Synthesis and antiproliferative effect of novel curcumin analogues

Article abstract of DOI:10.1248/cpb.c13-00295

Novel curcumin analogues with α,β-unsaturated ketone moiety and/or α,β-saturated ketone structure were synthesized from curcumin via alkylation at the central carbon and the phenolic hydroxy groups, and hydrogenation of α,β-unsaturated ketone moiety. The antiproliferative activities were tested in five human solid tumor cell lines in vitro. Most of the compounds exhibited increased antiproliferative activities comparing with that of curcumin. Structure-activity relationship (SAR) analysis revealed that the α,β-unsaturated ketone structure was not required for antiproliferative activity of these curcumin analogues. Among these compounds, 1,7-bis(3-methoxy-4-(3-(4-methylpiperazinyl-1-yl)propoxy)phenyl)-4, 4-dibenzylheptane-3,5-dione (16f) was the most effective one with IC ₅₀ value below 1μM, which was 9- to 81-fold more potent than curcumin.

Full text of DOI:10.1248/cpb.c13-00295

July 2013
Regular Article
Chem. Pharm. Bull. 61(7) 757–763 (2013)
757
Synthesis and Antiproliferative Effect of Novel Curcumin Analogues
,c
,a
Bingmi Liu,a,b Mingyu Xia,* Xiaoling Ji,c Liying Xu,a and Jinhua Dong*
a Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical
c
University: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University; Shenyang 110016,
b
P.R. China: and College of Pharmacy, Liaoning University; Shenyang 110036, P.R. China.
Received April 16, 2013; accepted May 7, 2013; advance publication released online May 11, 2013
Novel curcumin analogues with α,β-unsaturated ketone moiety and/or α,β-saturated ketone structure
were synthesized from curcumin via alkylation at the central carbon and the phenolic hydroxy groups, and
hydrogenation of α,β-unsaturated ketone moiety. The antiproliferative activities were tested in five human
solid tumor cell lines in vitro. Most of the compounds exhibited increased antiproliferative activities compar-
ing with that of curcumin. Structure–activity relationship (SAR) analysis revealed that the α,β-unsaturated
ketone structure was not required for antiproliferative activity of these curcumin analogues. Among these
compounds, 1,7-bis(3-methoxy-4-(3-(4-methylpiperazinyl-1-yl)propoxy)phenyl)-4,4-dibenzylheptane-3,5-di-
one (16f) was the most effective one with IC50 value below 1µm, which was 9- to 81-fold more potent than
curcumin.
Key words curcumin; curcumin analogue; antiproliferation
Curcumin (Fig. 1) is one of the bioactive components of
Curcuma longa Linn. (Turmeric) and has been found to pos-
Results and Discussion
Chemistry The synthetic routes of the target compounds
sess antiproliferative activity against different cancer cell were outlined in Chart 1 and in Chart 2. For regio-selective
lines.1) To improve its antitumor effects, a great of efforts have alkylation at the C-4 position of curcumin to get the interme-
been put to modify its structure,2,3) and several curcumin de- diates 4 and 5, the phenolic hydroxyl groups were protected
rivatives and analogues, such as dimethoxycurcumin,4,5) 4-eth- via acetylation, followed by alkylation at the central carbon of
oxycarbonylethylcurcumin (ECECur),6) hydrazinocurcumin,7) intermediate 1 with methyl iodide or benzyl bromide, subse-
EF24,8,9) and FLLL3210–12) were discovered to be more active quent deprotection of the acetyl groups. The heptadiene moi-
compounds (Fig. 2).
ety in the intermediate 5 was hydrogenized to obtain 14. The
Since the conjugated α,β-unsaturated diketone moiety in resulting compound 4 or 5, 14 was coupled with 1,2-dibromo-
curcumin skeleton is believed to play an important role in ethane or 1-bromo-3-chloropropane to yield halo-substituted
mediating the antitumor activity,13,14) most analogues synthe- intermediate 6–9 and 15, respectively. Nucleophilic substitu-
sized before retained α,β-unsaturated ketone moiety.6,7,15–22) tion of intermediate 6, or 7, 8, 9, 15 with various heterocyclic
However, a few of reports showed that analogues with bro- or aliphatic secondary amines afforded the target compounds.
ken α,β-unsaturated diketone moiety also have antitumor
Biological Activity The growth inhibitory effects of
activity.10–12,23–25) For further investigation of the effects of the target compounds and intermediates 4–9, 14 were evalu-
α,β-unsaturated ketone moiety, in this communication, two ated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
series of curcumin derivatives (10a–f, 11a–f, 12a–f and 13a–f bromide (MTT) assay in five human carcinoma cell lines
with α,β-unsaturated ketone moieties, and 16a–f with a α,β- including human breast adenocarcinoma (MCF-7), human he-
saturated ketone moiety, Fig. 3) were synthesized and tested patocellular carcinoma (HepG2), human colorectal carcinoma
for their antiproliferative activities in five human carcinoma (HCT116), human lung carcinoma (A549), and human fibro-
cell lines. In the target compounds, dialkylation at C-4 posi- sarcoma (HT-1080). The IC50 values for 48h exposure were
tion was aimed to block the conjugation of the diketone moi- summarized in Table 1.
eties, and hydrogenation of compounds 13a–f was proposed
As shown in Table 1, the intermediate 4 exhibited greater
to explore the impact of the olefin double bonds. In addition, growth inhibitory potency than curcumin in all the tested cell
modification on the phenolic hydroxy groups might be of ben- lines and the intermediate 5 had the similar antiproliferative
efit to physical stability as well as metabolism behavior,5) and activity as that of curcumin, suggesting that alkylation at the
introduction of the terminal hydrophilic amino groups in the C-4 position of curcumin was of benefit to antiproliferative
side chains was carried out in anticipation of improved water activity to some extent.11) The impact of the characteristic of
solubility or/and antitumor activity.26,27)
the O-alkylated side chains in the halo-substituted intermedi-
Fig. 1. The Keto-Enlo Tautomeric Structure of Curcumin
The authors declare no conflict of interest.
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: xmywd@vip.sina.com;
dongjh66@hotmail.com

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Vol. 61, No. 7
Fig. 2. The Structures of More Active Curcumin Analogues
Conclusion
Two series of novel curcumin analogues, a total of 30 title
compounds bearing O-aminoalkyl moieties were synthesized
and evaluated for their antiproliferative activity against five
human carcinoma cell lines in vitro. Most of them possessed
moderate to excellent growth inhibitory activity against one
or more cell lines. Compound 12c, 13c, 13d and 16f showed
dramatically increased antiproliferative effects in all five cell
lines as compared with curcumin.
Preliminary structure–activity relationships revealed that
the terminal amino moieties of the O-alkyl side chains were
critical for improving antiproliferative activity, and that the
conjugated α, β-unsaturated diketone moiety and the olefin
double bonds had no significant influence on growth inhibi-
tory effect. Moreover, sterically large substitution at the cen-
tral carbon of curcumin skeleton was favorable to improving
cytotoxic activity.
Fig. 3. The Structures of the Target Compounds
Experimental
Reagents and General Procedures Melting points were
ates on cytotoxicity was uncertain since the intermediate 6 determined with a Yanaco micro melting point apparatus and
1
possessed similar cytotoxic property in comparison with the were uncorrected. H-NMR spectra were recorded in CDCl3
intermediate 4 whereas the intermediates 7, 8 and 9 showed on a Bruker ARX-300 spectrometer or a Bruker AV-600 spec-
dramatically decreased antiproliferative activity.
trometer. The coupling constants were recorded in hertz (Hz)
Compared to the halo-substituted intermediates, most of and chemical shifts were reported in parts per million (δ, ppm)
the target compounds bearing various heterocyclic or aliphatic downfield from tetramethylsilane (TMS). High-resolution
amino moieties exhibited increased antiproliferative activities. mass spectra (HR-MS) were recorded on a high-resonance
The target compounds (10a–f) derived from 6 were less ac- electrospray time-of-flight mass spectrometer LC/MSD QTOF
tive than 6. The target compounds (11a–f, 12a–f and 13a–f) 6520 (Agilent). All reagents and solvents (analytical grade)
derived from 7, 8, and 9 showed more potent activity than were commercially available and used without further purifi-
that of the three intermediates, respectively, suggesting that cation.
the terminal amino moieties introduced into the O-alkyl side
Preparation of 1,7-Bis(4-acetoxy-3-methoxyphenyl)hep-
chains contributed to the improved antiproliferative activities. ta-1,6-diene-3,5-dione (1) To a solution of curcumin (2.50g,
Compounds 12a–f and 13af with 4,4-dibenzyl substitution 6.8mmol) in methylene chloride (30mL), acetic anhydride
were more potent than compounds 10a–f and 11a–f with (1.9mL, 20.4mmol) and pyridine (1.7mL, 20.4mmol) were
4,4-dimethyl substitution, which suggested that sterically large added. The mixture was refluxed for 2h and then concentrated
substitution at C-4 position might favor the enhancement of under reduced pressure. To the residue, methanol (50mL) was
cytotoxic activity.
added to give 1 as a yellow solid, 98% yield, mp 155–157°C.
The intermediate 14 exhibited the similar antiproliferative [lit. 154–155°C].28)
activity as that of curcumin and that of the intermediate 5,
General Procedure for the Preparation of Compounds
suggesting that the diketone moiety, but not α,β-unsaturated 2 and 3 To a stirred solution of 1 (4.5g, 10.0mmol) and
diketone moiety, is required for the antiproliferative activity. potassium carbonate (3.5g, 25.0mmol) in dry acetone (30mL),
More intriguing, it was found that compounds 16a–f with iodomethane or benzyl bromide (25mmol) was added. The
α,β-saturated ketone moiety were more active than compounds mixture was refluxed overnight and then cooled to room tem-
13a–f with α,β-unsaturated ketone moieties. The most potent perature. The filtrate was collected by filtration and concen-
compound 16f inhibited cell growth with IC50 values below trated under reduced pressure. The residue was crystallized
1µm, which was 9- to 81-fold more potent than curcumin.
from acetone-ethanol to give 2 and 3, respectively.
1,7-Bis(4-acetoxy-3-methoxyphenyl)-4,4-dimethyl-hep-

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759
Reagents and conditions: (i) (CH3CO)2O, pyridine, methylene chloride, reflux, 2h; (ii) CH3I or C6H5CH2Br, K2CO3, acetone, reflux, overnight; (iii) NaOH, methanol; rt.,
2h; (iv) BrCH2CH2Br or ClCH2CH2CH2Br, K2CO3, acetonitrile, reflux, 6h; (v) HNR1R2, acetonitrile, reflux, 5h.
Chart 1. Synthesis of the Target Compounds 10a–f, 11a–f, 12a–f and 13a–f
Reagents and conditions: (vi) H2/Pd–C, ethanol, rt., 12h.
Chart 2. Synthesis of the Target Compounds 16a–f
ta-1,6-diene-3,5-dione (2): Yellow solid, 75% yield, mp lized from petroleum ether–ethyl acetate to give 4 and 5.
1
160–163°C. H-NMR (300MHz) δ: 1.48 (6H, s), 2.30 (6H, s),
1,7-Bis(4-hydroxy-3-methoxyphenyl)-4,4-dimethyl-hep-
3.85 (6H, s), 6.70 (2H, d, J=15.6Hz), 7.02 (2H, d, J=8.1Hz), ta-1,6-diene-3,5-dione (4): Yellow solid, 74% yield, mp
7.06 (2H, d, J=1.8Hz), 7.13 (2H, dd, J=1.8, 8.1Hz), 7.68 (2H, 136–138°C. 1H-NMR (300MHz) δ: 1.47 (6H, s), 3.91 (6H,
d, J=15.6Hz). HR-MS m/z: 481.1857 (Calcd for C27H29O8: s), 6.62 (2H, d, J=15.6Hz), 6.89 (2H, d, J=8.4Hz), 6.99
481.1862).
(2H, d, J=1.8Hz), 7.09 (2H, dd, J=1.8, 8.4Hz), 7.66 (2H,
1,7-Bis(4-acetoxy-3-methoxyphenyl)-4,4-dibenzyl-hepta-1,6- d, J=15.6Hz); HR-MS m/z: 397.1646 (Calcd for C23H25O6:
diene-3,5-dione (3): Yellow solid, 88% yield, mp 178–179°C. 397.1651).
1H-NMR (600MHz) δ: 2.29 (6H, s), 3.38 (4H, s), 3.81 (6H,
1,7-Bis(4-hydroxy-3-methoxyphenyl)-4,4-dibenzyl-hep-
s), 6.53 (2H, d, J=15.6Hz), 6.91 (2H, d, J=1.8Hz), 6.99 (2H, ta-1,6-diene-3,5-dione (5): Yellow solid, 91% yield, mp
1
d, J=8.4Hz), 7.03 (2H, dd, J=1.8, 8.4Hz), 7.11 (4H, m), 7.18 115–117°C. H-NMR (600MHz): δ 3.38 (4H, s), 3.86 (6H, s),
(2H, m), 7.22 (4H, m), 7.68 (2H, d, J=15.6Hz). HR-MS m/z: 6.54 (2H, d, J=15.6Hz), 6.86 (4H, m), 7.03 (2H, dd, J=1.8,
633.2483 (Calcd for C39H37O8: 633.2488).
7.8Hz), 7.10 (4H, m), 7.17 (2H, m), 7.21 (4H, m), 7.69 (2H,
General Procedure for the Preparation of Compounds d, J=15.6Hz). HR-MS m/z: 549.2272 (Calcd for C35H33O6:
4 and 5 To a solution of intermediate 2 or 3 (7.9mmol) in 549.2277).
methanol (20mL), sodium hydroxide (0.7g, 17.4mmol) was
Preparation of 1,7-Bis(4-hydroxy-3-methoxyphenyl)-4,4-
added. The mixture was stirred for 2h at room temperature, dibenzylheptane-3,5-dione (14) To a solution of compound
and then evaporated to dryness in vacuo. The residue was 5 (5.5g, 0.01mol) in ethanol (50mL) was added 10% Pd–C
dissolved in methylene chloride (30mL), followed by neu- (0.5g). After degassing, the mixture was hydrogenated at
tralization with acetic acid. Then water (50mL) was added room temperature and at atmospheric pressure for 12h. Then,
and the organic phase was separated. The aqueous phase was methylene chloride (10mL) was added to dissolve the pre-
extracted with methylene chloride (2×20mL). The combined cipitate, and the reaction mixture was filtered. The filtrate was
organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 14 as a white
1
concentrated under reduced pressure. The residue was crystal- solid, 65% yield, mp 73–75°C. H-NMR (300MHz) δ: 2.55

760
Vol. 61, No. 7
Table 1. Antiproliferative Activities of These Synthetic Curcumin De-
rivatives in Five Solid Tumor Cell Lines
7, 8, 9 and 15.
1,7-Bis(4-(2-bromoethoxy)-3-methoxyphenyl)-4,4-dimethyl-
hepta-1,6-diene-3,5-dione (6): Yellow solid, 42% yield, mp
93–95°C. H-NMR (300MHz) δ: 1.48 (6H, s), 3.65 (4H, t,
J=6.6Hz), 3.88 (6H, s), 4.34 (4H, t, J=6.6Hz), 6.65 (2H, d,
J=15.6Hz), 6.85 (2H, d, J=8.1Hz), 7.02 (2H, d, J=1.5Hz), 7.10
(2H, dd, J=1.5, 8.1Hz), 7.67 (2H, d, J=15.6Hz). HR-MS m/z:
609.0482 (Calcd for C27H31Br2O6: 609.0487).
IC50 (µm)
1
Compd.
MCF-7
HepG2
HCT116
A549
HT1080
4
5
14
6
7
8
9
8.14
31.09
33.66
6.36
5.88
26.45
35.98
7.96
72.23
>100
>100
>100
>100
6.31
35.85
31.73
7.48
>100
>100
>100
47.48
94.36
7.42
8.54
7.68
7.25
27.72
35.32
31.88
>100
>100
>100
39.60
>100
41.15
48.54
73.30
43.45
33.05
7.72
5.18
15.50
49.50
5.42
>100
>100
>100
1,7-Bis(4-(3-chloropropoxy)-3-methoxyphenyl)-4,4-dimeth-
yl-hepta-1,6-diene-3,5-dione (7): Yellow solid, 50% yield, mp
42.45
>100
>100
7.62
>100
30.04
1
90–91°C. H-NMR (300MHz) δ: 1.48 (6H, s), 2.28 (4H, m),
3.75 (4H, t, J=6.0Hz), 3.87 (6H, s), 4.18 (4H, t, J=6.0Hz),
6.65 (2H, d, J=15.6Hz), 6.86 (2H, d, J=8.4Hz) 7.00 (2H,
d, J=1.8Hz), 7.11 (2H, dd, J=1.8, 8.4Hz), 7.68 (2H, d,
J=15.6Hz). HR-MS m/z: 549.1805 (Calcd for C29H35Cl2O6:
549.1810).
10a
10b
10c
10d
10e
10f
11a
11b
11c
11d
11e
11f
12a
12b
12c
12d
12e
12f
13a
13b
13c
13d
13e
13f
16a
16b
16c
16d
16e
16f
4.87
63.53
4.98
4.16
0.06
5.30
5.15
0.68
0.68
5.26
39.12
3.98
5.86
35.49
0.47
6.14
41.05
4.92
5.89
8.21
5.94
4.66
44.14
4.75
10.72
10.27
4.81
4.84
6.09
0.63
5.96
34.92
43.48
32.54
19.32
0.79
6.24
32.00
2.18
28.39
7.11
6.21
5.89
0.03
4.81
7.54
4.76
4.71
5.22
4.71
0.74
6.47
0.64
0.76
0.87
0.70
2.46
6.78
0.71
35.76
45.92
41.08
7.25
1,7-Bis(4-(2-bromoethoxy)-3-methoxyphenyl)-4,4-dibenzyl-
hepta-1,6-diene-3,5-dione (8): Yellow solid, 71% yield, mp
9.26
42.94
32.33
43.58
53.23
96.86
8.64
6.50
46.97
4.80
39.60
94.47
7.61
8.13
42.81
5.10
4.93
45.23
6.31
5.91
0.59
7.88
7.35
7.94
0.78
1
6.65
156–157°C. H-NMR (300MHz) δ: 3.38 (4H, s), 3.64 (4H, t,
44.63
36.80
70.67
44.80
2.64
72.01
5.17
5.38
58.37
5.42
5.98
28.96
0.64
0.66
43.88
5.79
5.73
0.38
0.93
4.70
6.55
0.51
37.37
34.37
43.93
>100
J=6.6Hz), 3.85 (6H, s), 4.33 (4H, t, J=6.6Hz), 6.52 (2H, d,
J=15.6Hz), 6.82 (2H, d, J=8.4Hz), 6.87 (2H, d, J=1.8Hz),
7.03 (2H, dd, J=1.8, 8.4Hz), 7.10 (4H, m), 7.20 (6H, m),
7.67 (2H, d, J=15.6Hz). HR-MS m/z: 761.1108 (Calcd for
C39H39Br2O6: 761.1113).
38.34
5.88
43.44
5.41
47.04
72.54
5.75
5.87
39.17
4.26
0.72
46.94
5.93
5.49
0.50
4.55
4.88
5.47
0.51
41.35
1,7-Bis(4-(3-chloropropoxy)-3-methoxyphenyl)-4,4-diben-
zyl-hepta-1,6-diene-3,5-dione (9): Yellow solid, 78% yield, mp
1
106–108°C. H-NMR (300MHz) δ: 2.27 (4H, m), 3.38 (4H,
s), 3.74 (4H, t, J=6.0Hz), 3.83 (6H, s), 4.17 (4H, t, J=6.0Hz),
6.53 (2H, d, J=15.3Hz), 6.84 (2H, d, J=8.4Hz), 6.87 (2H, d,
J=1.8Hz), 7.05 (2H, dd, J=1.8, 8.4Hz), 7.11 (4H, m), 7.20 (6H,
m), 7.68 (2H, d, J=15.3Hz). HR-MS m/z: 701.2431 (Calcd for
C41H43Cl2O6: 701.2436).
1,7-Bis(4-(3-chloropropoxy)-3-methoxyphenyl)-4,4-diben-
zylheptane-3,5-dione (15): White solid, 75% yield, mp
1
95–97°C. H-NMR (300MHz) δ: 2.25 (4H, m), 2.58 (4H, m),
2.71 (4H, m), 3.31 (4H, s), 3.75 (4H, t, J=6.0Hz), 3.82 (6H, s),
4.11 (4H, t, J=6.0Hz), 6.59 (4H, m), 6.79 (2H, d, J=8.7Hz),
6.94 (4H, m), 7.21 (6H, m). HR-MS m/z: 705.2744 (Calcd for
C41H47Cl2O6: 705.2751).
General Procedure for the Preparation of Target Com-
pounds 10a–f, 11a–f, 12a–f, 13a–f and 16a–f To a solution
of halo-substituted intermediate 6, or 7, 8, 9, 15 (2.0mmol)
in acetonitrile (10mL), a heterocyclic or aliphatic secondary
amine (20.0mmol) was added. The mixture was refluxed for
Curcumin 28.03
43.31
a) These cells were treated with a variety of concentrations of each compound
for 48h and the concentrations (IC50s) which inhibit 50% of cell growth were cal-
culated.
(4H, m), 2.69 (4H, m), 3.31 (4H, s), 3.83 (6H, s), 6.55 (4H, m), 5h and concentrated under reduced pressure. The residue
6.79 (2H, d, J=8.4Hz), 6.93 (4H, m), 7.21 (6H, m). HR-MS was dissolved in methylene chloride (20mL) and washed with
m/z: 553.2585 (Calcd for C35H37O6: 553.2592).
water (3×30mL), dried over anhydrous sodium sulfate and
General Procedure for the Preparation of Compounds concentrated under reduced pressure. The residue was purified
6, 7, 8, 9 and 15 To a solution of 4 or 5, 14 (12.0mmol) in by column chromatography with dichloromethane–methanol
acetonitrile (50mL), potassium carbonate (5.0g, 36.0mmol) as gradient elute to afford the corresponding target com-
was added. The mixture was stirred at 70°C, and then 1,2-di- pounds 10a–f, 11a–f, 12a–f, 13a–f and 16a–f.
bromoethane or 1-bromo-3-chloropropane (36.0mmol) diluted
1,7-Bis(4-(2-dimethylaminoethoxy)-3-methoxyphenyl)-4,4-
with acetonitrile (5mL) was added dropwise. The mixture dimethyl-hepta-1,6-diene-3,5-dione (10a): Yellow oil, 38%
1
was refluxed for 6h, and concentrated under reduced pressure. yield. H-NMR (300MHz) δ: 1.47 (6H, s), 2.40 (12H, s), 2.86
To the residue, methylene chloride (50mL) and water (50mL) (4H, t, J=5.7Hz), 3.86 (6H, s), 4.17 (4H, t, J=5.7Hz), 6.64 (2H,
were added. The organic phase was separated and the aqueous d, J=15.6Hz), 6.85 (2H, d, J=8.4Hz), 6.99 (2H, s), 7.10 (2H,
phase was extracted with methylene chloride (3×20mL). The d, J=8.4Hz), 7.67 (2H, d, J=15.6Hz). HR-MS m/z: 539.3166
combined organic phase was dried over anhydrous sodium (Calcd for C31H43N2O6: 539.3121).
sulfate and the filtrate was concentrated under reduced pres-
1,7-Bis(4-(2-diethylaminoethoxy)-3-methoxyphenyl)-4,4-
sure. The residue was purified by column chromatography dimethyl-hepta-1,6-diene-3,5-dione (10b): Yellow oil, 45%
1
with petroleum ether–ethyl acetate as gradient elute to give 6, yield. H-NMR (300MHz) δ: 1.05 (12H, t, J=7.2Hz), 1.47

July 2013
761
1
(6H, s), 2.62 (8H, q, J=7.2Hz), 2.91 (4H, t, J=6.9Hz), 3.87 yield. H-NMR (300MHz) δ: 1.42 (4H, m), 1.47 (6H, s), 1.57
(6H, s), 4.10 (4H, t, J=6.9Hz), 6.64 (2H, d, J=15.6Hz), 6.85 (8H, m), 2.02 (4H, m), 2.38 (8H, s), 2.45 (4H, t, J=7.2Hz), 3.87
(2H, d, J=8.4Hz), 6.99 (2H, d, J=1.5Hz), 7.10 (2H, dd, J=1.5, (6H, s), 4.09 (4H, t, J=6.6Hz), 6.64 (2H, d, J=15.6Hz), 6.86
8.4Hz), 7.67 (2H, d, J=15.6Hz). HR-MS m/z: 595.3742 (Calcd (2H, d, J=8.4Hz,), 7.00 (2H, d, J=1.5Hz), 7.10 (2H, dd, J=1.5,
for C35H51N2O6: 595.3747).
1,7-Bis(3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)phenyl)-4,4- for C39H55N2O6: 647.4060).
8.4Hz), 7.67 (2H, d, J=15.6Hz). HR-MS m/z: 647.4055 (Calcd
dimethyl-hepta-1,6-diene-3,5-dione (10c): Yellow oil, 57%
yield. H-NMR (300MHz) δ: 1.47 (6H, s), 1.80 (8H, m), 2.63 dimethyl-hepta-1,6-diene-3,5-dione (11e): Yellow oil, 69%
(8H, m), 2.95 (4H, t, J=6.3Hz), 3.87 (6H, s), 4.17 (4H, t, yield. H-NMR (300MHz) δ: 1.47 (6H, s), 2.01 (4H, m), 2.49
1,7-Bis(3-methoxy-4-(3-morpholinopropoxy)phenyl)-4,4-
1
1
J=6.3Hz), 6.64 (2H, d, J=15.3Hz), 6.85 (2H, d, J=8.4Hz), (12H, m), 3.71 (8H, m), 3.87 (6H, s), 4.10 (4H, t, J=6.3Hz),
7.00 (2H, d, J=1.5Hz), 7.10 (2H, dd, J=1.5, 8.4Hz), 7.67 (2H, 6.64 (2H, d, J=15.6Hz), 6.86 (2H, d, J=8.4Hz), 7.00 (2H, s),
d, J=15.3Hz). HR-MS m/z: 591.3429 (Calcd for C35H47N2O6: 7.10 (2H, d, J=8.4Hz), 7.67 (2H, d, J=15.6Hz). HR-MS m/z:
591.3434).
651.3640 (Calcd for C37H51N2O8: 651.3645).
1,7-Bis(3-methoxy-4-(2-piperidin-1-yl-ethoxy)phenyl)-4,4-
1,7-Bis(3-methoxy-4-(3-(4-methylpiperazinyl-1-yl)propoxy)-
dimethyl-hepta-1,6-diene-3,5-dione (10d): Yellow oil, 60% phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (11f): Yel-
1
1
yield. H-NMR (300MHz) δ: 1.46 (10H, m), 1.59 (8H, m), low oil, 63% yield. H-NMR (300MHz) δ: 1.47 (6H, s), 2.02
2.50 (8H, m), 2.80 (4H, t, J=6.6Hz), 3.87 (6H, s), 4.16 (4H, (4H, m), 2.28 (6H, s), 2.46 (20H, m), 3.87 (6H, s), 4.10 (4H,
t, J=6.6Hz), 6.64 (2H, d, J=15.6Hz), 6.85 (2H, d, J=8.4Hz), t, J=6.6Hz), 6.64 (2H, d, J=15.6Hz), 6.86 (2H, d, J=8.4Hz),
6.99 (2H, d, J=1.8Hz), 7.10 (2H, dd, J=1.8, 8.4Hz), 7.67 (2H, 7.00 (2H, d, J=1.8Hz), 7.10 (2H, dd, J=1.8, 8.4Hz), 7.68 (2H,
d, J=15.6Hz). HR-MS m/z: 619.3742 (Calcd for C37H51N2O6: d, J=15.6Hz). HR-MS m/z: 677.4273 (Calcd for C39H57N4O6:
619.3747).
677.4278).
1,7-Bis(3-methoxy-4-(2-morpholinoethoxy)phenyl)-4,4-
1,7-Bis(4-(2-dimethylaminoethoxy)-3-methoxyphenyl)-4,4-
dimethyl-hepta-1,6-diene-3,5-dione (10e): Yellow oil, 71% dibenzyl-hepta-1,6-diene-3,5-dione (12a): Yellow oil, 42%
1
yield. H-NMR (600MHz) δ: 1.47 (6H, s), 2.58 (8H, m), 2.83 yield. 1H-NMR (300MHz) δ: 2.36 (12H, m), 2.83 (4H, t,
(4H, t, J=6.0Hz), 3.71 (8H, m), 3.87 (6H, s), 4.17 (4H, t, J=6.0Hz), 3.38 (4H, s), 3.83 (6H, s), 4.14 (4H, t, J=6.0Hz),
J=6.0Hz), 6.64 (2H, d, J=15.6Hz), 6.85 (2H, d, J=8.4Hz), 6.53 (2H, d, J=15.3Hz), 6.82 (2H, d, J=8.1Hz), 6.86 (2H, d,
7.00 (2H, d, J=1.8Hz), 7.10 (2H, dd, J=1.8, 8.4Hz), 7.67 (2H, J=1.2Hz), 7.04 (2H, dd, J=1.2, 8.1Hz), 7.10 (4H, m), 7.19 (6H,
d, J=15.6Hz). HR-MS m/z: 623.3327 (Calcd for C35H47N2O8: m), 7.68 (2H, d, J=15.3Hz) HR-MS m/z: 691.3742 (Calcd for
623.3332).
C43H51N2O6: 691.3747).
1,7-Bis(3-methoxy-4-(2-(4-methylpiperazinyl-1-yl)ethoxy)-
1,7-Bis(4-(2-diethylaminoethoxy)-3-methoxyphenyl)-4,4-
phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (10f): Yel- dibenzyl-hepta-1,6-diene-3,5-dione (12b): Yellow oil, 48%
1
1
low oil, 70% yield. H-NMR (300MHz) δ: 1.47 (6H, s), 2.28 yield. H-NMR (300MHz) δ: 1.06 (12H, t, J=6.9Hz), 2.65
(6H, s), 2.45 (12H, s), 2.61 (8H, s), 3.87 (6H, s), 4.15 (4H, t, (8H, q, J=6.9Hz), 2.93 (4H, t, J=6.6Hz), 3.38 (4H, s), 3.83
J=5.7Hz), 6.64 (2H, d, J=15.6Hz), 6.84 (2H, d, J=8.1Hz), (6H, s), 4.11 (4H, t, J=6.6Hz), 6.53 (2H, d, J=15.3Hz), 6.83
7.00 (2H, s), 7.10 (2H, d, J=8.1Hz), 7.67 (2H, d, J=15.6Hz). (2H, d, J=8.4Hz), 6.86 (2H, d, J=1.5Hz), 7.05 (2H, dd, J=1.5,
HR-MS m/z: 649.3960 (Calcd for C37H53N4O6: 649.3965).
1,7-Bis(3-methoxy-4-(3-dimethylaminopropoxy)phenyl)-4,4- HR-MS m/z: 747.4368 (Calcd for C47H59N2O6: 747.4373).
dimethyl-hepta-1,6-diene-3,5-dione (11a): Yellow oil, 40% 1,7-Bis(3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)phenyl)-4,4-
8.4Hz), 7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.3Hz).
1
yield. H-NMR (300MHz) δ: 1.47 (6H, s), 2.02 (4H, m), 2.24 dibenzyl-hepta-1,6-diene-3,5-dione (12c): Yellow oil, 67%
(12H, s), 2.45 (4H, t, J=7.2Hz), 3.87 (6H, s), 4.09 (4H, t, yield. 1H-NMR (300MHz) δ: 1.80 (8H, m), 2.64 (8H, s),
J=6.6Hz), 6.64 (2H, d, J=15.6Hz), 6.86 (2H, d, J=8.4Hz), 2.96 (4H, t, J=6.6Hz), 3.38 (4H, s), 3.83 (6H, s), 4.17 (4H, t,
7.00 (2H, s), 7.10 (2H, d, J=8.4Hz), 7.68 (2H, d, J=15.6Hz). J=6.6Hz), 6.53 (2H, d, J=15.3Hz), 6.83 (2H, d, J=8.4Hz),
HR-MS m/z: 567.3429 (Calcd for C33H47N2O6: 567.3434).
6.86 (2H, d, J=1.8Hz), 7.04 (2H, dd, J=1.8, 8.4Hz), 7.10
1,7-Bis(3-methoxy-4-(3-diethylaminopropoxy)phenyl)-4,4- (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.3Hz). HR-MS m/z:
dimethyl-hepta-1,6-diene-3,5-dione (11b): Yellow oil, 53% 743.4055 (Calcd for C47H55N2O6: 743.4060).
1
yield. H-NMR (300MHz) δ: 1.01 (12H, t, J=7.2Hz), 1.47
1,7-Bis(3-methoxy-4-(2-piperidin-1-yl-ethoxy)phenyl)-4,4-
(6H, s), 1.98 (4H, m), 2.57 (12H, m), 3.87 (6H, s), 4.08 (4H, dibenzyl-hepta-1,6-diene-3,5-dione (12d): Yellow oil, 73%
t, J=6.9Hz), 6.64 (2H, d, J=15.6Hz), 6.85 (2H, d, J=8.4Hz), yield; H-NMR (300MHz) δ: 1.44 (4H, m), 1.59 (8H, m), 2.50
1
7.00 (2H, d, J=1.5Hz), 7.10 (2H, dd, J=1.5, 8.4Hz), 7.68 (2H, (8H, m), 2.80 (4H, t, J=6.3Hz), 3.38 (4H, s), 3.83 (6H, s),
d, J=15.6Hz). HR-MS m/z: 623.4055 (Calcd for C37H55N2O6: 4.15 (4H, t, J=6.3Hz), 6.53 (2H, d, J=15.6Hz), 6.82 (2H, d,
623.4060).
J=8.4Hz), 6.86 (2H, d, J=1.5Hz), 7.04 (2H, dd, J=1.5, 8.4Hz),
1,7-Bis(3-methoxy-4-(3-pyrrolidin-1-yl-propoxy)- 7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.6Hz). HR-MS
phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (11c): Yellow m/z: 771.4368 (Calcd for C49H59N2O66: 771.4373).
1
oil, 72% yield. H-NMR (300MHz) δ: 1.47 (6H, s), 1.80 (8H,
1,7-Bis(3-methoxy-4-(2-morpholinoethoxy)phenyl)-4,4-
m), 2.08 (4H, m), 2.56 (8H, m), 2.65 (4H, t, J=7.2Hz), 3.87 dibenzyl-hepta-1,6-diene-3,5-dione (12e): Yellow oil, 69%
(6H, s), 4.11 (4H, t, J=6.6Hz), 6.64 (2H, d, J=15.3Hz), 6.86 yield; 1H-NMR (300MHz) δ: 2.58 (8H, m), 2.83 (4H, t,
(2H, d, J=8.4Hz), 7.00 (2H, d, J=1.8Hz), 7.10 (2H, dd, J=1.8, J=6.0Hz), 3.38 (4H, s), 3.72 (8H, m), 3.83 (6H, s), 4.15 (4H,
8.4Hz), 7.67 (2H, d, J=15.3Hz). HR-MS m/z: 619.3742 (Calcd t, J=6.0Hz), 6.53 (2H, d, J=15.3Hz), 6.82 (2H, d, J=8.4Hz),
for C37H51N2O6: 619.3747).
6.86 (2H, d, J=1.5Hz), 7.04 (2H, dd, J=1.5, 8.4Hz), 7.10
1,7-Bis(3-methoxy-4-(3-piperidin-1-yl)propoxy)phenyl)-4,4- (4H, m), 7.19 (6H, m.), 7.68 (2H, d, J=15.3Hz). HR-MS m/z:
dimethyl-hepta-1,6-diene-3,5-dione (11d): Yellow oil, 78% 775.3953 (Calcd for C47H55N2O8: 775.3958).

762
Vol. 61, No. 7
1,7-Bis(3-methoxy-4-(2-(4-methylpiperazinyl-1-yl)ethoxy)- J=8.7Hz), 6.94 (4H, m), 7.21 (6H, m). HR-MS m/z: 723.4368
phenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (12f): Yellow (Calcd for C45H59N2O6: 722.4375).
1
oil, 63% yield. H-NMR (300MHz) δ: 2.29 (6H, s), 2.50 (8H,
1,7-Bis(4-(3-diethylaminopropoxy)-3-methoxyphenyl)-4,4-
s), 2.63 (8H, s), 2.84 (4H, t, J=6.0Hz), 3.38 (4H, s), 3.83 (6H, dibenzylheptane-3,5-dione (16b): Yellow oil, 53% yield.
s), 4.15 (4H, t, J=6.0Hz), 6.53 (2H, d, J=15.6Hz), 6.82 (2H, d, 1H-NMR (300MHz) δ: 1.07 (12H, t, J=7.2Hz), 2.00 (4H,
J=8.4Hz), 6.86 (2H, d, J=1.5Hz), 7.04 (2H, dd, J=1.5, 8.4Hz), m), 2.61 (12H, m), 2.68 (8H, m), 3.31 (4H, s), 3.81 (6H, s),
7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.6Hz). HR-MS 4.02 (4H, t, J=6.6Hz), 6.58 (4H, m), 6.77 (2H, d, J=8.7Hz),
m/z: 801.4586 (Calcd for C49H61N4O6: 801.4591).
6.94 (4H, m), 7.21 (6H, m). HR-MS m/z: 779.4994 (Calcd for
1,7-Bis(4-(3-dimethylaminopropoxy)-3-methoxyphenyl)-4,4- C49H67N2O6: 779.5001).
dibenzyl-hepta-1,6-diene-3,5-dione (13a): Yellow oil, 45%
yield. H-NMR (300MHz) δ: 2.06 (4H, m), 2.30 (12H, s), phenyl)-4,4-dibenzylheptane-3,5-dione (16c): Yellow oil, 66%
2.54 (4H, t, J=7.2Hz), 3.38 (4H, s), 3.84 (6H, s), 4.07 (4H, t, yield. H-NMR (300MHz) δ: 1.81 (8H, m), 2.51 (4H, m), 2.58
1,7-Bis(3-methoxy-4-(3-pyrrolidin-1-yl-propoxy)-
1
1
J=6.6Hz), 6.53 (2H, d, J=15.3Hz), 6.82 (2H, d, J=8.4Hz), (12H, m), 2.68 (8H, m), 3.31 (4H, s), 3.82 (6H, s), 4.04 (4H, t,
6.86 (2H, d, J=1.8Hz), 7.04 (2H, dd, J=1.8, 8.4Hz), 7.11 J=6.6Hz), 6.58 (4H, m), 6.78 (2H, d, J=8.7Hz), 6.94 (4H, m),
(4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.3Hz). HR-MS m/z: 7.21 (6H, m). HR-MS m/z: 775.4681 (Calcd for C49H63N2O6:
719.4055 (Calcd for C45H55N2O6: 719.4060).
775.4688).
1,7-Bis(4-(3-diethylaminopropoxy)-3-methoxyphenyl)-4,4-
1,7-Bis(3-methoxy-4-(3-piperidin-1-yl-propoxy)phenyl)-4,4-
dibenzyl-hepta-1,6-diene-3,5-dione (13b): Yellow oil, 50% dibenzylheptane-3,5-dione (16d): Yellow oil, 78% yield.
1
yield. H-NMR (300MHz) δ: 1.02 (12H, t, J=7.2Hz), 1.98 1H-NMR (300MHz) δ: 1.45 (4H, m), 1.59 (8H, m), 2.01 (4H,
(4H, m), 2.57 (8H, m), 2.63 (4H, m), 3.38 (4H, s), 3.83 (6H, s), m), 2.40 (8H, m), 2.49 (4H, t, J=7.2Hz), 2.59 (4H, m), 2.70
4.07 (4H, t, J=6.6Hz), 6.54 (2H, d, J=15.4Hz), 6.82 (2H, d, (4H, m), 3.31 (4H, s), 3.81 (6H, s), 4.02 (4H, t, J=6.6Hz), 6.58
J=8.4Hz), 6.86 (2H, d, J=1.8Hz), 7.04 (2H, dd, J=1.8, 8.4Hz), (4H, m), 6.78 (2H, d, J=8.7Hz), 6.94 (4H, m), 7.21 (6H, m).
7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.4Hz). HR-MS HR-MS m/z: 803.4994 (Calcd for C51H67N2O6: 803.5001).
m/z: 775.4681 (Calcd for C49H63N2O6: 775.4686).
1,7-Bis(3-methoxy-4-(3-morpholinopropoxy)phenyl)-4,4-
1,7-Bis(3-methoxy-4-(3-pyrrolidin-1-yl-propoxy)- dibenzylheptane-3,5-dione (16e): Yellow oil, 84% yield.
phenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (13c): Yellow 1H-NMR (300MHz) δ: 1.99 (4H, m), 2.46 (8H, m), 2.51 (4H, t,
1
oil, 68% yield. H-NMR (300MHz) δ: 1.80 (8H, s), 2.08 (4H, J=6.9Hz), 2.59 (4H, m), 2.71 (4H, m), 3.31 (4H, s), 3.71 (8H,
m), 2.59 (8H, s), 2.67 (4H, t, J=6.9Hz), 3.38 (4H, s), 3.83 (6H, m), 3.82 (6H, s), 4.03 (4H, t, J=6.6Hz), 6.59 (4H, m), 6.78 (2H,
s), 4.09 (4H, t, J=6.6Hz), 6.53 (2H, d, J=15.6Hz), 6.83 (2H, d, d, J=8.7Hz), 6.93 (4H, m), 7.21 (6H, m). HR-MS m/z: 807.4579
J=8.4Hz), 6.86 (2H, d, J=1.5Hz), 7.04 (2H, dd, J=1.5, 8.4Hz), (Calcd for C49H64N2O6: 807.4586).
7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.6Hz). HR-MS
m/z: 771.4368 (Calcd for C49H59N2O6: 771.4373).
1,7-Bis(3-methoxy-4-(3-(4-methylpiperazinyl-1-yl)propoxy)-
phenyl)-4,4-dibenzylheptane-3,5-dione (16f): Yellow oil, 73%
1
1,7-Bis(3-methoxy-4-(3-piperidin-1-yl-propoxy)phenyl)-4,4- yield. H-NMR (300MHz) δ: 1.99 (4H, m), 2.28 (6H, s), 2.52
dibenzyl-hepta-1,6-diene-3,5-dione (13d): Yellow oil, 75% (20H, m), 2.60 (8H, m), 3.31 (4H, s), 3.81 (6H, s), 4.02 (4H, t,
1
yield. H-NMR (300MHz) δ: 1.54 (4H, m), 1.77 (8H, m), 2.19 J=6.6Hz), 6.58 (4H, m), 6.78 (2H, d, J=8.7Hz), 6.94 (4H, m),
(4H, m), 2.86 (12H, m), 3.38 (4H, s), 3.82 (6H, s), 4.07 (4H, t, 7.21 (6H, m). HR-MS m/z: 833.5212 (Calcd for C51H69N4O6:
J=6.0Hz), 6.53 (2H, d, J=15.3Hz), 6.80 (2H, d, J=8.4Hz), 833.5219).
6.85 (2H, d, J=1.5Hz), 7.04 (2H, dd, J=1.5, 8.4Hz), 7.10
Antiproliferative Activity Assay The antiproliferative
(4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.3Hz). HR-MS m/z: activity of curcumin analogues were evaluated with five
799.4681 (Calcd for C51H63N2O6: 799.4686).
human tumor cell lines by MTT assay. Briefly, approximately
1,7-Bis(3-methoxy-4-(3-morpholinopropoxy)phenyl)-4,4- 5×103 cells (MCF-7, HepG2, HCT116, A549, and HT-1080)
dibenzyl-hepta-1,6-diene-3,5-dione (13e): Yellow oil, 80% were suspended in 0.1mL RPMI 1640 medium containing
1
yield. H-NMR (300MHz) δ: 2.09 (4H, m), 2.65 (12H, m), 10% fetal bovine serum (FBS) in triplicate in 96 well plate
3.38 (4H, s), 3.77 (8H, m), 3.83 (6H, s), 4.08 (4H, t, J=6.3Hz), and 0.1mL medium containing different concentrations of
6.53 (2H, d, J=15.3Hz), 6.81 (2H, d, J=8.4Hz), 6.87 (2H, d, each analogue was added in each well and then incubated
J=1.8Hz), 7.04 (2H, dd, J=1.8, 8.4Hz), 7.10 (4H, m), 7.19 (6H, at 37°C for 48h and then 0.1mL of MTT solution (0.5mg/
m), 7.68 (2H, d, J=15.3Hz). HR-MS m/z: 803.4266 (Calcd for mL) was added to each well. After 4h incubated at 37°C, the
C49H59N2O6: 803.4271).
mediums were removed carefully and 0.15mL of dimethyl
1,7-Bis(3-methoxy-4-(3-(4-methylpiperazinyl-1-yl)propoxy)- sulphoxide (DMSO) was added to dissolve the formazan crys-
phenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (13f): Yellow tals. The optical density (OD) values at 492nm were measured
oil, 75% yield. 1H-NMR (300MHz) δ: 2.02 (4H, m), 2.32 with the enzyme-linked immunosorbent assay (ELISA) reader.
(6H, s), 2.52 (20H, m), 3.38 (4H, s), 3.83 (6H, s), 4.08 (4H, t, The concentrations (IC50s) which inhibited 50% of cell growth
J=6.6Hz), 6.54 (2H, d, J=15.6Hz), 6.83 (2H, d, J=8.4Hz), were calculated using Sigma plot10.
6.87 (2H, d, J=1.8Hz), 7.04 (2H, dd, J=1.8, 8.4Hz), 7.10
(4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.6Hz). HR-MS m/z:
829.4899 (Calcd for C51H65N4O6: 829.4904).
Acknowledgment This work was supported by Na-
tional Key Technologies Program of China
R
& D
1,7-Bis(4-(3-dimethylaminopropoxy)-3-methoxyphenyl)-4,4- (2009ZX09103-057).
dibenzylheptane-3,5-dione (16a): Yellow oil, 49% yield.
1H-NMR (300MHz) δ: 1.95–2.04 (4H, m), 2.26 (12H, s), 2.47
(4H, t, J=7.2Hz), 2.59 (4H, m), 2.70 (4H, m), 3.31 (4H, s), 3.82
(6H, s), 4.02 (4H, t, J=6.6Hz), 6.58 (4H, m,), 6.78 (2H, d,
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