Antitumor agents. 250. Design and synthesis of new curcumin analogues as potential anti-prostate cancer agents

Article abstract of DOI:10.1021/jm051043z

In a continuing study of curcumin analogues as potential drug candidates to treat prostate cancer at both androgen-dependent and androgen-refractory stages, we designed and synthesized over 40 new analogues classified into four series: monophenyl analogues (series A), heterocycle-containing analogues (series B), analogues bearing various substituents on the phenyl rings (series C), and analogues with various linkers (series D). These new compounds were tested for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Antiandrogenic activity was also evaluated in LNCaP cells and PC-3 cells transfected with wild-type androgen receptor. Ten compounds possessed potent cytotoxicity against both LNCaP and PC-3 cells, seven only against LNCaP, and one solely against PC-3. This study established an advanced structure-activity relationship (SAR), and these correlations will guide the further design of new curcumin analogues with better anti-prostate cancer activity.

Full text of DOI:10.1021/jm051043z

J. Med. Chem. 2006, 49, 3963-3972
3963
Antitumor Agents. 250.† Design and Synthesis of New Curcumin Analogues as Potential
Anti-Prostate Cancer Agents
Li Lin,‡ Qian Shi,§ Alexander K. Nyarko,‡ Kenneth F. Bastow,‡ Chin-Chung Wu,‡ Ching-Yuan Su,§ Charles C.-Y Shih,§ and
Kuo-Hsiung Lee*,‡
Natural Products Laboratory, School of Pharmacy, UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, and
Androscience Corporation, 11175 Flintkote AVenue, Suite F, San Diego, California 92121
ReceiVed October 17, 2005
In a continuing study of curcumin analogues as potential drug candidates to treat prostate cancer at both
androgen-dependent and androgen-refractory stages, we designed and synthesized over 40 new analogues
classified into four series: monophenyl analogues (series A), heterocycle-containing analogues (series B),
analogues bearing various substituents on the phenyl rings (series C), and analogues with various linkers
(series D). These new compounds were tested for cytotoxicity against two human prostate cancer cell lines,
androgen-dependent LNCaP and androgen-independent PC-3. Antiandrogenic activity was also evaluated
in LNCaP cells and PC-3 cells transfected with wild-type androgen receptor. Ten compounds possessed
potent cytotoxicity against both LNCaP and PC-3 cells, seven only against LNCaP, and one solely against
PC-3. This study established an advanced structure-activity relationship (SAR), and these correlations will
guide the further design of new curcumin analogues with better anti-prostate cancer activity.
Introduction
decades, 1 has been studied fairly extensively and has been
found to have various biological properties including anti-
inflammatory,11 anti-oxidant,12 anti-HIV,13 chemopreventive,14
and anticancer15 effects in several cell types. In our laboratory,
we used 1 as a lead compound to design and synthesize
1-analogues as a new class of potential antiandrogenic agents
for the treatment of prostate cancer.16-18 Certain 1-analogues
showed antiandrogenic activity in human prostate cancer cells,
and two potent antiandrogens previously developed in our
laboratory, dimethylated curcumin (DMC, 2) and 4-ethoxycar-
bonylethyl curcumin (ECECur, 3), are currently under in vivo
investigation (Figure 1). Most recently, we found that the
curcumin analogue 4 possesses potent antiandrogenic activity.
From our prior studies, a preliminary antiandrogenic structure-
activity relationship (SAR) was established. In a continuing
study, we have now prepared four series of new 1-analogues
including monophenyl curcumin analogues (series A), heterocycle-
containing curcumin analogues (series B), curcumin analogues
bearing various substituents on the phenyl rings (series C), and
curcumin analogues with various linkers (series D). These new
1-analogues were evaluated in cytotoxicity and antiandrogenic
assays in two human prostate cancer cell lines, LNCaP and PC-
3. Based on the structures and anti-prostate cancer activities of
the new 1-analogues, a more detailed SAR has been formulated.
This advanced SAR better reveals the structural features of
1-analogues responsible for the cytotoxic as well as antiandro-
genic activities in human prostate cancer cells. This information
will guide our optimization of 1-analogues with better phar-
macological profiles as potential drug candidates for the
treatment of prostate cancer.
Prostate cancer is the most common cancer among males of
Western countries2 and is a complex heterogeneous disease that
acts differently in different men. The real cause of prostate
cancer is still unknown. However, androgen and the androgen
receptor (AR) are postulated to play crucial roles in the
development of prostate cancer.3 The current treatment for
prostate cancer is a combination of surgery, radiation, and
chemotherapy. The therapeutic agents used clinically include
steroidal antiandrogens, such as cyproterone acetate, and non-
steroidal antiandrogens, such as flutamide and bicalutamide. The
steroidal antiandrogens possess partial agonistic activity and
overlapping effects with other hormonal systems, leading to
many complications including severe cardiovascular problems,
gynecomastia, loss of libido, and erectile dysfunction.4-6 The
nonsteroidal antiandrogens show fewer side effects and have
improved oral bioavailability; therefore, they are favored over
the steroidal antiandrogens. However, antiandrogen withdrawal
syndrome has been discovered in patients receiving nonsteroidal
antiandrogens for several months.7,8 Long-term drug usage
probably leads to mutation of the AR, and the nonsteroidal
antiandrogens now exhibit agonistic activity to the mutant AR.9
In addition, the clinically available antiandrogens are unable to
kill prostate cancer cells, and within one to three years of drug
administration, the cancer usually develops into an androgen-
refractory stage, which is not curable. Therefore, it is urgent to
develop new classes of anti-prostate cancer drugs.
Prostate cancer incidence is much lower in Asian than in
Western countries,10 possibly due to differences in diet. Turmeric
is a spice and medicine much more highly consumed in Asian
countries such as India, Thailand, China, and Japan. Curcumin
(1) is the major constituent in the rhizome of Curcuma longa
(Zingiberaceae), commonly named turmeric. Over the last few
Chemistry
The general synthetic scheme for series A is shown in Scheme
1. To avoid the aldol condensation taking place at both terminals
of 2,4-pentanedione, excess pentanedione was used in this
reaction.19 Boric anhydride was first added to form a complex
with 2,4-pentanedione. The aim of this complexation is to protect
C-3 from Knoevenagel condensation so that the aldol condensa-
tion takes place at the terminal carbon.
* To whom correspondence should be addressed. Phone: (919)-962-
0066, Fax: (919)-966-3893, E-mail: khlee@unc.edu.
† Antitumor agents 250. For the prior paper in the series, see ref 1.
‡ University of North Carolina at Chapel Hill.
§ Androscience Corporation.
10.1021/jm051043z CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/08/2006

3964 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 13
Lin et al.
Figure 1. Structures of curcumin (1), DMC (2), ECECur (3), and 4
Scheme 1. The General Synthetic Method for Monophenyl
Curcumin Analogues
solution and 0.25 equivalent of 25% aqueous solution of
cetyltrimethylammonium bromide to afford the product (Scheme
4).
Curcumin analogues with an elongated linker were prepared
by employing Pederson’s synthetic method.20 2,4-Pentanedione
or ethyl 4-acetyl-5-oxohexanoate was reacted with 4-hydroxy-
3-methoxy-cinnamaldyhyde to give 35 or 36 as the target
analogue (Scheme 5).
Hydrogenation of DMC in the presence of 10% Pd/C gave
the saturated analogue 37 as the product (Scheme 6). The
partially saturated analogue 38 has a hydroxy group in the linker
instead of an enol, and was prepared as shown in Scheme 7.
3,4-Dimethoxycinnamone and 3, 4-dimethoxycinnamaldehyde
were both prepared from 3,4-dimethoxybenzaldyhyde by con-
densation with acetone and acetaldehyde, respectively. After
treating 3,4-dimethoxycinnamone with LDA at -78 °C, 3,4-
dimethoxycinnamoaldehyde was added to provide 38.21
To synthesize the imide curcumin analogue (39), 3,4-
dimethoxycinnamic acid was first converted to the acid chloride
by treatment with thionyl chloride. Then, two equivalents of
the acid chloride were reacted with one equivalent of (Me3-
Si)2NH in the presence of triethylamine to give the target product
39.22 (Scheme 8).
Scheme 2 The General Synthetic Strategies for Symmetric
Curcumin Analogues
Scheme 3. The General Synthetic Scheme for Asymmetric
Curcumin Analogues
The syntheses of curcumin analogues 4, 40-45, 47, and 48,
which have mono- or disubstitution at C-4, have been described
and discussed elsewhere.18 The preparation of 49 and 50 is
shown in Scheme 9. 4-Methyl DMC (49) was prepared by using
the methodology shown in Scheme 2 and then fluorinated by
SelectFluor under basic conditions to give 4-fluoro-4-methyl
DMC (50).23
Results and Discussion
The synthetic strategies for series B (heterocycle-containing
curcumin analogues) and series C (symmetric and asymmetric
curcumin analogues with various substituents on the phenyl
rings) are shown in Scheme 2 and Scheme 3, respectively. The
symmetric compounds were synthesized by using Pederson’s
method.20 At least two equivalents of the aldehyde are needed
to ensure aldol condensation at both terminals of the dione. To
prepare asymmetric compounds having different aryl rings, a
monoaryl intermediate was first prepared by using the method
shown in Scheme 1 and subsequently condensed with an
appropriate second aldehyde to give the target compounds.
The syntheses of series D with various linkers between the
two phenyl rings are shown in Schemes 4-9.
The target compounds were tested for cytotoxicity against
two human prostate cancer cell lines, LNCaP and PC-3. The
LNCaP cell line is an androgen-dependent human prostate
cancer cell line that expresses mutant AR, and the PC-3 cell
line is an androgen-independent human prostate cancer cell line
that does not express functional AR. The antiandrogenic activity
of these 1-analogues was examined in LNCaP cells and PC-3
cells transfected with wild-type AR.
The seven monophenyl analogues (5-11) did not exhibit
significant cytotoxicity in either LNCaP or PC-3 cells (Table
1A). The absence of one phenyl ring in the curcumin skeleton
apparently results in decreased cytotoxicity, indicating that both
phenyl rings must be present to retain cytotoxicity against human
prostate cancer cells.
In the general synthesis of 1, 5-diphenyl-1, 4-pentadien-3-
ones, one equivalent of acetone and two equivalents of
substituted benzaldehyde were treated with 0.25 M NaOH
In addition, none of the four heterocycle-containing series B
analogues (12-15) showed significant cytotoxicity in either

Curcumin Analogues
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 13 3965
Scheme 4. The General Synthetic Method of 1,5-Diphenyl-1,4-pentadien-3-ones
Scheme 5. The Synthesis of Curcumin Analogues Having a Long Linker
Scheme 6. The Preparation of 37 from DMC
Scheme 7. The Synthesis of 38
1.3 µM (LNCaP) (Table 1.C). Compound 19, which has 3′,4′,6′-
dimethoxy substitution on both phenyl rings, was active against
both human prostate cancer cell lines. Compounds 24 and 25,
which have 3′,5′-dimethoxy-4′-hydroxy and 3′-methyl-4′-hy-
droxyl substituted phenyl rings, respectively, were active against
androgen-dependent LNCaP cells. Among the five asymmetric
analogues, 27 and 31 also exhibited activity against LNCaP cells.
Both compounds have 3′,4′-dimethoxy substitution on one
phenyl ring and 3′-methoxy-4′-hydroxy substitution on the other
(Table 1.D). In addition, 31 has an ethoxycarbonylethyl side
chain at position C-4 of the linker. Thus, symmetry is not a
vital requirement for selective cytotoxic activity. The common
features of the phenyl rings of these active compounds are as
follows. (1) The C-2′ positions should be unsubstituted. (2) The
C-3′ positions should be substituted. However, while methoxy
or methyl substituents are favorable, hydroxy groups are not
favorable at these positions. (3) The C-4′ positions should also
be substituted. The substituents can either be two methoxy
groups, two hydroxy groups, or one methoxy and one hydroxy.
Ethoxy and isoprenyl substituents are not favorable at these
positions. (4) Except for 24, most of these synthesized com-
pounds are unsubstituted at the C-5′ position. However, 24 has
C-5′ methoxy substituents, and it was active in LNCaP cells.
5) Most of the new analogues have no substitution on the C-6′
LNCaP or PC-3 cells (Table 1.B). These results suggest that
replacing the phenyl ring(s) with five-membered-heterocyle(s)
will not improve the desired activity. This information will guide
us to design new 1-analogues with the phenyl rings intact.
Series C contains symmetric and asymmetric curcumin
analogues with various substituents on the phenyl rings. None
of these newly synthesized analogues showed better cytotoxicity
than DMC (2), which has IC50 values of 1.1 µM (PC-3) and
Scheme 8. The Synthesis of Imide Analogue 39
Scheme 9. The Synthesis of 49 and 50

3966 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 13
Lin et al.
Table 1. Cytotoxicity of 1-analogues against LNCaP and PC-3 Human Prostate Cancer Cellsa
a *: IC50 values are mean concentrations that inhibit growth by 50% and variation between replicates was less than 5%. The cutoff line is 4 µM. Compound
with IC50 less than 4 µM is considered to be active. **: [ ]: % inhibition of cell growth at 20 µg/mL. ***: ND, not determined.
positions. An exception is 19, which has methoxy substituents
on C-6′, and retained activity in both cell lines. Additional
investigation will be needed to probe what functional groups
can be accommodated at the C-5′ and C-6′ positions to keep or
even enhance the activity of curcumin analogues.
With 3′,4′-dimethoxy or 3′-methoxy-4′-hydroxy substituents
on the phenyl rings, compounds having a 1,4-pentadien-3-one
linker (e.g. 32 and 33) showed significant cytotoxicity against
both human prostate cancer cell lines (Table 1.E). However,
34, an analogue that also possesses a 1,4-pentadien-3-one linker
but has 2,4-dimethoxy substituted phenyl rings, was inactive.
These results once again confirm the importance of 3′,4′-
disubstitution on the phenyl rings. Curcumin analogues 35 and
36 have elongated linkers (11 carbons) connecting the 3′-
methoxy-4′-hydroxyphenyl rings. Compound 35 was not cyto-
toxic in either prostate cancer cell line, while 36 showed
cytotoxicity against LNCaP cells (IC50 3.1 µM), but activity
against PC-3 cells was not significant. Overall, compared with
1 and 3, the cytotoxicity of 35 and 36 decreased. Thus,
elongation of the linker did not improve the cytotoxic activity
of 1-analogues against prostate cancer cells. Compounds 37
(saturated DMC: 3-hydroxy-heptan-5-one linker) and 38 (par-
tially saturated DMC: 3-hydroxy-1,6-heptadien-5-one linker)
were not cytotoxic toward prostate cancer cells, suggesting that
an unsaturated and conjugated linker, such as the 3-hydroxy-
1,4,6-heptatrien-5-one found in 1 and 2, is required for the
bioactivity of 1-analogues. When NH replaced the CH2 between
the two carbonyl groups in a similar linking group, the resulting

Curcumin Analogues
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 13 3967
Conclusions
Table 2. The Antiandrogenic Activity of Compounds 3, 4, 40, and 44a
DHT (1 nM)
+ tested compounds
LNCaP
transactivation (%)
PC3+wt. AR
In conclusion, we synthesized over 40 new 1-analogues and
first examined their cytotoxicity against androgen-dependent
LNCaP and androgen-independent PC-3 human prostate cancer
cell lines. Ten compounds (2, 4, 19, 32, 33, 40, and 42-45)
showed significant cytotoxicity against both androgen-dependent
LNCaP cells and androgen-independent PC-3 cells. Seven
compounds [1 (curcumin), 3 (ECECur), 24, 25, 27, 31, and 39]
were cytotoxic only against androgen-dependent LNCaP cells.
Only one compound (49) was active against PC-3 cells but
inactive against LNCaP cells. The most potent antiandrogenic
compounds were 3 (ECECur), 4, 40, and 44. Those analogues
that were active in the cytotoxicity assay but inactive in the
antiandrogenic assay are presumed to act by a different
mechanism other than interrupting the AR signaling pathway.
All active compounds are potential drug candidates for the
treatment of prostate cancer at the androgen-dependent or
androgen-refractory stage. The study of their mechanism(s) of
action will be useful in exploring the causes of prostate cancer.
In addition, an advanced SAR has been established from this
work. This extensive SAR information will guide us to design
optimized 1-analogues having better, selective anti-prostate
cancer activity.
transactivation (%)
DHT (control)
100
65
4
6
54
42
100
31
13
40
46
68
DHT+ HF (5 µM)
DHT+ 3 (5 µM)
DHT+ 4 (5 µM)
DHT+ 40 (3 µM)
DHT+ 44 (5 µM)
a LNCaP and PC-3 human prostate cell lines were seeded and cotrans-
fected with reporter MMTV-luciferase (both cell lines), wild-type AR
expression plasmid (PC-3) using SuperFect. Subsequently, the transfected
cells were harvested and replated in 10% charcoal-stripped fetal bovine
serum DMEM medium. The cells were then treated with dehydrotestosterone
(DHT, 1 nM) and tested compounds (3 µM or 5 µM) and harvested for
detection of the luciferase activity. (cf. Experimental Section).
imide analogue (39) lost cytotoxicity against PC-3 cells but
remained cytotoxic against LNCaP cells with an IC50 of 2.2
µM. Compounds with both fluorine and either a propionic ethyl
ester or a methyl group at the middle (C-4) carbon (e.g. 47, 48,
50) were not cytotoxic against either tested cell line. However,
various unsaturated (acrylic ester, acrylamide, acrylonitrile, allyl
alcohol) monosubstitution at C-4 of the linker (e.g. 40, 42-45)
resulted in high cytotoxicity against both human prostate cancer
cell lines. These analogues were generally more potent than 1
and as potent as 2-4. From the bioassay results of Series D,
we can see that it is essential to design a proper linker connecting
the substituted phenyl rings in order to obtain potent anti-prostate
cancer analogues. The best linkers discovered so far are
3-hydroxy-1,4,6-heptatrien-5-one (the original curcumin linker),
1,4-pentadien-3-one (a shorter linker), and several 4-monosub-
stituted 3-hydroxy-1,4,6-heptatrien-5-ones that are shown in the
structures of ECECur (3), 4, 40, and 42-45.
New 1-analogues also were evaluated in an anti-AR assay in
LNCaP cells and PC-3 cells transfected with wild-type AR.
Table 2 shows the antiandrogenic activity of the most potent
compounds (3, 4, 40, and 44); the remaining analogues exhibited
no or weak activity in the antiandrogenic bioassay. All four
potent compounds have similar phenyl substitutions, linking
groups, and side chains. Because the most cytotoxic compounds
(42, 43, and 45) were inactive in the anti-AR bioassay, they
likely have mechanisms of action other than interrupting the
AR signaling pathway in human prostate cancer cells. Either
with or without antiandrogenic activity, these cytotoxic 1-an-
alogues have potential to treat both androgen-dependent prostate
cancer and androgen-refractory prostate cancer.
Experimental Section
Melting points were determined on a Fisher-Johns melting
apparatus and are uncorrected. 1H NMR spectra were recorded on
a Varian Gemini-300 spectrometer. The chemical shifts are
presented in terms of ppm with TMS as the internal reference. MS
spectra were recorded on Agilent 1100 series LC/MS trap and API-
3000 LC/MS/MS spectrometer. Column chromatography was
carried out on CombiFlash Companion (Isco, Inc.), and thin-layer
chromatography was performed on precoated silica gel or aluminum
plates (Aldrich, Inc.). Elemental analyses were performed by
Atlantic Microlab Inc., Norcross, GA, and agreed with theoretical
values to within (0.4%.
Preparation of Monophenyl Analogues 5-11. To a solution
of 2,4-pentanedione or 4-acetyl-5-oxo-hexanoate in EtOAc (3 equiv)
was added boric anhydride (0.7 equiv). The solution was stirred at
70 °C for 0.5 h. To the solution were added the aldehyde (1 equiv)
and tributyl borate (1 equiv). The mixture was stirred for 30 min.
At 85 °C, butylamine (1 equiv) dissolved in EtOAc was added
dropwise over 15 min. The stirring continued for 1 h at 100 °C.
The mixture was then hydrolyzed by adding 1 N HCl at 50 °C and
stirring for 0.5 h at 50 °C. The organic layer was separated, and
the aqueous layer was extracted with EtOAc. The combined organic
layers were washed until neutral and dried over anhydrous sodium
sulfate. After removal of the solvent in vacuo, the crude products
were purified by flash column chromatography eluting with a
hexanes-EtOAc gradient.
An advanced SAR has been established on the basis of the
structure information and bioactivities of the newly synthesized
1-analogues discussed above. The following SAR conclusions
were made. (1) Biphenyl rings are required for the cytotoxic
and antiandrogenic activities. (2) The C-2′ positions of the
phenyl rings should be unsubstituted. (3) The C-3′ and C-4′
positions should be substituted, with 3′,4′-dimethoxy and 3′-
methoxy-4′-hydroxy substituents on the phenyl rings found to
be most favorable. Substitution at the C-5′ and C-6′ positions
probably will not affect the cytotoxicity. (4) The length of the
linker impacts the cytotoxicity as well as antiandrogenic activity
in human prostate cancer cells. Elongation of the linker results
in the loss of cytotoxicity and antiandrogenic activity. (5) An
unsaturated and conjugated linker is required for the cytotoxic
and antiandrogenic activities. (6) Substitution at the C-4 position
of the linker is very crucial for improved anti-AR activity in
this compound class. Monosubstitution with proper side chains
improved the cytotoxicity significantly.
4-Hydroxy-6-(4-hydroxy-3-methoxyphenyl)-hexa-3,5-dien-2-
one (5): (from vanillin and 2,4-pentanedione) Yellow powder, 50%
yield. mp 146-147 °C (lit.24 146-147 °C); ESI MS m/z 235.0 (M
+ H)+; 1H NMR (300 MHz, CDCl3): δ 2.16 (3H, s), 3.94 (3H, s),
5.63 (H, s), 6.33 (H, d, J ) 15.9 Hz), 6.92 (H, d, J ) 8.1 Hz), 7.01
(H, d, J ) 1.8 Hz), 7.10 (H, dd, J ) 8.1 Hz, J ) 1.8 Hz), 7.53 (H,
d, J ) 15.9 Hz).
6-(3,4-Dimethoxyphenyl)-4-hydroxyhexa-3,5-dien-2-one (6):
(from 3,4-dimethoxybenzaldehyde and 2,4-pentanedione) 48%
yield. mp 78-79 °C; ESI MS m/z 249.0 (M + H)+; 1H NMR (300
MHz, CDCl3): δ 2.10 (3H, s), 3.92 (6H, s), 5.64 (H, s), 6.35 (H,
d, J ) 16.2 Hz), 6.87 (H, d, J ) 8.4 Hz), 7.04 (H, d, J ) 1.8 Hz),
7.11 (H, dd, J ) 8.4 Hz, J ) 1.8 Hz), 7.55 (H, d, J ) 16.2 Hz).
4-Hydroxy-6-(3-hydroxy-4-methoxyphenyl)-hexa-3,5-dien-2-
one (7): (from 3-hydroxy-4-methoxybenzaldehyde and 2,4-pen-
tanedione) 45% yield. mp 163-164 °C (lit.24 160-162 °C); ESI
1
MS m/z 233.2 (M - 1)+; H NMR (300 MHz, CDCl3): δ 2.16
(3H, s), 3.93 (3H, s), 5.63 (H, s), 6.32 (H, d, J ) 15.6 Hz), 6.85

3968 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 13
Lin et al.
(H, d, J ) 8.7 Hz), 7.02 (H, dd, J ) 8.7 Hz, J ) 2.1 Hz), 7.14 (H,
d, J ) 2.1 Hz), 7.51 (H, d, J ) 15.6 Hz).
5-Hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-thiophen-2-yl-
hepta-1,4,6-trien-3-one (14): (from thiophene-2-carbalydehyde)
1
38% yield. mp 130-132 °C; ESI MS m/z 327.1 (M - 1)+; H
6-(2,4-Dimethoxyphenyl)-4-hydroxyhexa-3,5-dien-2-one (8):
(from 2,4-dimethoxybenzaldehyde and 2,4-pentanedione) 44%
yield. mp 92-93 °C; ESI MS m/z 249.0 (M + H)+; 1H NMR (300
MHz, CDCl3): δ 2.15 (3H, s), 3.85 (3H, s), 3.87 (3H,s), 5.63 (H,
s), 6.48 (H, d, J ) 15.9 Hz), 6.50 (H, d, J ) 2.1 Hz), 6.51 (H, dd,
J ) 8.1 Hz, J ) 2.1 Hz), 7.46 (H, d, J ) 8.4 Hz), 7.84 (H, d, J )
15.9 Hz). Anal. (C14H16O4‚1/8 H2O) C, H.
4-Hydroxy-6-(2,3,4-trimethoxyphenyl)-hexa-3,5-dien-2-one
(9): (from 2,3,4-trimethoxybenzaldehyde and 2,4-pentanedione)
45% yield. mp 66-67 °C; ESI MS m/z 279.2 (M + H)+; 1H NMR
(300 MHz, CDCl3): δ 2.16 (3H, s), 3.88 (3H, s), 3.90 (3H, s),
3.92 (3H, s), 5.64 (H, s), 6.48 (H, d, J ) 15.9 Hz), 6.70 (H, d, J )
8.7 Hz), 7.27 (H, d, J ) 8.7 Hz), 7.79 (H, d, J ) 15.9 Hz). Anal.
(C15H18O5) C, H.
NMR (300 MHz, CDCl3): δ 3.89 (3H, s), 5.28 (H, s), 5.74 (H, s),
6.37 (H, d, J ) 15.6 Hz), 6.45 (H, d, J ) 15.9 Hz), 6.91 (H, d, J
) 7.8 Hz), 7.01 (H, d, J ) 2.4 Hz), 7.02 (H, d, J ) 1.2 Hz), 7.04
(H, s), 7.08 (H, dd, J ) 1.2 Hz, J ) 7.8 Hz), 7.21 (H, d, J ) 3.6
Hz), 7.34 (H, d, J ) 4.8 Hz), 7.57 (H, d, J ) 15.6 Hz), 7.73 (H,
d, J ) 15.3 Hz). Anal. (C18H16O4S) C, H.
5-Hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-(1H-pyrrol-2-
yl)-hepta-1,4,6-trien-3-one (15): (from 1H-pyrrole-2-carbaldehyde)
1
24% yield. mp 138-139 °C; ESI MS m/z 334.2 (M + Na)+; H
NMR (300 MHz, CD3COCD3): δ 3.92 (3H, s), 5.86 (H, s), 6.25
(H, s), 6.47 (H, d, J ) 15.9 Hz), 6.64 (H, s), 6.68 (H, d, J ) 15.9
Hz), 6.88 (H, d, J ) 7.8 Hz), 7.06 (H, s), 7.16 (H, d, J ) 7.8 Hz),
7.32 (H, s), 7.57 (H, d, J ) 15.9 Hz), 7.59 (H, d, J ) 15.9 Hz).
Anal. (C18H17NO4) C, H, N.
4-Hydroxy-6-(2,4,5-trimethoxyphenyl)-hexa-3,5-dien-2-one (10):
(from 2,4,5-trimethoxybenzaldehyde and 2,4-pentanedione) 48%
Preparation of Symmetric Curcumin Analogues 16-26.
Compounds 16-19 and 22-26 were prepared from corresponding
benzaldehydes by using the same procedure described above for
12 from 5-hydroxymethyl-2-furaldehyde. The preparation of 20 and
21 was reported elsewhere by us.
1
yield. mp 107-108 °C; ESI MS m/z 279.2 (M + H)+; H NMR
(300 MHz, CDCl3): δ 2.15 (3H, s), 3.88 (3H, s), 3.89 (3H, s),
3.94 (3H, s), 5.66 (H, s), 6.42 (H, d, J ) 15.9 Hz), 6.50 (H, s),
7.02 (H, s), 7.89 (H, d, J ) 15.9 Hz). Anal. (C15H18O5) C, H.
4-Acetyl-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-hepta-
4,6-dienoic acid ethyl ester (11): (from vanillin and ethyl 4-acetyl-
5-oxohexanoate) 40% yield. Yellow oil; ESI MS m/z 335.0 (M +
5-Hydroxy-1,7-bis-(3-hydroxy-4-methoxyphenyl)-hepta-1,4,6-
trien-3-one (16): (from 3-hydroxy-4-methoxybenzaldehyde and
2,4-pentanedione) 45% yield. mp 181-183 °C (lit.25 190-192 °C);
1
ESI-MS m/z 367.1 (M - 1)+; H NMR (300 MHz, CD3COCD3):
1
H)+; H NMR (300 MHz, CDCl3): δ 1.25 (3H, t, J ) 7.2 Hz),
δ 4.01 (6H, s), 6.01 (H, s), 6.66 (2H, d, J ) 15.6 Hz), 7.03 (2H,
d, J ) 8.1 Hz), 7.20 (2H, dd, J ) 2.1 Hz, J ) 8.1 Hz), 7.26 (2H,d,
J ) 2.1 Hz), 7.65 (2H, d, J ) 15.3 Hz).
2.18 (3H, s), 3.96 (3H, s), 4.13 (2H, quart, J ) 7.2 Hz), 5.97 (0.5H,
s), 6.67 (H, d, J ) 15.9 Hz), 6.94 (H, d, J ) 8.1 Hz), 7.06 (H, d,
J ) 1.8 Hz), 7.14 (H, dd, J ) 1.8 Hz, J ) 8.1 Hz), 7.63 (H, d, J
) 15.9 Hz). Anal. (C18H22O6‚7/4 H2O) C, H.
1,7-Bis-(2,4-dimethoxyphenyl)-5-hydroxy-hepta-1,4,6-trien-3-
one (17): (from 2,4-dimethoxybenzaldehyde and 2,4-pentanedione)
48% yield. mp 135-137 °C; ESI-MS m/z 367.1 (M + 1)+; 1H
NMR (300 MHz, CD3COCD3): δ 3.87 (12H, s), 5.81 (H, s), 6.46
(2H,d, J ) 2.4 Hz), 6.52 (2H, dd, J ) 2.4 Hz, J ) 8.7 Hz), 6.63
(2H, d, J ) 15.6 Hz), 7.49 (2H, d, J ) 8.7 Hz), 7.90 (2H, d, J )
15.9 Hz). Anal. (C23H24O6‚1/4H2O) C, H.
5-Hydroxy-1,7-bis-(2,3,4-trimethoxyphenyl)-hepta-1,4,6-trien-
3-one (18): (from 2,3,4-trimethoxybenzaldehyde and 2,4-pentanedi-
one) 30% yield. mp 108-109 °C; ESI MS m/z 457.2 (M + H)+;
1H NMR (300 MHz, CDCl3): δ 3.89 (6H, s), 3.90 (6H, s), 3.94
(6H, s), 5.83 (H, s), 6.64 (2H, d, J ) 15.9 Hz), 6.71 (2H, d, J )
9 Hz), 7.31 (2H, d, J ) 8.7 Hz), 7.85 (2H,d, J ) 16.2 Hz). Anal.
(C25H28O8) C, H.
5-Hydroxy-1,7-bis-(5-hydroxymethyl-furan-2-yl)-hepta-1,4,6-
trien-3-one (12). 2,4-Pentanedione (0.2 mL, 2 mmol) and boric
anhydride (100 mg, 1.4 mmol) were dissolved in 15 mL of EtOAc.
The solution was stirred at 70 °C for 0.5 h. 5-Hydroxymethyl-2-
furaldehyde (506 mg, 4 mmol) and tributyl borate (1.08 mL, 4
mmol) were added. After stirring for 30 min, butylamine (0.3 mL,
3 mmol) dissolved in 4 mL of EtOAc was added dropwise over 15
min. The stirring continued for 5 h at 85 °C. The mixture was then
hydrolyzed by adding 8 mL of 1 N HCl and stirring for 0.5 h at 60
°C. The organic layer was separated, and the aqueous layer was
extracted with EtOAc. The combined organic layers were washed
until neutral and dried over anhydrous sodium sulfate. The solvent
was removed in vacuo, and the crude product was purified by
CombiFlash column chromatography eluting with hexanes-EtOAc
to give 68 mg of red powder, obtained in 12% yield. mp 129-130
5-Hydroxy-1,7-bis-(2,4,5-trimethoxyphenyl)-hepta-1,4,6-trien-
3-one (19): (from 2,4,5-trimethoxybenzaldehyde and 2,4-pen-
tanedione) 28% yield, mp 140-142 °C; ESI MS m/z 457.2 (M +
1
°C; ESI MS m/z 339.2 (M + Na)+; H NMR (300 MHz, CDCl3):
1
δ 4.67 (4H, s), 5.74 (H, s), 6.40 (2H, d, J ) 3.3 Hz), 6.53 (2H, d,
J ) 15.3 Hz), 6.58 (2H, d, J ) 3.3 Hz), 7.43 (2H, d, J ) 15.6 Hz).
Anal. (C17H16O6) C, H.
H)+; H NMR (300 MHz, CDCl3): δ 3.88 (6H, s), 3.89 (6H, s),
3.94 (6H, s), 5.86 (H, s), 5.57 (2H, d, J ) 15.9 Hz), 6.51 (2H, s),
7.06 (2H, s), 7.95 (2H, d, J ) 15.9 Hz). Anal. (C25H28O8) C, H.
5-Hydroxy-7-[3-methoxy-4-(tetrahydropyran-2-yloxy)-phen-
yl]-4-{3-[3-methoxy-4-(tetrahydropyran-2-yloxy)-phenyl]-acryl-
oyl}-hepta-4,6-dienoic acid ethyl ester (20): Yellow powder, 59%
yield, mp 60-61 °C; ESI MS m/z 635.2 (M - 1)+; 1H NMR (300
MHz, CDCl3): δ 1.25 (3H, t), 1.57-2.17 (12H, m), 2.96 (0.57H,
t), 3.62 (4H, t), 3.91 (6H, s), 4.13 (2H, q), 5.47 (2H, t), 6.72 (2H,
d, J ) 15.6 Hz), 6.90-7.18 (6H, m), 7.44 (2H, d, J ) 15.6 Hz);
Anal. (C30H32O8) C, H.
Preparation of Heterocycle-Containing Curcumin Analogues
13-15. Compound 5 and boric anhydride (0.7 equiv.) dissolved in
EtOAc were stirred at 70 °C for 0.5 h. The appropriate benzaldehyde
(1 equiv) and tributyl borate (2 equiv) were added, and the mixture
was stirred for 0.5 h. Piperidine dissolved in EtOAc was added
dropwise. After increasing the temperature to 100 °C, stirring was
continued for 1 h. The mixture was then hydrolyzed by adding 1
N HCl and stirring at 60 °C for 0.5 h. The organic layer was
separated, and the aqueous layer was extracted with EtOAc three
times. The combined organic layers were washed with water until
neutral. The solvent was removed in vacuo. The crude products
were purified by flash column chromatography eluting with
hexanes-EtOAc.
5-Hydroxy-1,7-bis-[3-methoxy-4-(tetrahydropyran-2-yloxy)-
phenyl]-hepta-1,4,6-trien-3-one (21): Yellow powder; 67% yield,
mp 67-69 °C; ESI MS m/z 535.0 (M - 1)+; 1H NMR (300 MHz,
CDCl3): δ 1.57-2.17 (12H, m), 3.62 (4H, t), 3.91 (6H, s), 5.47
(2H, t), 5.83 (1H, s), 6.50 (2H, d, J ) 15.9 Hz), 7.09-7.16 (6H,
m), 7.60 (2H, d, J ) 15.9 Hz); Anal. (C31H36O8‚H2O) C, H.
1,7-Bis-(4-ethoxy-3-methoxyphenyl)-5-hydroxy-hepta-1,4,6-
trien-3-one (22): (from 4-ethoxy-3-methoxybenzaldehyde and 2,4-
pentanedione) 31% yield, mp 139-140°C (lit.26 102 °C); ESI-MS
5-Hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-(5-hydroxy-
methyl-furan-2-yl)-hepta-1,4,6-trien-3-one (13): (from 5-hy-
droxymethyl-2-furaldehyde) 32% yield. mp 140-142 °C; ESI MS
1
m/z 343.3 (M + H)+, 366.2 (M + Na)+; H NMR (300 MHz,
1
CDCl3): δ 3.90 (3H, s), 4.64 (2H, s), 5.71 (H, s), 6.36 (H, d, J )
2.7 Hz), 6.43 (H, d, J ) 7.5 Hz), 6.47 (H, d, J ) 7.2 Hz), 6.53
(2H, d, J ) 3.0 Hz), 6.90 (H, d, J ) 8.1 Hz), 7.01 (H, s), 7.08 (H,
d, J ) 7.5 Hz), 7.33 (H, d, ) 15.3 Hz), 7.55 (H, d, J ) 15.6 Hz).
Anal. (C19H18O6) C, H.
m/z 425.1 (M + 1)+; H NMR (300 MHz, CDCl3): δ1.49 (6H, t,
J ) 7.2 Hz), 3.93 (6H, s), 4.15 (4H, quart, J ) 8.4 Hz), 5.82 (H,
s), 6.49 (2H, d, J ) 15.6 Hz), 6.88 (2H, d, J ) 8.1 Hz), 7.08 (2H,d,
J ) 2.1 Hz), 7.14 (2H, dd, J ) 2.1 Hz, J ) 8.1 Hz), 7.61 (2H, d,
J ) 15.6 Hz).

Curcumin Analogues
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 13 3969
3-Methoxy-4-(3-methyl-but-2-enyloxy)-benzaldehyde. Vanillin
(1.52 g, 10 mmol) and anhydrous potassium carbonate (1.38 g, 10
mmol) were dissolved in dry acetone (20 mL). 1-Bromo-3-methyl-
but-2-ene (3.0 mL) was then added to the solution, and stirring
continued for 12 h. The solvent was evaporated in a vacuum, and
the resulting solid was extracted with CH2Cl2 three times. The CH2-
Cl2 solution was washed with water and dried over anhydrous
sodium sulfate. The organic solvent was removed in a vacuum. A
colorless liquid (418 mg) was obtained by flash column chroma-
tography eluting with a gradient hexanes-EtOAc solvent. 1H NMR
(300 MHz, CDCl3): δ1.76 (3H, s), 1.80 (3H, s), 3.94 (3H, s), 4.68
(2H, d, J ) 6.6 Hz), 5.52 (H, t, J ) 6.6 Hz), 6.98 (H, d, J ) 8.4
Hz), 7.41 (H,d, J ) 2.1 Hz), 7.44 (H, dd, J ) 2.1 Hz, J ) 8.4 Hz),
9.85 (H, s).
1-(3,4-Dimethoxyphenyl)-5-hydroxy-7-(2,4,5-trimethoxyphen-
yl)-hepta-1,4,6-trien-3-one (30): (from 6 and 2,4,5-trimethoxy-
benzaldehyde) 48% yield, mp 128-129 °C; ESI-MS m/z 427.2 (M
1
+ H)+, 449.3 (M + Na)+; H NMR (300 MHz, CDCl3): δ 3.89
(3H, s), 3.90 (3H, s), 3.93 (3H, s), 3.94 (3H, s), 3.95 (3H, s), 5.84
(H, s), 6.50 (H, d, J ) 15.6 Hz), 6.51 (H, s), 6.57 (H, d, J ) 16.2
Hz), 6.88 (H, d, J ) 8.1 Hz), 7.06 (H, s), 7.08 (H, d, J ) 2.1 Hz),
7.14 (H, dd, J ) 2.1 Hz, J ) 8.1 Hz), 7.60 (H, d, J ) 15.9 Hz),
7.96 (H, d, J ) 15.9 Hz). Anal. (C24H26O7‚1/4H2O) C, H.
4-[3-(3,4-Dimethoxyphenyl)-acryloyl]-7-(4-hydroxy-3-meth-
oxyphenyl)-5-oxo-hept-6-enoic acid ethyl ester (31): (from 11
and 3,4-dimethoxybenzaldehyde) 38% yield, mp 67-68 °C; ESI-
1
MS m/z 483.4 (M + H)+; H NMR (300 MHz, CDCl3): δ 1.25
(3H, t, J ) 7.2 Hz), 2.32-2.37 (2H, m), 2.55 (2H, t, J ) 7.8 Hz),
2.95 (0.5H, t, J ) 7.8 Hz), 3.91-3.97 (9H, m), 4.14 (2H, q, J )
7.2 Hz), 6.70 (H, dd, J ) 4.2 Hz, J ) 15.6 Hz), 6.84-7.19 (7H,
m), 7.62-7.76 (2H, m); Anal. (C27H30O8‚1/4H2O) C, H.
5-Hydroxy-1,7-bis-[3-methoxy-4-(3-methyl-but-2-enyloxy)-
phenyl]-hepta-1,4,6-trien-3-one (23): (from 3-methoxy-4-(3-
methyl-but-2-enyloxy)-benzaldehyde and 2,4-pentanedione) 25%
1
yield, mp 124-125°C; ESI MS m/z 527.2 (M + Na)+; H NMR
Preparation of 32, 33, and 34. To a solution of acetone (0.36
mL, 5 mmol) and the appropriate benzaldehyde (10 mmol) in 50
mL of a 0.25 M solution of aqueous NaOH was added 1.5 mL of
a 25% w/w aqueous solution of cetyltrimethylammonium bromide.
The mixture was allowed to stir vigorously at room temperature
for 20 h, diluted with brine, and extracted with EtOAc. The EtOAc
solution was concentrated and then subjected to column chroma-
tography to obtain the target product.
(300 MHz, CDCl3): δ1.75 (6H, s), 1.79 (6H, s), 3.92 (6H, s), 4.63
(4H, d, J ) 6.6 Hz), 5.52 (2H, t, J ) 6.6 Hz), 5.82 (H, s), 6.50
(2H, d, J ) 15.6 Hz), 6.88 (2H, d, J ) 8.4 Hz), 7.08 (2H,d, J )
1.8 Hz), 7.12 (2H, dd, J ) 1.8 Hz, J ) 8.4 Hz), 7.61 (2H, d, J )
15.9 Hz). Anal. (C31H36O6) C, H.
5-Hydroxy-1,7-bis-(4-hydroxy-3,5-dimethoxyphenyl)-hepta-
1,4,6-trien-3-one (24): (from 4-hydroxy-3,5-dimethoxybenzalde-
hyde and 2,4-pentanedione) 17% yield, mp 198-199 °C (lit.27 188-
1,5-Bis-(4-hydroxy-3-methoxyphenyl)-penta-1,4-dien-3-one (32):
50% yield. mp 83-84 °C (lit.25 84-86 °C); ESI MS m/z 327.3 (M
+ H)+; 1H NMR (300 MHz, CDCl3): δ 3.94 (6H, s), 6.90 (2H, d,
J ) 8.4 Hz), 6.95 (2H, d, J ) 15.6 Hz), 7.11 (2H, d, J ) 1.8 Hz),
7.20 (2H, dd, J ) 1.8 Hz, J ) 8.4 Hz), 7.68 (2H,d, J ) 15.6 Hz).
1,5-Bis-(3,4-dimethoxyphenyl)-penta-1,4-dien-3-one (33): Bright
yellow powder. 76% yield; mp 74-75 °C (lit.25 72-75 °C); ESI-
1
190 °C); ESI MS m/z 451.2 (M + Na)+; H NMR (300 MHz,
CDCl3): δ 3.94 (6H, s), 5.80 (H, s), 6.49 (2H, d, J ) 15.3 Hz),
6.80 (4H, s), 7.58 (2H, d, J ) 15.3 Hz).
5-Hydroxy-1,7-bis-(4-hydroxy-3-methylphenyl)-hepta-1,4,6-
trien-3-one (25): (from 4-hydroxy-3-methylbenzaldehyde and 2,4-
pentanedione) 52% yield, mp 217-218 °C; ESI MS m/z 337.2 (M
1
+ 1)+; H NMR (300 MHz, CDCl3): δ 2.26 (6H, s), 5.81 (H, s),
1
MS m/z 355.2 (M + H)+; H NMR (300 MHz, CDCl3): δ 3.94
6.50 (2H, d, J ) 15.9 Hz), 6.86 (2H, d, J ) 8.4 Hz), 7.27 (2H,d,
J ) 8.4 Hz), 7.36 (2H, s), 7.58 (2H, d, J ) 15.9 Hz). Anal.
(C21H20O4‚1/4H2O) C, H.
(6H, s), 3.96 (6H, s), 6.90 (2H, d, J ) 8.4 Hz), 6.95 (2H, d, J )
15.9 Hz), 7.15 (2H, d, J ) 1.8 Hz), 7.20 (2H, dd, J ) 1.8 Hz, J )
8.4 Hz), 7.69 (2H,d, J ) 15.9 Hz).
5-Hydroxy-1,7-bis-(4-methoxy-3-methylphenyl)-hepta-1,4,6-
trien-3-one (26): (from 4-methoxy-3-methylbenzaldehyde and 2,4-
pentanedione) 55% yield, mp 131-132 °C; ESI MS m/z 365.1 (M
+ 1)+; 1H NMR (300 MHz, CDCl3): δ 2.24 (6H, s), 3.87 (6H, s),
5.78 (H, s), 6.49 (2H, d, J ) 15.6 Hz), 6.83 (2H, d, J ) 8.7 Hz),
7.37 (2H,d, J ) 8.7 Hz), 7.38 (2H, s), 7.60 (2H, d, J ) 15.6 Hz).
Anal. (C23H24O4‚1/8H2O) C, H.
1,5-Bis-(2,4-dimethoxyphenyl)-penta-1,4-dien-3-one (34): Yel-
low powder. 85% yield; mp 130-132 °C (lit.25 138-140 °C); ESI-
1
MS m/z 355.2 (M + H)+; H NMR (300 MHz, CDCl3): δ 3.86
(3H, s), 3.90 (3H, s), 6.47 (2H, d, J ) 2.4 Hz), 6.53 (2H, dd, J )
2.4 Hz, J ) 8.4 Hz), 7.09 (2H, d, J ) 15.9 Hz), 7.57 (2H, d, J )
8.4 Hz), 7.69 (2H,d, J ) 15.9 Hz).
Preparation of 35 and 36. Compounds 35 and 36 were prepared
from 4-hydroxy-3-methoxy-cinnamaldehyde by using the same
procedure described above for 12 from 2,4-pentanedione and
5-hydroxymethyl-2-furaldehyde.
Preparation of Asymmetric Curcumin Analogues 27-31. By
using the same procedure described above for 13-15 from 5,
compounds 27-30 were prepared from 6, and 31 from 11.
1-(3,4-Dimethoxyphenyl)-5-hydroxy-7-(4-hydroxy-3-methoxy-
phenyl)-hepta-1,4,6-trien-3-one (27): (from 6 and vanillin) 55%
yield, mp 83-84 °C (lit.17 89-91 °C); ESI-MS m/z 381.1 (M -
7-Hydroxy-1,11-bis-(4-hydroxy-3-methoxyphenyl)-undeca-
1,3,6,8,10-pentaen-5-one (35): (from 4-hydroxy-3-methoxy-cin-
namaldehyde and 2,4-pentanedione) 15% yield; mp 162-164 °C;
1
1)+; H NMR (300 MHz, CDCl3): δ 3.94 (9H, s), 5.81 (H, s),
1
ESI-MS m/z 421.4 (M + 1)+; H NMR (300 MHz, CDCl3): δ
6.48 (2H, d, J ) 15.6 Hz), 6.87-7.14 (6H, m), 7.60 (2H, d, J )
3.95 (6H, s), 5.78 (H, s), 6.13 (2H, d, J ) 15.6 Hz), 6.78-7.04
(10H, m), 7.41 (H, d, J ) 15.0 Hz), 7.44 (H, d, J ) 15.3 Hz).
Anal. (C25H24O6) C, H.
15.6 Hz).
7-(3,4-Dimethoxyphenyl)-5-hydroxy-1-(3-hydroxy-4-methoxy-
phenyl)-hepta-1,4,6-trien-3-one (28): (from 6 and 3-hydroxy-4-
methoxybenzaldehyde) 45% yield, mp 157-158 °C; ESI-MS m/z
405.3 (M + Na)+; 1H NMR (300 MHz, CDCl3): δ 3.93 (3H, s),
3.94 (6H, s), 5.80 (H, s), 6.48 (H, d, J ) 16.2 Hz), 6.51 (H, d, J )
15.9 Hz), 6.86 (H, d, J ) 8.4 Hz), 6.89 (H, d, J ) 8.4 Hz), 7.06
(H, dd, J ) 8.4 Hz, J ) 1.8 Hz), 7.09 (H, d, J ) 1.8 Hz), 7.15 (H,
dd, J ) 8.4 Hz, J ) 1.8 Hz), 7.18 (H, d, J ) 1.8 Hz), 7.58 (H, d,
J ) 15.9 Hz), 7.61 (2H, d, J ) 15.6 Hz).
5-Hydroxy-9-(4-hydroxy-3-methoxyphenyl)-4-[5-(4-hydroxy-
3-methoxyphenyl)-penta-2,4-dienoyl]-nona-4,6,8-trienoic acid
ethyl ester (36): (from 4-hydroxy-3-methoxy-cinnamaldehyde and
ethyl 4-acetyl-5-oxohexanoate) 22% yield; mp 143-144 °C; ESI-
1
MS 519.3 (M - 1)-; H NMR (300 MHz, CD3COCD3): δ 1.24
(3H, t, J ) 7.2 Hz), 2.80-2.86 (4H, m), 3.89 (6H, s), 4.11 (2H,
quart, J ) 7.2 Hz), 6.78 (2H,d, J ) 14.4 Hz), 6.85 (2H, d, J ) 8.1
Hz), 7.02 (2H, d, J ) 15.0 Hz), 7.07 (2H, dd, J ) 1.8 Hz, J ) 8.1
Hz), 7.26 (2H, d, J ) 1.8 Hz), 7.52 (H, d, J ) 15.0 Hz), 7.55 (H,
d, J ) 14.4 Hz). Anal. (C30H16O4‚3/8H2O) C, H.
1-(3,4-Dimethoxyphenyl)-5-hydroxy-7-(2,3,4-trimethoxyphen-
yl)-hepta-1,4,6-trien-3-one (29): (from 6 and 2,3,4-trimethoxy-
benzaldehyde) 55% yield, mp 138-139 °C; ESI-MS m/z 427.2 (M
1
+ H)+, 449.3 (M + Na)+; H NMR (300 MHz, CDCl3): δ 3.89
1,7-Bis-(3,4-dimethoxyphenyl)-5-hydroxy-heptan-3-one (37).
Dimethylcurcumin (2) (80 mg, 0.2 mmol) was dissolved in 3 mL
of EtOAc. 10% Pd/C (80 mg) was added to the solution. After
hydrogenation for 24 h at 45 psi, the solution was filtered, and the
filtrate was concentrated. Flash column chromatography (hexane/
EA) 2:1) afforded white product in 25% yield. mp 93-94 °C (lit.17
(3H, s), 3.91 (3H, s), 3.93 (3H, s), 3.94 (6H, s), 5.83 (H, s), 6.51
(H, d, J ) 15.9 Hz), 6.63 (H, d, J ) 15.9 Hz), 6.71 (H, d, J ) 8.7
Hz), 6.89 (H, d, J ) 8.4 Hz), 7.09 (H, d, J ) 2.1 Hz), 7.15 (H, dd,
J ) 1.8 Hz, J ) 8.7 Hz), 7.31 (H, d, J ) 8.7 Hz), 7.61 (H, d, J )
15.9 Hz), 7.85 (H, d, J ) 16.2 Hz). Anal. (C24H26O7‚1/2H2O) C,
H.
1
94-95 °C). ESI-MS m/z 425.1 (M + Na)+; H NMR (300 MHz,

3970 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 13
Lin et al.
CDCl3): δ 1.61-1.85 (2H, m), 2.56-2.87 (8H, m), 3.85 (6H, s),
3.86 (6H, s), 4.07 (H, m), 6.69-6.90 (6H, m).
The preparation of compounds 4, 40-45, 47, and 48 was reported
by us in a recent publication.18
7-(3,4-Dimethoxyphenyl)-4-[3-(3,-dimethoxyphenyl)-acryloyl]-
3,4-Dimethoxycinnamone. 3,4-Dimethoxybenzaldehyde (1.5 g,
9 mmol) was dissolved in 10 mL of acetone. After 10 mL of sodium
hydroxide solution (0.5 g NaOH in 10 mL of H2O) was added, the
mixture was stirred for 24 h. Then the excess acetone was removed
in vacuo. Upon acidification with 1 N HCl, a green precipitate was
obtained. The precipitate was extracted with EtOAc. The organic
layer was dried over sodium sulfate and solvent removed in vacuo.
Flash column chromatography gave the desired product (1.5 g in
5-hydroxy-hepta-2,4,6-trienoic acid ethyl ester (4): Red powder,
1
54% yield; mp 170-171 °C; ESI MS m/z 494.6 (M + H)+; H
NMR (300 MHz, CDCl3): δ 1.34 (3H, t), 3.95 (12H, s), 4.29 (2H,
quart), 5.98 (2H, d, J ) 15.6 Hz), 6.95 (2H, d, J ) 8.4 Hz), 7.00
(1H, d, J ) 15.6 Hz), 7.08 (2H, d, J ) 1.8 Hz), 7.22 (2H, dd, J )
8.4 Hz, J ) 1.8 Hz), 7.77 (2H, d, J ) 15.3 Hz), 7.91 (1H, d, J )
15.6 Hz). Anal. (C28H30O8‚1/4H2O) C, H.
1
5-Hydroxy-7-[3-methoxy-4-(tetrahydropyran-2-yloxy)-phen-
yl]-4-{3-[3-methoxy-4-(tetrahydropyran-2-yloxy)-phenyl]-acryl-
oyl}-hepta-2,4,6-trienoic acid ethyl ester (40): Orange powder;
81% yield). H NMR (300 MHz, CD3COCD3): δ 2.27 (3H, s),
3.87 (6H, s), 6.67 (H, d, J ) 16.2 Hz), 7.00 (H, d, J ) 8.1 Hz),
7.04 (H, d, J ) 0.9 Hz), 7.22 (H, dd, J ) 2.1 Hz, J ) 8.1 Hz),
7.32 (H, d, J ) 2.1 Hz), 7.55 (H, d, J ) 16.2 Hz).
1
62% yield; mp 72-73 °C; ESI MS m/z 634.7 M+; H NMR (300
MHz, CDCl3): δ 1.34 (3H, t), 1.5-2.2 (12H, m), 3.62 (4H, t),
3.92 (6H, s), 4.28 (2H, q), 5.49 (2H, t) 5.96 (H, d, J ) 15.6 Hz),
7.00 (2H, d, J ) 15.6 Hz), 7.08-7. 16 (6H, m), 7.76 (2H, d, J )
15.3 Hz), 7.83 (H, d, J ) 15.9 Hz); Anal. (C36H42O10) C, H.
3, 4-Dimethoxycinnamaldehyde. To a solution of acetaldehyde
(0.84 mL, 15 mmol) in EtOH (10 mL) was added 3 M NaOH (5
mL, 15 mmol) at 0 °C. The solution was stirred for an additional
20 min. After 3, 4-dimethoxybenzaldehyde (2.5 g, 15 mmol) in
EtOH (5 mL) was added to the stirring solution dropwise, the
reaction was brought to room temperature and stirred for 2 h. Then
the mixture was poured into water and adjusted to pH 7 by adding
1 N HCl. After extraction with EtOAc, the organic layer was washed
with water three times and dried over anhydrous sodium sulfate.
After removal of the solvent under vacuum, the crude product was
purified with flash column chromatography. Pale yellow product
(1.1 g) was obtained in 38% yield.1H NMR (300 MHz, CDCl3): δ
3.93 (3H, s), 3.94 (3H, s), 6.62 (H, dd, J ) 7.8 Hz, J ) 16.2 Hz),
6.91 (H, d, J ) 8.1 Hz), 7.08 (H, d, J ) 2.1 Hz), 7.17 (H, dd, J )
1.8 Hz, J ) 8.1 Hz), 7.42 (H, d, J ) 15.9 Hz), 9.67 (H, d, J ) 7.8
Hz).
5-Hydroxy-7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-
3-methoxyphenyl)-acryloyl]-hepta-2,4,6-trienoic acid ethyl ester
(41): Orange powder, 93% yield; mp 106-106.5 °C; ESI MS m/z
1
465.2 (M - 1)+; H NMR (300 MHz, CDCl3): δ 1.34 (3H, t),
3.95 (6H, s), 4.29 (2H, quart), 5.96 (2H, d, J ) 15.6 Hz), 6.95
(2H, d, J ) 8.2 Hz), 6.96 (1H, d, J ) 15.6 Hz), 7.05 (2H, d, J )
2.1 Hz), 7.17 (2H, dd, J ) 8.2 Hz, J ) 2.1 Hz), 7.75 (2H, d, J )
15.3 Hz), 7.90 (1H, d, J ) 15.9 Hz). Anal. (C26H26O8‚11/8H2O)
C, H.
7-(3,4-Dimethoxyphenyl)-4-[3-(3,4-dimethoxyphenyl)-acryloyl]-
5-hydroxy-hepta-2,4,6-trienoic acid methyl ester (42): Orange
powder; 50% yield; mp 167-168 °C; ESI MS m/z 481.6 (M +
1
H)+; H NMR (300 MHz, CDCl3): δ 3.82 (3H, s), 3.93 (12H, s),
5.98 (H, d, J ) 15.6 Hz), 6.90 (2H, d, J ) 8.4 Hz), 6.98 (2H, d,
J ) 15.6 Hz), 7.07 (2H, d, J ) 1.8 Hz), 7. 20 (2H, dd, J ) 8.4 Hz,
J ) 1.8 Hz), 7.76 (2H, d, J ) 15.6 Hz), 7.90 (H, d, J ) 15.9 Hz);
Anal. (C27H28O8‚1/4H2O) C, H.
1,7-Bis-(3,4-dimethoxyphenyl)-5-hydroxy-hepta-1,6-dien-3-
one (38). To a stirring solution of lithium diisopropylamine (0.29
mL, 0.58 mmol) in THF (3 mL) was added a THF (3 mL) solution
of 3, 4-dimethoxycinnamone (100 mg, 0.48 mmol) at -78 °C. After
15 min, 3,4-dimethoxycinnamaldehyde (85 mg, 0.44 mmol) in THF
(3 mL) was added. After stirring for an additional 20 min at -78
°C, the mixture was quenched with saturated NH4Cl solution. The
solution was allowed to warm to ambient temperature and extracted
with EtOAc. The organic layer was washed with water and saturated
NaCl solution and dried over anhydrous sodium sulfate. The crude
product was purified by flash column chromatography to give 22
mg of pure product in13% yield. mp 88-89 °C; ESI MS m/z 399.3
7-(3,4-Dimethoxyphenyl)-4-[3-(3,4-dimethoxyphenyl)-acryloyl]-
5-hydroxy-hepta-2,4,6-trienoic acid ethylamide (43): Yellow
powder, 16% yield; mp 219-221 °C; ESI MS m/z 516.2 (M +
1
Na)+; H NMR (300 MHz, CDCl3): δ 1.32 (3H, t), 3.92 (6H, s),
3.92 (6H, s), 4.00 (2H, quart), 5.85 (H, d, J ) 15.3 Hz), 6.88 (2H,
d, J ) 8.4 Hz), 6.95 (2H, d, J ) 15.6 Hz), 7.06 (2H, d, J ) 1.5
Hz), 7.18 (2H, dd, J ) 8.4 Hz, J ) 1.5 Hz), 7.73 (2H, d, J ) 15.6
Hz), 7.82 (H, d, J ) 15.3 Hz); Anal. (C28H31NO7‚3/2H2O) C, H.
1
(M + H)+; H NMR (300 MHz, CDCl3): δ 2.93 (2H, d), 3.80
7-(3,4-Dimethoxyphenyl)-4-[3-(3,4-dimethoxyphenyl)-acryloyl]-
5-hydroxy-hepta-2,4,6-trienenitrile (44): 19% yield; mp 204-
205 °C; ESI MS m/z 448.3 (M + H)+; 1H NMR (300 MHz,
DMSO): δ 3.70 (3H, s), 3.75 (3H, s), 3.79 (3H, s), 3.80 (3H, s),
6.32 (H, d, J ) 9.6 Hz), 6.99 (2H, dd, J ) 8.4 Hz, J ) 1.5 Hz),
(2H, d, J ) 15.6 Hz), (2H, d, J ) 1.8 Hz), (2H, dd, J ) 8.4 Hz, J
) 1.8 Hz), (2H, d, J ) 15.6 Hz), (H, d, J ) 15.9 Hz); Anal. (C26H25-
NO6‚9/4H2O) C, H.
(6H, s), 3.85 (6H, s), 4.13 (H, d), 6.25 (H, dd, J ) 6 Hz, J ) 15.9
Hz), 6.58 (H, d, J ) 15.9 Hz), 6.80 (H, d, J ) 16.2 Hz), 6.88 (H,
d, J ) 8.7 Hz), 6.90 (H, dd, J ) 0.9 Hz, J ) 8.7 Hz), 7.00 (H, d,
J ) 8.4 Hz), 7.04 (H, d, J ) 0.9 Hz), 7.25 (H, dd, J ) 0.9 Hz, J
) 8.7 Hz), 7.34 (H, d, J ) 0.9 Hz), 7.61 (1H, d, J ) 16.2 Hz).
Anal. (C23H26O6) C, H.
3-(3,4-Dimethoxyphenyl)-N-[3-(3,4-dimethoxyphenyl)-acryloyl]-
acrylamide (39). 3,4-Dimethoxycinnamic acid (624 mg, 3 mmol)
was dissolved in 15 mL of dry methylene chloride. Thionyl chloride
(0.3 mL, 3.6 mmol) was added at 0 °C. The solution was stirred
under reflux for 5 h. The solvent was removed under vacuum to
give a yellow solid. In the same flask, 10 mL of anhydrous THF
was added, and the mixture was heated to reflux. HMDA (0.3 mL)
was added very slowly to the refluxing solution, followed by the
addition of triethylamine (0.4 mL). The solution was stirred under
reflux overnight. The solvent was then removed in vacuo. The solid
was extracted with CH2Cl2 three times. The combined CH2Cl2
solution was washed with water three times and brine once and
then dried over anhydrous sodium sulfate. The crude product was
obtained after flash column chromatography. 78 mg (13% yield),
pale yellow powder. mp 220-221 °C; ESI MS m/z 420.2 (M +
Na)+; 1H NMR (300 MHz, DMSO): δ 3.82 (12H, s), 7.04 (2H, d,
J ) 8.7 Hz), 7.10 (2H, d, J ) 15.9 Hz), 7.23 (2H, s), 7.24 (2H, d,
J ) 8.7 Hz), 7.66 (2H,d, J ) 15.9 Hz), 10.51 (0.5 H, s). Anal.
(C22H23NO6‚3/2H2O) C, H; N: 2.61.
1,7-Bis-(3,4-dimethoxyphenyl)-5-hydroxy-4-(3-hydroxypro-
penyl)-hepta-1,4,6-trien-3-one (45): Red powder. 19% yield; mp
178-179 °C; ESI MS m/z 453.2 (M + Na)+; 1H NMR (300 MHz,
CDCl3): δ 3.92 (6H, s), 3.93 (6H, s), 4.40 (2H, d, J ) 4.5 Hz),
5.30 (0.4 H, s), 5.88 (H, triplet of doublet, J ) 15.6 Hz, J ) 4.5
Hz), 6.59 (H, d, J ) 15.6 Hz), 6.88 (2H, d, J ) 8.4 Hz), 6.97 (2H,
d, J ) 15.6 Hz), 7.06 (2H, d, J ) 1.8 Hz), 7.17 (2H, dd, J ) 8.4
Hz, J ) 1.8 Hz), 7.68 (2H, d, J ) 15.6 Hz); Anal. (C26H28O7‚3/
4H2O) C, H.
3-[1-Hydroxy-3-(4-hydroxy-3-methoxyphenyl)-allylidene]-6-
(4-hydroxy-3-methoxy-phenyl)-hex-5-ene-2,4-dione (46): Com-
pound 46 was obtained from vanillin and triacetylmethane by using
the same procedure described above for 12 from 5-hydroxymethyl-
2-furaldehyde and 2,4-pentanedione. 8% yield; mp 162-164 °C;
1
ESI MS m/z 433.2 (M + Na)+; H NMR (300 MHz, CDCl3): δ
2.17 (3H, s), 3.94 (6H, s), 5.80 (H, s), 6.48 (2H, d, J ) 15.6 Hz),
6.94 (2H, d, J ) 8.1 Hz), 7.05 (2H,d, J ) 1.8 Hz), 7.13 (2H, dd,
J ) 1.8 Hz, J ) 8.1 Hz), 7.59 (2H, d, J ) 15.6 Hz). Anal.
(C23H22O7) C, H.

Curcumin Analogues
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 13 3971
4-Fluoro-7-[3-methoxy-4-(tetrahydropyran-2-yloxy)-phenyl]-
4-{3-[3-methoxy-4-(tetrahydropyran-2-yloxy)-phenyl]-acryloyl}-
5-oxo-hept-6-enoic acid ethyl ester (47): 13% yield; mp 59-60
°C; EIMS m/z 677.3 (M + Na)+, 655.3 (M + H)+; 1H NMR (300
MHz, CDCl3): δ 1.25 (3H, t), 1.5-2.1 (12H, m), 2.45 (2H, m),
2.65 (2H, m), 3.62 (4H, t), 3.90 (6H, s), 4.13 (2H, q), 5.49 (2H, t),
7.06 (2H, dd, J ) 3 Hz, J ) 15.6 Hz), 7.12-7.15 (6H, m), 7.75
(2H, d, J ) 15.6 Hz); Anal. (C36H44FO10) C, H.
for another 24 h. The cells were harvested for luciferase activity
assay using Dual Luciferase Assay System (Promega, Madison,
WI). The derived data were expressed as relative luciferase activity
normalized to the internal luciferase control. Cells cultured in
medium containing DHT (androgen), as a positive control, induced
a marked reporter gene expression. Test compounds capable of
significantly suppressing this DHT-induced reporter gene expression
were identified as potential antiandrogens.
4-Fluoro-7-(4-hydroxy-3-methoxyphenyl)-4-[3-(4-hydroxy-3-
methoxyphenyl)-acryloyl]-5-oxo-hept-6-enoic acid ethyl ester
(48): 97% yield; mp 63-63.5 °C; EIMS m/z 509.3 (M + Na)+,
Acknowledgment. This work was supported by National
Cancer Institute Grant CA-17625 awarded to K. H. Lee.
1
487.3 (M + H)+; H NMR (300 MHz, CDCl3): δ 1.25 (3H, t),
Supporting Information Available: Results of the elemental
analysis of 4, 8-15, 17, 19-21, 23, 25, 26, 29-31, 35, 36, 38-48,
and 50 are reported. This material is available free of charge via
the Internet at http://pubs.acs.org.
2.45 (2H, m), 2.65 (2H, m), 3.95 (6H, s), 6.93 (2H, d, J ) 7.8 Hz),
7.06 (2H, dd, J ) 3 Hz, J ) 15.6 Hz), 7.09 (2H, d, J ) 1.8 Hz),
7.16 (2H, dd, J ) 1.8 Hz, J ) 7.8 Hz), 7.75 (2H, d, J ) 15.6 Hz);
Anal. (C26H27FO8‚3/4H2O) C, H.
1,7-Bis-(3,4-dimethoxyphenyl)-4-methyl-hepta-1,6-diene-3,5-
dione (49). Compound 49 was prepared from 3-methyl-2,4-
pentanedione and 3,4-dimethoxybenzaldehyde by using the same
procedure described above for 12 from 2,4-pentanedione and
5-hydroxymethyl-2-furaldehyde. 51% yield; mp 129-130 °C (lit.28
142-145 °C); ESI MS m/z 433.2 (M + Na)+; 1H NMR (300 MHz,
CDCl3): δ 2.19 (3H, s), 3.91 (3H, s), 3.93 (3H, s), 3.95 (3H, s),
6.89 (2H, d, J ) 8.1 Hz), 6.99 (2H, d, J ) 15.3 Hz), 7.10 (2H, d,
J ) 1.8 Hz), 7.19 (2H, dd, J ) 8.1 Hz, J ) 1.8 Hz), 7.70 (2H, d,
J ) 15.6 Hz).
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