CN104098554B - Synthesis preparation method of silibinin amino-acid schiff base and application thereof - Google Patents
Synthesis preparation method of silibinin amino-acid schiff base and application thereof 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
Abstract
The present invention relates to synthesis preparation method of a kind of silibinin amino-acid schiff base and application thereof, it is by glycine or alanine, lysine carries out chemical reaction with sodium hydroxide respectively, it is dissolved in respectively in distilled water, put in conical flask, silibinin is dissolved in ethanol solution, drop to respectively in the conical flask carrying out chemical reaction, normal-temperature reaction, magnesium sulfate dehydration, water-bath, stirring, thin layer is followed the tracks of, reaction stops, mixed liquor sucking filtration, dehydrated alcohol recrystallization, vacuum drying, obtain the sodium salt of silibinin glycine Schiff base, the sodium salt of silibinin alanine Schiff's base, the sodium salt of silibinin lysine plus threonine.The compound obtained with this synthesis preparation method not only enhances silibinin antioxidation, antineoplastic activity, and has taken into account amino acid whose water solublity, biocompatibility, making it absorb in vivo rapidly, directly act on sick cell, synthetic method is simple, productivity is high, and cost is low.
Description
Technical field: the present invention relates to drug world, is specifically related to a kind of silibinin Schiff bases compound with amino acid condensation formation and application thereof.
Background technology: it is found that carcinoma of prostate, colon cancer, bladder cancer and hepatocarcinoma etc. are respectively provided with good inhibitory action by silibinin in recent years; in addition; silibinin also has treats the multiple pharmacologically actives such as hyperlipidemia, anti-gastric-ulcer, blood fat reducing, protecting myocardial cell, anti-platelet aggregation and immunomodulating; great Development volue; there is poorly water-soluble in silibinin, be practically insoluble in water and oils and fats, oral absorption is poor, bioavailability is low, to shortcomings such as tumor cell targeting are not strong.So the research of silibinin is increasingly received publicity by people.At present, the preparation method of the derivant of silibinin is introduce glycosyl at 3 hydroxyls of silibinin mostly, phosphate ester or carboxylate, also have at 23 hydroxyls introducing glycosyls water miscible to improve, although the synthesis of this compounds improves medicine water solublity, but pharmacological research shows that improved specific activity silibinin activity decreases, additionally, by silibinin moieties is oxidized to carboxylic acid, to improve water solublity, after silibinin changes into acid, water solublity can improve 10 times, but oxidation resistance reduces half, these synthesis preparation methods all can not meet silibinin antioxidation, active and the amino acid whose water solublity of antineoplastic, biocompatibility.
Summary of the invention: it is an object of the invention to overcome disadvantages mentioned above, synthesis preparation method of a kind of silibinin amino-acid schiff base and application thereof is provided, this preparation method makes silibinin have better absorption in vivo, with silibinin for precursor compound, utilize the carbonyl condensation formation Schiff's base of amino acid whose amino and silibinin, this compounds not only enhances silibinin antioxidation, antineoplastic activity, and has taken into account amino acid whose water solublity, biocompatibility.The object of the present invention is achieved like this:
A. 0.075g glycine or 0.089g alanine or 0.149g lysine are carried out chemical reaction with 0.04g sodium hydroxide respectively, it is dissolved in 1mL distilled water respectively, is respectively put in 3 conical flasks of 100mL standby；
B. 0.482g silibinin is dissolved in 50mL ethanol solution, is slowly added dropwise to the conical flask of 0.075g glycine and 0.04g sodium hydroxide chemical reaction, magnesium sulfate dehydration, pH value of solution=8.5,55 DEG C of water-baths, stir 0.5h,
Thin layer is followed the tracks of, and reaction stops, and mixed liquor sucking filtration, dehydrated alcohol recrystallization, vacuum drying, synthetic product is light yellow solid, i.e. the sodium salt of silibinin glycine Schiff base, and molecular formula is C27H24NO11Na, molecular weight is 561, yield 63%, and fusing point 222～224 DEG C, structural formula is as follows
0.482g silibinin is dissolved in 50mL ethanol solution, it is slowly added dropwise to the conical flask of 0.089g alanine and 0.04g sodium hydroxide chemical reaction, 60 DEG C of stirrings, reaction engenders yellow solid, after room temperature back flow reaction 20min, color burn becomes brown color
Thin layer is followed the tracks of, magnesium sulfate dehydration, pH value of solution=8.5,55 DEG C of water-baths, stirs 0.5h, thin layer is followed the tracks of, and reaction stops, mixed liquor sucking filtration, dehydrated alcohol recrystallization, vacuum drying, synthetic product is brown solid, i.e. the sodium salt of silibinin alanine Schiff's base, molecular formula C28H26NO11Na, molecular weight is 575, yield 42%, and fusing point 228～229 DEG C, structural formula is as follows
0.482g silibinin is dissolved in 50mL ethanol solution, it is slowly added dropwise in the conical flask carrying out chemical reaction to 0.149g lysine and 0.04g sodium hydroxide, engender yellow mercury oxide, normal-temperature reaction 20min, magnesium sulfate dehydration, rear color burn becomes brown color, pH value of solution=8.5,55 DEG C of water-baths, stir 0.5h
Thin layer is followed the tracks of, and reaction stops, and mixed liquor sucking filtration, dehydrated alcohol recrystallization, vacuum drying, synthetic product is light yellow solid, i.e. the sodium salt of silibinin lysine plus threonine, molecular formula C31H33N2O11Na, molecular weight is 632, yield 55%, and fusing point 243～245 DEG C, structural formula is as follows
This invention, except glycine, alanine and lysine, also includes other aminoacid, as: phenylalanine, glutamic acid, aspartic acid, cysteine.
Silibinin amino-acid schiff base has anti-hepatoma carcinoma cell and the effect of anti-gastric cancer cell.
This synthesis preparation method it be in the carbonyl of silibinin and the condensation in the basic conditions of amino acid whose amido, the sodium salt of synthesis silibinin amino-acid schiff base, the reaction condition of whole reaction system carries out under alkaline pH=8 9 conditions, wherein amino acid whose NH2For mainly reflecting gene, avoid the side reaction that carboxyl brings, the product respectively silibinin glycine Schiff base of synthesis, silibinin alanine Schiff's base, silibinin lysine plus threonine molecular weight respectively 561, 575, 632, fusing point respectively 222～224 DEG C, 228～229 DEG C, 243～245 DEG C, the compound obtained with this synthesis preparation method not only enhances silibinin antioxidation, antineoplastic activity, and taken into account amino acid whose water solublity, biocompatibility, it is made to absorb rapidly in vivo, directly act on sick cell, improve target-oriented drug, reduce medicine biological toxic and side effects in vivo, this compounds remains mother nucleus structure and the anti-tumor activity of silibinin, possess antioxidation and the anti-tumor activity of Schiff's base on this basis, the water-soluble target tropism of silibinin amino-acid schiff base and anti-tumor activity are better than silibinin, its synthesis preparation method is simple, productivity is high, cost is low.
Detailed description of the invention:
Embodiment 1: the synthesis step of silibinin glycine Schiff base
(1) 1mmol (0.075g) glycine and 1mmol (0.04g) NaOH are dissolved in 1mL distilled water, put in the conical flask of 100mL,
(2) 1mmol (0.482g) silibinin is dissolved in 50mL ethanol solution, is slowly added dropwise to conical flask, MgSO4Dehydration, pH value of solution=8.5,55 DEG C of water-baths, stir 0.5h,
(3) thin layer is followed the tracks of, and reaction stops, mixed liquor sucking filtration, dehydrated alcohol recrystallization, vacuum drying.Synthetic product is light yellow solid, yield 63%, fusing point 222～224 DEG C,
(4) Structural Identification result: mass spectrum ESI-MSm/z562 [M+Na+1]+；Nuclear-magnetism carbon is composed13C-NMR(D2O) 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 (OCH3), 178.63,41.53 (respectively C=O, CH in glycine2), identified compound is the sodium salt of silibinin glycine Schiff base, and molecular formula is C27H24NO11Na, molecular weight is 561, and structural formula is as follows
Embodiment 2: the synthesis step of silibinin alanine Schiff's base
(1) 1mmol (0.089g) alanine and 1mmol (0.04g) NaOH are dissolved in 1mL distilled water, put into the stirring of 100mL conical flask to dissolving,
(2) weigh 1mmol (0.482g) silibinin to be dissolved in and fill in 50mL dehydrated alcohol, slowly in addition conical flask dropwise, 60 DEG C of stirrings, reaction engenders yellow solid, after room temperature back flow reaction 20min, color burn becomes brown color,
(3) thin layer is followed the tracks of, MgSO4Dehydration, pH value of solution=8.5,55 DEG C of water-baths, stir 0.5h, thin layer is followed the tracks of, and reaction stops, mixed liquor sucking filtration, dehydrated alcohol recrystallization, vacuum drying, and synthetic product is brown solid, yield 42%, fusing point 228～229 DEG C,
(4) Structural Identification result: mass spectrum ESI-MSm/z576 [M+Na+1]+；Nuclear-magnetism carbon is composed13C-NMR(D2O), 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 (OCH3), 177.06,65.93,18.03 (respectively C=O, CH, CH in alanine3), identified compound is the sodium salt of silibinin alanine Schiff's base, and molecular formula is C28H26NO11Na, molecular weight is 575, and structural formula is as follows
Embodiment 3: the synthesis step of silibinin lysine plus threonine
(1) weigh 1mmol (0.149g) lysine and 1mmol (0.04g) NaOH is dissolved in 1mL distilled water, put in the conical flask of 100mL, 65 DEG C of water-baths, magnetic agitation makes it dissolve,
(2) 1mmol (0.482g) silibinin is dissolved in 50mL ethanol solution, is slowly added dropwise to mixed liquor, engender yellow mercury oxide, normal-temperature reaction 20min, MgSO4Dehydration, pH value of solution=8.5,55 DEG C of water-baths, stir 0.5h,
(3) thin layer is followed the tracks of, and reaction stops, mixed liquor sucking filtration, dehydrated alcohol recrystallization, vacuum drying, and synthetic product is light yellow solid, yield 55%, fusing point 243～245 DEG C,
(4) Structural Identification result: mass spectrum ESI-MSm/z633 [M+Na+1]+；Nuclear-magnetism carbon is composed13C-NMR(D2O), 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 (OCH3), 177.01,71.94,57.40,34.31,16.71 (for C=O, CH, CH in aminoacid2), identified compound is the sodium salt of silibinin lysine plus threonine, and molecular formula is C31H33N2O11Na, molecular weight is 632, and structural formula is as follows
This invention, except glycine, alanine and lysine, also includes other aminoacid, as: phenylalanine, glutamic acid, aspartic acid, cysteine.
Silibinin amino-acid schiff base has anti-hepatoma carcinoma cell and the effect of anti-gastric cancer cell.
The antioxidant activity of silibinin amino-acid schiff base
Precision weighs DPPH8.0mg, with anhydrous alcohol solution and be settled in the brown volumetric flask of 200mL, obtains the DPPH solution that concentration is 0.004%, keeps in Dark Place, standby.Take 40mg mL respectively-1、20mg·mL-1、8mg·mL-1、4mg·mL-1、2mg·mL-1The each 1mL of sample solution of series concentration, puts in 10mL centrifuge tube, adds the DPPH solution of 3.0mL, room temperature lucifuge reaction 30min, simultaneously with dehydrated alcohol for blank, measures light absorption value in 517nm place.Silibinin (Silybin) is positive control, the antioxidant activity of three kinds of silibinin amino-acid schiff bases is superior to silibinin, three's antioxidant activity power order is silibinin glycine Schiff base (sil-Gly) > silibinin lysine plus threonine (sil-Lys) > silibinin alanine Schiff's base (sil-Ala), and antioxidation experimental result is shown in following table.
The antioxidation result signal table of silibinin amino-acid schiff base
The anti-hepatoma carcinoma cell effect of silibinin amino-acid schiff base
Collect exponential phase hepatoma carcinoma cell, adjust concentration of cell suspension, make cell density to be measured to 5000～7000, it is inoculated in 96 well culture plates (edge hole is filled with aseptic PBS), added cell volume is 100 μ L, take silibinin standard substance, silibinin glycine, silibinin alanine and silibinin lysine plus threonine monomer successively, (be set to 160,80,40,20 and 10 μm of ol L with the drug level prepared-1, 5 gradients) and every hole 200 μ L, each concentration sets 5 multiple holes, sets blank (adding equal-volume DMSO), 5%CO simultaneously237 DEG C of incubator effect 48h, cultivate before terminating, suck culture fluid, after rinsing 2 times with PBS, add 5mg mL-1MTT20 μ L, is placed in 37 DEG C of incubators and continues reaction 4h, terminates cultivating, sucks supernatant, and every hole adds DMSO150 μ L, horizontal oscillations 10min, makes crystal fully dissolve, and measures absorbance (A) value in each hole at microplate reader 492nm place.Experimental result shows, in set dosage range, and the silibinin suppression ratio 39.0% to hepatoma carcinoma cell, 37.5%, 33.7%, 28.3%, 15.3%, 48h half-inhibition concentration IC50Value is 298.5 μm of ol L-1.The suppression ratio of hepatoma carcinoma cell is above the suppression ratio of comparable sodium silibinin by three kinds of noval chemical compounds of synthesis, silibinin glycine Schiff base, silibinin alanine Schiff's base, silibinin lysine plus threonine suppression ratio be respectively as follows: 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 48h half-inhibition concentration IC50Value is followed successively by 50.01 μm of ol L-1,143.95μmol·L-1,134.50μmol·L-1, illustrate that hepatoma carcinoma cell is had good inhibiting effect by silibinin amino-acid schiff base.
Silibinin amino-acid schiff base anti-gastric cancer cytosis
Same said method, the silibinin suppression ratio difference 33.3%, 22.9%, 23.2%, 19.1%, 11.5% to stomach cancer cell, IC50Value is 259.36 μm of ol L-1, silibinin glycine Schiff base, silibinin alanine Schiff's base, 5 kinds of concentration 48h suppression ratio of silibinin lysine plus threonine 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 half-inhibition concentration IC50Value respectively 64.41 μm of ol L-1, 162.18 μm of ol L-1,152.49μmol·L-1, stomach cancer cell is had good inhibiting effect by silibinin amino-acid schiff base.
Claims (7)
1. the synthesis preparation method of a silibinin amino-acid schiff base, it is characterised in that:
A. 0.075g glycine and 0.04g sodium hydroxide are carried out chemical reaction, be dissolved in 1mL distilled water, put in the conical flask of 100mL standby；
B. 0.482g silibinin is dissolved in 50mL ethanol solution, is slowly added dropwise to the conical flask of 0.075g glycine and 0.04g sodium hydroxide chemical reaction, magnesium sulfate dehydration, pH value of solution=8.5,55 DEG C of water-baths, stir 0.5h,
Thin layer is followed the tracks of, and reaction stops, and mixed liquor sucking filtration, dehydrated alcohol recrystallization, vacuum drying, synthetic product is light yellow solid, i.e. the sodium salt of silibinin glycine Schiff base, and molecular formula is C27H24NO11Na, molecular weight is 561, yield 63%, and fusing point 222～224 DEG C, structural formula is as follows
2. the synthesis preparation method of silibinin amino-acid schiff base as claimed in claim 1, it is characterised in that: described glycine is replaced by phenylalanine, glutamic acid, aspartic acid, cysteine.
3. the synthesis preparation method of a silibinin amino-acid schiff base, it is characterised in that:
A, 0.089g alanine and 0.04g sodium hydroxide are carried out chemical reaction, be dissolved in 1mL distilled water, put in the conical flask of 100mL standby；
B, 0.482g silibinin is dissolved in 50mL ethanol solution, it is slowly added dropwise to the conical flask of 0.089g alanine and 0.04g sodium hydroxide chemical reaction, 60 DEG C of stirrings, reaction engenders yellow solid, after room temperature back flow reaction 20min, color burn becomes brown color
Thin layer is followed the tracks of, magnesium sulfate dehydration, pH value of solution=8.5,55 DEG C of water-baths, stirs 0.5h, thin layer is followed the tracks of, and reaction stops, mixed liquor sucking filtration, dehydrated alcohol recrystallization, vacuum drying, synthetic product is brown solid, i.e. the sodium salt of silibinin alanine Schiff's base, molecular formula C28H26NO11Na, molecular weight is 575, yield 42%, and fusing point 228～229 DEG C, structural formula is as follows
4. the synthesis preparation method of silibinin amino-acid schiff base as claimed in claim 3, it is characterised in that: described alanine is replaced by phenylalanine, glutamic acid, aspartic acid, cysteine.
5. the synthesis preparation method of a silibinin amino-acid schiff base, it is characterised in that:
A, 0.149g lysine and 0.04g sodium hydroxide are carried out chemical reaction, be dissolved in 1mL distilled water, put in the conical flask of 100mL standby；
B, 0.482g silibinin is dissolved in 50mL ethanol solution, it is slowly added dropwise in the conical flask carrying out chemical reaction to 0.149g lysine and 0.04g sodium hydroxide, engender yellow mercury oxide, normal-temperature reaction 20min, magnesium sulfate dehydration, rear color burn becomes brown color, pH value of solution=8.5,55 DEG C of water-baths, stir 0.5h
Thin layer is followed the tracks of, and reaction stops, and mixed liquor sucking filtration, dehydrated alcohol recrystallization, vacuum drying, synthetic product is light yellow solid, i.e. the sodium salt of silibinin lysine plus threonine, molecular formula C31H33N2O11Na, molecular weight is 632, yield 55%, and fusing point 243～245 DEG C, structural formula is as follows
6. the synthesis preparation method of silibinin amino-acid schiff base as claimed in claim 5, it is characterised in that:
Described lysine is replaced by phenylalanine, glutamic acid, aspartic acid, cysteine.
7. the silibinin amino-acid schiff base prepared by claim 1-6 has the purposes in anti-hepatoma carcinoma cell and anti-gastric cancer cell drug in preparation.
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