CN104098554A - Preparation method and uses of silybin amino acid Schiff bases - Google Patents
Preparation method and uses of silybin amino acid Schiff bases Download PDFInfo
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention relates to a preparation method and uses of silybin amino acid Schiff bases. The method comprises the following steps: respectively chemically reacting glycine, alanine and lysine with sodium hydroxide, respectively dissolving the obtained materials in distilled water, respectively adding the obtained solutions to erlenmeyer flasks, dissolving silybin in an anhydrous ethanol solution, respectively adding the silybin dissolved anhydrous ethanol solution into the chemical reaction erlenmeyer flasks in a dropwise manner, carrying out a normal temperature reaction, carrying out magnesium sulfate dehydration, carrying out water bath heating, stirring, carrying out thin layer tracing, stopping the reaction, carrying out pumping filtration on the obtained mixed solutions, carrying out anhydrous ethoanol recrystallization, and carrying out vacuum drying to obtain a sodium salt of silybin glycine schiff base, a sodium salt of silybin alanine schiff base and a sodium salt of silybin lysine schiff base. Compounds obtained by using the preparation method enhance the oxidation and tumor resisting activity of silybin, and have the water solubility and biocompatibility of amino acids, so the compounds can be rapidly absorbed in organisms, and can directly act on pathologic cells. The method has the advantages of simplicity, high yield and low cost.
Description
Technical field: the present invention relates to pharmaceutical field, be specifically related to Schiff bases compound of a kind of silibinin and amino acid condensation formation and uses thereof.
Background technology: it is found that in recent years silibinin all has good restraining effect to prostate cancer, colorectal carcinoma, bladder cancer and liver cancer etc.; in addition; silibinin is treated the multiple pharmacologically actives such as hyperlipidemia, anti-gastric-ulcer, reducing blood-fat, protection myocardial cell, anti-platelet aggregation and immunomodulatory in addition; having exploitation is worth; there is poorly water-soluble in silibinin, hardly water-soluble and grease, oral absorption is poor, bioavailability is low, to shortcomings such as tumour cell targeting are not strong.So people more and more receive publicity to the research of silibinin.At present, the preparation method of the derivative of silibinin introduces glycosyl at 3 hydroxyls of silibinin, phosphoric acid ester or carboxylicesters, also have and improve water miscible at 23 hydroxyls introducing glycosyls, although it is water-soluble that this compounds synthetic improved medicine, but pharmacological research shows improved specific activity silibinin activity and decreases, in addition, by being carboxylic acid by silibinin part radical oxidation, water-soluble to improve, after silibinin changes into acid, water-solublely improve 10 times, but resistance of oxidation reduces half, it is anti-oxidant that these synthesis preparation methods all can not meet silibinin, antineoplastic activity and amino acid whose water-soluble, Bc.
Summary of the invention: the object of the invention is to overcome above-mentioned shortcoming, synthesis preparation method of a kind of silibinin amino-acid schiff base and uses thereof is provided, this preparation method makes silibinin have in vivo better absorption, take silibinin as precursor compound, utilize the carbonyl condensation of amino acid whose amino and silibinin to form Schiff's base, this compounds has not only strengthened anti-oxidant, the antineoplastic activity of silibinin, and taken into account amino acid whose water-soluble, Bc.The object of the present invention is achieved like this:
A. 0.075g glycine or 0.089g L-Ala or 0.149g Methionin are carried out to chemical reaction with 0.04g sodium hydroxide respectively, it is dissolved in respectively in 1mL distilled water, 3 Erlenmeyer flasks putting into respectively 100mL are standby;
B. 0.482g silibinin is dissolved in 50mL ethanol solution, slowly drops in the Erlenmeyer flask of 0.075g glycine and 0.04g sodium hydroxide chemical reaction, magnesium sulfate dehydration, pH value of solution=8.5,55 ℃ of water-baths, stir 0.5h,
Thin layer is followed the tracks of, and reaction stops, mixed solution suction filtration, and dehydrated alcohol recrystallization, vacuum-drying, synthetic product is light yellow solid, i.e. the sodium salt of silibinin glycine Schiff's base, molecular formula is C
27h
24nO
11na, molecular weight is 561, yield 63%, 222～224 ℃ of fusing points, composite structure is as follows:
0.482g silibinin is dissolved in 50mL ethanol solution, slowly drop in the Erlenmeyer flask of 0.089g L-Ala and 0.04g sodium hydroxide chemical reaction, 60 ℃ of stirrings, engender yellow solid in reaction, after room temperature back flow reaction 20min, color burn becomes brown color
Thin layer is followed the tracks of, magnesium sulfate dehydration, and pH value of solution=8.5,55 ℃ of water-baths, stir 0.5h, and thin layer is followed the tracks of, and reaction stops, mixed solution suction filtration, dehydrated alcohol recrystallization, vacuum-drying, synthetic product is yellowish brown solid, i.e. the sodium salt of silibinin L-Ala Schiff's base, molecular formula C
28h
26nO
11na, molecular weight is 575, yield 42%, 228～229 ℃ of fusing points, composite structure is as follows:
0.482g silibinin is dissolved in 50mL ethanol solution, slowly dropping to 0.149g Methionin and 0.04g sodium hydroxide carries out in the Erlenmeyer flask of chemical reaction, engender yellow mercury oxide, normal-temperature reaction 20min, magnesium sulfate dehydration, rear color burn becomes brown color, pH value of solution=8.5,55 ℃ of water-baths, stir 0.5h
Thin layer is followed the tracks of, and reaction stops, mixed solution suction filtration, and dehydrated alcohol recrystallization, vacuum-drying, synthetic product is light yellow solid, i.e. the sodium salt of silibinin Methionin Schiff's base, molecular formula C
31h
33n
2o
11na, molecular weight is 632, yield 55%, 243～245 ℃ of fusing points, composite structure is as follows:
This invention, except glycine, L-Ala and Methionin, also comprises other amino acid, as: phenylalanine, L-glutamic acid, aspartic acid, halfcystine.
Silibinin amino-acid schiff base has the effect of anti-liver cancer cell and anti-stomach cancer cell.
It is carbonyl and the condensation under alkaline condition of amino acid whose amido at silibinin for this synthesis preparation method, the sodium salt of synthetic silibinin amino-acid schiff base, and the reaction conditions of whole reaction system carries out under the condition of alkaline pH=8-9, wherein amino acid whose NH
2for main reflection gene, the side reaction of having avoided carboxyl to bring, synthetic product is respectively silibinin glycine Schiff's base, silibinin L-Ala Schiff's base, silibinin Methionin Schiff's base molecular weight is respectively 561, 575, 632, fusing point is respectively 222～224 ℃, 228～229 ℃, 243～245 ℃, with the compound that this synthesis preparation method obtains, not only strengthened silibinin anti-oxidant, antineoplastic activity, and taken into account amino acid whose water-soluble, Bc, it is absorbed rapidly in vivo, directly act on sick cell, improved target-oriented drug, reduced medicine biological toxic side effect in vivo, this compounds has retained mother nucleus structure and the anti-tumor activity of silibinin, anti-oxidant and the anti-tumor activity that has possessed on this basis Schiff's base, water-soluble target tropism and the anti-tumor activity of silibinin amino-acid schiff base are better than silibinin, its synthesis preparation method is simple, productive rate is high, cost is low.
Embodiment:
Embodiment 1: the synthesis step of silibinin glycine Schiff's base
(1) by 1 mmol(0.075g) glycine and 1 mmol(0.04 g) NaOH is dissolved in 1mL distilled water, puts into the Erlenmeyer flask of 100mL,
(2) by 1mmol(0.482 g) silibinin is dissolved in 50 mL ethanol solutions, slowly drops in Erlenmeyer flask MgSO
4dehydration, pH value of solution=8.5,55 ℃ of water-baths, stir 0.5h,
(3) thin layer is followed the tracks of, and reaction stops, mixed solution suction filtration, dehydrated alcohol recrystallization, vacuum-drying.Synthetic product is light yellow solid, yield 63%, and 222～224 ℃ of fusing points,
(4) Structural Identification result: mass spectrum ESI-MS m/z 562 [M+Na+1]+, nuclear-magnetism carbon spectrum
13c-NMR(D
2o) δ: 82.32(C-2), 76.18(C-3), 162.22(C-4), 172.73(C-5), 98.56(C-6), 162.80 (C-7), 97.57(C-8), 155.69(C-9), 111.35(C-10), 129.90(C-1 '), 120.87(C-2 '), 116.16(C-3 '), 143.57(C-4 '), 146. 25(C-5 '), 115.40(C-6 '), 127.68(C-1 ' '), 115.60(C-2 ' '), 147.69(C-3 ' '), 143.28(C-4 ' '), 117.10(C-5 ' '), 121.70(C-6 ' '), 77.80(α), 72.53(β), 60.28(γ), 55.78(OCH
3), 178.63,41.53(is respectively C=O in glycine, CH
2), through authenticating compound, be the sodium salt of silibinin glycine Schiff's base, molecular formula is C
27h
24nO
11na, molecular weight is 561, composite structure is as follows:
Embodiment 2: the synthesis step of silibinin L-Ala Schiff's base
(1) by 1 mmol(0.089g) L-Ala and 1mmol(0.04 g) NaOH is dissolved in 1mL distilled water, and put into 100mL Erlenmeyer flask and be stirred to dissolving,
(2) taking 1 mmol(0.482g) silibinin is dissolved in and fills in 50mL dehydrated alcohol, and slowly adding in Erlenmeyer flask dropwise, 60 ℃ of stirrings, engender yellow solid in reaction, and after room temperature back flow reaction 20 min, color burn becomes brown color,
(3) thin layer is followed the tracks of, MgSO
4dehydration, pH value of solution=8.5,55 ℃ of water-baths, stir 0.5 h, and thin layer is followed the tracks of, and reaction stops, mixed solution suction filtration, dehydrated alcohol recrystallization, vacuum-drying, synthetic product is yellowish brown solid, yield 42%, 228～229 ℃ of fusing points,
(4) Structural Identification result: mass spectrum ESI-MS m/z 576 [M+Na+1]+, nuclear-magnetism carbon spectrum
13c-NMR(D
2o), δ: 88.51(C-2), 75.33(C-3), 162.10(C-4), 166.08(C-5), 96.71(C-6), 163.84(C-7), 95.72(C-8), 160.85(C-9), 108.65(C-10), 132.76(C-1 '), 120.33(C-2 '), 117.35(C-3 '), 145.44(C-4 '), 146.68(C-5 '), 115.61(C-6 '), 132.76(C-1 ' '), 117.35(C-2 ' '), 151.90(C-3 ' '), 143.45(C-4 ' '), 120.33(C-5 ' '), 121.57(C-6 ' '), 78.07(α), 75.33(β), 61.66(γ), 56.68(OCH
3), 177.06,65.93,18.03(is respectively C=O in L-Ala, CH, CH
3), through authenticating compound, be the sodium salt of silibinin L-Ala Schiff's base, molecular formula is C
28h
26nO
11na, molecular weight is 575, composite structure is as follows:
Embodiment 3: the synthesis step of silibinin Methionin Schiff's base
(1) taking 1 mmol(0.149g) Methionin and 1 mmol (0.04 g) NaOH be dissolved in 1mL distilled water, puts into the Erlenmeyer flask of 100mL, 65 ℃ of water-baths, magnetic agitation is dissolved it,
(2) 1mmol (0.482 g) silibinin is dissolved in 50 mL ethanol solutions, slowly drops in mixed solution, engender yellow mercury oxide, normal-temperature reaction 20 min, MgSO
4dehydration, pH value of solution=8.5,55 ℃ of water-baths, stir 0.5h,
(3) thin layer is followed the tracks of, and reaction stops, mixed solution suction filtration, and dehydrated alcohol recrystallization, vacuum-drying, synthetic product is light yellow solid, yield 55%, 243～245 ℃ of fusing points,
(4) Structural Identification result: mass spectrum ESI-MS m/z 633 [M+Na+1]+, nuclear-magnetism carbon spectrum
13c-NMR(D
2o), δ: 88.26(C-2), 82.46(C-3), 162.60(C-4), 164.09(C-5), 97.95(C-6), 164.09(C-7), 95.22(C-8), 160.61(C-9), 111.61(C-10, C-6 ')), 132.51(C-1 '), 121.54(C-2 '), 116.50(C-3 '), 143.73(C-4 '), 145.94(C-5 '), 111.61(C-6 ')), 130.65(C-1 ' '), 116.50(C-2 ' '), 151.16(C-3 ' '), 143.51(C-4 ' '), 117.28(C-5 ' '), 121.89(C-6 ' '), 77.86(α), 76.94(β), 60.57(γ), 55.91(OCH
3), 177.01,71.94,57. 40,34.31,16.71(is C=O in amino acid, CH, CH
2), through authenticating compound, be the sodium salt of silibinin Methionin Schiff's base, molecular formula is C
31h
33n
2o
11na, molecular weight is 632, composite structure is as follows:
This invention, except glycine, L-Ala and Methionin, also comprises other amino acid, as: phenylalanine, L-glutamic acid, aspartic acid, halfcystine.
Silibinin amino-acid schiff base has the effect of anti-liver cancer cell and anti-stomach cancer cell.
The anti-oxidant activity of silibinin amino-acid schiff base
Precision takes DPPH 8.0 mg, with anhydrous alcohol solution and be settled in the brown volumetric flask of 200 mL, obtains concentration and be 0.004% DPPH solution, keeps in Dark Place, standby.Get respectively 40 mgmL
-1, 20 mgmL
-1, 8 mgmL
-1, 4 mgmL
-1, 2 mgmL
-1each 1 mL of the sample solution of series concentration, puts in 10 mL centrifuge tubes, adds the DPPH solution of 3.0 mL, and room temperature lucifuge is reacted 30 min, take dehydrated alcohol simultaneously as blank, in 517 nm places, measures light absorption value.The positive contrast of silibinin (Silybin), the anti-oxidant activity of three kinds of silibinin amino-acid schiff bases is all better than silibinin, the strong and weak order of three's anti-oxidant activity is silibinin glycine Schiff's base (sil-Gly) > silibinin Methionin Schiff's base (sil-Lys) > silibinin L-Ala Schiff's base (sil-Ala), and anti-oxidant experimental result sees the following form.
the anti-oxidant result signal table of silibinin amino-acid schiff base
The anti-liver cancer cell effect of silibinin amino-acid schiff base
Collect logarithmic phase liver cancer cell, adjust concentration of cell suspension, make cell density to 5000～7000 to be measured, be inoculated in (marginal pore is filled with aseptic PBS) in 96 well culture plates, it is 100 μ L that institute adds cell volume, get successively silibinin standard substance, silibinin glycine, silibinin L-Ala and silibinin Methionin Schiff's base monomer, with the drug level preparing, (be made as 160,80,40,20 and 10 μ molL
-1, 5 gradients) and every hole 200 μ L, each concentration is established 5 multiple holes, establishes blank (adding equal-volume DMSO), 5% CO simultaneously
237 ℃ of incubator effect 48 h, before cultivation finishes, suck nutrient solution, with PBS, rinse after 2 times, add 5 mgmL
-1mTT 20 μ L, are placed in 37 ℃ of incubators and continue reaction 4 h, stop cultivating, and suck supernatant liquor, and every hole adds DMSO 150 μ L, and level 10 min that vibrate, fully dissolve crystallisate, and the absorbancy (A) of measuring each hole at microplate reader 492nm place is worth.Experimental result demonstration, in the dosage range setting, inhibiting rate 39.0%, 37.5%, 33.7%, 28.3%, 15.3%, the 48 h half-inhibition concentration IC of silibinin to liver cancer cell
50value is 298.5 μ molL
-1.Three kinds of synthetic new compounds to the inhibiting rate of liver cancer cell all higher than the inhibiting rate of same isoconcentration silibinin, the inhibiting rate of silibinin glycine Schiff's base, silibinin L-Ala Schiff's base, silibinin Methionin Schiff's base is respectively: 70.2%, 54.1%, 45.3%, 33.7%, 30.2%; 47.2%, 40.9%, 37.1%, 16.2%, 12.1%; 47.1%, 42.8%, 35.2%, 25.7%, 10.5%.Three 48 h half-inhibition concentration IC
50value is followed successively by 50.01 μ molL
-1, 143.95 μ molL
-1, 134.50 μ molL
-1, illustrate that silibinin amino-acid schiff base has good restraining effect to liver cancer cell.
The anti-stomach cancer cell effect of silibinin amino-acid schiff base
Same aforesaid method, inhibiting rate difference 33.3%, 22.9%, 23.2%, 19.1%, 11.5%, the IC of silibinin to stomach cancer cell
50value is 259.36 μ molL
-1, silibinin glycine Schiff's base, silibinin L-Ala Schiff's base, 5 kinds of concentration of silibinin Methionin Schiff's base, 48 h inhibiting rates are respectively 62.3%, 53.5%, 40.7%, 35.3%, 30.2%; 41.5%, 33.5%, 27.3%, 20.1%, 15.6%; 48.1%, 42.4%, 33.9%, 29.6%, 16.3%.Three's half-inhibition concentration IC
50value is respectively 64.41 μ molL
-1, 162.18 μ molL
-1, 152.49 μ molL
-1, silibinin amino-acid schiff base has good restraining effect to stomach cancer cell.
Claims (2)
1. a synthesis preparation method for silibinin amino-acid schiff base, is characterized in that:
A. 0.075g glycine or 0.089g L-Ala or 0.149g Methionin are carried out to chemical reaction with 0.04g sodium hydroxide respectively, it is dissolved in respectively in 1mL distilled water, 3 Erlenmeyer flasks putting into respectively 100mL are standby;
B. 0.482g silibinin is dissolved in 50mL ethanol solution, slowly drops in the Erlenmeyer flask of 0.075g glycine and 0.04g sodium hydroxide chemical reaction, magnesium sulfate dehydration, pH value of solution=8.5,55 ℃ of water-baths, stir 0.5h,
Thin layer is followed the tracks of, and reaction stops, mixed solution suction filtration, and dehydrated alcohol recrystallization, vacuum-drying, synthetic product is light yellow solid, i.e. the sodium salt of silibinin glycine Schiff's base, molecular formula is C
27h
24nO
11na, molecular weight is 561, yield 63%, 222～224 ℃ of fusing points, composite structure is as follows:
0.482g silibinin is dissolved in 50mL ethanol solution, slowly drop in the Erlenmeyer flask of 0.089g L-Ala and 0.04g sodium hydroxide chemical reaction, 60 ℃ of stirrings, engender yellow solid in reaction, after room temperature back flow reaction 20min, color burn becomes brown color
Thin layer is followed the tracks of, magnesium sulfate dehydration, and pH value of solution=8.5,55 ℃ of water-baths, stir 0.5h, and thin layer is followed the tracks of, and reaction stops, mixed solution suction filtration, dehydrated alcohol recrystallization, vacuum-drying, synthetic product is yellowish brown solid, i.e. the sodium salt of silibinin L-Ala Schiff's base, molecular formula C
28h
26nO
11na, molecular weight is 575, yield 42%, 228～229 ℃ of fusing points, composite structure is as follows:
0.482g silibinin is dissolved in 50mL ethanol solution, slowly dropping to 0.149g Methionin and 0.04g sodium hydroxide carries out in the Erlenmeyer flask of chemical reaction, engender yellow mercury oxide, normal-temperature reaction 20min, magnesium sulfate dehydration, rear color burn becomes brown color, pH value of solution=8.5,55 ℃ of water-baths, stir 0.5h
Thin layer is followed the tracks of, and reaction stops, mixed solution suction filtration, and dehydrated alcohol recrystallization, vacuum-drying, synthetic product is light yellow solid, i.e. the sodium salt of silibinin Methionin Schiff's base, molecular formula C
31h
33n
2o
11na, molecular weight is 632, yield 55%, 243～245 ℃ of fusing points, composite structure is as follows:
This invention, except glycine, L-Ala and Methionin, also comprises other amino acid, as: phenylalanine, L-glutamic acid, aspartic acid, halfcystine.
2. the purposes of silibinin amino-acid schiff base according to claim 1, is characterized in that: silibinin amino-acid schiff base has the effect of anti-liver cancer cell and anti-stomach cancer cell.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866694A (en) * | 2017-02-22 | 2017-06-20 | 石家庄学院 | Oridonin Schiff base derivatives and its production and use |
| CN111925394A (en) * | 2020-09-25 | 2020-11-13 | 嘉兴金派特生物科技有限公司 | Silybin derivative or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
| CN114057710A (en) * | 2021-12-14 | 2022-02-18 | 沈阳化工大学 | Silibinin chemical modifier with anti-tumor activity and preparation method thereof |
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| EP0299770A2 (en) * | 1987-07-17 | 1989-01-18 | IDB HOLDING S.p.A. | Soluble derivatives of silybin, a method of preparing them, and pharmaceutical compositions containing them |
| CN101376654A (en) * | 2007-08-28 | 2009-03-04 | 北京美倍他药物研究有限公司 | Water-soluble aminoacid ester derivative of silibinin |
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| EP0299770A2 (en) * | 1987-07-17 | 1989-01-18 | IDB HOLDING S.p.A. | Soluble derivatives of silybin, a method of preparing them, and pharmaceutical compositions containing them |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866694A (en) * | 2017-02-22 | 2017-06-20 | 石家庄学院 | Oridonin Schiff base derivatives and its production and use |
| CN106866694B (en) * | 2017-02-22 | 2019-01-08 | 石家庄学院 | Oridonin Schiff base derivatives and its preparation method and application |
| CN111925394A (en) * | 2020-09-25 | 2020-11-13 | 嘉兴金派特生物科技有限公司 | Silybin derivative or pharmaceutically acceptable salt thereof, and preparation method and application thereof |
| CN114057710A (en) * | 2021-12-14 | 2022-02-18 | 沈阳化工大学 | Silibinin chemical modifier with anti-tumor activity and preparation method thereof |
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