Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
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Synthesis and Biological Evaluation of Curcumin Analogs as Antiplatelet Inhibitor

  • Lee, Dong Won (Department of Organic Synthesis, Shinpoong Pharmaceutical Co., LTD) ;
  • Park, Jin Hun (Department of Organic Synthesis, Shinpoong Pharmaceutical Co., LTD) ;
  • Yoon, Seung Soo (Department of Chemistry, Sungkyunkwan University)
  • Received : 2013.12.30
  • Accepted : 2014.01.07
  • Published : 2014.05.20
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Abstract

Keywords

Experimental

Preparation of Platelets. Whole blood for experiment was collected from abdominal aorta in male SD rat. And it was anticoagulated with 1 mL of 3.2% sodium citrate solu-tion for the preparation of platelet rich plasma (PRP) and pletelets were activated in the presence of 100 μL of PGE1 for the preparation of washed platelets (WPs). PRP was prepared by centrifugation for 15 min at 150 g, and platelet-poor plasma was obtained from the precipitated fraction of PRP by centrifugation for 20 min at 2000 g. The platelet count in PRP was adjusted to 1 × 108 cells/mL by using platelet-poor plasma. For preparation of WPs, PRP was centrifuged for 10 min at 500 g, and platelet pellets were washed in Tyrode buffer.

Measurement of Aggregation. Washed platelets were adjusted to 1 × 108 cells/mL with suspension buffer . After incubation with 10 mM of each compound for 3 min at 37 °C, 500 μL of suspention buffer was loaded on the aggrego-meter and stimulated 20 μL of thrombin (20 u/mL), 20 μL of ADP (1 mM) and 20 μL of collagen (1 mg/mL). Platelet aggregation was measured by light transmission.

Purification of Curcumin and Bisdemethoxycurcumin from Commercial Curcumi-noids. A solution of curcuminoids (5.0 g) in ethanol (50 mL) was heated under reflux for 1 h and the mixture was cooled to room temperature and filtered and washed with a small amount of ethanol. 2.6 g of curcumin was obtained and the mother liquid was concen-trated under reduced pressure. 50 mL of dichloromethane was added to the residue and heated under reflux for 1 h. The mixture was cooled to room temperature, filtered, and washed with a small amount of dichloromethane. 1.1 g of bisdemethoxycurcumin was obtained.

Synthesis of (1E,6E)-1,7-Bis(4-cyclopentyloxy-3-meth-oxyphenyl)-1,6-heptadiene-3,5-dione (2c) (General pro-cedure). Cyclopentanecarbonyl chloride (1.0 mL, 8.14 mmol) was added to a solution of curcumin (1.0 g, 2.71 mmol) and TEA (1.1 mL, 8.14 mmol) in acetone (10 mL). The reaction mixture was stirred at 0 °C for 0.5 h. The mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL). The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. EtOH was added to the residue and stirred overnight at room temperature. The formed solid was filtered and washed with a small amount of EtOH and dried under vacuum at 40 °C. 0.9 g of the title compound was obtained as a dark yellow solid. (yield 66%) 1H NMR (400 MHz DMSO-d6) δ 7.66 (d, J = 16.0 Hz, 2H), 7.52 (s, 2H), 7.33 (dd, J = 1.6 and 1.2 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 16.0 Hz, 2H), 6.20 (s, 1H), 3.84 (s, 6H), 3.08-3.01 (m, 2H), 2.00-1.84 (m, 8H), 1.70-1.64 (m, 8H); 13C NMR δ 183.7, 174.4, 151.7, 141.6, 140.3, 134.1, 125.0, 123.7, 121.9, 122.5, 102.2, 56.5, 43.2, 30.0, 25.9; Mass m/z 561.6 [M+1].

Synthesis of Pentanedioic Acid Mono-(4-{7-[4-(4-carboxybutyryl-oxy)-3-methoxy-phenyl]-3,5-dioxo-hepta-1,6-di-enyl}-2-methoxyphenyl) (2d) (General procedure). Glutaric anhydride (0.93 g, 8.14 mmol) was added to a solution of curcumin (1.0 g, 2.71 mmol) and TEA (1.1 mL, 8.14 mmol) in dichloromethane (10 mL). The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. EtOAc (20 mL) and water (20 mL) were added to the residue, and the pH of the mixture was adjusted to 4 by dropwise addition of conc. HCl. The combined organic layer extracts were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. IPA (10 mL) was added to the residue and water was added dropwise until a solid was formed. The mixture was stirred overnight at room temperature. The formed solid was filter-ed and washed with a small amount of IPA and dried under vacuum at 40 °C. 1.0 g of the title compound was obtained as a dark yellow solid. (yield 31%) 1H NMR (400 MHz DMSO-d6) δ 12.15 (brs, 2H), 7.66 (d, J = 16.0 Hz, 2H), 7.33 (dd, J = 1.6 and 1.2 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 16.0 Hz, 2H), 6.21 (s, 1H), 3.87 (s, 1H), 2.63 (t, J = 7.2 Hz, 4H), 2.37 (t, J = 7.2 Hz, 4H), 1.87 (p, J = 7.2 Hz, 4H); 13C NMR δ 183.7, 174.5, 171.2, 151.6, 141.4, 140.3, 134.2, 125.1, 123.8, 121.9, 112.5, 54.5, 32.9, 29.8, 20.5; Mass m/z 597.3 [M+1].

Synthesis of 4-{3,5-Bis-[2-(4-hydroxy-3-methoxy-phenyl)-vinyl]-pyrazol-1-yl}-benzenesulfonamide (4b) (General procedure). Catalytic amount of acetic acid was added to a solution of curcumin (10.0 g, 27.1 mmol) and 4-hydrazino-benzenesulfonamide hydrochloride (12.0 g, 54.3 mmol) in EtOH (100 mL). The reaction mixture was heated under reflux for 6 h and cooled to room temperature. The formed solid was filtered and washed with a small amount of EtOH and dried overnight under vacuum at 40 °C. 13.7 g of the title compound was obtained as a yellow solid. (Yield 82%) 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.50 (s, 2H), 7.25-7.15 (m, 4H), 7.12 (s, 1H), 7.05 (d, J = 16.0 Hz, 1H), 7.02-6.99 (m, 2H), 6.88 (d, J = 16.0 Hz, 1H), 6.80 (dd, J = 1.2 and 1.6 Hz, 2H), 3.85 (s, 3H), 3.81 (s, 3H); 13C NMR δ 152.33, 148.4, 148.3, 148.0, 147.5, 143.3, 142.9, 142.2, 134.1, 131.9, 128.9, 128.7, 128.2, 127.5, 125.1, 124.9, 121.0, 120.9, 117.5, 111.8, 111.3, 110.1, 102.2, 56.2, 56.1; Mass m/z 520.5 [M+1].

(1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-hept-adiene- 3,5-dione (1a): 1H NMR (400 MHz, DMSO-d6) δ 9.68 (brs, 2H), 7.55 (d, J = 15.6 Hz, 2H), 7.33 (d, J = 1.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 16.0 Hz, 2H), 6.06 (s, 1H), 3.84 (s, 6H); 13C NMR δ 183.7, 149.8, 148.4, 141.2, 126.8, 123.6, 121.5, 116.2, 111.8, 101.3, 56.1.

(1E,6E)-1,7-Bis(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (1b): 1H NMR (400 MHz, DMSO-d6) δ 10.06 (brs, 2H), 7.58-7.53 (m, 6H), 6.82 (d, J = 8.4 Hz, 4H), 6.70 (d, J = 16.0 Hz, 2H), 6.04 (s, 1H); 13C NMR δ 183.7, 160.3, 140.8, 130.8, 126.3, 121.2, 116.4, 101.5.

(1E,6E)-1,7-Bis(4-cyclohexyloxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (2a): 1H NMR (400 MHz CDCl3) δ 7.61 (d, J = 16.0 Hz, 2H), 7.16-7.02 (m, 6H), 6.56 (d, J = 16.0 Hz, 2H), 5.85 (s, 1H), 3.86 (s, 6H), 2.65-2.58 (m, 2H), 2.17-2.06 (m, 4H), 1.85-1.82 (m, 4H), 1.71-1.58 (m, 6H), 1.42-1.32 (m, 6H); 13C NMR δ 183.1, 173.9, 151.5, 141.7, 140.0, 133.7, 124.1, 123.3, 122.2, 121.1, 111.5, 101.8, 55.9, 43.0, 29.0, 25.8, 25.3; Mass m/z 589.6 [M+1].

(1E,6E)-1,7-Bis-(4-furyloxy-3-methoxyphenyl)-1,6-hepta-diene-3,5-dione (2b): 1H NMR (400 MHz, CDCl3) δ 7.68 (s, 2H), 7.64 (d, J = 16.0 Hz, 2H), 7.41 (d, J = 3.6 Hz, 2H), 7.18 (s, 4H), 7.16 (s, 2H), 6.60-6.57 (m, 4H), 5.87 (s, 1H), 3.87 (s, 1H); 13C NMR δ 183.1, 156.2, 151.6, 147.2, 143.7, 140.7, 139.9, 134.3, 124.4, 123.4, 121.1, 119.8, 112.3, 111.6, 101.9, 56.0; Mass m/z 557.7 [M+1].

1,7-Bis-[4-(4-4-methyl-piperazin-1-ylmethyl-benzoyloxy)-3-methoxyphenyl]-hepta-1,6-diene-3,5-dione (2e): 1H NMR (400 MHz CDCl3) δ 8.17 (d, J = 8.0, 4H), 7.67 (d, J = 16.0, 2H), 7.50 (d, J = 8.0, 4H), 7.28-7.18 (m, 6H), 6.61 (d, J = 16.0, 2H), 5.90 (s, 1H), 3.88 (s, 3H), 3.62 (s, 4H), 2.53 (brs, 16H), 2.34 (s, 6H); 13C NMR δ 183.1, 164.5, 151.7, 144.7, 141.6, 140.0, 134.0, 130.4, 129.1, 127.9, 124.3, 123.5, 121.2, 111.6, 101.9, 62.6, 56.0, 55.1, 53.0, 46.0; Mass m/z 801.4 [M+1].

(1E,6E)-1,7-Bis(4-cyclopentyloxyphenyl)-1,6-heptadiene-3,5-dione (3): 1H NMR (400 MHz DMSO-d6) δ 7.72 (d, J = 8.4 Hz, 4H), 7.65 (d, J = 16.0 Hz, 2H), 7.19 (d, J = 8.8 Hz, 4H), 6.83 (d, J = 16.0 Hz, 2H), 6.20 (s, 1H), 3.09-3.01 (m, 2H), 2.05-1.88 (m, 8H), 1.78-1.66 (m, 8H); 13C NMR δ 183.6, 174.5, 152.7, 139.7, 132.9, 129.7, 125.2, 122.5, 101.5, 44.0, 30.0, 25.8; Mass m/z 497.4 [M+1].

4-{(1E,1'E)-2-[5-(4-Hydroxy-3-methoxystyryl)-1H-pyra-zole-3-yl]vinyl}-2-methoxyphenol (4a): 1H NMR (400 MHz, DMSO-d6) δ 12.82 (brs, 1H), 9.18 (brs, 2H), 7.14 (s, 2H), 7.04 (d, J = 16.0 Hz, 2H), 6.95-6.91 (m, 4H), 6.77 (d, J = 8.0 Hz, 2H), 6.62 (s, 1H), 3.83 (s, 6H); 13C NMR δ 157.8, 148.3, 147.2, 130.0, 129.7, 128.8, 128.2, 120.5, 116.1, 109.9, 99.7, 56.0.

4-{(1E,1'E)-2-[5-(4-Hydroxy-styryl)-1H-pyrazole-3-yl]-vinyl}-phenol (5a): 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 9.62 (brs, 2H), 7.38 (d, J = 8.8 Hz, 4H), 6.96 (dd, J = 14.8 and 16.0 Hz, 4H), 6.79 (d, J = 8.4 Hz, 4H), 6.63 (s, 1H); 13C NMR δ 157.7, 130.1, 129.3, 128.0, 118.5, 116.2, 112.9, 99.6.

4-{(1E,1'E)-2-[5-(4-Hydroxy-styryl)-1-(4-aminosulfonyl-phenyl)-1H-pyrazole-3-yl]vinyl}-phenol (5b): 1H NMR (400 MHz, CDCl3) δ 10.6 (brs, 2H), 8.01 (dd, J = 1.6 and 1.6 Hz, 2H), 7.75 (d, J = 1.6 and 2.0 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.22 (t, J = 16.0 Hz, 2H), 7.14 (s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 16.8 Hz, 2H), 6.82-6.78 (m, 4H); 13C NMR δ 158.6, 158.1, 152.3, 148.8, 143.2, 143.0, 142.1, 136.6, 133.7, 131.6, 128.8, 128.4, 128.1, 127.5, 127.4, 125.1, 117.1, 116.2, 113.8, 112.0, 102.0; Mass m/z 460.3 [M+1].

4-{3,5-[2-(4-Furoyloxy-3-methoxyphenyl)-vinyl]-pyrazol-1-yl}-benzenesulfonamide (6): 1H NMR (400 MHz, Acetone-d6) δ 8.12 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 1.2 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.49-7.48 (m, 3H), 7.41-7.37 (m, 3H), 7.30-7.20 (m, 5H), 6.78-6.77 (m, 4H), 3.94 (s, 3H), 3.85 (s, 3H); 13C NMR δ 169.8, 155.9, 151.8, 147.9, 147.8, 143.9, 142.9, 142.6, 142.3, 139.5, 139.1, 136.5, 135.9, 132.6, 130.5, 127.4, 124.7, 123.3, 123.2, 120.7, 119.5, 119.4, 115.8, 112.4, 111.0, 110.1, 102.6, 55.5, 48.9; Mass m/z 708.3 [M+1].

4-{3,5-Bis-[2-(4-furoyloxy-phenyl)-vinyl]-pyrazol-1-yl}-benzenesulfonamide (7): 1H NMR (400 MHz, DMSO-d6) δ 8.13 (t, J = 1.6 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.61-7.58 (m, 2H), 7.53 (s, 2H), 7.43-7.24 (m, 8H), 7.08 (d, J = 16.4 Hz, 2H), 6.83-6.81 (m, 2H); 13C NMR δ 156.8, 151.8, 150.3, 149.9, 149.2, 143.3, 142.8, 141.9, 135.1, 134.6, 130.6, 128.6, 128.2, 127.6, 125.3, 122.8, 120.8, 115.8, 113.3; Mass m/z 648.4 [M+1].

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