Synthesis and Antiproliferative Effect of Novel Curcumin Analogues

Bingmi Liu; Mingyu Xia; Xiaoling Ji; Liying Xu; Jinhua Dong

doi:10.1248/cpb.c13-00295

Abstract

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 IC₅₀ value below 1 µM, which was 9- to 81-fold more potent than curcumin.

Curcumin (Fig. 1) is one of the bioactive components of Curcuma longa LINN. (Turmeric) and has been found to possess antiproliferative activity against different cancer cell lines.¹⁾ To improve its antitumor effects, a great of efforts have been put to modify its structure,^2,3) and several curcumin derivatives and analogues, such as dimethoxycurcumin,^4,5) 4-ethoxycarbonylethylcurcumin (ECECur),⁶⁾ hydrazinocurcumin,⁷⁾ EF24,^8,9) and FLLL32^10–12) were discovered to be more active compounds (Fig. 2).

Fig. 1. The Keto-Enlo Tautomeric Structure of Curcumin

Fig. 2. The Structures of More Active Curcumin Analogues

Since the conjugated α,β-unsaturated diketone moiety in curcumin skeleton is believed to play an important role in mediating the antitumor activity,^13,14) most analogues synthesized before retained α,β-unsaturated ketone moiety.^6,7,15–22) However, a few of reports showed that analogues with broken α,β-unsaturated diketone moiety also have antitumor activity.^{10–12,23–25)} For further investigation of the effects of α,β-unsaturated ketone moiety, in this communication, two series of curcumin derivatives (10a–f, 11a–f, 12a–f and 13a–f with α,β-unsaturated ketone moieties, and 16a–f with a α,β-saturated ketone moiety, Fig. 3) were synthesized and tested for their antiproliferative activities in five human carcinoma cell lines. In the target compounds, dialkylation at C-4 position was aimed to block the conjugation of the diketone moieties, and hydrogenation of compounds 13a–f was proposed to explore the impact of the olefin double bonds. In addition, modification on the phenolic hydroxy groups might be of benefit to physical stability as well as metabolism behavior,⁵⁾ and introduction of the terminal hydrophilic amino groups in the side chains was carried out in anticipation of improved water solubility or/and antitumor activity.^26,27)

Fig. 3. The Structures of the Target Compounds

Results and Discussion

Chemistry

The synthetic routes of the target compounds were outlined in Chart 1 and in Chart 2. For regio-selective alkylation at the C-4 position of curcumin to get the intermediates 4 and 5, the phenolic hydroxyl groups were protected via acetylation, followed by alkylation at the central carbon of intermediate 1 with methyl iodide or benzyl bromide, subsequent deprotection of the acetyl groups. The heptadiene moiety in the intermediate 5 was hydrogenized to obtain 14. The resulting compound 4 or 5, 14 was coupled with 1,2-dibromoethane or 1-bromo-3-chloropropane to yield halo-substituted intermediate 6–9 and 15, respectively. Nucleophilic substitution of intermediate 6, or 7, 8, 9, 15 with various heterocyclic or aliphatic secondary amines afforded the target compounds.

Chart 1. Synthesis of the Target Compounds 10a–f, 11a–f, 12a–f and 13a–f

Reagents and conditions: (i) (CH₃CO)₂O, pyridine, methylene chloride, reflux, 2 h; (ii) CH₃I or C₆H₅CH₂Br, K₂CO₃, acetone, reflux, overnight; (iii) NaOH, methanol; rt., 2 h; (iv) BrCH₂CH₂Br or ClCH₂CH₂CH₂Br, K₂CO₃, acetonitrile, reflux, 6 h; (v) HNR¹R², acetonitrile, reflux, 5 h.

Chart 2. Synthesis of the Target Compounds 16a–f

Reagents and conditions: (vi) H₂/Pd–C, ethanol, rt., 12 h.

Biological Activity

The growth inhibitory effects of the target compounds and intermediates 4–9, 14 were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in five human carcinoma cell lines including human breast adenocarcinoma (MCF-7), human hepatocellular carcinoma (HepG2), human colorectal carcinoma (HCT116), human lung carcinoma (A549), and human fibrosarcoma (HT-1080). The IC₅₀ values for 48 h exposure were summarized in Table 1.

Table 1. Antiproliferative Activities of These Synthetic Curcumin Derivatives in Five Solid Tumor Cell Lines

Compd.	IC₅₀ (µM)
Compd.	MCF-7	HepG2	HCT116	A549	HT1080
4	8.14	5.88	6.31	7.25	5.18
5	31.09	26.45	35.85	27.72	15.50
14	33.66	35.98	31.73	35.32	49.50
6	6.36	7.96	7.48	31.88	5.42
7	42.45	72.23	>100	>100	>100
8	>100	>100	>100	>100	>100
9	>100	>100	>100	>100	>100
10a	7.62	>100	47.48	39.60	4.87
10b	>100	>100	94.36	>100	63.53
10c	30.04	34.92	7.42	41.15	4.98
10d	43.48	35.76	8.54	48.54	4.16
10e	32.54	45.92	7.68	73.30	0.06
10f	19.32	41.08	9.26	43.45	5.30
11a	0.79	7.25	42.94	33.05	5.15
11b	6.24	6.65	32.33	7.72	0.68
11c	32.00	44.63	43.58	34.37	0.68
11d	2.18	36.80	53.23	43.93	5.26
11e	28.39	70.67	96.86	>100	39.12
11f	7.11	44.80	8.64	38.34	3.98
12a	6.21	2.64	6.50	5.88	5.86
12b	5.89	72.01	46.97	43.44	35.49
12c	0.03	5.17	4.80	5.41	0.47
12d	4.81	5.38	39.60	47.04	6.14
12e	7.54	58.37	94.47	72.54	41.05
12f	4.76	5.42	7.61	5.75	4.92
13a	4.71	5.98	8.13	5.87	5.89
13b	5.22	28.96	42.81	39.17	8.21
13c	4.71	0.64	5.10	4.26	5.94
13d	0.74	0.66	4.93	0.72	4.66
13e	6.47	43.88	45.23	46.94	44.14
13f	0.64	5.79	6.31	5.93	4.75
16a	0.76	5.73	5.91	5.49	10.72
16b	0.87	0.38	0.59	0.50	10.27
16c	0.70	0.93	7.88	4.55	4.81
16d	2.46	4.70	7.35	4.88	4.84
16e	6.78	6.55	7.94	5.47	6.09
16f	0.71	0.51	0.78	0.51	0.63
Curcumin	28.03	37.37	43.31	41.35	5.96

a) These cells were treated with a variety of concentrations of each compound for 48 h and the concentrations (IC₅₀s) which inhibit 50% of cell growth were calculated.

As shown in Table 1, the intermediate 4 exhibited greater growth inhibitory potency than curcumin in all the tested cell lines and the intermediate 5 had the similar antiproliferative activity as that of curcumin, suggesting that alkylation at the C-4 position of curcumin was of benefit to antiproliferative activity to some extent.¹¹⁾ The impact of the characteristic of the O-alkylated side chains in the halo-substituted intermediates on cytotoxicity was uncertain since the intermediate 6 possessed similar cytotoxic property in comparison with the intermediate 4 whereas the intermediates 7, 8 and 9 showed dramatically decreased antiproliferative activity.

Compared to the halo-substituted intermediates, most of the target compounds bearing various heterocyclic or aliphatic amino moieties exhibited increased antiproliferative activities. The target compounds (10a–f) derived from 6 were less active than 6. The target compounds (11a–f, 12a–f and 13a–f) derived from 7, 8, and 9 showed more potent activity than that of the three intermediates, respectively, suggesting that the terminal amino moieties introduced into the O-alkyl side chains contributed to the improved antiproliferative activities. Compounds 12a–f and 13af with 4,4-dibenzyl substitution were more potent than compounds 10a–f and 11a–f with 4,4-dimethyl substitution, which suggested that sterically large substitution at C-4 position might favor the enhancement of cytotoxic activity.

The intermediate 14 exhibited the similar antiproliferative activity as that of curcumin and that of the intermediate 5, suggesting that the diketone moiety, but not α,β-unsaturated diketone moiety, is required for the antiproliferative activity. More intriguing, it was found that compounds 16a–f with α,β-saturated ketone moiety were more active than compounds 13a–f with α,β-unsaturated ketone moieties. The most potent compound 16f inhibited cell growth with IC₅₀ values below 1 µM, which was 9- to 81-fold more potent than curcumin.

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 inhibitory effect. Moreover, sterically large substitution at the central carbon of curcumin skeleton was favorable to improving cytotoxic activity.

Experimental

Reagents and General Procedures

Melting points were determined with a Yanaco micro melting point apparatus and were uncorrected. ¹H-NMR spectra were recorded in CDCl₃ on a Bruker ARX-300 spectrometer or a Bruker AV-600 spectrometer. The coupling constants were recorded in hertz (Hz) and chemical shifts were reported in parts per million (δ, ppm) downfield from tetramethylsilane (TMS). High-resolution mass spectra (HR-MS) were recorded on a high-resonance electrospray time-of-flight mass spectrometer LC/MSD QTOF 6520 (Agilent). All reagents and solvents (analytical grade) were commercially available and used without further purification.

Preparation of 1,7-Bis(4-acetoxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (1)

To a solution of curcumin (2.50 g, 6.8 mmol) in methylene chloride (30 mL), acetic anhydride (1.9 mL, 20.4 mmol) and pyridine (1.7 mL, 20.4 mmol) were added. The mixture was refluxed for 2 h and then concentrated under reduced pressure. To the residue, methanol (50 mL) was added to give 1 as a yellow solid, 98% yield, mp 155–157°C. [lit. 154–155°C].²⁸⁾

General Procedure for the Preparation of Compounds 2 and 3

To a stirred solution of 1 (4.5 g, 10.0 mmol) and potassium carbonate (3.5 g, 25.0 mmol) in dry acetone (30 mL), iodomethane or benzyl bromide (25 mmol) was added. The mixture was refluxed overnight and then cooled to room temperature. The filtrate was collected by filtration and concentrated under reduced pressure. The residue was crystallized from acetone-ethanol to give 2 and 3, respectively.

1,7-Bis(4-acetoxy-3-methoxyphenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (2): Yellow solid, 75% yield, mp 160–163°C. ¹H-NMR (300 MHz) δ: 1.48 (6H, s), 2.30 (6H, s), 3.85 (6H, s), 6.70 (2H, d, J=15.6 Hz), 7.02 (2H, d, J=8.1 Hz), 7.06 (2H, d, J=1.8 Hz), 7.13 (2H, dd, J=1.8, 8.1 Hz), 7.68 (2H, d, J=15.6 Hz). HR-MS m/z: 481.1857 (Calcd for C₂₇H₂₉O₈: 481.1862).

1,7-Bis(4-acetoxy-3-methoxyphenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (3): Yellow solid, 88% yield, mp 178–179°C. ¹H-NMR (600 MHz) δ: 2.29 (6H, s), 3.38 (4H, s), 3.81 (6H, s), 6.53 (2H, d, J=15.6 Hz), 6.91 (2H, d, J=1.8 Hz), 6.99 (2H, d, J=8.4 Hz), 7.03 (2H, dd, J=1.8, 8.4 Hz), 7.11 (4H, m), 7.18 (2H, m), 7.22 (4H, m), 7.68 (2H, d, J=15.6 Hz). HR-MS m/z: 633.2483 (Calcd for C₃₉H₃₇O₈: 633.2488).

General Procedure for the Preparation of Compounds 4 and 5

To a solution of intermediate 2 or 3 (7.9 mmol) in methanol (20 mL), sodium hydroxide (0.7 g, 17.4 mmol) was added. The mixture was stirred for 2 h at room temperature, and then evaporated to dryness in vacuo. The residue was dissolved in methylene chloride (30 mL), followed by neutralization with acetic acid. Then water (50 mL) was added and the organic phase was separated. The aqueous phase was extracted with methylene chloride (2×20 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from petroleum ether–ethyl acetate to give 4 and 5.

1,7-Bis(4-hydroxy-3-methoxyphenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (4): Yellow solid, 74% yield, mp 136–138°C. ¹H-NMR (300 MHz) δ: 1.47 (6H, s), 3.91 (6H, s), 6.62 (2H, d, J=15.6 Hz), 6.89 (2H, d, J=8.4 Hz), 6.99 (2H, d, J=1.8 Hz), 7.09 (2H, dd, J=1.8, 8.4 Hz), 7.66 (2H, d, J=15.6 Hz); HR-MS m/z: 397.1646 (Calcd for C₂₃H₂₅O₆: 397.1651).

1,7-Bis(4-hydroxy-3-methoxyphenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (5): Yellow solid, 91% yield, mp 115–117°C. ¹H-NMR (600 MHz): δ 3.38 (4H, s), 3.86 (6H, s), 6.54 (2H, d, J=15.6 Hz), 6.86 (4H, m), 7.03 (2H, dd, J=1.8, 7.8 Hz), 7.10 (4H, m), 7.17 (2H, m), 7.21 (4H, m), 7.69 (2H, d, J=15.6 Hz). HR-MS m/z: 549.2272 (Calcd for C₃₅H₃₃O₆: 549.2277).

Preparation of 1,7-Bis(4-hydroxy-3-methoxyphenyl)-4,4-dibenzylheptane-3,5-dione (14)

To a solution of compound 5 (5.5 g, 0.01 mol) in ethanol (50 mL) was added 10% Pd–C (0.5 g). After degassing, the mixture was hydrogenated at room temperature and at atmospheric pressure for 12 h. Then, methylene chloride (10 mL) was added to dissolve the precipitate, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give 14 as a white solid, 65% yield, mp 73–75°C. ¹H-NMR (300 MHz) δ: 2.55 (4H, m), 2.69 (4H, m), 3.31 (4H, s), 3.83 (6H, s), 6.55 (4H, m), 6.79 (2H, d, J=8.4 Hz), 6.93 (4H, m), 7.21 (6H, m). HR-MS m/z: 553.2585 (Calcd for C₃₅H₃₇O₆: 553.2592).

General Procedure for the Preparation of Compounds 6, 7, 8, 9 and 15

To a solution of 4 or 5, 14 (12.0 mmol) in acetonitrile (50 mL), potassium carbonate (5.0 g, 36.0 mmol) was added. The mixture was stirred at 70°C, and then 1,2-dibromoethane or 1-bromo-3-chloropropane (36.0 mmol) diluted with acetonitrile (5 mL) was added dropwise. The mixture was refluxed for 6 h, and concentrated under reduced pressure. To the residue, methylene chloride (50 mL) and water (50 mL) were added. The organic phase was separated and the aqueous phase was extracted with methylene chloride (3×20 mL). The combined organic phase was dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with petroleum ether–ethyl acetate as gradient elute to give 6, 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. ¹H-NMR (300 MHz) δ: 1.48 (6H, s), 3.65 (4H, t, J=6.6 Hz), 3.88 (6H, s), 4.34 (4H, t, J=6.6 Hz), 6.65 (2H, d, J=15.6 Hz), 6.85 (2H, d, J=8.1 Hz), 7.02 (2H, d, J=1.5 Hz), 7.10 (2H, dd, J=1.5, 8.1 Hz), 7.67 (2H, d, J=15.6 Hz). HR-MS m/z: 609.0482 (Calcd for C₂₇H₃₁Br₂O₆: 609.0487).

1,7-Bis(4-(3-chloropropoxy)-3-methoxyphenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (7): Yellow solid, 50% yield, mp 90–91°C. ¹H-NMR (300 MHz) δ: 1.48 (6H, s), 2.28 (4H, m), 3.75 (4H, t, J=6.0 Hz), 3.87 (6H, s), 4.18 (4H, t, J=6.0 Hz), 6.65 (2H, d, J=15.6 Hz), 6.86 (2H, d, J=8.4 Hz) 7.00 (2H, d, J=1.8 Hz), 7.11 (2H, dd, J=1.8, 8.4 Hz), 7.68 (2H, d, J=15.6 Hz). HR-MS m/z: 549.1805 (Calcd for C₂₉H₃₅Cl₂O₆: 549.1810).

1,7-Bis(4-(2-bromoethoxy)-3-methoxyphenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (8): Yellow solid, 71% yield, mp 156–157°C. ¹H-NMR (300 MHz) δ: 3.38 (4H, s), 3.64 (4H, t, J=6.6 Hz), 3.85 (6H, s), 4.33 (4H, t, J=6.6 Hz), 6.52 (2H, d, J=15.6 Hz), 6.82 (2H, d, J=8.4 Hz), 6.87 (2H, d, J=1.8 Hz), 7.03 (2H, dd, J=1.8, 8.4 Hz), 7.10 (4H, m), 7.20 (6H, m), 7.67 (2H, d, J=15.6 Hz). HR-MS m/z: 761.1108 (Calcd for C₃₉H₃₉Br₂O₆: 761.1113).

1,7-Bis(4-(3-chloropropoxy)-3-methoxyphenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (9): Yellow solid, 78% yield, mp 106–108°C. ¹H-NMR (300 MHz) δ: 2.27 (4H, m), 3.38 (4H, s), 3.74 (4H, t, J=6.0 Hz), 3.83 (6H, s), 4.17 (4H, t, J=6.0 Hz), 6.53 (2H, d, J=15.3 Hz), 6.84 (2H, d, J=8.4 Hz), 6.87 (2H, d, J=1.8 Hz), 7.05 (2H, dd, J=1.8, 8.4 Hz), 7.11 (4H, m), 7.20 (6H, m), 7.68 (2H, d, J=15.3 Hz). HR-MS m/z: 701.2431 (Calcd for C₄₁H₄₃Cl₂O₆: 701.2436).

1,7-Bis(4-(3-chloropropoxy)-3-methoxyphenyl)-4,4-dibenzylheptane-3,5-dione (15): White solid, 75% yield, mp 95–97°C. ¹H-NMR (300 MHz) δ: 2.25 (4H, m), 2.58 (4H, m), 2.71 (4H, m), 3.31 (4H, s), 3.75 (4H, t, J=6.0 Hz), 3.82 (6H, s), 4.11 (4H, t, J=6.0 Hz), 6.59 (4H, m), 6.79 (2H, d, J=8.7 Hz), 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 Compounds 10a–f, 11a–f, 12a–f, 13a–f and 16a–f

To a solution of halo-substituted intermediate 6, or 7, 8, 9, 15 (2.0 mmol) in acetonitrile (10 mL), a heterocyclic or aliphatic secondary amine (20.0 mmol) was added. The mixture was refluxed for 5 h and concentrated under reduced pressure. The residue was dissolved in methylene chloride (20 mL) and washed with water (3×30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography with dichloromethane–methanol as gradient elute to afford the corresponding target compounds 10a–f, 11a–f, 12a–f, 13a–f and 16a–f.

1,7-Bis(4-(2-dimethylaminoethoxy)-3-methoxyphenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (10a): Yellow oil, 38% yield. ¹H-NMR (300 MHz) δ: 1.47 (6H, s), 2.40 (12H, s), 2.86 (4H, t, J=5.7 Hz), 3.86 (6H, s), 4.17 (4H, t, J=5.7 Hz), 6.64 (2H, d, J=15.6 Hz), 6.85 (2H, d, J=8.4 Hz), 6.99 (2H, s), 7.10 (2H, d, J=8.4 Hz), 7.67 (2H, d, J=15.6 Hz). HR-MS m/z: 539.3166 (Calcd for C₃₁H₄₃N₂O₆: 539.3121).

1,7-Bis(4-(2-diethylaminoethoxy)-3-methoxyphenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (10b): Yellow oil, 45% yield. ¹H-NMR (300 MHz) δ: 1.05 (12H, t, J=7.2 Hz), 1.47 (6H, s), 2.62 (8H, q, J=7.2 Hz), 2.91 (4H, t, J=6.9 Hz), 3.87 (6H, s), 4.10 (4H, t, J=6.9 Hz), 6.64 (2H, d, J=15.6 Hz), 6.85 (2H, d, J=8.4 Hz), 6.99 (2H, d, J=1.5 Hz), 7.10 (2H, dd, J=1.5, 8.4 Hz), 7.67 (2H, d, J=15.6 Hz). HR-MS m/z: 595.3742 (Calcd for C₃₅H₅₁N₂O₆: 595.3747).

1,7-Bis(3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (10c): Yellow oil, 57% yield. ¹H-NMR (300 MHz) δ: 1.47 (6H, s), 1.80 (8H, m), 2.63 (8H, m), 2.95 (4H, t, J=6.3 Hz), 3.87 (6H, s), 4.17 (4H, t, J=6.3 Hz), 6.64 (2H, d, J=15.3 Hz), 6.85 (2H, d, J=8.4 Hz), 7.00 (2H, d, J=1.5 Hz), 7.10 (2H, dd, J=1.5, 8.4 Hz), 7.67 (2H, d, J=15.3 Hz). HR-MS m/z: 591.3429 (Calcd for C₃₅H₄₇N₂O₆: 591.3434).

1,7-Bis(3-methoxy-4-(2-piperidin-1-yl-ethoxy)phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (10d): Yellow oil, 60% yield. ¹H-NMR (300 MHz) δ: 1.46 (10H, m), 1.59 (8H, m), 2.50 (8H, m), 2.80 (4H, t, J=6.6 Hz), 3.87 (6H, s), 4.16 (4H, t, J=6.6 Hz), 6.64 (2H, d, J=15.6 Hz), 6.85 (2H, d, J=8.4 Hz), 6.99 (2H, d, J=1.8 Hz), 7.10 (2H, dd, J=1.8, 8.4 Hz), 7.67 (2H, d, J=15.6 Hz). HR-MS m/z: 619.3742 (Calcd for C₃₇H₅₁N₂O₆: 619.3747).

1,7-Bis(3-methoxy-4-(2-morpholinoethoxy)phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (10e): Yellow oil, 71% yield. ¹H-NMR (600 MHz) δ: 1.47 (6H, s), 2.58 (8H, m), 2.83 (4H, t, J=6.0 Hz), 3.71 (8H, m), 3.87 (6H, s), 4.17 (4H, t, J=6.0 Hz), 6.64 (2H, d, J=15.6 Hz), 6.85 (2H, d, J=8.4 Hz), 7.00 (2H, d, J=1.8 Hz), 7.10 (2H, dd, J=1.8, 8.4 Hz), 7.67 (2H, d, J=15.6 Hz). HR-MS m/z: 623.3327 (Calcd for C₃₅H₄₇N₂O₈: 623.3332).

1,7-Bis(3-methoxy-4-(2-(4-methylpiperazinyl-1-yl)ethoxy)phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (10f): Yellow oil, 70% yield. ¹H-NMR (300 MHz) δ: 1.47 (6H, s), 2.28 (6H, s), 2.45 (12H, s), 2.61 (8H, s), 3.87 (6H, s), 4.15 (4H, t, J=5.7 Hz), 6.64 (2H, d, J=15.6 Hz), 6.84 (2H, d, J=8.1 Hz), 7.00 (2H, s), 7.10 (2H, d, J=8.1 Hz), 7.67 (2H, d, J=15.6 Hz). HR-MS m/z: 649.3960 (Calcd for C₃₇H₅₃N₄O₆: 649.3965).

1,7-Bis(3-methoxy-4-(3-dimethylaminopropoxy)phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (11a): Yellow oil, 40% yield. ¹H-NMR (300 MHz) δ: 1.47 (6H, s), 2.02 (4H, m), 2.24 (12H, s), 2.45 (4H, t, J=7.2 Hz), 3.87 (6H, s), 4.09 (4H, t, J=6.6 Hz), 6.64 (2H, d, J=15.6 Hz), 6.86 (2H, d, J=8.4 Hz), 7.00 (2H, s), 7.10 (2H, d, J=8.4 Hz), 7.68 (2H, d, J=15.6 Hz). HR-MS m/z: 567.3429 (Calcd for C₃₃H₄₇N₂O₆: 567.3434).

1,7-Bis(3-methoxy-4-(3-diethylaminopropoxy)phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (11b): Yellow oil, 53% yield. ¹H-NMR (300 MHz) δ: 1.01 (12H, t, J=7.2 Hz), 1.47 (6H, s), 1.98 (4H, m), 2.57 (12H, m), 3.87 (6H, s), 4.08 (4H, t, J=6.9 Hz), 6.64 (2H, d, J=15.6 Hz), 6.85 (2H, d, J=8.4 Hz), 7.00 (2H, d, J=1.5 Hz), 7.10 (2H, dd, J=1.5, 8.4 Hz), 7.68 (2H, d, J=15.6 Hz). HR-MS m/z: 623.4055 (Calcd for C₃₇H₅₅N₂O₆: 623.4060).

1,7-Bis(3-methoxy-4-(3-pyrrolidin-1-yl-propoxy)phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (11c): Yellow oil, 72% yield. ¹H-NMR (300 MHz) δ: 1.47 (6H, s), 1.80 (8H, m), 2.08 (4H, m), 2.56 (8H, m), 2.65 (4H, t, J=7.2 Hz), 3.87 (6H, s), 4.11 (4H, t, J=6.6 Hz), 6.64 (2H, d, J=15.3 Hz), 6.86 (2H, d, J=8.4 Hz), 7.00 (2H, d, J=1.8 Hz), 7.10 (2H, dd, J=1.8, 8.4 Hz), 7.67 (2H, d, J=15.3 Hz). HR-MS m/z: 619.3742 (Calcd for C₃₇H₅₁N₂O₆: 619.3747).

1,7-Bis(3-methoxy-4-(3-piperidin-1-yl)propoxy)phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (11d): Yellow oil, 78% yield. ¹H-NMR (300 MHz) δ: 1.42 (4H, m), 1.47 (6H, s), 1.57 (8H, m), 2.02 (4H, m), 2.38 (8H, s), 2.45 (4H, t, J=7.2 Hz), 3.87 (6H, s), 4.09 (4H, t, J=6.6 Hz), 6.64 (2H, d, J=15.6 Hz), 6.86 (2H, d, J=8.4 Hz,), 7.00 (2H, d, J=1.5 Hz), 7.10 (2H, dd, J=1.5, 8.4 Hz), 7.67 (2H, d, J=15.6 Hz). HR-MS m/z: 647.4055 (Calcd for C₃₉H₅₅N₂O₆: 647.4060).

1,7-Bis(3-methoxy-4-(3-morpholinopropoxy)phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (11e): Yellow oil, 69% yield. ¹H-NMR (300 MHz) δ: 1.47 (6H, s), 2.01 (4H, m), 2.49 (12H, m), 3.71 (8H, m), 3.87 (6H, s), 4.10 (4H, t, J=6.3 Hz), 6.64 (2H, d, J=15.6 Hz), 6.86 (2H, d, J=8.4 Hz), 7.00 (2H, s), 7.10 (2H, d, J=8.4 Hz), 7.67 (2H, d, J=15.6 Hz). HR-MS m/z: 651.3640 (Calcd for C₃₇H₅₁N₂O₈: 651.3645).

1,7-Bis(3-methoxy-4-(3-(4-methylpiperazinyl-1-yl)propoxy)phenyl)-4,4-dimethyl-hepta-1,6-diene-3,5-dione (11f): Yellow oil, 63% yield. ¹H-NMR (300 MHz) δ: 1.47 (6H, s), 2.02 (4H, m), 2.28 (6H, s), 2.46 (20H, m), 3.87 (6H, s), 4.10 (4H, t, J=6.6 Hz), 6.64 (2H, d, J=15.6 Hz), 6.86 (2H, d, J=8.4 Hz), 7.00 (2H, d, J=1.8 Hz), 7.10 (2H, dd, J=1.8, 8.4 Hz), 7.68 (2H, d, J=15.6 Hz). HR-MS m/z: 677.4273 (Calcd for C₃₉H₅₇N₄O₆: 677.4278).

1,7-Bis(4-(2-dimethylaminoethoxy)-3-methoxyphenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (12a): Yellow oil, 42% yield. ¹H-NMR (300 MHz) δ: 2.36 (12H, m), 2.83 (4H, t, J=6.0 Hz), 3.38 (4H, s), 3.83 (6H, s), 4.14 (4H, t, J=6.0 Hz), 6.53 (2H, d, J=15.3 Hz), 6.82 (2H, d, J=8.1 Hz), 6.86 (2H, d, J=1.2 Hz), 7.04 (2H, dd, J=1.2, 8.1 Hz), 7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.3 Hz) HR-MS m/z: 691.3742 (Calcd for C₄₃H₅₁N₂O₆: 691.3747).

1,7-Bis(4-(2-diethylaminoethoxy)-3-methoxyphenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (12b): Yellow oil, 48% yield. ¹H-NMR (300 MHz) δ: 1.06 (12H, t, J=6.9 Hz), 2.65 (8H, q, J=6.9 Hz), 2.93 (4H, t, J=6.6 Hz), 3.38 (4H, s), 3.83 (6H, s), 4.11 (4H, t, J=6.6 Hz), 6.53 (2H, d, J=15.3 Hz), 6.83 (2H, d, J=8.4 Hz), 6.86 (2H, d, J=1.5 Hz), 7.05 (2H, dd, J=1.5, 8.4 Hz), 7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.3 Hz). HR-MS m/z: 747.4368 (Calcd for C₄₇H₅₉N₂O₆: 747.4373).

1,7-Bis(3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)phenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (12c): Yellow oil, 67% yield. ¹H-NMR (300 MHz) δ: 1.80 (8H, m), 2.64 (8H, s), 2.96 (4H, t, J=6.6 Hz), 3.38 (4H, s), 3.83 (6H, s), 4.17 (4H, t, J=6.6 Hz), 6.53 (2H, d, J=15.3 Hz), 6.83 (2H, d, J=8.4 Hz), 6.86 (2H, d, J=1.8 Hz), 7.04 (2H, dd, J=1.8, 8.4 Hz), 7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.3 Hz). HR-MS m/z: 743.4055 (Calcd for C₄₇H₅₅N₂O₆: 743.4060).

1,7-Bis(3-methoxy-4-(2-piperidin-1-yl-ethoxy)phenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (12d): Yellow oil, 73% yield; ¹H-NMR (300 MHz) δ: 1.44 (4H, m), 1.59 (8H, m), 2.50 (8H, m), 2.80 (4H, t, J=6.3 Hz), 3.38 (4H, s), 3.83 (6H, s), 4.15 (4H, t, J=6.3 Hz), 6.53 (2H, d, J=15.6 Hz), 6.82 (2H, d, J=8.4 Hz), 6.86 (2H, d, J=1.5 Hz), 7.04 (2H, dd, J=1.5, 8.4 Hz), 7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.6 Hz). HR-MS m/z: 771.4368 (Calcd for C₄₉H₅₉N₂O₆₆: 771.4373).

1,7-Bis(3-methoxy-4-(2-morpholinoethoxy)phenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (12e): Yellow oil, 69% yield; ¹H-NMR (300 MHz) δ: 2.58 (8H, m), 2.83 (4H, t, J=6.0 Hz), 3.38 (4H, s), 3.72 (8H, m), 3.83 (6H, s), 4.15 (4H, t, J=6.0 Hz), 6.53 (2H, d, J=15.3 Hz), 6.82 (2H, d, J=8.4 Hz), 6.86 (2H, d, J=1.5 Hz), 7.04 (2H, dd, J=1.5, 8.4 Hz), 7.10 (4H, m), 7.19 (6H, m.), 7.68 (2H, d, J=15.3 Hz). HR-MS m/z: 775.3953 (Calcd for C₄₇H₅₅N₂O₈: 775.3958).

1,7-Bis(3-methoxy-4-(2-(4-methylpiperazinyl-1-yl)ethoxy)phenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (12f): Yellow oil, 63% yield. ¹H-NMR (300 MHz) δ: 2.29 (6H, s), 2.50 (8H, s), 2.63 (8H, s), 2.84 (4H, t, J=6.0 Hz), 3.38 (4H, s), 3.83 (6H, s), 4.15 (4H, t, J=6.0 Hz), 6.53 (2H, d, J=15.6 Hz), 6.82 (2H, d, J=8.4 Hz), 6.86 (2H, d, J=1.5 Hz), 7.04 (2H, dd, J=1.5, 8.4 Hz), 7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.6 Hz). HR-MS m/z: 801.4586 (Calcd for C₄₉H₆₁N₄O₆: 801.4591).

1,7-Bis(4-(3-dimethylaminopropoxy)-3-methoxyphenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (13a): Yellow oil, 45% yield. ¹H-NMR (300 MHz) δ: 2.06 (4H, m), 2.30 (12H, s), 2.54 (4H, t, J=7.2 Hz), 3.38 (4H, s), 3.84 (6H, s), 4.07 (4H, t, J=6.6 Hz), 6.53 (2H, d, J=15.3 Hz), 6.82 (2H, d, J=8.4 Hz), 6.86 (2H, d, J=1.8 Hz), 7.04 (2H, dd, J=1.8, 8.4 Hz), 7.11 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.3 Hz). HR-MS m/z: 719.4055 (Calcd for C₄₅H₅₅N₂O₆: 719.4060).

1,7-Bis(4-(3-diethylaminopropoxy)-3-methoxyphenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (13b): Yellow oil, 50% yield. ¹H-NMR (300 MHz) δ: 1.02 (12H, t, J=7.2 Hz), 1.98 (4H, m), 2.57 (8H, m), 2.63 (4H, m), 3.38 (4H, s), 3.83 (6H, s), 4.07 (4H, t, J=6.6 Hz), 6.54 (2H, d, J=15.4 Hz), 6.82 (2H, d, J=8.4 Hz), 6.86 (2H, d, J=1.8 Hz), 7.04 (2H, dd, J=1.8, 8.4 Hz), 7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.4 Hz). HR-MS m/z: 775.4681 (Calcd for C₄₉H₆₃N₂O₆: 775.4686).

1,7-Bis(3-methoxy-4-(3-pyrrolidin-1-yl-propoxy)phenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (13c): Yellow oil, 68% yield. ¹H-NMR (300 MHz) δ: 1.80 (8H, s), 2.08 (4H, m), 2.59 (8H, s), 2.67 (4H, t, J=6.9 Hz), 3.38 (4H, s), 3.83 (6H, s), 4.09 (4H, t, J=6.6 Hz), 6.53 (2H, d, J=15.6 Hz), 6.83 (2H, d, J=8.4 Hz), 6.86 (2H, d, J=1.5 Hz), 7.04 (2H, dd, J=1.5, 8.4 Hz), 7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.6 Hz). HR-MS m/z: 771.4368 (Calcd for C₄₉H₅₉N₂O₆: 771.4373).

1,7-Bis(3-methoxy-4-(3-piperidin-1-yl-propoxy)phenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (13d): Yellow oil, 75% yield. ¹H-NMR (300 MHz) δ: 1.54 (4H, m), 1.77 (8H, m), 2.19 (4H, m), 2.86 (12H, m), 3.38 (4H, s), 3.82 (6H, s), 4.07 (4H, t, J=6.0 Hz), 6.53 (2H, d, J=15.3 Hz), 6.80 (2H, d, J=8.4 Hz), 6.85 (2H, d, J=1.5 Hz), 7.04 (2H, dd, J=1.5, 8.4 Hz), 7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.3 Hz). HR-MS m/z: 799.4681 (Calcd for C₅₁H₆₃N₂O₆: 799.4686).

1,7-Bis(3-methoxy-4-(3-morpholinopropoxy)phenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (13e): Yellow oil, 80% yield. ¹H-NMR (300 MHz) δ: 2.09 (4H, m), 2.65 (12H, m), 3.38 (4H, s), 3.77 (8H, m), 3.83 (6H, s), 4.08 (4H, t, J=6.3 Hz), 6.53 (2H, d, J=15.3 Hz), 6.81 (2H, d, J=8.4 Hz), 6.87 (2H, d, J=1.8 Hz), 7.04 (2H, dd, J=1.8, 8.4 Hz), 7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.3 Hz). HR-MS m/z: 803.4266 (Calcd for C₄₉H₅₉N₂O₆: 803.4271).

1,7-Bis(3-methoxy-4-(3-(4-methylpiperazinyl-1-yl)propoxy)phenyl)-4,4-dibenzyl-hepta-1,6-diene-3,5-dione (13f): Yellow oil, 75% yield. ¹H-NMR (300 MHz) δ: 2.02 (4H, m), 2.32 (6H, s), 2.52 (20H, m), 3.38 (4H, s), 3.83 (6H, s), 4.08 (4H, t, J=6.6 Hz), 6.54 (2H, d, J=15.6 Hz), 6.83 (2H, d, J=8.4 Hz), 6.87 (2H, d, J=1.8 Hz), 7.04 (2H, dd, J=1.8, 8.4 Hz), 7.10 (4H, m), 7.19 (6H, m), 7.68 (2H, d, J=15.6 Hz). HR-MS m/z: 829.4899 (Calcd for C₅₁H₆₅N₄O₆: 829.4904).

1,7-Bis(4-(3-dimethylaminopropoxy)-3-methoxyphenyl)-4,4-dibenzylheptane-3,5-dione (16a): Yellow oil, 49% yield. ¹H-NMR (300 MHz) δ: 1.95–2.04 (4H, m), 2.26 (12H, s), 2.47 (4H, t, J=7.2 Hz), 2.59 (4H, m), 2.70 (4H, m), 3.31 (4H, s), 3.82 (6H, s), 4.02 (4H, t, J=6.6 Hz), 6.58 (4H, m,), 6.78 (2H, d, J=8.7 Hz), 6.94 (4H, m), 7.21 (6H, m). HR-MS m/z: 723.4368 (Calcd for C₄₅H₅₉N₂O₆: 722.4375).

1,7-Bis(4-(3-diethylaminopropoxy)-3-methoxyphenyl)-4,4-dibenzylheptane-3,5-dione (16b): Yellow oil, 53% yield. ¹H-NMR (300 MHz) δ: 1.07 (12H, t, J=7.2 Hz), 2.00 (4H, m), 2.61 (12H, m), 2.68 (8H, m), 3.31 (4H, s), 3.81 (6H, s), 4.02 (4H, t, J=6.6 Hz), 6.58 (4H, m), 6.77 (2H, d, J=8.7 Hz), 6.94 (4H, m), 7.21 (6H, m). HR-MS m/z: 779.4994 (Calcd for C₄₉H₆₇N₂O₆: 779.5001).

1,7-Bis(3-methoxy-4-(3-pyrrolidin-1-yl-propoxy)phenyl)-4,4-dibenzylheptane-3,5-dione (16c): Yellow oil, 66% yield. ¹H-NMR (300 MHz) δ: 1.81 (8H, m), 2.51 (4H, m), 2.58 (12H, m), 2.68 (8H, m), 3.31 (4H, s), 3.82 (6H, s), 4.04 (4H, t, J=6.6 Hz), 6.58 (4H, m), 6.78 (2H, d, J=8.7 Hz), 6.94 (4H, m), 7.21 (6H, m). HR-MS m/z: 775.4681 (Calcd for C₄₉H₆₃N₂O₆: 775.4688).

1,7-Bis(3-methoxy-4-(3-piperidin-1-yl-propoxy)phenyl)-4,4-dibenzylheptane-3,5-dione (16d): Yellow oil, 78% yield. ¹H-NMR (300 MHz) δ: 1.45 (4H, m), 1.59 (8H, m), 2.01 (4H, m), 2.40 (8H, m), 2.49 (4H, t, J=7.2 Hz), 2.59 (4H, m), 2.70 (4H, m), 3.31 (4H, s), 3.81 (6H, s), 4.02 (4H, t, J=6.6 Hz), 6.58 (4H, m), 6.78 (2H, d, J=8.7 Hz), 6.94 (4H, m), 7.21 (6H, m). HR-MS m/z: 803.4994 (Calcd for C₅₁H₆₇N₂O₆: 803.5001).

1,7-Bis(3-methoxy-4-(3-morpholinopropoxy)phenyl)-4,4-dibenzylheptane-3,5-dione (16e): Yellow oil, 84% yield. ¹H-NMR (300 MHz) δ: 1.99 (4H, m), 2.46 (8H, m), 2.51 (4H, t, J=6.9 Hz), 2.59 (4H, m), 2.71 (4H, m), 3.31 (4H, s), 3.71 (8H, m), 3.82 (6H, s), 4.03 (4H, t, J=6.6 Hz), 6.59 (4H, m), 6.78 (2H, d, J=8.7 Hz), 6.93 (4H, m), 7.21 (6H, m). HR-MS m/z: 807.4579 (Calcd for C₄₉H₆₄N₂O₆: 807.4586).

1,7-Bis(3-methoxy-4-(3-(4-methylpiperazinyl-1-yl)propoxy)phenyl)-4,4-dibenzylheptane-3,5-dione (16f): Yellow oil, 73% yield. ¹H-NMR (300 MHz) δ: 1.99 (4H, m), 2.28 (6H, s), 2.52 (20H, m), 2.60 (8H, m), 3.31 (4H, s), 3.81 (6H, s), 4.02 (4H, t, J=6.6 Hz), 6.58 (4H, m), 6.78 (2H, d, J=8.7 Hz), 6.94 (4H, m), 7.21 (6H, m). HR-MS m/z: 833.5212 (Calcd for C₅₁H₆₉N₄O₆: 833.5219).

Antiproliferative Activity Assay

The antiproliferative activity of curcumin analogues were evaluated with five human tumor cell lines by MTT assay. Briefly, approximately 5×10³ cells (MCF-7, HepG2, HCT116, A549, and HT-1080) were suspended in 0.1 mL RPMI 1640 medium containing 10% fetal bovine serum (FBS) in triplicate in 96 well plate and 0.1 mL medium containing different concentrations of each analogue was added in each well and then incubated at 37°C for 48 h and then 0.1 mL of MTT solution (0.5 mg/mL) was added to each well. After 4 h incubated at 37°C, the mediums were removed carefully and 0.15 mL of dimethyl sulphoxide (DMSO) was added to dissolve the formazan crystals. The optical density (OD) values at 492 nm were measured with the enzyme-linked immunosorbent assay (ELISA) reader. The concentrations (IC₅₀s) which inhibited 50% of cell growth were calculated using Sigma plot10.

Acknowledgment

This work was supported by National Key Technologies R & D Program of China (2009ZX09103-057).

References

1) Aggarwal B. B., Kumar A., Bharti A. C., Anticancer Res., 23 (1A), 363–398 (2003).
2) Agrawal D. K., Mishra P. K., Med. Res. Rev., 30, 818–860 (2010).
3) Vyas A., Dandawate P., Padhye S., Ahmad A., Sarkar F., Curr. Pharm. Des., 19, 2047–2069 (2013).
4) Skehan P., Storeng R., Scudiero D., Monks A., McMahon J., Vistica D., Warren J. T., Bokesch H., Kenney S., Boyd M. R., J. Natl. Cancer Inst., 82, 1107–1112 (1990).
5) Tamvakopoulos C., Dimas K., Sofianos Z. D., Hatziantoniou S., Han Z., Liu Z.-L., Wyche J. H., Pantazis P., Clin. Cancer Res., 13, 1269–1277 (2007).
6) Ohtsu H., Xiao Z., Ishida J., Nagai M., Wang H. K., Itokawa H., Su C. Y., Shih C., Chiang T., Chang E., Lee Y., Tsai M. Y., Chang C., Lee K. H., J. Med. Chem., 45, 5037–5042 (2002).
7) Shim J. S., Kim D. H., Jung H. J., Kim J. H., Lim D., Lee S. K., Kim K. W., Ahn J. W., Yoo J. S., Rho J. R., Shin J., Kwon H. J., Bioorg. Med. Chem., 10, 2439–2444 (2002).
8) Adams B. K., Ferstl E. M., Davis M. C., Herold M., Kurtkaya S., Camalier R. F., Hollingshead M. G., Kaur G., Sausville E. A., Rickles F. R., Snyder J. P., Liotta D. C., Shoji M., Bioorg. Med. Chem., 12, 3871–3883 (2004).
9) Adams B. K., Cai J., Armstrong J., Herold M., Lu Y. J., Sun A., Snyder J. P., Liotta D. C., Jones D. P., Shoji M., Anticancer Drugs, 16, 263–275 (2005).
10) Lin L., Hutzen B., Zuo M., Ball S., Deangelis S., Foust E., Pandit B., Ihnat M. A., Shenoy S. S., Kulp S., Li P. K., Li C., Fuchs J., Lin J., Cancer Res., 70, 2445–2454 (2010).
11) Lin L., Deangelis S., Foust E., Fuchs J. R., Li C., Li P.-K., Schwartz E. B., Lesinski G. B., Benson D., Lü J., Hoyt D., Lin J., Mol. Cancer, 9, 217 (2010).
12) Fossey S. L., Bear M. D., Lin J., Li C., Schwartz E. B., Li P.-K., Fuchs J. R., Fenger J., Kisseberth W. C., London C. A., BMC Cancer, 11, 112 (2011).
13) Yoysungnoen P., Wirachwong P., Changtam C., Suksamrarn A., Patumraj S., World J. Gastroenterol., 14, 2003–2009 (2008).
14) Anand P., Thomas S. G., Kunnumakkara A. B., Sundaram C., Harikumar K. B., Sung B., Tharakan S. T., Misra K., Priyadarsini I. K., Rajasekharan K. N., Aggarwal B. B., Biochem. Pharmacol., 76, 1590–1611 (2008).
15) Simon A., Allais D. P., Duroux J. L., Basly J. P., Durand-Fontanier S., Delage C., Cancer Lett., 129, 111–116 (1998).
16) Ohtsu H., Itokawa H., Xiao Z., Su C. Y., Shih C. C. Y., Chiang T., Chang E., Lee Y., Chiu S. Y., Chang C., Lee K. H., Bioorg. Med. Chem., 11, 5083–5090 (2003).
17) Lin L., Shi Q., Nyarko A. K., Bastow K. F., Wu C. C., Su C. Y., Shih C. C., Lee K. H., J. Med. Chem., 49, 3963–3972 (2006).
18) Lin L., Shi Q., Su C. Y., Shih C. C.-Y., Lee K. H., Bioorg. Med. Chem., 14, 2527–2534 (2006).
19) Youssef D., Nichols C. E., Cameron T. S., Balzarini J., De Clercq E., Jha A., Bioorg. Med. Chem. Lett., 17, 5624–5629 (2007).
20) Fuchs J. R., Pandit B., Bhasin D., Etter J. P., Regan N., Abdelhamid D., Li C. L., Lin J., Li P.-K., Bioorg. Med. Chem. Lett., 19, 2065–2069 (2009).
21) Amolins M. W., Peterson L. B., Blagg B. S. J., Bioorg. Med. Chem., 17, 360–367 (2009).
22) Qiu X., Du Y., Lou B., Zuo Y., Shao W., Huo Y., Huang J., Yu Y., Zhou B., Du J., Fu H., Bu X., J. Med. Chem., 53, 8260–8273 (2010).
23) Li P.-K., Li C., Lin J., Fuchs J. R., W. O. Patent 121007 (2010) [Chem. Abstr., 153, 546757 (2010)].
24) Han Y. M., Shin D. S., Lee Y. J., Ismail I. A., Hong S. H., Han D. C., Kwon B. M., Bioorg. Med. Chem. Lett., 21, 747–751 (2011).
25) Bayomi S., El-Kashef H., El-Ashmawy M., Nasr M. A., El-Sherbeny M., Badria F., Abou-zeid L., Ghaly M., Abdel-Aziz N., Med. Chem. Res., 22, 1147–1162 (2013).
26) Manohar S., Khan S. I., Kandi S. K., Raj K., Sun G., Yang X., Calderon Molina A. D., Ni N., Wang B., Rawat D. S., Bioorg. Med. Chem. Lett., 23, 112–116 (2013).
27) Fang X., Fang L., Gou S., Cheng L., Bioorg. Med. Chem. Lett., 23, 1297–1301 (2013).
28) Pedersen U., Rasmussen P. B., Lawesson S.-O., Liebigs Ann. Chem., 1557–1569 (1985).

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