CN102126938B - Curcumin analog and preparation method and application thereof - Google Patents
Curcumin analog and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a curcumin analog and a preparation method and application thereof, relates to a curcumin analog and provides a curcumin analog. The curcumin analog is red powder, and has the chemical name of 1,7-di(4-hydroxyl-3-allyl benzene)-1,6-heptadiene-3,5-diketone and the molecular weight of 388.1. The molecular structure of curcumin is modified and reformed on the basis of known active compound curcumin, so that a novel compound which is the 1,7-di(4-hydroxyl-3-allyl benzene)-1,6-heptadiene-3,5-diketone with higher antitumor activity is prepared. The curcumin analog remarkably suppresses the growth of nasopharyngeal darcinoma CNE2 cells, human cervical carcinoma Hela cells, human fibrosarcoma HT1080 cells and human liver cancer Bel-7402 cells, and can be widely applied to preparation of antitumor medicaments.
Description
Technical field
The present invention relates to a kind of compound, particularly a kind of curcumin analogue and its preparation method and application.
Background technology
The chemical structural formula of curcumine is:
Curcumine (curcumin) is a kind of phenol pigment that extracts from Zingiber curcuma turmeric rhizome, its antitumor action in 1985 by India scholar Kuttan propose first (1, Ramadasan Kuttan, P.Bhanumathy, and be subject to the extensive concern of Chinese scholars K.Nirmala et al.CancerLetters (1985) 29:197-202), always.Experiment in vivo and vitro in recent years shows, curcumine can change carcinogen metabolic detoxification process and activation process, and can change the essence of carcinogen, reduce or remove and to enter the carcinogen that target spot and key component are similar in the cell, can suppress carcinogen to the startup of tumorigenesis and promoter action (2, Wang Chunbin. the progress of curcumine and the application in cardiovascular disorder. the angiocardiology progress, 2005,26 (6), 614-616; 3, Jin Li, Yang Shiyong. the progress of curcumine. foreign medical science traditional Chinese medicine fascicle, 1997,19 (3): 49-50), and have that toxicity is low, bioavailability is high and the advantage such as aboundresources.Curcumine can the inducing cell cycle arrest and apoptosis (4, Huang Dongsheng, Chen Jin and, Wu Jiliang. curcumine is induced the experimental study of human lung carcinoma cell apoptosis. Xianning medical college journal, 2002,16 (4): 251-255), can suppress simultaneously the invasion and attack of tumour and transfer (5, Xiao Xuyang. curcumine antitumor mechanism progress. Jinzhou Medical College's journal, 2006,27 (1), 56-58), be a kind of very promising antitumour drug.Curcumine the definite activity of anti-tumor aspect and it simple in structure, be easy to advantage synthetic and that transform, a good drug development primer is provided.
At present, in the transformation to the curcumine structure, a lot of valuable conclusions have been obtained, especially on the substituting group kind on the phenyl ring and position, beta-diketon part, 4 methylene radical replace, the pharmacophores such as planarity of flexible and variation and the molecule integral body of middle connection chain are on impact and the contribution of pharmacologically active, can be used for instructing the further research and development of curcumin novel drugs.
Summary of the invention
The first purpose of the present invention is to provide a kind of curcumin analogue.
The second purpose of the present invention is to provide a kind of preparation method of curcumin analogue.
The 3rd purpose of the present invention is to provide the application of a kind of curcumin analogue in the preparation antitumor drug.
The chemistry of described a kind of curcumin analogue is called BHDD, and molecular weight is 388.1, and structural formula is:
The described curcumin analogue powder that takes on a red color.
The preparation method of described a kind of curcumin analogue may further comprise the steps:
1) preparation 4-allyloxy phenyl aldehyde
Under nitrogen protection, 4-hydroxy benzaldehyde, Anhydrous potassium carbonate are joined in the organic solvent to get solution A, allyl bromide 98 is added organic solvent get solution B, again solution B is added in the solution A, carry out heating reflux reaction; Reaction is removed organic solvent after finishing, and residuum adds by in the solution C that is comprised of ethyl acetate and salt brine solution, and concussion separates organic layer, removes ethyl acetate after the drying and namely gets 4-allyloxy phenyl aldehyde;
2) preparation 3-allyl group-4-hydroxy benzaldehyde
With step 1) the 4-allyloxy phenyl aldehyde of gained carries out rearrangement reaction, and reaction product is carried out silica gel column chromatography and is separated and namely get 3-allyl group-4-hydroxy benzaldehyde;
3) preparation BHDD
Methyl ethyl diketone and boron trioxide are dissolved in the ethyl acetate to get solution D, n-Butyl Amine 99 are added ethyl acetate get solution E; With tributyl borate and step 2) the 3-allyl group of gained-4-hydroxy benzaldehyde adds ethyl acetate and gets solution F, will solution F adds in the solution D to get solution G; Again solution E is added and get Solution H among the solution G; With Solution H acid solution acidifying, separate water layer and organic layer, behind the merging organic layer, carry out drying, decompression, remove ethyl acetate, residue is carried out silica gel column chromatography separate, namely get curcumin analogue: 1,7-two (4-hydroxyl-3-allyl phenyl)-1,6-heptadiene-3,5-diketone.
In step 1) in, described organic solvent can be acetone or tetrahydrofuran (THF) etc.; The volumetric molar concentration of 4-hydroxy benzaldehyde can be 0.05～0.5mmol/L in the described solution A, Anhydrous potassium carbonate volumetric molar concentration can be 0.1～1.0mmol/L, the volumetric molar concentration of allyl bromide 98 can be 0.1～1.0mmol/L in the described solution B; The temperature of described heating reflux reaction can be 78～80 ℃, and the time can be 2～5h; Described salt brine solution can be sodium chloride solution or metabisulfite solution etc., and the volume ratio of ethyl acetate and salt brine solution can be 2 in the described solution C: (1～2).
In step 2) in, the condition of described rearrangement reaction is: 160～200 ℃ of temperature, time 5～8h; The silica gel of described silica gel column chromatography is 200～400 orders.
In step 3) in, the volumetric molar concentration of methyl ethyl diketone can be 0.11～1.1mmol/L in the described solution D, and the volumetric molar concentration of boron trioxide can be 0.07～0.7mmol/L, and the n-Butyl Amine 99 volumetric molar concentration in the described solution E can be 0.11～1.1mmol/L; The volumetric molar concentration of described solution G mesoboric acid tri-n-butyl can be 0.21～2.1mmol/L, the volumetric molar concentration of 3-allyl group-4-hydroxy benzaldehyde can be 0.21～2.1mmol/L, the volume ratio of solution E and solution G can be 1: 1 in the described Solution H, the volume ratio of described Solution H and acid solution can be 5: (1～2), described acid solution can be sulphuric acid soln or hydrochloric acid soln.
The present invention is from known activity compound curcumine, the molecular structure of curcumine is modified and transformed, prepared the new compound with better anti-tumor activity: 1,7-two (4-hydroxyl-3-allyl phenyl)-1,6-heptadiene-3, the 5-cyclohexadione compounds.It suppresses the growth of nasopharyngeal carcinoma CNE2 cell, the thin HeLa cell of human cervical carcinoma, human fibrosarcoma HT1080 cell and Human hepatocarcinoma Bel-7402 cell significantly, can have widely at the preparation antitumor drug to use.
Embodiment
Embodiment 11,7-two (4-hydroxyl-3-allyl phenyl)-1,6-heptadiene-3, the preparation of 5-diketone
The preparation method of BHDD may further comprise the steps:
1) under nitrogen protection, disubstituted-4-hydroxy phenyl aldehyde 1.22g, Anhydrous potassium carbonate 2.76g join in the 50mL anhydrous propanone, and stirring at room 30min gets mixing solutions;
The acetone soln 50mL that 2) will contain the 1.73mL allyl bromide 98 joins step 1) in the mixing solutions of gained, 80 ℃ of heating reflux reaction 3h, can't detect raw material point to silica-gel plate till.Removal of solvent under reduced pressure, the residuum after must concentrating.Add the ethyl acetate solution of 40mL and the sodium chloride aqueous solution of 20mL, concussion.Separate organic layer, filter behind the anhydrous magnesium sulfate drying, removal of solvent under reduced pressure obtains intermediate product one: 4-allyloxy phenyl aldehyde, 1.60g, yellow oily liquid, productive rate 98%.
3) 4-allyloxy phenyl aldehyde 1.60g is packed into round-bottomed flask is loaded onto prolong, and 200 ℃ of lower 5h that reset are cooled to room temperature afterwards.Product is carried out silica gel column chromatography again and separate, V (normal hexane): V (ethyl acetate)=5: 1 obtains intermediate product two: 3-allyl group-4-hydroxy benzaldehyde, 1.38g, colourless oil liquid, productive rate 86% as eluent.
4) methyl ethyl diketone 426mg and boron trioxide 209mg are dissolved in the 10mL ethyl acetate, 50 ℃ of lower 30min that stir.Add afterwards and contain in steps 3) the ethyl acetate solution 10ml of the 3-allyl group of gained-4-hydroxy benzaldehyde 1.38g and tributyl borate 1.96g, after stirring 30min, the ethyl acetate solution 10mL that will contain n-Butyl Amine 99 0.43mL slowly drops in the above-mentioned reaction solution.Under 50 ℃, stirring reaction spends the night.
5) reaction mixture shakes with HCl (0.4N, 6mL) acidifying.Separate water layer and organic layer, water layer ethyl acetate extraction three times.Merge organic layer solution, with filtering behind the anhydrous sodium sulfate drying.After organic solvent is removed in decompression, residue is carried out silica gel column chromatography to be separated, V (sherwood oil): V (acetone)=3: 1 obtains the target product of purifying: 1,7-two (4-hydroxyl-3-allyl phenyl)-1 as eluent, 6-heptadiene-3, the 5-diketone, 1.12g (2.89mmol), red powder, productive rate 68%, the overall yield of whole reaction is: 57.8%.The product Mass Spectrometric Identification.
Curcumine is bought from Chemical Reagent Co., Ltd., Sinopharm Group, and used reagent is analytical pure in synthesizing.
1H-NMR,
13C-NMR is by measuring on the Bruker av400 NMR spectrometer with superconducting magnet, take TMS as in be marked on deuterium for recording in the organic solvent.Mass spectrum system uses Applied Biosystems 3200Q TRAP LC/MS/MS System quadrupole mass spectrometer to record.Infraredly record at infrared absorption spectrometer Nicolet Avatar 360.That ultraviolet spectroscopy uses is the UV-260spectrometer of Shimadzu company; Microplate reader is used the product of Bio-Rad company.Test result is as follows:
The spectroscopic data of BHDD:
UV(H
2O)λmax(logε)285nm(4.03)，471nm(4.23)。
1H?NMR(400M?Hz，DMSO-d
6)：δ3.30(d，J＝6.4Hz，4H)，5.04(m，4H)，5.98(m，2H)，6.07(s，1H)，6.62(d，J＝15.9Hz，2H)，6.85(d，J＝7.8Hz，2H)，7.41(brd，J＝7.8Hz，2H)，7.42(brs，2H)，7.52(d，J＝15.9Hz，2H)，10.09(s，2H).
13CNMR(400M?Hz，DMSO-d
6)：33.64，100.75，115.37，115.62，120.62，125.76，126.80，128.32，130.07，136.61，140.44，157.53，183.12.MS-ESI，m/z?387.4[M-H]
-。
Prepared product is a kind of curcumin analogue, chemistry BHDD by name, and molecular weight is 338.1.Structural formula is:
Embodiment 21,7-two (4-hydroxyl-3-allyl phenyl)-1,6-heptadiene-3, the anti-tumor activity of 5-diketone
The present invention is to 1,7-two (4-hydroxyl-3-allyl phenyl)-1,6-heptadiene-3, the anti-tumor activity of 5-diketone is studied, find that it has obvious anti-tumor activity, the tumour cell of research comprises nasopharyngeal carcinoma CNE2 cell, HeLa Cells, human fibrosarcoma HT 1080 cells and Human hepatocarcinoma Bel-7402 cell.Different concns BHDD (BHDD) and curcumine (Curcumin) can be referring to tables 1 to the inhibiting rate (%) of tumour cell.
Table 1
The tumour cell of taking the logarithm vegetative period is made single cell suspension, by every hole 1 * 10
4Individual cell is inoculated in 3 96 orifice plates, places 37 ℃, contains 5%CO
2Cultivate 24h in the cell culture incubator of saturated humidity, treat that cell attachment growth merges to 80% the time, adding respectively final concentration is 1 of 6.25,12.5,25,50,100,200 μ mol/L, 7-two (4-hydroxyl-3-allyl phenyl)-1,6-heptadiene-3, the 5-diketone, not contain 1,7-two (4-hydroxyl-3-allyl phenyl)-1,6-heptadiene-3, the cell of 5-diketone substratum is the blank well zeroing as negative control.37 ℃ on cell transposition contains 1%O
2, 5%CO
2And 95%N
2The saturated humidity incubator in, continue to cultivate 48h.Measure again the light absorption value (A) in each hole at microplate reader 475nm place.Calculate as follows inhibiting rate: inhibiting rate (%)=[1-(average light absorption value is organized in the average light absorption value-zeroing of experimental group)]/(average light absorption value is organized in the average light absorption value-zeroing of control group) * 100%.
1) BHDD is to the restraining effect of nasopharyngeal carcinoma CNE2 cell
BHDD and curcumine show the anti-tumor activity result of nasopharyngeal carcinoma CNE2 cell: this compound all has remarkable restraining effect to the propagation of nasopharyngeal carcinoma CNE2 cell.Do the time spent at 50,100 μ mol/L, the compound BHDD shows the effect of the inhibition nasopharyngeal carcinoma CNE2 cell proliferation stronger than curcumine.
2) BHDD is to the restraining effect of HeLa Cells
1,7-two (4-hydroxyl-3-allyl phenyl)-1,6-heptadiene-3,5-diketone and curcumine show the anti-tumor activity result of HeLa Cells: 50,100,200 μ M do the time spent, and this compound shows the restraining effect stronger than curcumine to the propagation of HeLa Cells, and has the significant concn dependency.
3) BHDD is to the restraining effect of human fibrosarcoma HT 1080 cells
1,7-two (4-hydroxyl-3-allyl phenyl)-1,6-heptadiene-3,5-diketone and curcumine show the anti-tumor activity result of human fibrosarcoma HT 1080 cells: 50,100 μ mol/L do the time spent, compound 1,7-two (4-hydroxyl-3-allyl phenyl)-1,6-heptadiene-3,5-diketone show the effect of inhibition human fibrosarcoma HT 1080 cell proliferations stronger than curcumine.
4) BHDD is to the restraining effect of Human hepatocarcinoma Bel-7402 cell
1,7-two (4-hydroxyl-3-allyl phenyl)-1,6-heptadiene-3,5-diketone and curcumine show the anti-tumor activity result of Human hepatocarcinoma Bel-7402 cell: 50,100,200 μ mol/L do the time spent, and this compound shows the restraining effect stronger than curcumine to the propagation of Human hepatocarcinoma Bel-7402 cell, and has the significant concn dependency.
Claims (8)
1. the preparation method of a curcumin analogue is characterized in that the chemistry of described curcumin analogue is called BHDD, and molecular weight is 388.1, and structural formula is:
Described preparation method may further comprise the steps:
1) preparation 4-allyloxy phenyl aldehyde
Under nitrogen protection, 4-hydroxy benzaldehyde, Anhydrous potassium carbonate are joined in the organic solvent to get solution A, allyl bromide 98 is added organic solvent get solution B, again solution B is added in the solution A, carry out heating reflux reaction; Reaction is removed organic solvent after finishing, and residuum adds by in the solution C that is comprised of ethyl acetate and salt brine solution, and concussion separates organic layer, removes ethyl acetate after the drying and namely gets 4-allyloxy phenyl aldehyde;
2) preparation 3-allyl group-4-hydroxy benzaldehyde
The 4-allyloxy phenyl aldehyde of step 1) gained is carried out rearrangement reaction, and reaction product is carried out the silica gel column chromatography separation and is namely got 3-allyl group-4-hydroxy benzaldehyde;
3) preparation BHDD
Methyl ethyl diketone and boron trioxide are dissolved in the ethyl acetate to get solution D, n-Butyl Amine 99 are added ethyl acetate get solution E; With tributyl borate and step 2) the 3-allyl group of gained-4-hydroxy benzaldehyde adds ethyl acetate and gets solution F, will solution F adds in the solution D to get solution G; Again solution E is added and get Solution H among the solution G; With Solution H acid solution acidifying, separate water layer and organic layer, behind the merging organic layer, carry out drying, decompression, remove ethyl acetate, residue is carried out silica gel column chromatography separate, namely get curcumin analogue: 1,7-two (4-hydroxyl-3-allyl phenyl)-1,6-heptadiene-3,5-diketone.
2. the preparation method of a kind of curcumin analogue as claimed in claim 1 is characterized in that in step 1), and described organic solvent is acetone or tetrahydrofuran (THF).
3. the preparation method of a kind of curcumin analogue as claimed in claim 1, it is characterized in that in step 1), the volumetric molar concentration of 4-hydroxy benzaldehyde is 0.05～0.5mmol/L in the described solution A, the volumetric molar concentration of Anhydrous potassium carbonate is 0.1～1.0mmol/L, and the volumetric molar concentration of allyl bromide 98 is 0.1～1.0mmol/L in the described solution B.
4. the preparation method of a kind of curcumin analogue as claimed in claim 1 is characterized in that in step 1), and the temperature of described heating reflux reaction is 78～80 ℃, and the time is 2～5h.
5. the preparation method of a kind of curcumin analogue as claimed in claim 1 is characterized in that in step 1), and described salt brine solution is sodium chloride solution or metabisulfite solution, and the volume ratio of ethyl acetate and salt brine solution is 2: 1～2 in the described solution C.
6. the preparation method of a kind of curcumin analogue as claimed in claim 1 is characterized in that in step 2) in, the condition of described rearrangement reaction is: 160～200 ℃ of temperature, time 5～8h.
7. the preparation method of a kind of curcumin analogue as claimed in claim 1 is characterized in that in step 2) in, the silica gel of described silica gel column chromatography is 200～400 orders.
8. the preparation method of a kind of curcumin analogue as claimed in claim 1, it is characterized in that in step 3), the volumetric molar concentration of methyl ethyl diketone is 0.11～1.1mmol/L in the described solution D, the volumetric molar concentration of boron trioxide is 0.07～0.7mmol/L, and the n-Butyl Amine 99 volumetric molar concentration in the described solution E is 0.11～1.1mmol/L; The volumetric molar concentration of described solution G mesoboric acid tri-n-butyl is 0.21～2.1mmol/L, the volumetric molar concentration of 3-allyl group-4-hydroxy benzaldehyde is 0.21～2.1mmol/L, the volume ratio of solution E and solution G is 1: 1 in the described Solution H, the volume ratio of described Solution H and acid solution is 5: 1～2, and described acid solution is sulphuric acid soln or hydrochloric acid soln.
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| CN103159835B (en) * | 2011-12-13 | 2015-03-25 | 首都医科大学 | Lys and oligopeptide-modified curcumin derivatives, and synthesis and medical application thereof |
| JP6548632B2 (en) * | 2013-03-15 | 2019-07-24 | グランビア ニュートリショナルズ （アイルランド） リミテッド | Products and methods for enhancing the bioavailability of therapeutic compounds |
| CN103524318B (en) * | 2013-10-12 | 2016-04-13 | 温州医科大学 | One class is preparing the application in anti-inflammatory drug containing allylic single carbonyl curcumin analogue |
| CN110183320B (en) * | 2019-04-15 | 2021-06-11 | 四川大学 | Polyene diketone antitumor compound |
| CN110229056B (en) * | 2019-06-21 | 2022-11-08 | 天津科技大学 | Novel curcumin analogue and preparation method and application thereof |
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| CN1646473A (en) * | 2002-04-17 | 2005-07-27 | 北卡罗来纳查佩尔山大学 | Novel curcumin analogues and uses thereof |
| CN101076336A (en) * | 2004-10-15 | 2007-11-21 | 北卡罗来纳查佩尔山大学 | Novel curcumin analogues and uses thereof |
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| CN1646473A (en) * | 2002-04-17 | 2005-07-27 | 北卡罗来纳查佩尔山大学 | Novel curcumin analogues and uses thereof |
| CN101076336A (en) * | 2004-10-15 | 2007-11-21 | 北卡罗来纳查佩尔山大学 | Novel curcumin analogues and uses thereof |
Non-Patent Citations (2)
| Title |
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| Somepalli Venkateswarlu et al..Synthesis and biological evaluation of polyhydroxycurcuminoids.《Bioorganic & Medicinal Chemistry》.2005,(第13期),第6374–6380页. |
| Synthesis and biological evaluation of polyhydroxycurcuminoids;Somepalli Venkateswarlu et al.;《Bioorganic & Medicinal Chemistry》;20050819(第13期);第6374–6380页 * |
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