CN1644588A - Preparation of tellurium contained transparent acid with activity of high glutathione peroxidase - Google Patents
Preparation of tellurium contained transparent acid with activity of high glutathione peroxidase Download PDFInfo
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- CN1644588A CN1644588A CN 200410011380 CN200410011380A CN1644588A CN 1644588 A CN1644588 A CN 1644588A CN 200410011380 CN200410011380 CN 200410011380 CN 200410011380 A CN200410011380 A CN 200410011380A CN 1644588 A CN1644588 A CN 1644588A
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Abstract
Production of transparent acid containing tellurium with high glutathione oxide enzyme activity is artificial enzyme process with GPX activity. It consists of transparent acid activating, tellurium sodium hydride preparing, transparent acid tellurium reacting, tellurium transparent acid oxidizing and after processing. The production is carried out by activating transparent acid with tolylsulfonyl chlorin, preparing transparent acid benzene sulfonyl ester, dialyzing in distilled water, adding tellurium powder and sodium borohydride into anhydrous alcohol, heating and reverse flowing in nitrogen system, adding anaerobic glacial acetic acid, preparing alcohol solution of tellurium sodium hydride preparing, alcohol of tellurium sodium hydride reacting with transparent acid benzene sulfonyl ester solution, obtaining transparent acid containing the, the reacting system expose in air, centrifugal oxidizing, alcohol settling, and washing. It achieves simple process, high output, higher resistance to oxidation and GPX activity.
Description
Technical field
The invention belongs to biochemical field, relate to the method that preparation has the artificial enzyme of higher activity of glutathione peroxidase, particularly, the present invention relates to the hyaluronic chemical preparation process of telluriumization.
Background technology
Hyaluronic acid has very strong water retention; In makeup, can play thickening and stable effect; In skin, can remove active oxygen radical, play sunscreen effect.Therefore, hyaluronic acid has the application of all many-sides in cosmetic field.Hyaluronic acid and derivative thereof are again as the carrier in the compound preparation of basic medicine and all kinds of medicine composition, different medicine guiding and be retained in the pathogenic site of human body, make drug effect to more accurate target position, when increasing curative effect greatly, avoided the systemic side effects of medicine.With the hyaluronic acid be carrier anticancer targeting medicine as: hyaluronic acid-Fluracil, the hyaluronic acid-dichloro pain etc. of going out has entered three phase clinical stages.
Tellurium belongs to metalloid element, and telluromercaptan has the ability of higher hydroperoxide decomposition.The toxicity of inorganic tellurium is very little.Organic tellurium be studies show that its biological action is similar to Selenoperoxidase (GPX) activity.The tellurious propylhomoserin that the tellurium yeast produces can be used as carcinostatic agent and is applied in the clinical treatment.Organic telluride (AS101) has the effect of the Leukemia Cell Proliferation of inhibition, increases splenocyte NK activity, improves peripheral blood leucocyte phagocytic function and oxidation disinfection ability.
Selenoperoxidase (GPX) has distortion of preventing, pre-anti-aging and participate in important physiological actions such as prostaglandin(PG) is synthetic in the active oxygen metabolism of body.People source GPX should be the most effective anti-oxidation medicine in theory, but because the source is extremely limited; From animal, extract GPX and can not solve limited, the expensive drawback in source fully.So people begin applied chemistry synthesis method manual simulation GPX enzyme.Disclose the application of cyclodextrin derivative in makeup as Chinese patent 03119444.3, but compared with hyaluronic acid, cyclodextrin is a micromolecular compound, and what the shortage makeup should have preserves moisture and trophism, and does not have oilness and thickening property.Chinese patent 03119443.5 discloses the pharmaceutical use and the pharmaceutical composition thereof of cyclodextrin derivative, but compare with hyaluronic acid, cyclodextrin does not possess the effect of target medicine carrier, and be that substrate synthetic selenium-containing compound is applied to clinical treatment with the cyclodextrin, it is big to have side effect, the characteristics that curative effect of medication is low.
The prior art close with the present invention is that Chinese patent 03127134.0 is disclosed, name is called " chemical modification method preparation have activity of glutathione peroxidase contain selenium hyaluronic acid compound ", introduced and adopted simple chemical synthesis, preparation contains the hyaluronic method of selenium, hyaluronic acid after the selenizing has higher GPX activity, but also has anti-oxidant activity preferably.The said selenium hyaluronic acid that contains is selenium and hyaluronic compound.Its preparation technology is: NaHSe and hyaluronic acid aqueous solution carry out selenylation reaction and generate and to contain-hyaluronic acid of she; Reaction is exposed to oxidation in the air with reaction system after finishing, and removes excessive selenium; Product is through ethanol sedimentation, centrifugal, and collecting precipitation with ethanol, acetone repetitive scrubbing, is flung to organic solvent, and the sample lyophilize must contain the pure product of selenium hyaluronic acid.
Summary of the invention
The technical problem to be solved in the present invention is, a kind of simple process is provided, and, modifies in the hyaluronan molecule-the OH position as modifier with NaHTe, and what preparation had GPX activity and an anti-oxidant activity contains the tellurium hyaluronic acid.
The tellurium hyaluronic acid that contains of the present invention is tellurium and hyaluronic compound.Containing the tellurium hyaluronic acid is pale yellow powder shape thing.Contained tellurium valence state is-1 valency.The GPX activity is 80.2～174.2U/umol.
The preparation process that contains tellurium hyaluronic acid compound with activity of glutathione peroxidase of the present invention has hyaluronic activation, the hyaluronic oxidation of preparation, transparent acid tellurium reacting, telluriumization of sodium hydrogen telluride (NaHTe), aftertreatment.Said hyaluronic activation with tolysulfonyl chlorine activation hyaluronic acid, is prepared the hyaluronic acid benzenesulfonyl, dialyses in distilled water again; The preparation of said sodium hydrogen telluride, the preparation of said sodium hydrogen telluride is that tellurium powder and sodium borohydride are added dehydrated alcohol, in the enclosed system reaction, obtains the ethanolic soln of sodium hydrogen telluride; Said transparent acid tellurium reacting is ethanolic soln and the hyaluronic acid benzenesulfonyl reactant aqueous solution with sodium hydrogen telluride, generation contains-and the hyaluronic acid of TeH.The hyaluronic oxidation of said telluriumization, be generation is contained-the hyaluronic acid reaction system of TeH is exposed to oxidation in the air; Said aftertreatment, be product through centrifugal, ethanol sedimentation, centrifugal collecting precipitation is used ethanol and acetone repetitive scrubbing respectively, flings to organic solvent, the sample lyophilize obtains containing the pure product of tellurium hyaluronic acid.
Compare with background technology, raw material has used sodium hydrogen telluride, has increased hyaluronic reactivation process.The hyaluronic oxidation of telluriumization is identical with the respective process of background technology with last handling process.
The detailed process of the preparation of sodium hydrogen telluride, be that tellurium powder and sodium borohydride are added dehydrated alcohol, make system keep under the oxygen free condition reflux 0.6～1.5 hour at logical nitrogen, be cooled to room temperature and add the anaerobic Glacial acetic acid again, be heated to boiling, there is black precipitate to produce, obtains the ethanolic soln of sodium hydrogen telluride.The preparation of sodium hydrogen telluride can be with reference to the article of " synthetic chemistry " the 4th volume the 1st phase (1996) P73～75, and exercise question is " one-step synthesis that sodium hydrogen telluride is present in 3-oxo carbothioic acid ester ".
Hyaluronic activation detailed process, be that hyaluronic acid is dissolved in the NaOH solution, it is Tosyl chloride (p-TsCL) acetonitrile solution of 0.4g/ml that room temperature drips concentration, makes pH＞12.5 of system, dropwise through stirring and transfer to neutrality with HCl again, add methyl alcohol, the elimination insolubles, pressure reducing and steaming methyl alcohol is separated out salt under 5 ℃ of environment, the elimination insolubles, make the hyaluronic acid benzenesulfonyl, in distilled water, dialysed again 1～3 day, standby.The mass ratio of hyaluronic acid and Tosyl chloride consumption is 1: 2～5.
The detailed process of transparent acid tellurium reacting, be that hyaluronic acid benzenesulfonyl water is dissolved to concentration is 8～15mg/ml, logical nitrogen makes reaction system add the sodium hydrogen telluride alcoholic solution under inert environments, and the confined reaction system also places 30～70 ℃ of water-baths, reacts 12～60 hours.The consumption mol ratio of hyaluronic acid benzenesulfonyl and NaHTe is 1: 1000～15000, and its optimum mole ratio is 1: 5000.
The invention has the beneficial effects as follows:
Method of the present invention preparation contain the tellurium hyaluronic acid, have the higher anti-oxidant activity of more former hyaluronic acid, also increased the GPX activity.It is stable to contain the hyaluronic physico-chemical property of tellurium.And tellurium and selenium belong to same main group element, and they have identical redox characteristic, and the easier hydroperoxide decomposition of telluromercaptan.The toxicity of inorganic tellurium is significantly less than the toxicity of inorganic selenium.Contain the tellurium hyaluronic acid and can overcome the instability of natural GPX as the additive of medicine or makeup, it is limited to originate, and the molecular weight conference causes shortcomings such as human immunity reaction.Therefore, contain the tellurium hyaluronic acid and the huge applications potentiality are arranged at cosmetic field and field of medicaments.Contain the tellurium hyaluronic acid and do not appear in the newspapers both at home and abroad, the present invention has synthesized and has contained the tellurium hyaluronic acid, for the exploitation of the stand-in of enzyme provides a new thinking.
Hyaluronic acid can prepare by extraction and microbial fermentation in the organism in a large number as main raw materials for production, and this is with regard to the good high problem of cost that solved.Tosyl chloride is comparatively cheap activator, with this material activation hyaluronic acid, purified product after the telluriumization has so just been simplified the steps such as preparation, separation purification of product, the cost of stand-in is reduced greatly, and biological activity improve nearly 4 times than cyclodextrin tellurium product.Therefore, of the present invention to contain the hyaluronic preparation technology of tellurium simple, and synthesis step is few, productive rate height, easy purification of products, but mass production.
Embodiment
Embodiment 1 contains the hyaluronic synthetic route of tellurium:
(1) preparation of hyaluronic acid benzenesulfonyl
Getting the 2.0g hyaluronic acid is dissolved in 80ml NaOH (0.15mol/L) solution, room temperature drips the NaOH that constantly adds 1mol/L in acetonitrile solution (8.0g/20ml) the dropping process of p-TsCL makes pH value of solution＞12.5,3 hour dropwise restir 1 hour, transfers to neutrality with 1mol/LHCl, add 100ml methyl alcohol, elimination insolubles, pressure reducing and steaming methyl alcohol are put into 5 ℃ of refrigerators to 80ml, salt out after eight days, the elimination insolubles, dialysis is 2 days in distilled water, and is standby.
(2) preparation of sodium hydrogen telluride (NaHTe)
2.54g tellurium powder, 1.8g sodium borohydride are added the 40ml dehydrated alcohol, have gas to produce, and be attended by heat and emit.Logical nitrogen number minute makes system keep anaerobic.About 1 hour of little fiery reflux is cooled to room temperature, adds 2.4ml anaerobic Glacial acetic acid, is heated to boiling.Have black precipitate to produce, solution is water white transparency.After the cooling, solution can use.
(3) activatory hyaluronic acid benzenesulfonyl water fully being dissolved to concentration is 10mg/ml, get this aqueous solution of 100ml and in container, led to high pure nitrogen 25 minutes, guarantee the inert environments of reaction system, the sodium hydrogen telluride alcoholic solution for preparing is added rapidly in this container, rapid confined reaction system, prevent that sodium hydrogen telluride is oxidized, the reaction of beginning tellurium.
The tellurium reaction system is placed 60 ℃ of water-baths, reacted 48 hours.
(4) after the reaction of hyaluronic acid tellurium, product fully is exposed in the air, makes the abundant oxidation of excessive sodium hydrogen telluride.With 12000rpm centrifugal 10 minutes, collect and contain the yellow supernatant liquor of tellurium hyaluronic acid.
(5) with the NaOH adjust pH to 7.0 of tellurium hyaluronic acid with 1mol/L.To contain tellurium hyaluronic acid precipitation with ethanol, collecting precipitation, behind ethanol, acetone repetitive scrubbing, cooling drying must contain the pure product of tellurium hyaluronic acid.
The active mensuration of embodiment 2 tellurium hyaluronic acids
1, the hyaluronic GPX activity of telluriumization
Surveying live body is 500ul, contains the 50mmol/L potassium phosphate buffer, pH7.0,1mmol/L sodium azide.The 1mmol/L gsh, 0.25mmol/L coenzyme (NADPH), the 1U glutathione reductase adds the 0.5mmol/L hydrogen peroxide and starts reaction, and the oxidized absorbancy of monitoring NADPH changes at the 340nm place.When the mensuration enzyme is lived, replace containing the tellurium polysaccharide as blank with distilled water.Enzyme activity unit is defined as the every micromole of per minute and contains the tellurium polysaccharide to consume 1 micromole NADPH be a unit of activity.The ratio vigor that contains the tellurium polysaccharide that final mensuration obtains under these conditions is 174.2U/umol.
2, the hyaluronic anti-oxidant activity research of telluriumization
Surveying live body is 3ml, take the tellurium hyaluronic acid solution 100ul of above-mentioned preparation, add 2ml distilled water, the sodium salicylate 300ul that adds 20mmol/L successively, 0.5mmol/L ferrous sulfate 300ul, the hydrogen peroxide 300ul that adds 60mmol/L at last, reaction system reacted 1 hour in 32 ℃ water-bath after, on 752 spectrophotometers, measure its absorbance at the 510nm place.Replace sugar soln to make reference with distilled water during the mensuration vigor, the pure hyaluronic acid aqueous solution with same concentrations replaces sugar soln to compare, the final inhibiting rate of activity when 15ug/ml of measuring its anti--OH reaches 81%, is not modified hyaluronic more than 460 times.
Embodiment 3 activation conditions are to the influence of product GPX vigor
Press the technological process of embodiment 1, just the mass ratio with hyaluronic acid and Tosyl chloride consumption was respectively 1: 1, and 1: 2,1: 3,1: 4,1: 5.The tellurium hyaluronic acid that contains that obtains is recorded its GPX vigor respectively by the detection method of embodiment 2, and the result is 62.5,91.3,130.5,174.2,178.3U/umol.Except 1: 1 proportioning, the result is all greater than the result of 75.2 U/umol of background technology.Finally obtain in reactivation process, hyaluronic acid and Tosyl chloride optimum quality ratio are 1: 4, and its product contains the tellurium hyaluronic acid and has the high and high characteristics of Tosyl chloride utilization ratio of GPX vigor concurrently.
Embodiment 4 tellurium conditions are to the influence of product GPX vigor
Press the technological process of embodiment 1, just hyaluronic acid benzenesulfonyl water is dissolved to different concns, concentration is respectively, 5mg/ml, 8mg/ml, 10mg/ml, 12mg/ml, 15mg/ml.Get this aqueous solution of 100ml and carry out the tellurium reaction, the tellurium hyaluronic acid that contains that obtains is recorded its GPX vigor by the detection method of embodiment 2 and is respectively 51.3,95.6,135.7,174.2,152.3.The concentration of aqueous solution of hyaluronic acid benzenesulfonyl except 5mg/ml than, GPX vigor result is all greater than the result of background technology.Obtain at last when hyaluronic acid benzenesulfonyl aqueous solution optimum concn is 10mg/ml, its product contains the tellurium hyaluronic acid and has the high and good characteristics of solvability of GPX vigor concurrently.
The hyaluronic acid benzenesulfonyl of 10mg/ml and the consumption mol ratio of NaHTe were mixed with respectively 1: 1000,1: 2500,1: 5000,1: 10000,1: 15000, carry out the tellurium reaction with different hyaluronic acid benzenesulfonyls and NaHTe consumption mol ratio by the technological process of embodiment 1, the tellurium hyaluronic acid that contains that obtains is recorded its GPX vigor by the detection method of embodiment 2 and is respectively 120.1,140.3,171.5,178.2,180.2.The result of aforementioned proportion all is better than background technology.The consumption mol ratio of activatory hyaluronic acid benzenesulfonyl and sodium hydrogen telluride be 1: 5000 o'clock be best proportioning, its product contains the tellurium hyaluronic acid and has the high and high characteristics of tellurium utilization ratio of GPX vigor concurrently.
The activatory hyaluronic acid benzenesulfonyl of 10mg/ml carry out telluriumization, reaction times is respectively 12,24, and 36,48,60 hours, carry out the tellurium reaction by the technological process of embodiment 1 with the different hyaluronic acid tellurium time, product records its GPX vigor by the detection method of embodiment 2 and is respectively 80.2,110.3,140.8,174.5,176.3.The result in above-mentioned reaction times all is better than background technology.And definite hyaluronic acid tellurium reaction Best Times is 48 hours, and its product contains the tellurium hyaluronic acid and has the high characteristics of GPX vigor.
The activatory hyaluronic acid benzenesulfonyl of 10mg/ml carry out telluriumization, and temperature of reaction is respectively 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, carry out the tellurium reaction with different hyaluronic acid tellurium temperature by the technology of embodiment 1, gained contains the tellurium hyaluronic acid and records its GPX vigor by embodiment 2 methods and be respectively 40.1,76.1,90.5,135.8,172.5,176.1.Can determine that hyaluronic acid tellurium temperature of reaction all can reach effect of the present invention at 30～70 ℃.And can determine that hyaluronic acid tellurium reaction optimum temps is 60 ℃, its product contains the tellurium hyaluronic acid and has the high and little characteristics of hyaluronic acid degradation degree of GPX vigor concurrently.
Claims (3)
1, a kind of have a homoglutathion peroxidase activity contain the hyaluronic preparation method of tellurium, technological process has the hyaluronic oxidation of telluriumization, aftertreatment; The hyaluronic oxidation of said telluriumization, be generation is contained-the hyaluronic acid reaction system of TeH is exposed to oxidation in the air; Said aftertreatment, be product through centrifugal, ethanol sedimentation, centrifugal collecting precipitation is used ethanol and acetone repetitive scrubbing respectively, flings to organic solvent, the sample lyophilize obtains containing the pure product of tellurium hyaluronic acid; It is characterized in that before the hyaluronic oxidation of telluriumization, the preparation of hyaluronic activation, sodium hydrogen telluride, the technological process of transparent acid tellurium reacting being arranged; Said hyaluronic activation with tolysulfonyl chlorine activation hyaluronic acid, is prepared the hyaluronic acid benzenesulfonyl, dialyses in distilled water again; The preparation of said sodium hydrogen telluride is that tellurium powder and sodium borohydride are added dehydrated alcohol, in the enclosed system reaction, obtains the ethanolic soln of sodium hydrogen telluride; Said transparent acid tellurium reacting is ethanolic soln and the hyaluronic acid benzenesulfonyl reactant aqueous solution with sodium hydrogen telluride, generation contains-and the hyaluronic acid of TeH.
2, according to claim 1 described have a homoglutathion peroxidase activity contain the hyaluronic preparation method of tellurium, it is characterized in that, said hyaluronic activation, be that hyaluronic acid is dissolved in the NaOH solution, it is the Tosyl chloride acetonitrile solution of 0.4g/ml that room temperature drips concentration, make pH＞12.5 of system, dropwise through stirring and transfer to neutrality with HCl again, add methyl alcohol, the elimination insolubles, pressure reducing and steaming methyl alcohol is separated out salt under 5 ℃ of environment, the elimination insolubles, make the hyaluronic acid benzenesulfonyl, in distilled water, dialysed again 1～3 day; The mass ratio of hyaluronic acid and Tosyl chloride consumption is 1: 2～5.
3, according to claim 1 or 2 described have a homoglutathion peroxidase activity contain the hyaluronic preparation method of tellurium, it is characterized in that, said transparent acid tellurium reacting, be that hyaluronic acid benzenesulfonyl water is dissolved to concentration is 8～15mg/ml, logical nitrogen makes reaction system add the sodium hydrogen telluride alcoholic solution under inert environments, the confined reaction system also places 30～70 ℃ of water-baths, reacts 12～60 hours; The consumption mol ratio of hyaluronic acid benzenesulfonyl and sodium hydrogen telluride is 1: 1000～15000.
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| CNB2004100113805A CN100391984C (en) | 2004-12-23 | 2004-12-23 | Preparation of tellurium contained transparent acid with activity of high glutathione peroxidase |
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| CNB2004100113805A CN100391984C (en) | 2004-12-23 | 2004-12-23 | Preparation of tellurium contained transparent acid with activity of high glutathione peroxidase |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114410711A (en) * | 2022-01-25 | 2022-04-29 | 北部湾大学 | Preparation method of nano-starch-based bionic glutathione peroxidase |
| CN115536846A (en) * | 2022-09-21 | 2022-12-30 | 上海臻臣化妆品有限公司 | Preparation method of amino silicone oil modified hyaluronic acid for cosmetics, amino silicone oil modified hyaluronic acid and application |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5185036A (en) * | 1991-06-27 | 1993-02-09 | Calgon Corporation | Soluble tellurium compositions |
| CN1261458C (en) * | 2003-09-04 | 2006-06-28 | 吉林大学 | Process for preparing hyaluronic acid compound containing selenium with glutathione peroxidase activity by chemical modification method |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114410711A (en) * | 2022-01-25 | 2022-04-29 | 北部湾大学 | Preparation method of nano-starch-based bionic glutathione peroxidase |
| CN114410711B (en) * | 2022-01-25 | 2023-07-18 | 北部湾大学 | Preparation method of nano starch-based bionic glutathione peroxidase |
| CN115536846A (en) * | 2022-09-21 | 2022-12-30 | 上海臻臣化妆品有限公司 | Preparation method of amino silicone oil modified hyaluronic acid for cosmetics, amino silicone oil modified hyaluronic acid and application |
| CN115536846B (en) * | 2022-09-21 | 2023-08-11 | 上海臻臣化妆品有限公司 | Preparation method of amino silicone oil modified hyaluronic acid for cosmetics, amino silicone oil modified hyaluronic acid and application |
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