CN103333140A - Preparation method of curcumin derivatives, and antitumor drug - Google Patents
Preparation method of curcumin derivatives, and antitumor drug Download PDFInfo
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- CN103333140A CN103333140A CN2013102736759A CN201310273675A CN103333140A CN 103333140 A CN103333140 A CN 103333140A CN 2013102736759 A CN2013102736759 A CN 2013102736759A CN 201310273675 A CN201310273675 A CN 201310273675A CN 103333140 A CN103333140 A CN 103333140A
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Abstract
The invention discloses a preparation method of curcumin derivatives, and an antitumor drug. The preparation method comprises the steps of: weighing curcumin to be dissolved into methanol-chloroform mixture solution, and dropwise adding hexahydropyridine as a catalyst; dropwise adding furan formaldehyde methanol solution under stirring, reacting at room temperature, and standing; filtering to retain precipitation product, washing with petroleum ether to remove unreacted active ingredients, and drying; concentrating the filtered mother liquor, washing the reaction liquid with water, separating out the product, filtering to obtain precipitation, washing with petroleum ether, filtering and drying; combining to obtain the product, placing the chloroform-methanol mixture solution for recrystalization, and drying the product to be constant-weight. The new curcumin derivatives synthesized by structure improvement of two curcumin derivatives: 4-(2-fural) curcumin and hydrazinobenzoic acid curcumin which are synthesized by adopting the preparation method of curcumin derivatives is good in water solubility, slow in in-vivo metabolism, high in bioavailability, and higher in activity, and has important application prospects.
Description
Technical field
The invention belongs to the curcumin derivate preparation field, relate in particular to a kind of preparation method and application in the preparation antitumor drug thereof of curcumin derivate.
Background technology
Curcumine (curcumin) is a kind of natural constituent that extracts from rhizome such as Zingiber turmeric (Curcumagenus) plant turmeric, curcuma zedoary, root tuber of aromatic turmeric.
Curcumine is the most important activeconstituents of performance pharmacological action in the turmeric curcuma, and its structural formula as shown in the figure.
It is antitumor to have proved that now curcumine and some analogues thereof have, pharmacological actions widely such as anti-inflammatory, antitumor, anti-oxidant, anti-hepatotoxicity, rheumatism, antibacterial, anti-anti-Alzheimer disease, reducing cholesterol.But curcumine also has shortcomings such as poorly water-soluble, internal metabolism is fast, bioavailability is low, activity is lower, is primer with it therefore, and is significant by curcumin analogue or derivative that structure of modification is synthetic new.
Summary of the invention
Problems such as the purpose of the embodiment of the invention is to provide a kind of preparation method of curcumin derivate, and curcumine poorly water-soluble, the internal metabolism that is intended to solve existing method preparation is fast, bioavailability is low, activity is lower.
The embodiment of the invention is achieved in that a kind of preparation method of curcumin derivate, the 4-(2-furfurylidene) the concrete preparation method of curcumine is:
Step 1, take by weighing curcumine and be dissolved in methyl alcohol-chloroform mixing solutions, drip hexahydropyridine and make catalyzer;
Step 2, under agitation drip the methanol solution of furtural, at room temperature reaction is left standstill;
Step 3, filter to keep precipitated product, wash with sherwood oil, remove behind the unreacted raw material dry;
Step 4, will filter the back mother liquor and concentrate, wash reaction solution with water, separate out product, filter the gained throw out, and wash, filter with sherwood oil, drying;
Step 5, combining step three and step 4 products obtained therefrom are put into chloroform-methanol mixed solution recrystallization, and product drying to constant weight, is obtained yellow powder.
Another purpose of the embodiment of the invention is to provide a kind of concrete preparation method to the carboxyl phenylhydrazine curcumine:
Step 1: take by weighing curcumine and be dissolved in the Glacial acetic acid, add the carboxyl phenylhydrazine heating reflux reaction;
Step 2: remove solvent under reduced pressure, obtain red-brown oily product;
Step 3, red-brown oily product is poured in the beaker that rubble ice is housed, it is Powdered under constantly stirring product to be become, suction filtration, drying;
Step 4: the step 3 products obtained therefrom is carried out recrystallization with ethanol-ethyl acetate, and the vacuum-drying product is to constant weight.
Further, preparation 4-(2-furfurylidene) during curcumine in the mixing solutions of methyl alcohol-chloroform the ratio of methyl alcohol and chloroform be 29:13ml.
Further, preparation 4-(2-furfurylidene) curcumine drips in the methanol solution of furtural and contains furfural, furtural is with preceding heavily steaming, at room temperature the reaction times is 48h.
Further, preparation 4-(2-furfurylidene) precipitated product is washed 4 times with sherwood oil during curcumine.
Further, preparation 4-(2-furfurylidene) chloroform in step 5 chloroform-methanol mixed solution during curcumine: methyl alcohol is 1:1.
Further, preparation curcumine during to the carboxyl phenylhydrazine curcumine: be 1.0g:0.45g to carboxyl phenylhydrazine.
Further, preparation during to the carboxyl phenylhydrazine curcumine reflux temperature be 120 ℃, the reaction times is 12 hours.
Further, recrystallization prepares ethanol in the carboxyl phenylhydrazine curcumine: ethyl acetate is 5:2.
Further, curcumine and all good than curcumine to the value-added restraining effect of A549 cell to carboxyl phenylhydrazine curcumine 4-(2-furfurylidene).
Another object of the present invention is to provide a kind of antitumor drug that utilizes preparation method's preparation of above-mentioned any described curcumin derivate.
The preparation method of curcumin derivate provided by the invention synthesizes the 4-(2-furfurylidene) curcumine and to two kinds of curcumin derivates of carboxyl phenylhydrazine curcumine, these two kinds by the synthetic new curcumin derivate good water solubility of structure of modification, internal metabolism is slow, bioavailability is high, active higher, have important application prospects.
Description of drawings
Fig. 1 is the 4-(2-furfurylidene that the embodiment of the invention provides) concrete preparation method's schema of curcumine;
Fig. 2 is the concrete preparation method's schema to the carboxyl phenylhydrazine curcumine that the embodiment of the invention provides;
Fig. 3 is the chemical equation synoptic diagram to the carboxyl phenylhydrazine curcumine that the embodiment of the invention provides;
Fig. 4 is the 4-(2-furfurylidene that the embodiment of the invention provides) the chemical equation synoptic diagram of curcumine.
Embodiment
In order to make purpose of the present invention, technical scheme and advantage clearer, below in conjunction with embodiment, the present invention is further elaborated.Should be appreciated that specific embodiment described herein only in order to explaining the present invention, and be not used in restriction the present invention.
Fig. 1 shows 4-(2-furfurylidene provided by the invention) the concrete preparation method's of curcumine flow process, Fig. 2 is the flow process to the concrete preparation method of carboxyl phenylhydrazine curcumine that the embodiment of the invention provides.For convenience of explanation, only show part related to the present invention.
The preparation method of a kind of curcumin derivate that embodiments of the invention provide, 4-(2-furfurylidene) the concrete preparation method of curcumine is:
Step 1, take by weighing curcumine and be dissolved in methyl alcohol-chloroform mixing solutions, drip hexahydropyridine and make catalyzer;
Step 2, under agitation drip the methanol solution of furtural, at room temperature reaction is left standstill;
Step 3, filter to keep precipitated product, wash with sherwood oil, remove behind the unreacted raw material dry;
Step 4, will filter the back mother liquor and concentrate, wash reaction solution with water, separate out product, filter the gained throw out, and wash, filter with sherwood oil, drying;
Step 5, combining step three and step 4 products obtained therefrom are put into chloroform-methanol mixed solution recrystallization, and product drying to constant weight, is obtained yellow powder.
Another purpose of the embodiment of the invention is to provide a kind of concrete preparation method to the carboxyl phenylhydrazine curcumine:
Step 1: take by weighing curcumine and be dissolved in the Glacial acetic acid, add the carboxyl phenylhydrazine heating reflux reaction;
Step 2: remove solvent under reduced pressure, obtain red-brown oily product;
Step 3, red-brown oily product is poured in the beaker that rubble ice is housed, it is Powdered under constantly stirring product to be become, suction filtration, drying;
Step 4: the step 3 products obtained therefrom is carried out recrystallization with ethanol-ethyl acetate, and the vacuum-drying product is to constant weight.
As a prioritization scheme of the embodiment of the invention, preparation 4-(2-furfurylidene) during curcumine in the mixing solutions of methyl alcohol-chloroform the ratio of methyl alcohol and chloroform be 29:13ml.
As a prioritization scheme of the embodiment of the invention, preparation 4-(2-furfurylidene) curcumine drips in the methanol solution of furtural and contains furfural, and furtural is with preceding heavily steaming, and at room temperature the reaction times is 48h.
As a prioritization scheme of the embodiment of the invention, preparation 4-(2-furfurylidene) precipitated product is washed 4 times with sherwood oil during curcumine.
As a prioritization scheme of the embodiment of the invention, preparation 4-(2-furfurylidene) chloroform in step 5 chloroform-methanol mixed solution during curcumine: methyl alcohol is 1:1.
As a prioritization scheme of the embodiment of the invention, preparation curcumine during to the carboxyl phenylhydrazine curcumine: be 1.0g:0.45g to carboxyl phenylhydrazine.
As a prioritization scheme of the embodiment of the invention, the reflux temperature is 120 ℃ when preparing the carboxyl phenylhydrazine curcumine, and the reaction times is 12 hours.
As a prioritization scheme of the embodiment of the invention, recrystallization prepares ethanol in the carboxyl phenylhydrazine curcumine: ethyl acetate is 5:2.
As a prioritization scheme of the embodiment of the invention, 4-(2-furfurylidene) curcumine and all good than curcumine to the value-added restraining effect of A549 cell to the carboxyl phenylhydrazine curcumine.
Below in conjunction with drawings and the specific embodiments application principle of the present invention is further described.
Embodiment one 4-(2-furfurylidene) curcumine is synthetic.
Take by weighing curcumine 1.0g(2.72mmol) be dissolved in (methyl alcohol 29ml in the mixing solutions of methyl alcohol-chloroform, chloroform 13ml), and dropping 0.2ml hexahydropyridine is made catalyzer, the methanol solution that under agitation drips furtural (wherein contains furfural 0.23ml, about 0.26g, furtural heavily steams with preceding), at room temperature react 48h, reactant is left standstill, filter out precipitated product (reservation mother liquor), and wash 4 times with the 20ml sherwood oil, remove unreacted raw material, will be behind the product drying yellow powder 0.25g.
Above-mentioned mother liquor is concentrated into about 10ml, washes reaction solution with water, product is separated out from reaction solution, filter the gained throw out, add with the 20ml sherwood oil again and wash 4 times, filter, drying gets product 0.68g.Merge above-mentioned products obtained therefrom, put into chloroform: methyl alcohol (1:1) mixing solutions recrystallization to constant weight, gets product 0.83g with product drying.
Product is yellow powder, and productive rate is 68.4%, 188 ℃-189 ℃ of fusing points.
UV-Visλmax（EtOH）:365nm。IR(KBr): 3304cm
-1(ν
OH); 1630cm
-1(ν
C=O); 3000cm
-1-3100cm
-1(ν
=CH); 1516cm
-1(ν
C=C); 1429cm
-1, 1598cm
-1(phenyl ring skeletal vibration); 2949cm
-1(ν
=C-H); 1021cm
-1, 1381cm
-1(ν
C-H); 1460cm
-1, 1573cm
-1(furan nucleus); 979cm
-1(ν
H-C=C-H); 761cm
-1, 821cm
-1(position replaces between phenyl ring).
1HNMR (400HZ, CDCl
3), δ: 3.91(s, 6H, 2 * OCH
3); 6.79-6.91 (m, 3H ,-C
4H
3The O furan nucleus); 6.80-7.14 (m, 6H, Ar-H); 6.92 (d, 2H ,=C-H, J=2.82Hz); 6.91 (d, 2H ,=C-H, J=3.17Hz); 7.78 (s, 1H ,=CH-C
4H
3O).ESI-MS（m/z）:448.2，[M+H]
+。
Synthesizing of two pairs of carboxyl phenylhydrazine curcumines of embodiment
Taking by weighing 1.0g(2.72mmol) curcumine is dissolved in the 35ml Glacial acetic acid, adds 0.45g (3.48mmol) to 120 ℃ of heating reflux reactions of carboxyl phenylhydrazine 12 hours.Reaction removes solvent under reduced pressure after finishing, and obtains red-brown oily product, this product is poured in the 150ml beaker that rubble ice is housed, and it is Powdered under constantly stirring product to be become, suction filtration, drying.Product ethanol: ethyl acetate (5:2) is carried out recrystallization, and the vacuum-drying product is to constant weight, and 0.85g weighs.
Product is the orange powder, and productive rate is 64.4%, fusing point 157-159 ℃.
UV-Vis:λmax（EtOH）332nm,429nm。IR (KBr): 3381cm
-1(ν
OH), 3015cm
-1(ν
=CH2), 2937cm
-1(ν
CH2), 1699cm
-1(ν
C=O), 1604cm
-1(ν
C=N), 1031cm
-1, 1369cm
-1(ν
C-H), 792cm
-1, 866cm
-1(position replaces between phenyl ring).
1HNMR(400HZ,DMSO),δ:3.79(d,3H,OCH
3),3.84(d,6H,OCH
3),6.78(d,2H,-C=CH-C=N,J=8.11Hz),7.00(d,2H,-CH=C-C=N,J=8.11Hz),7.07～7.23(m,6H,Ar-H),7.64(d,2H,Ar-H,J=8.44Hz),8.11(d,2H,Ar-H,J=8.44Hz)。ESI-MS（m/z）:488.3，[M+H+2]
+。
The detection of embodiment three compound anti tumor activity in vitro
The strain of employed tumor cell line behaviour lung cancer A549 cell, with the A549 cell seeding of logarithmic phase to 96 orifice plates, treat long to logarithmic phase dosing processing, control group adds certain volume DMSO, experimental group adds the different concns medicine, place incubator to cultivate different time sections, 4h before drug treating time finishes, organize to each and to add 20 μ lMTT storage liquid in every hole respectively, lucifuge places and continues in the incubator to cultivate, abandon each hole supernatant liquor behind the 4h, every hole adds 100 μ lDMSO respectively, microplate reader detects the OD value of each hole under 490nm behind 37 ℃ of following shaking table concussion 15min, calculates cell survival rate: survival rate=(OD experimental group/OD control group) * 100%, maximum inhibition=100%-survival rate;
The result shows, the 4-(2-furfurylidene) curcumine and to the carboxyl phenylhydrazine curcumine to the value-added restraining effect of A549 cell free and concentration dependent, the IC behind the drug treating 24h
50Be respectively 27.46 μ Μ and 59.64 μ Μ, curcumine is then greater than 100 μ Μ, during 24h, 20 μ Μ 4-(2-furfurylidenes) curcumine is not worse than the effect effect that 80 μ Μ curcumines suppress cell, both are respectively 56.91 ± 1.16% and 17.23 ± 7.57%, and when 24h40 μ M, the carboxyl phenylhydrazine curcumine is reached 27.43 ± 2.40% to the cytoactive inhibiting rate, reach 76.68 ± 5.81% during 80 μ M, curcumine is 12.30 ± 8.57% and 17.23 ± 7.57% then to the inhibiting rate of cytoactive when 24h40 μ M and 80 μ M concentration, and the 4-(2-furfurylidene is described) curcumine and all good than curcumine to the value-added restraining effect of A549 cell to the carboxyl phenylhydrazine curcumine.
The above only is preferred embodiment of the present invention, not in order to limiting the present invention, all any modifications of doing within the spirit and principles in the present invention, is equal to and replaces and improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. the preparation method of a curcumin derivate is characterized in that, the 4-(2-furfurylidene) the concrete preparation method of curcumine is:
Step 1, take by weighing curcumine and be dissolved in methyl alcohol-chloroform mixing solutions, drip hexahydropyridine and make catalyzer;
Step 2, under agitation drip the methanol solution of furtural, at room temperature reaction is left standstill;
Step 3, filter to keep precipitated product, wash with sherwood oil, remove behind the unreacted raw material dry;
Step 4, will filter the back mother liquor and concentrate, wash reaction solution with water, separate out product, filter the gained throw out, and wash, filter with sherwood oil, drying;
Step 5, combining step three and step 4 products obtained therefrom are put into chloroform-methanol mixed solution recrystallization, and product drying to constant weight, is obtained yellow powder.
2. the preparation method of a curcumin derivate as claimed in claim 1 is characterized in that, to the concrete preparation method of carboxyl phenylhydrazine curcumine is:
Step 1: take by weighing curcumine and be dissolved in the Glacial acetic acid, add the carboxyl phenylhydrazine heating reflux reaction;
Step 2: remove solvent under reduced pressure, obtain red-brown oily product;
Step 3, red-brown oily product is poured in the beaker that rubble ice is housed, it is Powdered under constantly stirring product to be become, suction filtration, drying;
Step 4: the step 3 products obtained therefrom is carried out recrystallization with ethanol-ethyl acetate, and the vacuum-drying product is to constant weight.
3. the preparation method of curcumin derivate as claimed in claim 1 is characterized in that, preparation 4-(2-furfurylidene) during curcumine in the mixing solutions of methyl alcohol-chloroform the ratio of methyl alcohol and chloroform be 29:13ml.
4. the preparation method of curcumin derivate as claimed in claim 1 is characterized in that, preparation 4-(2-furfurylidene) curcumine drips in the methanol solution of furtural and contains furfural, and furtural is with preceding heavily steaming, and at room temperature the reaction times is 48h.
5. the preparation method of curcumin derivate as claimed in claim 1 is characterized in that, preparation 4-(2-furfurylidene) precipitated product is washed 4 times with sherwood oil during curcumine.
6. the preparation method of curcumin derivate as claimed in claim 1 is characterized in that, preparation 4-(2-furfurylidene) chloroform in step 5 chloroform-methanol mixed solution during curcumine: methyl alcohol is 1:1.
7. the preparation method of curcumin derivate as claimed in claim 2 is characterized in that, preparation curcumine during to the carboxyl phenylhydrazine curcumine: be 1.0g:0.45g to carboxyl phenylhydrazine.
8. the preparation method of curcumin derivate as claimed in claim 2 is characterized in that, the reflux temperature is 120 ℃ when preparing the carboxyl phenylhydrazine curcumine, and the reaction times is 12 hours; Recrystallization prepares ethanol in the carboxyl phenylhydrazine curcumine: ethyl acetate is 5:2.
9. the preparation method of curcumin derivate as claimed in claim 2 is characterized in that, the 4-(2-furfurylidene) curcumine and all good than curcumine to the value-added restraining effect of A549 cell to the carboxyl phenylhydrazine curcumine.
10. the antitumor drug of the preparation method's preparation that utilizes any described curcumin derivate of claim 1-9.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107163030A (en) * | 2017-06-20 | 2017-09-15 | 河南工业大学 | Small molecule heterocyclic compound with pyrazoles parent nucleus and its for prepare antibacterial, antineoplastic application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003105751A2 (en) * | 2002-06-17 | 2003-12-24 | Ho-Jeong Kwon | Novel curcumin derivatives |
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2013
- 2013-06-27 CN CN2013102736759A patent/CN103333140A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003105751A2 (en) * | 2002-06-17 | 2003-12-24 | Ho-Jeong Kwon | Novel curcumin derivatives |
Non-Patent Citations (3)
| Title |
|---|
| JOONG SUP SHIM，等: "Development of a new Ca2+/calmodulin antagonist and its anti-proliferative activity against colorectal cancer cells", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》 * |
| JOONG SUP SHIM，等: "Hydrazinocurcumin, a Novel Synthetic Curcumin Derivative, Is a Potent Inhibitor of Endothelial Cell Proliferation", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 李俊海，等: "姜黄素类似物的合成及其生物活性的测定", 《化学研究与应用》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107163030A (en) * | 2017-06-20 | 2017-09-15 | 河南工业大学 | Small molecule heterocyclic compound with pyrazoles parent nucleus and its for prepare antibacterial, antineoplastic application |
| CN107163030B (en) * | 2017-06-20 | 2020-03-24 | 河南工业大学 | Micromolecular heterocyclic compound with pyrazole mother nucleus and application thereof in preparing antibacterial and antitumor drugs |
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Application publication date: 20131002 |