ham, J.; Kim, S. N.; Ahn, C. M.;
Lee, S. Bioorg. Med. Chem. 2008, 16, 3608.
20. Structure of asymmetric alkyl or aryl amide curcumin mimics with weak
vasodilatation effect on the basilar artery of the rabbits.
O
H
H3CO
HO
N
R
O
CH3
CH3
S
(25),
(28)
CH2CH2CH3 (24),
CH3 (23),
7. Miller, A. A.; Drummond, G. R.; Sobey, C. G. Drug Discovery Today: Ther. Strateg.
2005, 2, 187.
8. Kearney, P. M.; Whelton, M.; Reynolds, K.; Muntner, P.; Whelton, P. K.; He, J.
Lancet 2005, 365, 217.
Cl
O
(27),
(26),
Cl