Structure-activity relationship studies of curcumin analogues

Article abstract of DOI:10.1016/j.bmcl.2009.01.104

Two series of curcumin analogues, a total of twenty-four compounds, were synthesized and evaluated. The most potent compound, compound 23, showed potent growth inhibitory activities on both prostate and breast cancer lines with IC₅₀ values in sub-micromolar range, fifty times more potent than curcumin. Curcumin analogues might be potential anti-tumor agents for breast and prostate cancers.

Full text of DOI:10.1016/j.bmcl.2009.01.104

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2065–2069
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity relationship studies of curcumin analogues
James R. Fuchs a, Bulbul Pandit a, Deepak Bhasin a, Jonathan P. Etter a, Nicholas Regan a, Dalia Abdelhamid a,
Chenglong Li a, Jiayuh Lin b, Pui-Kai Li a,
*
a Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 338 Parks Hall, 500 West 12th Avenue, Columbus, OH 43210, USA
b Center for Childhood Cancer, Columbus Children’s Research Institute, Ohio State University, Columbus, OH 43205, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Two series of curcumin analogues, a total of twenty-four compounds, were synthesized and evaluated.
The most potent compound, compound 23, showed potent growth inhibitory activities on both prostate
and breast cancer lines with IC50 values in sub-micromolar range, fifty times more potent than curcumin.
Curcumin analogues might be potential anti-tumor agents for breast and prostate cancers.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 1 October 2008
Revised 28 January 2009
Accepted 29 January 2009
Available online 5 February 2009
Keywords:
Curcumin
Breast
Prostate Cancers
Curcumin, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadi-
en-3,5-dione (Fig. 1), is the primary bioactive compound isolated
from turmeric, the dietary spice made from the rhizome of Cur-
cuma longa. Turmeric has been a mainstay of traditional Indian folk
medicine, and it has been used for the treatment of many diseases
such as diabetes, liver disease, rheumatoid arthritis, atherosclero-
sis, infectious diseases and cancers. The therapeutic effects of cur-
cumin are attributed to its activity on a wide range of molecular
targets.
ural product (i.e., improve their selectivity, bioavailability, and
stability).5,20–29 The simple molecular scaffold of curcumin along
with the relative density of functional groups provides medicinal
chemists with an outstanding target for lead optimization and
structure–activity relationship (SAR) studies. Typical strategies
dramatically simplify the molecule into two (or three) distinct
functional elements: aromatic rings joined via olefin bonds to a
b-diketone (Fig. 2). The olefin double bonds, while acknowledged
to be important for activity, are generally only considered to be
a linker between the two key structural elements and have not
been widely modified. Instead, synthetic efforts have primarily
been directed at variation of the aromatic rings and their
substituents.
In our continuing efforts toward the design of anti-tumor agents
for the treatment of both prostate and breast cancers, several series
of curcumin analogues (compounds 1–24) were synthesized and
evaluated to investigate their structure–activity relationships
(Fig. 3). Structurally, the compounds can be divided into two ser-
ies—(1) a heptadiendione series (compounds 1–13) and (2) a pen-
tadienone series (compounds 14–24).
The synthesis of curcumin, compounds 1–4, 6, and 10 were car-
ried out using 2,4-pentanedione and commercially available benz-
aldehydes according to the procedure of Venkateswarlu (Fig. 4).26
Compounds 12 and 13 were obtained by treating curcumin with
hydrazine and N-methylhydrazine in acetic acid, respectively (Fig
5).23,24,30
The syntheses of compounds 14–19 and 23–24 were carried out
via condensation of acetone with the appropriately substituted
benzaldehydes under standard protic conditions31 (methods A
and B, Fig. 6).
One of the most important aspects of curcumin is its effective-
ness against various types of cancer with both chemopreventive
and chemotherapeutic properties.1,2 Unlike most chemotherapeu-
tic agents, curcumin is reported to show little to no toxicity (no
dose-limiting toxicity at doses up to 10 g/day in humans).3 Unfor-
tunately, the potential utility of curcumin is somewhat limited due
to poor bioavailability4 and poor selectivity. The lack of selectivity
is due to the numerous molecular targets with which curcumin is
known to interact. These include several targets closely associated
with cancer cell proliferation such as the transcription factors NF-
j
B,5 STATs,6,7 AP-18 and PPAR-g.9 Other targets include inflamma-
tory enzymes such as COX-2,10,11 lipoxygenases (LOX)12 and pro-
tein kinases which include EGFR, HER2/neu,13,14 MAPK15 and
AKT.16 In addition, proteins regulating the cell cycle and apoptosis
are also the targets of curcumin.17–19
Numerous analogues of curcumin have been synthesized and
tested to investigate their activity against known biological tar-
gets and to improve upon the pharmacological profile of the nat-
* Corresponding author. Tel.: +1 614 688 0253; fax: +1 614 688 8556.
E-mail address: li.27@osu.edu (P.-K. Li).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.01.104

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J. R. Fuchs et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2065–2069
H
O
O
O
O
CH3O
HO
OCH3
OH
CH3O
HO
OCH3
OH
diketone form
keto-enol form
Figure 1. The keto–enol tautomerization of curcumin.
For the synthesis of sulfamoylated curcumin analogues (com-
pounds 5, 8, 9, 11, 20–22), an established procedure32 was
employed, utilizing chlorosulfonamide (ClSO2NH2) in dimethyl-
acetamide (DMA) at room temperature for 24 h. The synthesis of
compound 5 from curcumin is shown in Figure 7.
Since curcumin and its analogues have been reported to affect
multiple molecular targets, the observed effect could be due to
the analogues interfering with either a single or multiple targets
in the cells. In addition, the effects are also further complicated
by the differences in the cancer cells used in the studies. Different
cancer cells have significantly different altered signaling pathways.
Thus, it is extremely difficult to study the structure–activity rela-
tionships of the analogues. Our initial approach is to determine
their anticancer activities through measuring the anti-proliferative
activities of the compounds. The compounds were examined for
their anti-proliferative activities against four cancer cell lines,
which included: an androgen-dependent prostate cancer cell line
(LNCaP), an androgen-independent prostate cancer cell line (PC-
3), an estrogen-dependent (MCF-7) and an estrogen-independent
(MDA-MB-231) breast cancer cell line. Cells were treated with test
β-diketone
aromatic
O
O
CH3O
HO
OCH3
OH
olefinic
"linker"
Figure 2. Functional regions of curcumin.
H
H
O
O
O
O
R1
R2
R1
R2
CH3O
R4
OCH3
R5
R4
R5
R3
R3
OCH3
OH
10
11
OSO2NH2
OH
R1
R3
H
R2
R1
R2
R3
H
R6
1
2
3
OCH3
H
OCH3
OCH3
6
N
N
OH
H
H
H
OCH3
OAc
H
7
8
9
CH3O
HO
OCH3
OH
OH
OCH3
OH
OCH3
OSO2NH2 OCH3
R6
OCH3
OCH3
H
4
5
OSO2NH2
OCH3
H
12
13
H
OCH3
OSO2NH2
CH3
O
R1
R2
R1
R2
O
OCH3
OCH3
R3
R3
R3
H
OCH3 CH3O
23
CH3O
OCH3
R2
OH
R1
OCH3
14
15 OH
OCH3
H
16
17
18
H
OH
OCH3
H
H
H
OCH3
O
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
19
20
21
22
OH
CH3O
OCH3
OSO2NH2
OSO2NH2
OSO2NH2
H
H
OCH3
OCH3
H
OCH3
24
Figure 3. Heptadiendione and pentadienone analogues of curcumin.
H
B2O3, DMF,
(BuO)3B,
65 oC
O
O
AcOH (aq.)
70 oC, 1 h
R1
R2
CHO
B
B
+
R1
R2
R1
R2
O
O
O
O
O
O
+
THQ, AcOH,
95 oC, 4 h;
R3
R3
R3
Curcumin,
Compounds 1 - 4, 6 and 10
Figure 4. Syntheses of compounds 1–4, 6 and 10.

J. R. Fuchs et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2065–2069
2067
H2N-NHR
(R = H, CH3)
H
R
N
N
O
O
AcOH
CH3O
HO
OCH3
OH
CH3O
R4
OCH3
R5
85 ºC, 6 h
Compounds 12, R = H
13, R = CH3
Figure 5. Synthesis of compounds 12 and 13.
Method A
O
NaOH,
R1
R2
CHO
R1
R2
R1
R2
O
EtOH, rt, 24 h
+
Method B
HCl (g), AcOH,
rt, 24 h
R3
R3
R3
Compounds 14 - 19, 23, 24
Figure 6. Synthesis of compounds 14–19, 23 and 24.
H
H
O
O
O
O
CH3O
HO
OCH3
OH
CH3O
OCH3
ClSO2NH2
DMA, rt, 24 h
H2NO2SO
OSO2NH2
Compound 5
Curcumin
Figure 7. Synthesis of compound 5 from curcumin.
Table 1
Anti-proliferative activities of curcumin and compounds 1–13
R6
H
H
N
N
O
O
O
O
R1
R2
R1
R2
CH3O
R4
OCH3
R5
CH3O
HO
OCH3
OH
R3
R3
1-9
12-13
10-11
Compound
R1
R2
R3
R4
R5
PC-3 (IC50
lM)
LNCap (IC50
l
M)
MCF-7 (IC50
l
M)
MDA-MD-231 (IC50 lM)
Curcumin
1
2
3
4
5
6
7
8
OCH3
OCH3
H
OH
H
OH
OCH3
OH
OSO2NH2
OCH3
OAc
OSO2NH2
OCH3
—
H
H
H
H
OCH3
H
H
H
OCH3
H
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
OH
OH
—
19.8 2.1
40 4.9
27.3 6.6
>40
19.6 3.7
34.7 6.6
19.7 2.9
>40
21.1 4.3
5.9 1.7
3.9 0.6
20.2 1.7
10.4 1.6
7.7 1.5
6.8 0.6
20 1.0
21.5 4.7
25.9 9.5
24.3 1.9
>40
25.6 4.8
31.9 11.1
21.9 2.0
>40
OH
OCH3
OCH3
OCH3
OAc
OCH3
OSO2NH2
—
—
—
—
37.2 4.1
7.5 1.8
5.9 1.3
12.9 2.3
13.1 2.1
7.4 1.6
20.9 4.8
193 5.4
5.6 2.0
16.2 1.4
37.6 6.1
5.5 1.2
5.4 0.8
17.8 5.9
4.7 0.7
5.5 0.4
I5.4 1.5
15.1 3.5
5.9 0.6
I5.8 1.2
41.7 1.2
3.1 1.3
4.9 0.9
12.3 1.0
5.5 0.1
6.5 0.8
7.2 1.1
14.3 1.1
6.6 1.9
20.4 3.0
9
10
11
12
13
OCH3
OSO2NH2
—
—
—
—
—
—
—
—
3.4 0.9
12.1 1.3
—
compounds for 72 h and cell viability was determined by the MTT
assay.
Curcumin exists as a mixture of two tautomeric structures
(diketone and keto–enol form) (Fig. 1). Computational chemistry
has predicted that, due to (1) the acidic nature of the protons on
the central methylene carbon, (2) stabilization of the enol via an
intramolecular hydrogen bond, and (3) the establishment of a fully
conjugated system, the enol form is 6.7 kcal/mol lower in energy
than the diketone tautomer.33 This prediction has been confirmed
through X-ray crystal structures34 and more recently via NMR
analysis of the solution structure of curcumin35 in which the com-
pound existed solely in the enol form. Thus, compounds 12 and 13,
which mimic the enol form of curcumin, were synthesized to eval-
uate their anti-proliferative activities. The anti-proliferative activi-
ties of compound 12 was similar among all 4 cell lines and was
3–4-fold better than curcumin itself (Table 1). The activities were
For the heptadienedione series, the modifications focused on
the aromatic ring and the b-diketone regions (Fig. 2). The results
are summarized in Table 1. Our first structure–activity relationship
study was to investigate the substitution pattern of the 3-OCH3
and 4-OH groups on the aromatic ring in curcumin. Elimination
of the 4-OH groups (compound 1) or incorporation of an additional
OCH3 group (compound 4) onto curcumin resulted in a slight de-
crease in anti-proliferative activities. However, the activities re-
mained the same if the 3-OCH3 groups in curcumin are removed
(compound 2). In addition, it is also interesting to note that when
the 3-OCH3 and 4-OH groups exchanged position (compound 3),
this resulted in the elimination of its anti-proliferative activity.

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J. R. Fuchs et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2065–2069
similar to those reported by Ishida et al.21 Interestingly, N-methyl-
ation of the pyrazole ring on compound 12 to form compound 13
resulted in the reduction of anti-proliferative activity by 3-fold (Ta-
ble 1). In addition to its anti-proliferative activity, compound 12
was also reported to have anti-angiogenic and androgen receptor
antagonistic activities.23,36 It is not clear if there is any correlation
between the anti-proliferative activity and anti-angiogenic or anti-
androgenic activity.
more potent than curcumin (Table 2). Compound 14, which has
the same substitution pattern on the aromatic rings as curcumin,
is 5–8 times more potent than curcumin. However, unlike com-
pound 3, there was no change in anti-proliferative activities when
the 3-OCH3 and 4-OH groups exchanged position (compound 15).
In addition, eliminating or adding OCH3 groups to compound 14
(compounds 16 and 19, respectively) did not result in any change
in anti-proliferative activities. In curcumin, the 4-OH groups are
metabolically active and protecting the functional groups resulted
in an increase in anti-proliferative activity. However, for the penta-
dienone series, converting the 4-OH groups to methoxy or sulfa-
mate (compounds 17, 20–22) did not result in any increase in
anti-proliferative activity (Table 2) suggesting that a different
mechanism of action or a different metabolic pathway of the com-
pounds may be operative.
One of the major criteria for cancer drug development is that
the agents should be selective against cancer cells. MCF-10A, a
spontaneous immortalized but non-malignant mammary epithe-
lial cell line, was used to examine the selectivity of the curcumin
analogues on normal versus cancer cells. The anti-proliferative
activities of selected compounds on both cancer cells and MCF-
10A cells are shown in Table 3. Selectivity ratio was calculated as
the ratio of the IC50 of the compounds on MCF-10A versus cancer
cells with the lowest IC50 values. Five compounds (6, 12, 18, 23,
and 24) had selectivity ratio of at least 5-fold or higher (Table 3).
Interestingly, curcumin did not show any selectivity against cancer
cells. Compound 23 is not only the most potent but also the most
selective analogue among the 25 compounds tested.
Despite its widely reported biological activities, the potential
utility of curcumin is somewhat limited due to poor bioavailabil-
ity.4 Part of the reason is the physical and metabolic instability of
the molecule. Curcumin decomposes rapidly in neutral and basic
conditions. In phosphate buffer solution at pH 7.2, approximately
90% of curcumin decomposes in 30 min.37 In addition, curcumin
has been reported to undergo extensive in vitro and in vivo phase
I and phase II metabolism through oxidation, reduction, glucuron-
idation, and sulfation.38–41 The glucuronidation and sulfation oc-
curs on the 4-OH groups of curcumin.39,40 It was reported that
protection of the 4-OH groups through methylation (to form 4-
OCH3) improved its stability.42 Thus, compounds 5–8 were synthe-
sized with the 4-OH groups converted to methoxy (compound 6),
acetate (compound 7) and sulfamate (compounds 5 and 8) deriva-
tives. The rationale for using sulfamate as a protecting group was
based on the fact that the sulfamate derivatives of various steroids
including estradiol have been shown to increase absorption, lead-
ing to increased activity.43,44 All of the compounds had signifi-
cantly higher anti-proliferative activity than curcumin.
Interestingly, the mono-protected analogues of compounds 5 and
6 (compounds 10 and 11) were less active than when the OH
groups were fully protected (Table 1).
In conclusion, we have examined two series of curcumin ana-
logues with potent anti-proliferative activities in both breast and
prostate cancer cell lines. Compound 23 is the most potent analogue
with IC50 values in sub-micromolar range and a selectivity ratio over
25. This presents the possibility that curcumin analogues might
serve as potential anti-tumor agents for breast and prostate cancers.
The second series of curcumin analogues contained a pentadie-
none moiety (compounds 14–24). The results are summarized in
Table 2. The compounds exhibited potent anti-proliferative activity
with IC50 values between 0.4 and 9.5 lM, which is 2–50 times
Table 2
Anti-proliferative activities of compounds 14–24
Compound
R1
R2
R3
PC-3 (IC50
lM)
LNCap (IC50
lM)
MCF-7 (IC50
l
M)
MDA-MB-231 (IC50 lM)
14
15
16
17
18
19
20
21
22
23
24
OCH3
OH
H
OCH3
OCH3
OCH3
OCH3
H
OH
OCH3
OH
OCH3
H
OH
OSO2NH2
OSO2NH2
OSO2NH2
—
H
H
H
H
OCH3
OCH3
H
H
OCH3
—
3.9 1.1
5.9 0.9
9.5 0.9
2.9 0.6
2.5 0.5
3.6 1.3
6.1 0.3
5.1 0.8
2.4 0.2
2.1 1.1
4.6 0.2
2.7 0.4
2.6 0.4
5.8 0.9
2.2 0.5
2.1 0.9
2.5 0.3
2.4 0.6
5.1 0.7
1.9 0.4
0.5 0.1
1.7 0.6
2.4 0.4
2.9 0.9
6.9 2.1
2.5 0.4
2.7 0.5
1.7 0.3
6.6 1.1
3.5 0.5
1.5 0.1
0.4 0.1
2.4 1.0
2.8 1.0
3.1 0.8
3.9 0.6
1.6 0.4
1.5 0.1
2.7 1.4
1.7 0.1
4.2 0.6
0.6 0.2
0.6 0.1
2.4 0.4
OCH3
—
—
—
—
Table 3
Anti-proliferative activities of selected curcumin analogues on cancer and normal cells
Compound
MCF-10A (IC50
l
M)
PC-3 (IC50
l
M)
LNCap (IC50
lM)
MCF-7 (IC50
lM)
MDA-MB-231 (IC50 lM)
Curcumin
30.1 3.7
31.5 7.8
>50
>50
>50
19.8 2.1
5.9 1.3
5.6 2.0
2.5 0.5
2.1 1.1
4.6 0.2
19.6 3.7
3.9 0.6
3.4 0.9
2.1 0.9
0.5 0.1
1.7 0.6
21.5 4.7
5.4 0.8
5.9 0.6
2.7 0.5
0.4 0.1
2.4 1.0
25.6 4.8
4.9 0.9
6.6 1.9
1.5 0.1
0.6 0.1
2.4 0.4
6
12
18
23
24
>50

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