LIST OF SYMBOLS AND ABBREVIATIONS
STT
Symbol | Notes | |
1. | 13 C-NMR | Carbon-13 Nuclear Magnetic Resonance spectroscopy |
2. | 1 H-NMR | Proton nuclear magnetic resonance spectroscopy ( 1 H-Nuclear Magnetic Resonance spectroscopy) |
3. | Ac | Acetyl (CH 3 CO-) |
4. | AR | Analytical reagent |
5. | BDMC | Bisdemethoxycurcumin (curcumin III) |
6. | COSY | Correlation spectroscopy |
7. | CTCT | Structural formula |
8. | CTPT | Molecular formula |
9. | DCC | N , N Ɵ-Dicyclohexylcarbodiimide |
10. | DCM | Dichloromethane |
11. | DCU | N , N -Dicyclohexylurea |
12. | dd | Solution |
13. | DDMC | Di- O -Demethylcurcumin |
14. | DEPT | DEPT spectrum (distortionless enhancement by polarization transfer) |
15. | DMAP | 4-Dimethylaminopyridine |
16. | DMC | Demethoxycurcumin (curcumin II) |
17. | DMEM | DulbeccoƟs Modified EagleƟs Medium |
18. | DMF | Dimethylformamide |
19. | DMSO | Dimethyl sulfoxide |
20. | DPPH | 1,1-Diphenyl-2-picrylhydrazyl |
21. | unit | Carbon unit |
22. | EPP | Ethyl phenylpropiolate |
23. | eq | Equivalent |
24. | Et | Ethyl (C 2 H 5 -) |
25. | FBS | Fetal bovine serum |
26. | H % | Reaction efficiency (%) |
27. | Hela | Human cervix carcinoma cell lines |
28. | HEPES | 4-(2-hydroxyethyl)-1-piperazinethansulfonic acid |
29. | HepG2 | Human hepatocellular carcinoma cell lines |
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30.
HIV | Human immunodeficiency virus | |
31. | HL-60 | Human leukemia cell lines |
32. | HPLC | High-performance liquid chromatography |
33. | HMBC | Heteronuclear multiple bond correlation |
34. | HSQC | Heteronuclear single quantum coherence |
35. | IC 50 | Inhibition concentration at 50% of the test object (Inhibition concentration at 50%) |
36. | IPA | Isopropanol |
37. | IR | Infrared spectroscopy |
38. | IUPAC | Chemical Nomenclature according to the International Union of Pure and Applied Chemistry (International Union of Pure and Applied Chemistry Nomenclature) |
39. | K562 | Human acute leukemia cell line myelogenous leukemia cell lines) |
40. | KL | Mass |
41. | LD 100 | Lowest dose that kills 100% of experimental animals |
42. | LD 50 | Lethal dose for 50% of experimental animals |
43. | L -NMMA | N G -methyl- L -arginine acetate |
44. | logP | Oil-water distribution coefficient |
45. | LPS | Lipopolysaccharide |
46. | MCF7 | Human breast carcinoma cell lines |
47. | Me | Methyl (CH 3 -) |
48. | MS | Mass spectrometry |
49. | MTT | 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide |
50. | OD | Optical density |
51. | PEG | Polyethylene glycol |
52. | PH1 | Dimethyl 3,3-bis(( E )-3-(3-methoxy-4-(2-methoxy-2-oxoethoxy)phenyl)acryloyl)pentandioate (4,4, O,O Ɵ-tetra(methoxycarbonyl-methyl)curcumin) |
53. | PH2 | Diethyl 3,3-bis(( E )-3-(4-(2-ethoxy-2-oxoethoxy)-3- methoxyphenyl)acryloyl)pentandioate (4,4, O,O Ɵ-tetra(ethoxycarbonyl-methyl)curcumin) |
54.
PH3 | 3,3-bis(( E )-3-(4-(carboxymethoxy)-3- methoxyphenyl)acryloyl)pentandioic acid (4,4,O,OƟ-tetra(carboxymethyl)curcumin) | |
55. | PH4 | Sodium 3,3-bis(( E )-3-(4-(carboxylatomethoxy)-3- methoxyphenyl)acryloyl)pentandioate (Tetrasodium 4,4, O,O Ɵ-tetra(carboxylatomethyl)curcumin) |
56. | PH5 | Sodium 2,2'-((((1 E ,6 E )-3,5-dioxohepta-1,6-dien-1,7-diyl)bis(2- methoxy-4,1-phenylene))bis(oxy))bis(ethane-1-sulfonate) (Disodium O,OƟ -bis(2-sulfonatoethyl)curcumin) |
57. | PH6 | (1 E ,6 E )-1-(4-hydroxy-3-methoxyphenyl)-7-(4-(2- hydroxyethoxy)-3-methoxyphenyl)hepta-1,6-dien-3,5-dion (Mono- O -(2-hydroxyethyl)curcumin) |
58. | PH7 | (1 E ,6 E )-1,7-bis(4-(2-hydroxyethoxy)-3-methoxyphenyl)hepta- 1,6-dien-3,5-dion (Di- O -(2-hydroxyethyl)curcumin) |
59. | PH8 | Acid 5-(2-(4-((1 E ,6 E )-7-(4-hydroxy-3-methoxyphenyl)-3,5- dioxohepta-1,6-dien-1-yl)-2-methoxyphenoxy)ethoxy)-5- oxopentanoic acid (Mono- O -(2-(glutaryloxy)ethyl)curcumin) |
60. | PH9 | Acid 4-(2-(4-((1 E ,6 E )-7-(4-hydroxy-3-methoxyphenyl)-3,5- dioxohepta-1,6-dien-1-yl)-2-methoxyphenoxy)ethoxy)-4- oxobutanoic acid (mono- O -(2-(succinyloxy)ethyl)curcumin) |
61. | PH10 | Sodium 4-(2-(4-((1 E ,6 E )-7-(4-hydroxy-3-methoxyphenyl)-3,5- dioxohepta-1,6-dien-1-yl)-2-methoxyphenoxy)ethoxy)-4- oxobutanoate (Disodium salt mono- O -(2-(succinyloxy)ethyl)curcumin) |
62. | PH11 | 2-(4-((1 E ,6 E )-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta- 1,6-dien-1-yl)-2-methoxyphenoxy)ethyl dihydrophosphate (2-(curcumin- O -yl)ethyl dihydrophosphate) |
63. | PH12 | Sodium 2-(4-((1 E ,6 E )-7-(4-hydroxy-3-methoxyphenyl)-3,5- dioxohepta-1,6-dien-1-yl)-2-methoxyphenoxy)ethyl phosphate (Sodium salt of 2-(curcumin- O -yl)ethyl dihydrophosphate) |
64. | PH13 | Sodium salt 2-(4-((1 E ,6 E )-7-(4-(2-hydroxyethoxy)-3- methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2- methoxyphenoxy)ethyl sulfate (Sodium 2-(O-(2-hydroxyethyl)-curcumin)ethyl sulfate) |
65.
PH14 | 5,5'-((((((1 E ,6 E )-3,5-dioxohepta-1,6-dien-1,7-diyl)bis(2- methoxy-4,1-phenylene))bis(oxy))bis(ethan-2,1- diyl))bis(oxy))bis(5-oxopentanoic acid) (Di- O -(2-(glutaryloxy)ethyl)curcumin) | |
66. | PH15 | 4,4'-((((((1 E ,6 E )-3,5-dioxohepta-1,6-dien-1,7-diyl)bis(2- methoxy-4,1-phenylene))bis(oxy))bis(ethan-2,1- diyl))bis(oxy))bis(4-oxobutanoic acid) (Di- O -(2-(succinyloxy)ethyl)curcumin) |
67. | PH16 | ((((1 E ,6 E )-3,5-dioxohepta-1,6-dien-1,7-diyl)bis(2-methoxy-4,1- phenylene))bis(oxy))bis(ethan-2,1-diyl)bis(2-amino-3- methylbutanoate) (Di- O -(2-( ւ -valinoyloxy)ethyl)curcumin) |
68. | RAW 264.7 | Mouse macrophage line 264.7 |
69. | R f | Retention factor |
70. | ROS | Reactive oxygen species |
71. | RSD | Relative Standard Deviation |
72. | SA | Scavenging activity |
73. | SC 50 | Scavenging concentration at 50% |
74. | SD | Standard Deviation |
75. | SKLM | Thin layer chromatography |
76. | SOD | Superoxide dismutase |
77. | SP | Product |
78. | SRB | Sulforhodamine B |
79. | t 1/2 | Half-life |
80. | Boc | tert -Butyloxycarbonyl |
81. | TCA | Trichloroacetic acid |
82. | THF | Tetrahydrofuran |
83. | TLTK | References |
84. | to country | Melting temperature |
85. | UV | Ultraviolet spectroscopy |
86. | ν ̃ max | Wave number |
87. | V | Volume |
88. | Ł | Chemical shift |
LIST OF TABLES
Table 1.1. Table of pKa values of curcumin molecule 4
Table 2.1. Raw materials and chemicals used in the study 43
Table 2.2. List of tools and equipment used 45
Table 2.3. Solubility classification table of a substance according to Vietnamese Pharmacopoeia V 53
Table 3.1. Results of synthesis of curcumin derivatives 83
Table 3.2. IR spectra results of curcumin derivatives 84
Table 3.3. MS spectra results of curcumin derivatives 85
Table 3.4. 1H-NMR spectral results of PH6, PH8 - PH12 derivatives 85
Table 3.5. Results of 1H-NMR spectral analysis of PH1-PH4, PH5, PH7, derivatives
and PH13 - PH16 86
Table 3.6. 13C-NMR spectral results of PH3, PH4, PH7, PH14 and PH15 derivatives ..86 Table 3.7. 13C-NMR spectral results of PH6 and PH8 - PH12 derivatives 87
Table 3.8. Results of determining the solubility of new derivatives of curcumin 88
Table 3.9. Results of antioxidant activity test of derivatives 89
Table 3.10. Inhibitory ability of NO production on RAW 264.7 cell line and the impact of the studied sample on the survival of RAW 264.7 cells 90
Table 3.11. Results of cytotoxic activity test of derivatives (µM) 91
Table 3.12. Results of comparison of biological activities of selected derivatives (µM)...92 Table 3.13. Results of Maestro docking on COX-1 target (PDB ID: 6Y3C) 94
Table 3.14. Maestro docking results on MCF-7 target (PDB ID: 4XO6) 95
Table 3.15. Results of the survey on the effect of reaction time on PH6 99 generation
Table 3.16. Results of the survey on the influence of molar ratio of reactants on the reaction to create PH6 100
Table 3.17. Results of the survey on the effect of solvent on reaction efficiency 100
Table 3.18. Results of the investigation of the effect of DMF solvent added to 101
Table 3.19. Best parameters for PH6 101 synthesis process
Table 3.20. Results of the survey on the effect of agent concentration on reaction efficiency at a scale of 5 g/batch 102
Table 3.21. Results of the survey on the influence of the method of loading the agent on the reaction efficiency at the scale of 5 g/batch 103
Table 3.22. Results of repeatability survey of PH6 synthesis process at 5 g/batch scale 104
Table 3.23. Summary table of reaction survey results, process development and scale-up of PH6 105 synthesis
Table 3.24. Results of the survey on the effect of mole ratio on the reaction efficiency
PH6 108
Table 3.25. Results of the reaction temperature survey to create PH9 108
Table 3.26. Results of reaction time survey to create PH9 109
Table 3.27. Summary table of the best parameters for the PH9 109 synthesis process
Table 3.28. Results of repeatability survey of PH9 synthesis process at 2 g/batch scale 111
Table 3.29. Summary table of reaction survey results, process development and scale-up of PH9 112 synthesis
Table 3.30. Thin layer chromatography results of PH9 derivative obtained at 20 g/batch scale
................................................................................................................................113
Table 3.31. Results of PH9 content according to the area standardization method 113
Table 3.32. Results of evaluating some quality indicators of PH9 114
Table 3.33. Proposed basic standards for potential 115 derivatives
Table 3.34. Solubility results of curcumin and PH9 at different pH environments
...................................................................................................................................115
Table 3.35. Log DpH results of PH9 at different pH environments 116
Table 3.36. Ear swelling over time 117
Table 3.37. Number of dead mice, external manifestations when drinking sample 118
Table 3.38. Results of monitoring the weight of mice in batches 119
Table 4.1. Table of 1H-NMR, 13C-NMR and DEPT spectral analysis results of PH9 146
Table 4.2. HSQC and HMBC two-dimensional spectral results of PH9 derivative 147
Table 4.3. Table of results of biological effects evaluation of curcumin derivatives according to modification position 157
LIST OF DIAGRAM
Scheme 2.1. Synthesis of carboxylic acid derivatives of curcumin and formation of sodium carboxylate salt 48
Scheme 2.2. Scheme of synthesis of disodium salt O,OƟ-bis(2-sulfonatoethyl)curcumin (PH5)
...................................................................................................................................48
Scheme 2.3. Synthesis of mono-O-(2-hydroxyethyl)curcumin (PH6) and di-
O-(2-hydroxyethyl)curcumin (PH7) 49
Scheme 2.4. Scheme of synthesis of mono-O-(2-(glutaryloxy)ethyl)curcumin (PH8) 49
Scheme 2.5. Scheme of synthesis of mono-O-(2-(succinyloxy)ethyl)curcumin (PH9) and mono-O-(2-(succinyloxy)ethyl)curcumin sodium salt (PH10) 49
Scheme 2.6. Scheme of synthesis of derivative PH11 and formation of salt PH12 50
Scheme 2.7. Scheme of the reaction for synthesizing sulfate salt PH13 from PH7 50
Scheme 2.8. Reaction scheme for the synthesis of glutarate diester PH14 from PH7 50
Scheme 2.9. Scheme of synthesis of diesters of di-O-(2-hydroxyethyl)curcumin 51
Scheme 2.10. Scheme of synthesis of hybrid derivatives of PH7 with valine 51
Diagram 3.1. PH1 64 synthesis reaction diagram
Diagram 3.2. PH2 65 synthesis reaction diagram
Scheme 3.3. Scheme of the reaction for synthesizing PH3 from PH1 65
Scheme 3.4. Scheme of the reaction for synthesizing PH3 from PH2 66
Diagram 3.5. PH4 67 synthesis reaction diagram
Scheme 3.6. Scheme of synthesis of sodium salt 2-bromoethanesulfonate 67
Scheme 3.7. Scheme of the reaction for synthesizing PH5 derivatives 68
Scheme 3.8. Scheme of PH6 synthesis reaction using 2-bromoethanol 69
Scheme 3.9. Scheme of the reaction for the synthesis of PH7 with 2-bromoethanol 70 as the reagent
Diagram 3.10. PH8 71 synthesis reaction diagram
Scheme 3.11. PH9 72 synthesis reaction scheme
Diagram 3.12. PH10 73 synthesis reaction diagram
Scheme 3.13. Scheme of synthesis of PH11 from PH6 using phosphoric acid 74
Scheme 3.14. Scheme of the reaction for the synthesis of PH11 from PH6 using phosphoryl oxychloride ...75
Scheme 3.15. PH12 76 synthesis reaction scheme
Scheme 3.16. PH13 77 synthesis reaction scheme
Scheme 3.17. PH14 78 synthesis reaction scheme
Scheme 3.18. PH15 79 synthesis reaction scheme
Scheme 3.19. Scheme of the synthesis reaction of N-Boc-valine 80
Figure 3.20. TG3 81 synthesis diagram
Figure 3.21. Schematic diagram of Boc group elimination from N-Boc-valine- bis-O-(2-hydroxyethyl)curcumin
...................................................................................................................................82