CN110229056B - Novel curcumin analogue and preparation method and application thereof - Google Patents
Novel curcumin analogue and preparation method and application thereof Download PDFInfo
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
The invention relates to a novel curcumin analogue, which is obtained by modifying curcumin by using common substituent groups in natural products, and specifically, the analogue has a structural general formula as follows:
wherein R is 1 And R 2 Is one of hydrogen, allyl, isopentenyl and geranyl; alternatively, the structural formula of the analog is:
wherein R is 1 And R 2 Is one of hydrogen, allyl, isopentenyl and geranyl. The curcumin analogue has good antioxidant activity, short preparation route and simple and easy synthetic process.
Description
Technical Field
The invention belongs to the technical field of synthesis of new compounds and application of medicaments, and relates to a new curcumin analogue and a preparation method thereof, in particular to a novel curcumin analogue and a preparation method and application thereof.
Background
Curcumin is a chemical component extracted from rhizomes of some plants in Zingiberaceae and Araceae, is a rare pigment with diketone in plant world, and is a diketone compound. Curcumin is orange yellow crystal powder, slightly bitter in taste and insoluble in water, and is mainly used for coloring products such as sausage products, cans, sauced and marinated products and the like in food production. The medical research shows that curcumin has wide pharmacological activities of resisting inflammation, resisting oxidation, regulating lipid, resisting virus, resisting infection, resisting tumor, resisting coagulation, resisting hepatic fibrosis, resisting atherosclerosis and the like, and has low toxicity and small adverse reaction. Due to various pharmacological activities of curcumin and derivatives thereof, but curcumin is insoluble in water, the aqueous solution of curcumin is unstable under neutral to alkaline conditions, the curcumin has low biological activity in vivo, little absorption in vivo, too fast metabolism and low bioavailability, and the application of curcumin is greatly limited. In order to improve the stability of the medicine, enhance the biological activity of the medicine and reduce the toxic and side effect of the medicine, the molecular with high bioavailability is screened out to be used in the field of medicine, and the method has important significance for carrying out corresponding structure modification on curcumin or synthesizing curcumin analogues.
Through searching, the following patent publications related to the patent application of the invention are found:
1. the synthesis of curcumin analogues containing bis [3- (substituted phenyl) acryloyl ] benzene (CN 101475460) has good medicinal activities of resisting tumor, inflammation, oxidation and the like, and the novel analogue medicine has the chemical formula (I) on the right. The curcumin analogue provided by the invention is a curcumin analogue which is designed and prepared by replacing a beta-diketone active methylene part of curcumin with a benzene ring according to the principle of drug structure-activity molecular and the special symmetrical alpha, beta-unsaturated 3, 5-diketone structure of curcumin and performing structural modification on drug molecules and has higher medicinal activity on the aspects of tumor, inflammation, oxidation and the like.
2. A method for catalytically synthesizing chiral curcumin analogues (CN 102115446A) is a method for catalytically synthesizing chiral curcumin analogues, nitroolefin and curcumin analogues are used as raw materials, a tertiary amine-thiourea organic catalyst is used as a catalytic system, the reaction is carried out in a solvent for 0.5-15 days at-40 ℃, a conjugate addition product is generated, and the reaction general formula is as follows: in the formula, R1 and R2 are aliphatic and aromatic groups; the structural formula of the tertiary amine-thiourea organic catalyst is as follows: in the formula: r1 is a cinchona alkaloid derivative containing tertiary amine; r2 and R3 are respectively different or same aromatic substituent; r4 is a sulfonyl substituent; the tertiary amine-thiourea organic catalyst has high catalytic activity and stereoselectivity in the Michael addition reaction of nitroolefin and curcumin analogue, the highest enantioselectivity is 97%, the highest yield is 96%, and the reaction substrate range is wide.
3. Curcumin analogues and preparation and application thereof (CN 105348219A), relating to preparation and application of a series of curcumin analogues, have structures shown in formula I, formula II and formula III, wherein R, R1 and R2 are described in the specification. The pharmaceutically acceptable salts and solvates of the curcumin analogs, and medicaments containing the curcumin analogs or pharmaceutically acceptable salts thereof as active ingredients can be used for treating cancers. The curcumin analogue and the medicinal salt thereof have good anticancer activity, and the preparation method is simple, feasible and easy to operate.
By contrast, the present patent application is substantially different from the above patent publications.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a novel curcumin analogue, a preparation method and application thereof.
The technical scheme adopted by the invention for solving the technical problem is as follows:
a novel curcumin analogue is obtained by modifying curcumin by using a substituent commonly seen in natural products, and specifically, the analogue has a structural general formula as follows:
wherein R is 1 And R 2 Is one of hydrogen, allyl, isopentenyl and geranyl;
alternatively, the structural formula of the analog is:
wherein R is 1 And R 2 Is one of hydrogen, allyl, isopentenyl and geranyl.
Moreover, the analog has the structural formula:
compound 1:
or the following steps:
compound 2:
or the following steps:
compound 3:
or the following steps:
compound 4:
or the following steps:
compound 5:
or the following steps:
compound 6:
or the following steps:
compound 7:
or the following steps:
compound 8:
the preparation method of the novel curcumin analogue comprises the following synthetic routes:
synthesizing a final product I by reacting a known compound vanillin;
alternatively, the synthetic route of the method is as follows:
the synthesized compound I is further reacted with hydrazine hydrate to synthesize a final product II.
The preparation method of the novel curcumin analogue comprises the following steps:
the first synthetic route is as follows:
vanillin is taken as a raw material and divided into two paths, isopentene is introduced at the ortho position of phenolic hydroxyl group in the upper path through rearrangement reaction to obtain an intermediate a, another intermediate b is formed in the lower path through aldol condensation reaction with acetylacetone, and finally the two obtained intermediates are subjected to aldol condensation again to finally obtain a compound 1;
the second synthetic route is as follows:
vanillin is taken as a raw material and divided into two paths, the upper path introduces allyl at the ortho position of phenolic hydroxyl through rearrangement reaction to generate an intermediate d, the lower path forms another intermediate b through aldol condensation reaction with acetylacetone, and finally, the two obtained intermediates are subjected to aldol condensation again to finally obtain a compound 2;
the third synthetic route is as follows:
taking vanillin as a raw material, introducing allyl at the ortho-position of phenolic hydroxyl through rearrangement reaction, and then carrying out aldol condensation reaction on the obtained intermediate d and acetylacetone to finally obtain a compound 3;
the fourth synthetic route is as follows:
vanillin is taken as a raw material and divided into two paths, allyl is introduced into the upper path through a rearrangement reaction, then a final intermediate e of the upper path is generated through an aldol condensation reaction, isopentenyl is introduced into the lower path at the ortho position of a phenolic hydroxyl group through a rearrangement reaction to obtain an intermediate a, and finally the two obtained intermediates are subjected to aldol condensation again to finally obtain a compound 4;
the fifth synthetic route is as follows:
the final products obtained by the previous four routes are used as raw materials and further react with hydrazine hydrate to finally obtain the compounds 5-8.
The novel curcumin analogue is applied to the aspect of antioxidation.
The invention has the advantages and positive effects that:
1. the curcumin analogue has good antioxidant activity, can be applied to the aspect of antioxidation, and provides a thought for modification of other natural products.
2. The method has the advantages of simple synthetic route, less intermediates, simple synthetic process and easy operation.
3. The raw materials and reagents used in the synthetic route of the method are cheap and easy to obtain, and the cost is saved.
Detailed Description
The following detailed description of the embodiments of the present invention is provided for the purpose of illustration and not limitation, and should not be construed as limiting the scope of the invention.
The raw materials used in the invention are conventional commercial products unless otherwise specified; the methods used in the present invention are, unless otherwise specified, conventional in the art.
A novel curcumin analogue is obtained by modifying curcumin by using a substituent commonly seen in natural products, and specifically, the analogue has a structural general formula as follows:
wherein R is 1 And R 2 Is one of hydrogen, allyl, isopentenyl and geranyl;
alternatively, the structural formula of the analog is:
wherein R is 1 And R 2 Is one of hydrogen, allyl, isopentenyl and geranyl.
Preferably, the analog has the formula:
compound 1:
or the following steps:
compound 2:
or the following steps:
compound 3:
or the following steps:
compound 4:
or the following steps:
compound 5:
or the following steps:
compound 6:
or the following steps:
compound 7:
or the following steps:
compound 8:
the preparation method of the novel curcumin analogue comprises the following synthetic routes:
synthesizing a final product I from a known compound vanillin through reaction;
alternatively, the synthetic route of the method is as follows:
the synthesized compound I is further reacted with hydrazine hydrate to synthesize a final product II.
The preparation method of the novel curcumin analogue comprises the following steps:
the first synthetic route is as follows:
vanillin is taken as a raw material and divided into two paths, isopentenyl is introduced at the ortho position of phenolic hydroxyl group through rearrangement reaction in the upper path to obtain an intermediate a, the other intermediate b is formed through aldol condensation reaction with acetylacetone in the lower path, and finally the two obtained intermediates are subjected to aldol condensation again to finally obtain a compound 1;
the second synthetic route is as follows:
vanillin is taken as a raw material and divided into two paths, the upper path introduces allyl at the ortho position of phenolic hydroxyl through rearrangement reaction to generate an intermediate d, the lower path forms another intermediate b through aldol condensation reaction with acetylacetone, and finally, the two obtained intermediates are subjected to aldol condensation again to finally obtain a compound 2;
the third synthetic route is as follows:
introducing allyl to the ortho position of phenolic hydroxyl by rearrangement reaction by using vanillin as a raw material, and then carrying out aldol condensation reaction on the obtained intermediate d and acetylacetone to finally obtain a compound 3;
the fourth synthetic route is as follows:
vanillin is taken as a raw material and divided into two paths, allyl is firstly introduced into the upper path through a rearrangement reaction, then a final intermediate e of the upper path is generated through an aldol condensation reaction, isopentenyl is directly introduced into the lower path at the ortho position of phenolic hydroxyl through the rearrangement reaction to obtain an intermediate a, finally the two obtained intermediates are subjected to aldol condensation again, and finally a compound 4 is obtained;
the fifth synthetic route is as follows:
the final products obtained in the previous four routes are used as raw materials and further react with hydrazine hydrate to finally obtain the compound 5-8.
The novel curcumin analogue is applied to the aspect of antioxidation.
Example 1: synthesis of 4-hydroxy-3-methoxy-5-isopentenylbenzaldehyde (a):
weighing 2.63g (65.7 mmol) of sodium hydroxide solid, preparing 1N sodium hydroxide solution under ice bath stirring, weighing 10g (65.7 mmol) of vanillin to dissolve in the sodium hydroxide solution, wherein the solution is suspension, and completely dissolving the vanillin solution by ultrasonic wave until the vanillin solution is clear and transparent. Then, 10mL (85.4 mmol) of isopentenyl bromide is slowly added into the solution dropwise in the ice bath, the addition is completed in 45 minutes in batches, and the stirring is carried out in an ice bath under the protection of argon. The progress of the reaction was monitored by TLC. 4 hours of post-treatment: adjusting the pH value of the system to 6 by using 1N HCl solution, extracting by using dichloromethane, combining organic phases, washing by using saturated NaCl solution, drying by using anhydrous sodium sulfate, and spin-drying the system to obtain a crude product. The crude product was purified by column chromatography (eluent petroleum ether-ethyl acetate) to give 3.5g of a white solid with a yield of 24%.
1 H-NMR(400MHz,CDCl 3 )δ1.76,1.74(2s,6H),3.40(d,J＝7.2Hz,2H),3.95(s,3H),5.33 (m,1H),6.28(s,1H),7.29(m,2H),9.80(s,1H)
Example 2: synthesis of 6- (4-hydroxy-3-methoxyphenyl) -5-hexene-2, 4-dione (b):
5.5g (79 mmol) of boron trioxide and 9mL (87.6 mmol) of acetylacetone are dissolved in 50mL of ethyl acetate and stirred at 80 ℃ under reflux for 30min to protect the methylene groups which are not involved in the reaction. 2g (13 mmol) of vanillin and 4.5mL (16.7 mmol) of tributyl borate are weighed out again and mixed with 30mL of ethyl acetate solution, then the mixture is added to the system, and the mixture is stirred under reflux at 80 ℃ for 30min. Finally, 1.3ml (13 mmol) of n-butylamine was added dropwise to the system, and the mixture was stirred under reflux at 100 ℃. The progress of the reaction was monitored by TLC. After 3 hours, 20ml of HCl solution (1N) was added to the system, and the mixture was stirred at 50 ℃ for 1 hour to deprotect the methylene group which had not reacted. And finally, extracting the system by using ethyl acetate, combining organic phases, washing by using a saturated NaCl solution, drying by using anhydrous sodium sulfate, and spin-drying the system to obtain a crude product. The crude product was purified by column chromatography (eluent petroleum ether-ethyl acetate) to give 1.8g of a yellow solid in 60% yield.
1 H-NMR(400MHz,DMSO-d 6 )δ2.12(s,3H),3.84(s,3H),5.84(s,1H),6.64(d,J＝15.6Hz, 1H),6.80(d,J＝8.0Hz,1H),7.12(d,J＝2.48Hz,1H),7.29(s,1H),7.48(d,J＝15.6Hz,1H), 9.61(s,1H)
Example 3: synthesis of 1- (4-hydroxy-3-methoxy-5-isopentenylphenyl) -7- (4-hydroxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (Compound 1):
1.33g (5.7 mmol) of 6- (4-hydroxy-3-methoxyphenyl) -5-ene-2, 4-hexanedione (b) and 792mg (11.3 mmol) of boron trioxide are dissolved in 20ml of ethyl acetate and stirred at 80 ℃ under reflux for 30min to protect the methylene groups which are not involved in the reaction. Then, 1.5g (6.8 mmol) of 4-hydroxy-3-methoxy-5-isopentenyl benzaldehyde (a) and 3mL (11.3 mmol) of tributyl borate were mixed with 20mL of an ethyl acetate solution, and the mixture was added to the system, followed by stirring at 80 ℃ under reflux for 30min. Finally 673ul (6.8 mmol) of n-butylamine were added dropwise to the system, and stirred under reflux at 100 ℃. The progress of the reaction was monitored by TLC. After 2 hours, 10ml of HCl solution (1N) was added to the system, and the mixture was stirred at 50 ℃ for 1 hour to deprotect the methylene group which had not reacted. And finally, extracting the system by using ethyl acetate, combining organic phases, washing by using a saturated NaCl solution, drying by using anhydrous sodium sulfate, and spin-drying the system to obtain a crude product. The crude product was purified by column chromatography (eluent petroleum ether-ethyl acetate) to give 1.3g of a dark red solid, 43% yield.
1 H-NMR(400MHz,DMSO-d 6 )δ1.69(s,6H),3.24(d,J＝7.2Hz,2H),3.84,3.86(2s,6H), 5.28(t,J＝7.2Hz,1H),6.08(s,1H),6.72(d,J＝4.4Hz,1H),6.76(d,J＝4.8Hz,1H),6.82(d,J＝8.0Hz,1H),7.04(s,1H),7.15(d,J＝8.0Hz,1H),7.22(s,1H),7.32(s,1H),7.51(d,J＝8.4Hz,1H), 7.55(d,J＝8.8Hz,1H),9.18(s,1H),9.66(s,1H)
Example 4: synthesis of 4-allyloxy-3-methoxybenzaldehyde (c):
weighing 5g (32.9 mmol) of vanillin in 100ml of acetone solution, fully stirring and dissolving, weighing 9.1g (65.8 mmol) of potassium carbonate, adding 3ml (34.7 mmol) of allyl bromide, and stirring under argon protection at 30 ℃. And after 12 hours, removing acetone in the system by rotary evaporation under reduced pressure, adding a proper amount of water for dilution, extracting by using ethyl acetate, combining organic phases, washing by using a saturated NaCl solution, drying by using anhydrous sodium sulfate, and performing rotary drying on the system to obtain a crude product. The crude product was purified by column chromatography (eluent petroleum ether-ethyl acetate) to give 6g of a white solid in 95% yield.
1 H-NMR(400MHz,DMSO-d 6 )δ3.83(s,3H),4.66(d,J＝5.6Hz,2H),5.28(dd,J＝1.2Hz, J＝10.4Hz,1H),5.42(dd,J＝1.6Hz,J＝17.2Hz,1H),6.01-6.10(m,1H),7.14(d,J＝8.0Hz,1H), 7.39(d,J＝1.6Hz,1H),7.51(dd,J＝1.6Hz,J＝8.0Hz,1H),9.83(s,1H)
Example 5: synthesis of 3-allyl-4-hydroxy-5-methoxybenzaldehyde (d):
5g (26 mmol) of 4-allyloxy-3-methoxybenzaldehyde (c) was dissolved in 20ml of NMP (N-methylpyrrolidone) and reacted with a microwave at 200 ℃ for 3 hours. Adding a proper amount of water into the system for dilution, extracting by using dichloromethane, combining organic phases, washing by using a saturated NaCl solution, drying by using anhydrous sodium sulfate, and spin-drying the system to obtain a crude product. The crude product was purified by column chromatography (eluent petroleum ether-ethyl acetate) to give 4.6g of a white solid with a yield of 92%.
1 H-NMR(400MHz,DMSO-d 6 )δ3.36(d,J＝6.8Hz,2H),3.88(s,3H),5.03-5.09(m,2H), 5.91-6.01(m,1H),7.32(s,2H),9.76(s,1H),9.80(s,1H)
Example 6: synthesis of 1- (3-allyl-4-hydroxy-5-methoxyphenyl) -7- (4-hydroxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (Compound 2):
253mg (1 mmol) of 6- (4-hydroxy-3-methoxyphenyl) -5-en-2, 4-hexanedione (b) and 150mg (2.2 mmol) of boron trioxide are weighed out and dissolved in 10ml of ethyl acetate and stirred at 80 ℃ under reflux for 30min to protect the methylene groups which are not involved in the reaction. 0.25g (1.3 mmol) of 3-allyl-4-hydroxy-5-methoxybenzaldehyde (d) and 586uL (2.2 mmol) of tributyl borate were weighed out and mixed with 10ml of an ethyl acetate solution, and the mixture was added to the system, followed by stirring at 80 ℃ under reflux for 30min. Finally, 43ul (0.43 mmol) of piperidine was added dropwise to the system, and the mixture was stirred under reflux at 100 ℃. The progress of the reaction was monitored by TLC. After 1 hour, 10ml of HCl solution (0.4N) was added to the system, and the mixture was stirred at 50 ℃ for 1 hour to deprotect the methylene group which had not reacted. And finally, extracting the system by using ethyl acetate, combining organic phases, washing by using a saturated NaCl solution, drying by using anhydrous sodium sulfate, and spin-drying the system to obtain a crude product. The crude product was purified by column chromatography (eluent petroleum ether-ethyl acetate) to give 270mg of a red solid, 61% yield.
1 H-NMR(400MHz,DMSO-d 6 )δ3.32(d,J＝6.4Hz,2H),3.84,3.87(2s,6H),5.01-5.07(m, 1H),6.08(s,1H),6.75(d,J＝16.0Hz,1H),6.83(d,J＝8.0Hz,1H),7.06(s,1H),7.15(d,J＝8.4 Hz,1H),7.24(s,1H),7.32(s,1H),7.52(d,J＝8.0Hz,1H),7.56(d,J＝8.0Hz,1H),9.24(s,1H), 9.66(s,1H)
Example 7: synthesis of 1, 7-bis (3-allyl-4-hydroxy-5-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (Compound 3):
91mg (1.3 mmol) of boron trioxide and 267uL (2.6 mmol) of acetylacetone are dissolved in 10ml of ethyl acetate and stirred at 80 ℃ under reflux for 30min to protect the methylene groups which are not involved in the reaction. Then, 1g (5.2 mmol) of 3-allyl-4-hydroxy-5-methoxybenzaldehyde (d) and 2.8mL (10.4 mmol) of tributyl borate were mixed with 10mL of an ethyl acetate solution, and the mixture was added to the system, followed by stirring at 80 ℃ under reflux for 30min. Finally, 129ul (1.3 mmol) of n-butylamine was added dropwise to the system, and the mixture was stirred under reflux at 100 ℃. The progress of the reaction was monitored by TLC. After 2 hours, 10ml of HCl solution (1N) was added to the system, and the mixture was stirred at 50 ℃ for 1 hour to deprotect the methylene group which had not reacted. And finally, extracting the system by using ethyl acetate, combining organic phases, washing by using a saturated NaCl solution, drying by using anhydrous sodium sulfate, and spin-drying the system to obtain a crude product. Separating and purifying the crude product by column chromatography (eluent petroleum ether-ethyl acetate) to obtain yellow solid 0.6g with yield of 52%
1 H-NMR(400MHz,DMSO-d 6 )δ3.32(d,J＝6.0Hz,4H),3.87(s,6H),5.91-6.01(m,2H),6.10 (s,1H),6.74(d,J＝15.6Hz,2H),7.06(s,2H),7.24(s,2H),7.53(d,J＝16.0Hz,2H),9.24(s,2H)
Example 8: synthesis of 6- (3-allyl-4-hydroxy-5-methoxyphenyl) -5-hexene-2, 4-dione (e):
2.17g (31.2 mmol) of boron trioxide and 3.58mL (34.9 mmol) of acetylacetone are dissolved in 20mL of ethyl acetate and stirred at 80 ℃ under reflux for 30min to protect the methylene groups which are not involved in the reaction. 1g (5.2 mmol) of 3-allyl-4-hydroxy-5-methoxybenzaldehyde (d) and 1.77mL (6.6 mmol) of tributyl borate were mixed in 20mL of an ethyl acetate solution, added to the system, and stirred under reflux at 80 ℃ for 30min. Finally, 510ul (5.2 mmol) of n-butylamine was added dropwise to the system, and the mixture was stirred under reflux at 100 ℃. The progress of the reaction was monitored by TLC. After 2 hours, 10ml of HCl solution (1N) was added to the system, and the mixture was stirred at 50 ℃ for 1 hour to deprotect the methylene group which had not reacted. And finally, extracting the system by using ethyl acetate, combining organic phases, washing by using a saturated NaCl solution, drying by using anhydrous sodium sulfate, and spin-drying the system to obtain a crude product. Separating and purifying the crude product by column chromatography (eluent petroleum ether-ethyl acetate) to obtain light yellow solid 0.9g with yield of 63%
1 H-NMR(400MHz,DMSO-d 6 )δ2.11(s,3H),3.31(d,J＝6.4Hz,2H),3.86(s,3H), 5.00-5.06(m,2H),5.85(s,1H),5.90-6.05(m,1H),6.63(d,J＝16.0Hz,1H),7.02(s,1H),7.20(s, 1H),7.47(d,J＝16.0Hz,1H),9.19(s,1H)
Example 9: synthesis of 1- (3-allyl-4-hydroxy-5-methoxyphenyl) -7- (4-hydroxy-3-methoxy-5-isopentenylphenyl) -1, 6-heptadiene-3, 5-dione (Compound 4):
517mg (1.9 mmol) of 6- (3-allyl-4-hydroxy-5-methoxyphenyl) -5-hexene-2, 4-dione (e) and 264mg (3.8 mmol) of boron trioxide are weighed out and dissolved in 20ml of ethyl acetate and stirred under reflux at 80 ℃ for 30min to protect the methylene groups which are not involved in the reaction. 0.5g (2.3 mmol) of 4-hydroxy-3-methoxy-5-isopentenyl benzaldehyde (a) and 1mL (3.8 mmol) of tributyl borate were then mixed with 20mL of an ethyl acetate solution, added to the system, and stirred at 80 ℃ under reflux for 30min. Finally 74ul (0.75 mmol) of piperidine was added dropwise to the system and stirred at 100 ℃ under reflux. The progress of the reaction was monitored by TLC. After 1 hour, 10ml of HCl solution (1N) was added to the system, and the mixture was stirred at 50 ℃ for 1 hour to deprotect the methylene group which had not reacted. And finally, extracting the system by using ethyl acetate, combining organic phases, washing by using a saturated NaCl solution, drying by using anhydrous sodium sulfate, and spin-drying the system to obtain a crude product. Separating and purifying the crude product by column chromatography (eluent petroleum ether-ethyl acetate) to obtain red solid 0.7g with yield of 78%
1 H-NMR(400MHz,DMSO-d 6 )δ1.69(s,6H),3.25(d,J＝7.2Hz,2H),3.32(d,J＝6.8Hz, 2H),3.86,3.87(2s,6H),5.01-5.08(m,2H),5.28(t,J＝7.6Hz,1H),5.91-6.01(m,1H),6.10(s, 1H),6.71(d,J＝6.0Hz,1H),6.75(d,J＝6.4Hz,1H),7.04,7.06(2s,2H),7.21,7.23(2s,2H),7.51, 7.55(2s,2H),9.19(s,1H),9.24(s,1H)
Example 10: synthesis of 4,4'- [ (1E, 1' E) -1H-pyrazole-3, 5-bis (2, 1-vinyl) ] bis [ 2-allyl-6-methoxyphenol ] (Compound 5):
0.2g (0.45 mmol) of 1, 7-bis (3-allyl-4-hydroxy-5-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (compound 3) is weighed out and dissolved in 10ml of acetic acid with stirring, 108ul (2.25 mmol) of hydrazine monohydrate is weighed out and added into the system, and stirring is carried out at 60 ℃ under the protection of argon. After 12 hours, adding a proper amount of water into the system for dilution, extracting with dichloromethane, combining organic phases, washing with a saturated NaCl solution, drying with anhydrous sodium sulfate, and spin-drying the system to obtain a crude product. Separating and purifying the crude product by column chromatography (eluent petroleum ether-ethyl acetate) to obtain yellow solid 180mg with yield of 91%
1 H-NMR(400MHz,DMSO-d 6 )δ3.32(d,J＝6.4Hz,4H),3.86(s,6H),5.01-5.09(m,4H), 5.91-6.01(m,2H),6.63(s,1H),6.84-7.06(m,8H),8.75(s,1H),12.81(s,1H)
Example 11: synthesis of 4- [ (E) -2- (3- ((E) -4-hydroxy-3-methoxystyryl) -1H-pyrazol-5-yl) vinyl ] -2-methoxy-6-isopentenylphenol (Compound 6):
0.3g (0.69 mmol) of 1- (4-hydroxy-3-methoxy-5-isopentenylphenyl) -7- (4-hydroxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (compound 1) was weighed out and dissolved in 10ml of acetic acid with stirring, 167ul (3.44 mmol) of hydrazine monohydrate was measured and added to the system, and stirring was carried out at 60 ℃ under the protection of argon. After 12 hours, adding a proper amount of water into the system for dilution, extracting with dichloromethane, combining organic phases, washing with a saturated NaCl solution, drying with anhydrous sodium sulfate, and spin-drying the system to obtain a crude product. Separating and purifying the crude product by column chromatography (eluent petroleum ether-ethyl acetate) to obtain yellow solid 150mg with yield 51%
1 H-NMR(400MHz,DMSO-d 6 )δ1.69(s,6H),3.24(d,J＝6.8Hz,2H),3.83,3.85(2s,6H), 5.29(t,J＝7.2Hz,1H),6.63(s,1H),6.77-7.14(m,9H),8.69(s,1H),9.17(s,1H),12.81(s,1H)
Example 12: synthesis of 2-allyl-4- [ (E) -2- (5- ((E) -4-hydroxy-3-methoxy-5-prenylstyryl) -1H-pyrazol-3-yl) vinyl ] -6-methoxyphenol (Compound 7):
0.3g (0.63 mmol) of 1- (3-allyl-4-hydroxy-5-methoxyphenyl) -7- (4-hydroxy-3-methoxy-5-isopentenylphenyl) -1, 6-heptadiene-3, 5-dione (compound 4) was weighed out and dissolved in 10ml of acetic acid with stirring, 153ul (3.15 mmol) of hydrazine monohydrate was weighed out and added to the system, and stirred at 60 ℃ under the protection of argon. After 12 hours, adding a proper amount of water into the system for dilution, extracting with dichloromethane, combining organic phases, washing with a saturated NaCl solution, drying with anhydrous sodium sulfate, and spin-drying the system to obtain a crude product. The crude product was purified by column chromatography (eluent petroleum ether-ethyl acetate) to give 230mg of yellow solid, 78% yield 1 H-NMR(400MHz,DMSO-d 6 )δ1.70(s,6H),3.24(d,J＝7.2Hz,2H),3.32(d,J＝6.4Hz,2H), 3.85,3.86(2s,6H),4.95-5.09(m,2H),5.29(t,J＝7.2Hz,1H),5.91-6.01(m,1H),6.63(s,1H), 6.81-7.12(m,8H),8.70(s,1H),8.75(s,1H),12.80(s,1H)
Example 13: synthesis of 4- [ (E) -2- (3- ((E) -4-hydroxy-3-methoxystyryl) -1H-pyrazol-5-vinyl) vinyl ] -2-methoxy-6-allylphenol (Compound 8):
0.3g (0.73 mmol) of 1- (3-allyl-4-hydroxy-5-methoxyphenyl) -7- (4-hydroxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (compound 2) was weighed out and dissolved in 10ml of acetic acid with stirring, 179ul (3.65 mmol) of hydrazine monohydrate was weighed out and added to the system, and stirred at 60 ℃ under the protection of argon. And adding a proper amount of water into the system after 6 hours for dilution, then extracting by using dichloromethane, combining organic phases, washing by using a saturated NaCl solution, drying by using anhydrous sodium sulfate, and spin-drying the system to obtain a crude product. Separating and purifying the crude product by column chromatography (eluting with petroleum ether-ethyl acetate) to obtain yellow solid 230mg with yield of 77%
1 H-NMR(400MHz,DMSO-d 6 )δ3.32(d,J＝5.2Hz,2H),3.83,3.86(2s,6H),5.01-5.08(m, 2H),5.93-6.00(m,1H),6.62(s,1H),6.76-7.15(m,9H),8.75(s,1H),9.17(s,1H),12.81(s,1H)
Relevant activity tests of the invention:
antioxidant activity of partial compounds (1-4) was measured.
The cell strain used in the experiment is rat adrenal pheochromocytoma cell (PC-12), hydrogen peroxide is used for causing cell oxidative damage in the experiment, and gallic acid, resveratrol and curcumin are used as positive controls. Cell viability was determined by setting compound concentrations to four concentration gradients of 1. Mu.M, 3. Mu.M, 10. Mu.M, 30. Mu.M, and 100. Mu.M.
Table 1 antioxidant activity test of compounds
As can be seen from table 1, the novel curcumin analogs of the present invention can be applied in terms of anti-oxidative effect.
Although the embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that: various substitutions, changes and modifications are possible without departing from the spirit and scope of the invention and the appended claims, and therefore the scope of the invention is not limited to the embodiments disclosed.
Claims (2)
1. A curcumin analog characterized by: the analogue is obtained by modifying curcumin by using a substituent group commonly seen in natural products, and the structural formula of the analogue is as follows:
compound 2:
or the following steps:
compound 3:
the preparation method of the curcumin analogue comprises the following steps:
the second synthetic route is as follows:
vanillin is taken as a raw material and divided into two paths, the upper path introduces allyl at the ortho position of phenolic hydroxyl through rearrangement reaction to generate an intermediate d, the lower path forms another intermediate b through aldol condensation reaction with acetylacetone, and finally, the two obtained intermediates are subjected to aldol condensation again to finally obtain a compound 2;
the third synthetic route is as follows:
vanillin is used as a raw material, allyl is introduced to the ortho position of phenolic hydroxyl through rearrangement reaction, and the obtained intermediate d and acetylacetone are subjected to aldol condensation reaction to finally obtain a compound 3.
2. Use of a curcumin analogue as claimed in claim 1 for anti-oxidative purposes other than for disease diagnosis and therapy.
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