CN103724219A - Crocetin amides derivative and preparation method and application thereof - Google Patents
Crocetin amides derivative and preparation method and application thereof Download PDFInfo
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- CN103724219A CN103724219A CN201210390567.5A CN201210390567A CN103724219A CN 103724219 A CN103724219 A CN 103724219A CN 201210390567 A CN201210390567 A CN 201210390567A CN 103724219 A CN103724219 A CN 103724219A
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- crocetin
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- amide derivatives
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- PANKHBYNKQNAHN-JTBLXSOISA-N Crocetin Natural products OC(=O)C(\C)=C/C=C/C(/C)=C\C=C\C=C(\C)/C=C/C=C(/C)C(O)=O PANKHBYNKQNAHN-JTBLXSOISA-N 0.000 title claims abstract description 38
- PANKHBYNKQNAHN-JUMCEFIXSA-N carotenoid dicarboxylic acid Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C(=O)O)C=CC=C(/C)C(=O)O PANKHBYNKQNAHN-JUMCEFIXSA-N 0.000 title claims abstract description 38
- -1 Crocetin amides Chemical class 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title abstract description 61
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- PANKHBYNKQNAHN-MQQNZMFNSA-N crocetin Chemical compound OC(=O)C(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)C(O)=O PANKHBYNKQNAHN-MQQNZMFNSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 13
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- 239000010931 gold Substances 0.000 description 1
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- 230000009036 growth inhibition Effects 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a crocetin amides derivative. The crocetin amides derivative is characterized by having the following general formula: (img file='DSA00000789203800011.tif' wi='1009' he='177'/), wherein R in the formula is (img file='DSA00000789203800012.tif' wi='1529' he='751'/). The crocetin amides derivative has obvious inhibiting effect on human lung cancer cells A549 and human gastric carcinoma cells SGC7901. Therefore, the crocetin amides derivative can be applied to preparing anti-cancer drug. The invention also discloses a preparation method of the crocetin amides derivative.
Description
Technical field
The present invention relates to class crocetin amide derivatives and preparation method thereof and purposes as cancer therapy drug.
Background technology
Stigma Croci is Iridaceae crocus napiform root class herbaceous plant, originates in the ground such as Spain, Greece, various countries, southern Europe and Iran, and also there are cultivation in India, Japan, through India, import China Tibet into, thereby are called Stigma Croci.At present, croceous main product ground, in states such as Greece, Spain and Iran, only has a small amount of cultivation in China.Since ancient times, Stigma Croci is just widely applied by between east and west as medicinal material, spices or dyestuff.Because its output is extremely low, the time and effort consuming of gathering, causes it expensive, is described as " plant gold ", in China, is listed in rare rare traditional Chinese medicine.Stigma Croci has the strong promoting blood circulation and removing blood stasis and loose strongly fragrant effect of opening knot, is used to clinical always.In recent years; along with the develop rapidly of modern medicine pharmacy and Protocols in Molecular Biology; find that Stigma Croci has good efficacy at aspects such as antitumor, neuroprotective system and anti-cardiovascular system diseases; especially remarkable in anti-tumor aspect effect; and almost non-toxic side effect, so again caused people's attention.
Croceous column cap has the multiple material with pharmacological action, and its main component is crocetin and crocin.Crocetin is one of main effective constituent in Stigma Croci column cap, unsaturated conjugated polyenoic acid structure, for carotenoid compounds, there is the effects such as antitumor, atherosclerosis, hypertension and treatment hemorrhagic shock, anti-oxidant, hepatic cholagogic, become rising cancer prevention, treatment preparation.Bibliographical information shows, crocetin may be in the different steps performance effect of tumorigenesis, its anticancer mechanism relate to inhibition tumor cell proto-oncogene expression, suppress the many aspects such as synthetic and anti-oxidant of PKC activity, inhibition tumor cell nucleic acid.Its clear and definite antitumor mechanism is still needed and will further be studied.
The more difficult establishing in large scale of Stigma Croci, column cap yields poorly, and extracts separation costs very high, has limited its exploitation.Cape jasmine as traditional Chinese medicine also contains crocin and crocetin.At present, can from cape jasmine, extract Gardenia Yellow, through hydrolysis and purifying, make highly purified crocetin.
In order to study the antitumour activity of crocetin, and screening antitumour activity and pharmacokinetic property better, the derivative that toxicity is less, we carry out relevant structural modification to it.The compound of the present invention's design is introduced amido linkage and is connected with the phenyl ring of different substituents, synthesizes a class crocetin amide derivatives, may contribute to strengthen the antitumour activity of compound, is problem highly significant.
Summary of the invention
The object of the present invention is to provide a class crocetin amide derivatives and their preparation method and purposes.
Technical scheme of the present invention is as follows:
One class crocetin amide derivatives, is characterized in that it has following general formula:
In formula, R is:
A method of preparing an above-mentioned class crocetin amide derivatives, is characterized in that it is comprised of the following step:
Step 1. is added to 1mmol crocetin in 50mL round-bottomed flask, with 10mL organic solvent DMF or DMSO dissolving; Under cold condition, (10 ℃ to 10 ℃) successively drip 2.2mmol oxalyl chloride and 2.1mmol triethylamine in crocetin solution, magnetic agitation 4h;
Step 2. (10 ℃ to 10 ℃) under cold condition is added to 2mmol substituting group aniline in step 1 gained solution, magnetic agitation reaction 8h;
After step 3. reaction finishes, reaction solution is poured into water, is extracted with ethyl acetate, then saturated common salt water washing, anhydrous sodium sulfate drying, ethyl acetate is removed in underpressure distillation, obtains final product with mixing solutions (volume ratio 5: the 1) recrystallization of ethanol and acetone.
Experimental result shows, the novel crocetin amide derivatives of a class of the present invention all has obvious restraining effect to human lung cancer cell A549 and gastric carcinoma cells SGC7901.Therefore a class crocetin amide derivatives of the present invention can be used as the preparation of potential anticancer compound for cancer therapy drug.
Embodiment
By following examples, further describe the present invention, but scope of the present invention is not subject to any restriction of these embodiment.
Embodiment mono-: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(4-fluorophenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 1)
1mmol crocetin is added in 50mL round-bottomed flask, with 10mL organic solvent DMF or DMSO dissolving; At 0 ℃, successively drip 2.2mmol oxalyl chloride and 2.1mmol triethylamine in crocetin solution, magnetic agitation 4h; 2.1mmol substituting group aniline is added in step 1 gained solution to magnetic agitation reaction 8h under 0 ℃ of cold condition; After reaction finishes, reaction solution is poured into water, is extracted with ethyl acetate, then saturated common salt water washing, anhydrous sodium sulfate drying, ethyl acetate is removed in underpressure distillation, obtains final product with mixing solutions (volume ratio 5: the 1) recrystallization of ethanol and acetone.Brick-red powder, productive rate 54%.m.p.254-255 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.90 (s, 6H), 2.01 (s, 6H), 6.35-6.37 (d, J=2.24Hz, 2H), 6.51-6.53 (dd, J=6.41Hz, 2H), 6.59-6.62 (d, J=7.32Hz, 2H), 6.87-6.91 (dd, J=5.72Hz, 2H), 7.18-7.20 (d, J=4.62Hz, 4H), 7.24-7.27 (d, J=6.29Hz, 2H), (7.88-7.90 d, J=3.27Hz, 4H), 10.13 (s, 2H) .MS (ES) I:515.24 (C
32h
33f
2n
2o
2, [M+H]
+) .Anal.Calcd for C
32h
32f
2n
2o
2: C, 74.69; H, 6.27; N, 5.44%.Found:C, 74.46; H, 6.27; N, 5.40%.
Embodiment bis-: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(4-chloro-phenyl-s)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 2)
Preparation method is with embodiment mono-.With 4-chloroaniline, replace 4-fluoroaniline, obtain target compound.Common brick toner end, productive rate 45%, m.p.265-266 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.92 (s, 6H), 1.99 (s, 6H), 6.33-6.36 (d, J=2.51Hz, 2H), 6.54-6.55 (dd, J=5.64Hz, 2H), 6.57-6.60 (d, J=7.17Hz, 2H), 6.86-6.72 (dd, J=5.45Hz, 2H), 7.17-7.19 (d, J=4.69Hz, 4H), 7.22-7.25 (d, J=6.26Hz, 2H), (7.86-7.89 d, J=3.42Hz, 4H), 10.11 (s, 2H) .MS (ESI): 547.18 (C
32h
33cl
2n
2o
2, [M+H]
+) .Anal.Calcd for C
32h
32cl
2n
2o
2: C, 70.20; H, 5.89; N, 5.12%.Found:C, 70.06; H, 5.91; N, 5.12%.
Embodiment tri-: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(4-bromophenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 3)
Preparation method is with embodiment mono-.With 4-bromaniline, replace 4-fluoroaniline, obtain target compound.Common brick toner end, productive rate 48%, m.p.291-292 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.90 (s, 6H), 2.02 (s, 6H), 6.31-6.34 (d, J=3.01Hz, 2H), 6.55-6.58 (dd, J=5.61Hz, 2H), 6.57-6.59 (d, J=6.21Hz, 2H), 6.85-6.89 (dd, J=5.43Hz, 2H), 7.17-7.20 (d, J=4.79Hz, 4H), 7.22-7.25 (d, J=6.21Hz, 2H), (7.83-7.85 d, J=3.46Hz, 4H), 10.14 (s, 2H) .MS (ESI): 635.08 (C
32h
33br
2n
2o
2, [M+H]
+) .Anal.Calcd for C
32h
32br
2n
2o
2: C, 60.39; H, 5.07; N, 4.40%.Found:C, 60.26; H, 5.08; N, 4.32%.
Embodiment tetra-: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(4-hydroxy phenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 4)
Preparation method is with embodiment mono-.With 4-hydroxyanilines, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 42%, m.p.245-246 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.93 (s, 6H), 1.95 (s, 6H), 5.35 (s, 2H), (6.38-6.40 d, J=3.64Hz, 2H), (6.57-6.59 dd, J=5.54Hz, 2H), (6.60-6.62 d, J=6.42Hz, 2H), (6.83-6.85 dd, J=5.32Hz, 2H), (7.21-7.24 d, J=4.69Hz, 4H), (7.24-7.26 d, J=6.34Hz, 2H), (7.85-7.87 d, J=3.51Hz, 4H), 10.11 (s, 2H) .MS (ESI): 511.25 (C
32h
35n
2o
4, [M+H]
+) .Anal.Calcd for C
32h
34n
2o
4: C, 75.27; H, 6.71; N, 5.49%.Found:C, 75.06; H, 6.72; N, 5.42%.
Embodiment five: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(4-p-methoxy-phenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 5)
Preparation method is with embodiment mono-.With 4-anisidine, replace 4-fluoroaniline, obtain target compound.White powder, productive rate 87%, m.p.265-266 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.91 (s, 6H), 1.97 (s, 6H), 3.83 (s, 6H), (6.37-6.39 d, J=3.53Hz, 2H), (6.56-6.59 dd, J=5.44Hz, 2H), (6.61-6.64 d, J=6.47Hz, 2H), (6.82-6.85 dd, J=5.35Hz, 2H), (6.93-6.96 d, J=5.32Hz, 4H), (7.25-7.27 d, J=6.21Hz, 2H), (7.51-7.53 d, J=4.21Hz, 4H), 10.14 (s, 2H) .MS (ESI): 539.28 (C
34h
38n
2o
4, [M+H]
+) .Anal.Calcd for C
34h
38n
2o
4: C, 75.81; H, 7.11; N, 5.20%.Found:C, 75.65; H, 7.12; N, 5.28%.
Embodiment six: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(4-aminomethyl phenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 6)
Preparation method is with embodiment mono-.With 4-monomethylaniline, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 58%, m.p.263-264 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.92 (s, 6H), 1.94 (s, 6H), 2.34 (s, 6H), (6.34-6.36 d, J=3.65Hz, 2H), (6.55-6.60 dd, J=5.58Hz, 2H), (6.62-6.64 d, J=6.41Hz, 2H), 6.82-6.87 (dd, J=5.37Hz, 2H), 7.17-7.20 (d, J=4.73Hz, 4H), 7.21-7.24 (m, 6H), 10.16 (s, 2H) .MS (ESI): 507.29 (C
34h
39n
2o
2, [M+H]
+) .Anal.Calcd for C
34h
38n
2o
2: C, 80.06; H, 7.56; N, 5.53%.Found:C, 80.25; H, 7.58; N, 5.58%.
Embodiment seven: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(4-nitrophenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 7)
Preparation method is with embodiment mono-.With 4-N-methyl-p-nitroaniline, replace 4-fluoroaniline, obtain target compound.White powder, productive rate 87%, m.p.265-266 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.94 (s, 6H), 1.99 (s, 6H), 6.36-6.39 (d, J=3.64Hz, 2H), 6.57-6.60 (dd, J=5.54Hz, 2H), 6.60-6.63 (d, J=6.42Hz, 2H), 6.83-6.86 (dd, J=5.32Hz, 2H), (7.24-7.27 d, J=6.34Hz, 2H), 7.82-7.83 (d, 4H), 8.23-8.25 (d, 4H), 10.15 (s, 2H) .MS (ESI): 569.23 (C
32h
33n
4o
6, [M+H]
+) .Anal.Calcd for C
32h
32n
4o
6: C, 67.59; H, 5.67; N, 9.85%.Found:C, 67.41; H, 5.66; N, 9.88%.
Embodiment eight: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(3-fluorophenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 8)
Preparation method is with embodiment mono-.With 3-fluoroaniline, replace 4-fluoroaniline, obtain target compound.Brick-red powder, productive rate 54%.m.p.274-275 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.92 (s, 6H), 1.98 (s, 6H), 6.36-6.38 (d, J=2.24Hz, 2H), 6.52-6.55 (dd, J=6.41Hz, 2H), 6.88-6.92 (m, 4H), (7.19-7.21 d, J=4.62Hz, 4H), 7.42-7.45 (m, 2H), 7.71-7.75 (m, 4H), 10.12 (s, 2H) .MS (ESI): 515.24 (C
32h
33f
2n
2o
2, [M+H]
+) .Anal.Calcd forC
32h
32f
2n
2o
2: C, 74.69; H, 6.27; N, 5.44%.Found:C, 74.49; H, 6.26; N, 5.46%.
Embodiment nine: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(3-chloro-phenyl-s)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 9)
Preparation method is with embodiment mono-.With 3-chloroaniline, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 62%, m.p.268-269 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.90 (s, 6H), 1.99 (s, 6H), 6.33-6.35 (d, J=2.24Hz, 2H), 6.59-6.62 (d, J=11.62Hz, 2H), 6.89-6.93 (m, 4H), (7.19-7.22 d, J=9.42Hz, 4H), 7.43-7.46 (m, 2H), 7.72-7.77 (m, 4H), 10.16 (s, 2H) .MS (ESI): 547.18 (C
32h
33cl
2n
2o
2, [M+H]
+) .Anal.Calcd for C
32h
32cl
2n
2o
2: C, 70.20; H, 5.89; N, 5.12%.Found:C, 70.32; H, 5.90; N, 5.15%.
Embodiment ten: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(3-bromophenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 10)
Preparation method is with embodiment mono-.With 3-bromaniline, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 81%, m.p.265-266 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.89 (s, 6H), 1.97 (s, 6H), 6.31-6.33 (d, J=2.34Hz, 2H), 6.51-6.53 (dd, J=6.33Hz, 2H), 6.58-6.62 (d, J=7.39Hz, 2H), 6.88-6.92 (m, 4H), 7.19-7.22 (d, J=4.52Hz, 4H), 7.26-7.29 (d, J=6.29Hz, 2H), 7.43-7.46 (m, 2H), 10.16 (s, 2H) .MS (ESI): 635.08 (C
32h
33br
2n
2o
2, [M+H]
+) .Anal.Calcd for C
32h
32br
2n
2o
2: C, 60.39; H, 5.07; N, 4.40%.Found:C, 60.26; H, 5.08; N, 4.32%.
Embodiment 11: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(3-hydroxy phenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 11)
Preparation method is with embodiment mono-.With 3-hydroxyanilines, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 37%, m.p.291-293 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.90 (s, 6H), 1.98 (s, 6H), 5.35 (s, 2H), (6.38-6.39 d, J=3.64Hz, 2H), (6.57-6.59 dd, J=5.54Hz, 2H), 6.62-6.67 (m, 4H), 6.83-6.86 (dd, J=5.32Hz, 2H), 7.17-7.19 (d, J=4.24Hz, 2H), 7.24-7.27 (m, 4H), 7.32 (s, 2H), 10.16 (s, 2H) .MS (ESI): 511.25 (C
32h
35n
2o
4, [M+H]
+) .Anal.Calcd for C
32h
34n
2o
4: C, 75.27; H, 6.71; N, 5.49%.Found:C, 75.06; H, 6.72; N, 5.42%.
Embodiment 12: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(3-p-methoxy-phenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 12)
Preparation method is with embodiment mono-.With 3-anisidine, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 82%, m.p.273-274 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.91 (s, 6H), 1.98 (s, 6H), 3.83 (s, 6H), (6.34-6.36 d, J=3.67Hz, 2H), 6.57-6.61 (m, 2H), 6.60-6.63 (d, J=6.42Hz, 2H), 6.73-6.75 (m, 2H), 6.83-6.86 (dd, J=5.32Hz, 2H), 7.17 (m, 2H), (7.24-7.26 d, J=6.34Hz, 2H), 7.32-7.36 (m, 4H), 10.13 (s, 2H) .MS (ESI): 539.28 (C
34h
39n
2o
4, [M+H]
+) .Anal.Calcd for C
34h
38n
2o
4: C, 75.81; H, 7.11; N, 5.20%.Found:C, 75.65; H, 7.12; N, 5.28%.
Embodiment 13: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(3-aminomethyl phenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 13)
Preparation method is with embodiment mono-.With 3-monomethylaniline, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 67%, m.p.241-242 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.93 (s, 6H), 1.99 (s, 6H), 2.31 (s, 6H), (6.35-6.37 d, J=3.67Hz, 2H), 6.58-6.62 (m, 2H), 6.62-6.65 (d, J=6.42Hz, 2H), 6.71-6.75 (m, 2H), 6.82-6.86 (dd, J=5.32Hz, 2H), 7.15 (m, 2H), (7.25-7.28 d, J=6.34Hz, 2H), 7.32-7.36 (m, 4H), 10.17 (s, 2H) .MS (ESI): 507.29 (C
34h
39n
2o
2, [M+H]
+) .Anal.Calcd for C
34h
38n
2o
2: C, 80.06; H, 7.56; N, 5.53%.Found:C, 80.25; H, 7.58; N, 5.58%.
Embodiment 14: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(3-oil of mirbane-2,6,11,15-tetramethyl-, 16 carbon-2, the preparations of 4,6,8,10,12,14-heptamide (compound 14)
Preparation method is with embodiment mono-.With 3-N-methyl-p-nitroaniline, replace 4-fluoroaniline, obtain target compound.White powder, productive rate 80%, m.p.251-252 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.93 (s, 6H), 1.95 (s, 6H), 6.38-6.41 (d, J=3.64Hz, 2H), 6.57-6.60 (dd, J=5.54Hz, 2H), 6.60-6.62 (d, J=6.42Hz, 2H), 6.83 (m, 2H), (7.24-7.26 d, J=6.34Hz, 2H), 7.69 (m, 2H), 8.00-8.03 (m, 4H), 8.24 (m, 2H), 10.11 (s, 2H) .MS (ESI): 569.23 (C
32h
33n
4o
6, [M+H]
+) .Anal.Calcd for C
32h
32n
4o
6: C, 67.59; H, 5.67; N, 9.85%.Found:C, 67.43; H, 5.67; N, 9.81%.
Embodiment 15: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(2-fluorophenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 15)
Preparation method is with embodiment mono-.With 2-fluoroaniline, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 60%, m.p.261-262 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.92 (s, 6H), 1.95 (s, 6H), 6.38-6.41 (d, J=3.64Hz, 2H), 6.57 (m, 2H), 6.60-6.62 (d, J=6.42Hz, 2H), 6.83 (m, 2H), 7.01 (m, 2H), 7.20-7.26 (m, 6H), 7.96 (d, J=6.44Hz, 2H), 10.18 (s, 2H) .MS (ESI): 515.24 (C
32h
33f
2n
2o
2, [M+H]
+) .Anal.Calcd for C
32h
32f
2n
2o
2: C, 74.69; H, 6.27; N, 5.44%.Found:C, 74.46; H, 6.27; N, 5.40%.
Embodiment 16: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(2-chloro-phenyl-s)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 16)
Preparation method is with embodiment mono-.With 2-chloroaniline, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 61%, m.p.277-278 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.92 (s, 6H), 1.95 (s, 6H), 6.38-6.41 (d, J=3.64Hz, 2H), 6.57 (m, 2H), 6.60-6.62 (d, J=6.42Hz, 2H), 6.83 (m, 2H), 7.01 (m, 2H), 7.20-7.26 (m, 6H), 7.96 (d, J=6.44Hz, 2H), 10.18 (s, 2H) .MS (ESI): 547.18 (C
32h
33cl
2n
2o
2, [M+H]
+) .Anal.Calcd for C
32h
32cl
2n
2o
2: C, 70.20; H, 5.89; N, 5.12%.Found:C, 70.06; H, 5.91; N, 5.17%.
Embodiment 17: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(2-bromophenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 17)
Preparation method is with embodiment mono-.With 2-5-trifluoromethylaniline, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 60%, m.p.298-299 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.93 (s, 6H), 1.99 (s, 6H), 6.40-6.43 (d, J=3.64Hz, 2H), 6.59 (m, 2H), 6.62-6.64 (d, J=6.42Hz, 2H), 6.84 (m, 2H), 7.03 (m, 2H), 7.22-7.28 (m, 6H), 7.99 (d, J=6.44Hz, 2H), 10.16 (s, 2H) .MS (ESI): 635.08 (C
32h
33br
2n
2o
2, [M+H]
+) .Anal.Calcd for C
32h
32br
2n
2o
2: C, 60.39; H, 5.07; N, 4.40%.Found:C, 60.48; H, 5.07; N, 4.31%.
Embodiment 18: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(2-hydroxy phenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 18)
Preparation method is with embodiment mono-.With 2-hydroxyanilines, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 32%, m.p.241-242 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.92 (s, 6H), 1.97 (s, 6H), 5.34 (s, 2H), (6.38-6.40 d, J=5.44Hz, 2H), (6.56-6.59 dd, J=5.41Hz, 2H), 6.60-6.65 (m, 4H), 6.83-6.86 (dd, J=4.56Hz, 2H), 7.17-7.19 (d, J=5.34Hz, 2H), 7.25-7.287 (m, 4H), 7.32 (s, 2H), 10.16 (s, 2H) .MS (ESI): 511.25 (C
32h
35n
2o
4, [M+H]
+) .Anal.Calcd for C
32h
34n
2o
4: C, 75.27; H, 6.71; N, 5.49%.Found:C, 75.06; H, 6.72; N, 5.42%.
Embodiment 19: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(2-p-methoxy-phenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 19)
Preparation method is with embodiment mono-.With 2-anisidine, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 52%, m.p.231-232 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.91 (s, 6H), 1.99 (s, 6H), 3.83 (s, 6H), 6.36 (d, J=3.64Hz, 2H), 6.55 (dd, J=5.54Hz, 2H), 6.64 (d, J=6.42Hz, 2H), 6.83 (m, 2H), 6.97-7.01 (m, 2H), 7.08-7.12 (m, 4H), (7.24-7.26 d, J=6.34Hz, 2H), 7.85 (m, 2H), 10.14 (s, 2H) .MS (ESI): 539.28 (C
34h
39n
2o
4, [M+H]
+) .Anal.Calcd for C
34h
38n
2o
4: C, 75.81; H, 7.11; N, 5.20%.Found:C, 75.65; H, 7.12; N, 5.28%.
Embodiment 20: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(2-aminomethyl phenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 20)
Preparation method is with embodiment mono-.With 2-aminotoluene, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 56%, m.p.272-273 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.93 (s, 6H), 1.99 (s, 6H), 2.27 (s, 6H), (6.35-6.37 d, J=3.67Hz, 2H), 6.58-6.62 (m, 2H), 6.62-6.65 (d, J=6.42Hz, 2H), 6.71-6.75 (m, 2H), 6.82-6.86 (dd, J=5.32Hz, 2H), 7.15 (m, 2H), (7.25-7.28 d, J=6.34Hz, 2H), 7.32-7.36 (m, 4H), 10.17 (s, 2H) .MS (ESI): 507.29 (C
34h
39n
2o
2, [M+H]
+) .Anal.Calcd for C
34h
38n
2o
2: C, 80.06; H, 7.56; N, 5.53%.Found:C, 80.25; H, 7.58; N, 5.58%.
Embodiment 21: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(2-nitrophenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 21)
Preparation method is with embodiment mono-.With 2-N-methyl-p-nitroaniline, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 56%, m.p.274-275 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.93 (s, 6H), 1.95 (s, 6H), 6.38-6.41 (d, J=3.64Hz, 2H), 6.57-6.60 (dd, J=5.54Hz, 2H), 6.60-6.62 (d, J=6.42Hz, 2H), 6.83 (m, 2H), (7.24-7.26 d, J=6.34Hz, 2H), 7.69 (m, 2H), 8.00-8.03 (m, 4H), 8.24 (m, 2H), 10.11 (s, 2H) .MS (ESI): 569.23 (C
32h
33n
4o
6, [M+H]
+) .Anal.Calcd for C
32h
32n
4o
6: C, 67.59; H, 5.67; N, 9.85%.Found:C, 67.41; H, 5.68; N, 9.79%.
Embodiment 22: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(phenyl)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 22)
Preparation method is with embodiment mono-.To replace 4-fluoroaniline without substituted aniline, obtain target compound.Red powder, productive rate 69%, m.p.227-228 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.89 (s, 6H), 1.98 (s, 6H), 6.35-6.37 (d, J=3.64Hz, 2H), 6.59-6.62 (dd, J=5.54Hz, 2H), 6.60-6.63 (d, J=6.72Hz, 2H), 6.83-6.85 (dd, J=4.45Hz, 2H), 7.19 (s, 2H), (7.24-7.27 d, J=6.34Hz, 2H), 7.43 (m, 4H), 7.67 (m, 4H), 10.15 (s, 2H) .MS (ESI): 479.26 (C
32h
35n
2o
2, [M+H]
+) .Anal.Calcd for C
32h
34n
2o
2: C, 80.30; H, 7.16; N, 5.85%.Found:C, 80.40; H, 7.15; N, 5.86%.
Embodiment 23: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(2,4-3,5-dimethylphenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 23)
Preparation method is with embodiment mono-.With 2,4-xylidine, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 53%, m.p.245-246 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.93 (s, 6H), 1.95 (s, 6H), 2.12 (s, 6H), 2.34 (s, 6H), 6.38-6.41 (d, J=3.64Hz, 2H), 6.57-6.61 (m, 2H), 6.60-6.62 (d, J=6.42Hz, 2H), (6.81-6.85 dd, J=6.33Hz, 2H), 7.02-7.06 (m, 4H), 7.21-7.26 (m, 4H), 10.16 (s, 2H) .MS (ESI): 535.32 (C
36h
43n
2o
2, [M+H]
+) .Anal.Calcd for C
36h
42n
2o
2: C, 80.86; H, 7.92; N, 5.24%.Found:C, 80.69; H, 7.92; N, 5.27%.
Embodiment 24: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(3,4-3,5-dimethylphenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 24)
Preparation method is with embodiment mono-.With 3,4-xylidine, replace 4-fluoroaniline, obtain target compound.White powder, productive rate 62%, m.p.289-290 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.94 (s, 6H), 1.99 (s, 6H), 2.11 (s, 6H), 2.36 (s, 6H), 6.41-6.44 (d, J=3.64Hz, 2H), 6.57-6.63 (m, 4H), 6.83-6.86 (dd, J=6.33Hz, 2H), 7.05-7.08 (m, 4H), 7.21-7.25 (m, 4H), 10.15 (s, 2H) .MS (ESI): 535.32 (C
36h
43n
2o
2, [M+H]
+) .Anal.Calcd for C
36h
42n
2o
2: C, 80.86; H, 7.92; N, 5.24%.Found:C, 80.69; H, 7.92; N, 5.27%.
Embodiment 25: (2E, 4E, 6E, 8E, 10E, 12E, 14E)-N
1, N
16-bis-(2,4-Dimethoxyphenyls)-2,6,11,15-tetramethyl-16 carbon-2, the preparation of 4,6,8,10,12,14-heptamide (compound 25)
Preparation method is with embodiment mono-.With 2,4-dimethoxyaniline, replace 4-fluoroaniline, obtain target compound.Red powder, productive rate 45%, m.p.238-239 ℃;
1h NMR (300MHz, DMSO-d
6) δ: 1.92 (s, 6H), 1.98 (s, 6H), 3.83 (s, 12H), 6.38-6.42 (m, 2H), 6.53-6.58 (dd, J=4.58Hz, 6H), 6.60-6.63 (d, J=6.42Hz, 2H), 6.81-6.84 (dd, J=5.32Hz, 2H), (7.23-7.26 d, J=6.34Hz, 2H), 8.09 (m, 2H), 10.15 (s, 2H) .MS (ESI): 599.30 (C
36h
43n
2o
6, [M+H]
+) .Anal.Calcd for C
36h
42n
2o
6: C, 72.22; H, 7.07; N, 4.68%.Found:C, 72.35; H, 7.08; N, 4.74%.
Embodiment 26: the anti tumor activity in vitro research of novel crocetin amide derivatives
Adopting MTT[3-(4,5)-bis-methyl-2-thiazole-(2,5)-phenyl bromination tetrazole indigo plant] method measures the half-inhibition concentration (IC of acyl crocetin amide derivatives to human lung cancer cell A549 and gastric carcinoma cells SGC7901
50).
(1) preparation of nutrient solution (every liter): 1. suspension cell: RPMI-1640 cultivates one bag, powder (10.4g), new-born calf serum 100mL, penicillin solution (200,000 U/mL) 0.5mL, Streptomycin sulphate solution (200,000 U/mL) 0.5mL, add after tri-distilled water dissolving, with 5.6% NaHCO
3solution adjusts pH value to 7.2-7.4, is finally settled to 1000mL.Filtration sterilization.2. attached cell: the same, then add NaHCO
32.00g, HEPES 2.38g.
(2) preparation of D-Hanks damping fluid (every liter): NaCl 8.00g, KCl 0.40g, Na
2hPO
412H
2o 0.06g, KH
2pO
40.06g, NaHCO
30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of experiment liquid: test sample is dissolved and is made into storing solution with a small amount of tri-distilled water, general by 10 times of preparation storing solutions of experiment maximum concentration.According to compound dissolution difference, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, then adds tri-distilled water and dissolve.The concentration of DMSO in nutrient solution is unsuitable excessive, and in the every porocyte suspension after dosing, the final concentration of DMSO is generally no more than 0.05%-0.1%.Storing solution is stored in-20 ℃ of refrigerators standby.
(5) human lung cancer cell A549's cultivation: be suspension growth cell, cellar culture is (containing 10% calf serum, 100U/mL Streptomycin sulphate) in RPMI-1640 nutrient solution, is placed in 37 ℃, 5%CO
2in incubator, cultivate, every 3-4 days, go down to posterity once.While going down to posterity, nutrient solution in former bottle is transferred in centrifuge tube, the centrifugal 5min of 1000rpm, discard original fluid, add equivalent fresh medium, piping and druming evenly, pipette in right amount to fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(6) cultivation of gastric carcinoma cells SGC7901: be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/mL Streptomycin sulphate) in RPMI-1640 nutrient solution, puts 37 ℃, 5%CO
2in incubator, cultivate, every 3-4 days, go down to posterity once.While going down to posterity, first discard original fluid, then wash with D-Hanks damping fluid; Then use 0.5% tryptic digestion about 30 seconds, add a small amount of fresh medium to stop digestion; Piping and druming, makes attached cell split away off from culturing bottle wall; Pipette in right amount to fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(7) cell is hatched: 2 kinds of tumour cells in the vegetative period of taking the logarithm, tune concentration of cell suspension is 1-1.5 × 10
5individual mL
-1.In 96 well culture plates, every hole adds cell suspension 100 μ l, puts 37 ℃, 5%CO
2in incubator, cultivate 24h.Cultivate after 24h, by design, add liquid respectively.
(8) dosing: test liquid is joined respectively in each hole according to the concentration gradient of ultimate density, and each concentration is established 6 parallel holes.Experiment is divided into drug test group (adding respectively the test medicine of different concns), control group (only add nutrient solution and cell, do not add test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after dosing are placed in to 37 ℃, 5%CO
2in incubator, cultivate 48h.The activity of positive control medicine is measured according to the method for test sample.
(9) mensuration of survivaling cell: having cultivated in 96 orifice plates after 48h, every hole adds MTT 40 μ l (being made into 4mg/mL with D-Hanks damping fluid).At 37 ℃, place after 4h, remove supernatant liquor.Every hole adds 150 μ 1DMSO, and vibration 5min, makes formazan dissolving crystallized.Finally, utilize automatic microplate reader at 570nm wavelength place, to detect the optical density(OD) (OD value) in each hole.
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to the following formula:
Growth inhibition ratio=(1-survival rate) × 100%=[1-(OD
experiment-OD
blank)/(OD
contrast-OD
empty in vain)] × 100% (OD
experimentrepresent the average optical of testing drug group, OD
contrastrepresent the average optical of control group, OD
blankrepresent the average optical of control group).
Half-inhibition concentration (IC
50) be defined as the drug level when the survival of 50% tumour cell.According to the optical density(OD) (OD value) of measuring, make the typical curve of inhibitory rate of cell growth, on typical curve, try to achieve its corresponding drug level.
The IC recording
50be shown in Table 1
The inhibition IC of the listed crocetin amide derivatives of table 1 the present invention to tumour cell
50value (μ M)
Claims (6)
1. a class crocetin amide derivatives, is characterized in that it has following general formula:
In formula, R is:
2. prepare a method for a class crocetin amide derivatives claimed in claim 1, it is characterized in that it is comprised of the following step:
Step 1. is added to crocetin in round-bottomed flask, with organic solvent dissolution; Under cold condition, successively drip oxalyl chloride and triethylamine in crocetin solution, magnetic agitation for some time;
Step 2. is added to substituting group aniline in step 1 gained solution under cold condition, magnetic agitation reaction for some time;
After step 3. reaction finishes, reaction solution is poured into water, with organic solvent extraction, then washing, dry, organic solvent is removed in underpressure distillation, and recrystallization obtains final product.
3. according to the class crocetin amide derivatives described in claim 1 and 2, it is characterized in that in step 1, the molar ratio of crocetin and oxalyl chloride is 1: (2-4), best molar ratio is 1: 2.2; Crocetin described in step 1 and the molar ratio of triethylamine are 1: (2-3), best molar ratio is 1: 2.1; Organic solvent described in step 1 is DMF (DMF) or DMSO (methyl-sulphoxide);
Cold condition described in step 1 is-10 ℃ to 10 ℃, and optimum temps is 0 ℃; The stirring reaction time described in step 1 is half an hour to 10 hour, and Best Times is 4 hours.
4. according to the class crocetin amide derivatives described in claim 1 and 2, it is characterized in that the cold condition described in step 2 is-10 ℃ to 30 ℃, optimum temps is 0 ℃; The substituting group aniline that step 2 adds and the molar ratio of step 1 crocetin are 1: (2-3), optimum proportion is 2: 2.1; The reaction times of step 2 is half an hour to 24 hour, and Best Times is 8 hours.
5. according to the class crocetin amide derivatives described in claim 1 and 2, it is characterized in that the extraction organic solvent described in step 3 is ethyl acetate, chloroform or methylene dichloride, optimum solvent is ethyl acetate; Described in step 3, recrystallization solvent for use is the mixed solvent of acetone and ethanol or methyl alcohol, and best mixed volume ratio is 1: 5.
6. a class crocetin amide derivatives according to claim 1 is in the application of preparing in cancer therapy drug.
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| CN106397253A (en) * | 2016-06-23 | 2017-02-15 | 丽珠医药集团股份有限公司 | A crocetin derivative GX-E, a preparing method thereof and applications of the crocetin derivative in prevention or treatment of cardiovascular and cerebrovascular diseases |
| CN106431950A (en) * | 2016-06-23 | 2017-02-22 | 丽珠医药集团股份有限公司 | Crocetin derivative GX-Ring, preparation method thereof, and application thereof in preventing or treating cardiovascular and cerebrovascular diseases |
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| CN106187949A (en) * | 2016-06-23 | 2016-12-07 | 丽珠医药集团股份有限公司 | A kind of α-crocetin derivant GX B and preparation method thereof and the application in prevention or treatment cardiovascular and cerebrovascular disease |
| CN106187806A (en) * | 2016-06-23 | 2016-12-07 | 丽珠医药集团股份有限公司 | A kind of α-crocetin derivant GX F and preparation method thereof and the application in prevention or treatment cardiovascular and cerebrovascular disease |
| CN106243063A (en) * | 2016-06-23 | 2016-12-21 | 丽珠医药集团股份有限公司 | A kind of α-crocetin derivant GX D and preparation method thereof and the application in prevention or treatment cardiovascular and cerebrovascular disease |
| CN106397253A (en) * | 2016-06-23 | 2017-02-15 | 丽珠医药集团股份有限公司 | A crocetin derivative GX-E, a preparing method thereof and applications of the crocetin derivative in prevention or treatment of cardiovascular and cerebrovascular diseases |
| CN106431950A (en) * | 2016-06-23 | 2017-02-22 | 丽珠医药集团股份有限公司 | Crocetin derivative GX-Ring, preparation method thereof, and application thereof in preventing or treating cardiovascular and cerebrovascular diseases |
| CN106187949B (en) * | 2016-06-23 | 2018-05-22 | 丽珠医药集团股份有限公司 | A kind of crocetin derivative GX-B and preparation method thereof and the application in preventing or treating cardiovascular and cerebrovascular disease |
| CN106243063B (en) * | 2016-06-23 | 2018-06-26 | 丽珠医药集团股份有限公司 | A kind of crocetin derivative GX-D and preparation method thereof and the application in preventing or treating cardiovascular and cerebrovascular disease |
| CN106397253B (en) * | 2016-06-23 | 2018-06-26 | 丽珠医药集团股份有限公司 | A kind of crocetin derivative GX-E and preparation method thereof and the application in preventing or treating cardiovascular and cerebrovascular disease |
| CN106431950B (en) * | 2016-06-23 | 2018-06-29 | 丽珠医药集团股份有限公司 | A kind of crocetin derivative GX-Ring and preparation method thereof and the application in preventing or treating cardiovascular and cerebrovascular disease |
| CN106187806B (en) * | 2016-06-23 | 2018-06-29 | 丽珠医药集团股份有限公司 | A kind of crocetin derivative GX-F and preparation method thereof and the application in preventing or treating cardiovascular and cerebrovascular disease |
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