CN106986955A - A kind of Azide method of modifying of heparin and Azide heparin and application - Google Patents
A kind of Azide method of modifying of heparin and Azide heparin and application Download PDFInfo
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- CN106986955A CN106986955A CN201710292924.7A CN201710292924A CN106986955A CN 106986955 A CN106986955 A CN 106986955A CN 201710292924 A CN201710292924 A CN 201710292924A CN 106986955 A CN106986955 A CN 106986955A
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- heparin
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0003—General processes for their isolation or fractionation, e.g. purification or extraction from biomass
Abstract
The invention belongs to the technical field of biomaterial, Azide method of modifying and Azide heparin and the application of a kind of heparin are disclosed.It the described method comprises the following steps：(1) azido compound containing carboxyl is carried out by activation process, the azido compound activated using activating reagent；The condition of the activation process is：0~1~14h is reacted at room temperature；(2) heparin salting liquid is added into the azido compound of the activation of step (1), pH to 7~9 is adjusted, in 0~reacted at room temperature, dialysis removes small molecule, dry, obtains Azide heparin.The method of the present invention is simple, successfully by azido group modification to heparin molecule chain, has obtained Azide heparin.Described Azide heparin can preferable modified biological material, by heparin to be introduced into the form of chemical bond in biomaterial, expanded the application field of heparin.
Description
Technical field
The invention belongs to the technical field of biomaterial, it is related to the modification to heparin, more particularly to the Azide of heparin
Azide heparin and the Azide heparin obtained by modification and modification are used for modified biological material.
Background technology
Biomaterial has substantial amounts of application in clinicing aspects such as current vessel catheter, cardiac valves, haemodialysis, still
When biomaterial and contacting blood, one layer of plasma protein can be adsorbed rapidly；Bad Hemocompatible surfaces can make albumen structure
As transformation, the albumen of conformation transition can interact with platelet membrane surface receptor again, make platelet activation, and finally induce blood
Bolt.The surface anti-freezing processing of associated materials has great importance.Heparin is a kind of main clinical anticoagulant, is also a kind of
Important anticoagulant material modifying agent, is biomaterial surface anti-freezing skill conventional at present by heparin molecule introducing material surface
Art.
Current heparin mainly directly coats heparin molecule (such as with the method that biomaterial surface is combined including material surface
Antithrombus formation graft, for patent documents such as the method and systems of biocompatible surfaces), but this method due to combine compared with
Weak, in prolonged application requirement, the use of the heparin-surface-modified IOL material carried out using this method is limited to.By changing
Heparin molecule is attached to material surface and can preferably solved the above problems by combination, is used conventional method on material more
Carboxyl on carboxyl or heparin is activated, then heparin molecule is grafted into material surface with chemical bond by amidation process
(such as：Application No. 200410009002.3 discloses a kind of method of covalent grafting heparin on surface of polymer film, Application No.
201310176950.5 disclose a kind of preparation method of anticoagulation polylactic acid hemodialysis membrane).Such method requires biological material
Material must contain active group (amino or carboxyl), and the clinical painstaking effort tube material overwhelming majority is inert material, in shortage
Active group is stated, is generally required by methods, such as low temperature plasma, corona discharge and chemical attack side such as surface treatments
Method is handled, and this then further increases the synthesis technique and cost of material.
The present invention has good light reaction and thermal reaction characteristic, under these conditions, azido group using azido group
The free radical of formation can carry out dehydrogenation substitution reaction to corresponding molecular structure on material, so that by mesh in the way of chemical bond
Mark molecule is incorporated into material surface.By using azido group it is good can response characteristic, azido group is entered to heparin molecule
Row chemical modification, introduces azido group so that the heparin molecule of Azide can be illuminated the way by ultraviolet light in heparin molecule side base
Hair azido group is decomposed to form free radical and heparin is grafted on material surface so that the technique of heparin modified biological material is more
Simply, cost is lower.
The content of the invention
An object of the present invention is the Azide method of modifying for providing a kind of heparin, and heparin is modified, makes liver
Plain side chain contains azido group, using this Azide heparin, can increase a kind of simplicity side for synthesizing heparin modified biological material
Method.
Another object of the present invention is to provide the Azide heparin obtained by the above method.
It is still another object of the present invention to provide the application of above-mentioned Azide heparin.The Azide heparin is used for modified give birth to
Thing material, the particularly modified biomaterial containing alkynyl.
The purpose of the present invention is achieved through the following technical solutions：
A kind of Azide method of modifying of heparin, comprises the following steps：
(1) azido compound containing carboxyl is carried out by activation process, the nitrine chemical combination activated using activating reagent
Thing；The condition of the activation process is：0~1~14h is reacted at room temperature；The activation process is that having the organic solvent of water
Carried out in middle progress or anhydrous organic solvent；When the activation process in the organic solvent for have water, the pH of reaction solution need to be adjusted
For 4~7；When the activation process in anhydrous organic solvent, inert gas need to be passed through, without adjusting pH；
(2) heparin salting liquid is added into the azido compound of the activation of step (1), pH to 7~9 is adjusted, in 0~room temperature
Lower to be reacted, dialysis removes small molecule, dries, obtains Azide heparin.
Step (1) the carboxylic azido compound is p-azidobenzoic acid, 2- azidobenzoic acids, 3- (4- phenylazides
Base) propionic acid, 4- azidosalicylic acids, nitrine acetic acid, 4- azidos butyric acid, more than one in 6- azido caproic acids.
Step (1) described activating reagent is 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate
(EDC.HCl) system with N- hydroxy thiosuccinimides (sulfo-NHS), 1- ethyls-(3- dimethylaminopropyls) carbon
System, 1- ethyls-(the 3- dimethylaminopropyls) of acyl diimmonium salt hydrochlorate (EDC.HCl) and I-hydroxybenzotriazole (HOBT)
The system of phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl) and n-hydroxysuccinimide (NHS), N, N'- dicyclohexylcarbodiimides
(DCC) system with n-hydroxysuccinimide (NHS), O- BTAs-tetramethylurea hexafluorophosphate (HBTU) and two
System, hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl phosphorus (PyBOP) and the 4- diformazan ammonia of ethyl cyano group phosphate
It is a kind of in the system of yl pyridines (DMAP).
In each system, the 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl) and N- hydroxyls
The mol ratio of base thiosuccimide (sulfo-NHS) is 1:1~1:10；The 1- ethyls-(3- dimethylaminopropyls)
The mol ratio of phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl) and I-hydroxybenzotriazole (HOBT) is 1:1~1:10；1- ethyls-(3-
Dimethylaminopropyl) mol ratio of phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl) and n-hydroxysuccinimide (NHS) is 1:1
~1:10；The mol ratio of the N, N'- dicyclohexylcarbodiimide (DCC) and n-hydroxysuccinimide (NHS) is 1:1~1:
10；The mol ratio of the O- BTAs-tetramethylurea hexafluorophosphate (HBTU) and diethyl cyano group phosphate is 1:1~
1:10；Hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl the phosphorus (PyBOP) and DMAP (DMAP)
Mol ratio be 1:1~1:10.
The total amount and the mol ratio of carboxylic azido compound of activating reagent described in step (1) be：1:1~10:1.
Organic solvent described in step (1) is conventional organic solvent, such as：Dimethyl sulfoxide (DMSO) (DMSO), dimethyl methyl
Acid amides (DMF) etc..
Heparinate described in step (2) be liquaemin, heparin lithium or calciparine in more than one, molecular weight be 4000~
3000000.The heparin salting liquid is the aqueous solution of heparinate.
The time reacted described in step (2) is 1~14h；
The consumption of heparinate described in step (2) is carboxylic azido compound mole dosage in step (1)
0.1%-10%.
The material that pH is adjusted described in step (2) is NaOH solution.
The azido compound activated described in step (1) can carry out separating-purifying, then add heparin salting liquid and carry out instead
Should, it can improve Azide heparin yield, the azido group content increase in product.
By taking p-azidobenzoic acid as an example, the structure of described Azide heparin is：
The condition dialysed described in step (2) is：The temperature of dialysis is：20~40 DEG C；Dialyzate is：Deionized water；With
It is dialysis terminal that material containing nitrine can not be detected in dialyzate.
The reaction of step (2) and (1) is carried out under conditions of lucifuge.
The Azide heparin is prepared by the above method.
The Azide heparin is used for modified biological material, the particularly modified biomaterial containing alkynyl.
Compared with prior art, advantages of the present invention：
(1) heparin side introduces azido group, and Azide heparin and other lifes containing alkynyl can be made by click-reaction
Thing material and reagent highly effective reaction；
(2) heparin side introduces azido group, by increasing capacitance it is possible to increase the synthetic method of heparin modified material.
Brief description of the drawings
Fig. 1 is the infrared absorption spectroscopy of the Azide heparin synthesized by embodiment 1；
Fig. 2 is the ultra-violet absorption spectrum of the Azide heparin synthesized by embodiment 1.
Embodiment
The present invention is done with reference to embodiment and accompanying drawing and is further described in detail, but embodiments of the present invention are not limited
In this.
Embodiment 1
Into the container equipped with 20ml dimethyl sulfoxide (DMSO)s (DMSO contains water), sequentially add 0.815g p-azidobenzoic acids,
0.958g EDC.HCl, 0.575g NHS, are adjusted after pH to 4.7 with 0.1M dilute hydrochloric acid solution after being sufficiently stirred for, are placed in 4 DEG C of environment
Middle magnetic agitation, lucifuge reaction (preventing azido group from being decomposed by illumination) 4h；Add 10ml (0.1g/ml) liquaemin (molecule
Measure as the 12000) aqueous solution, adjusted with 0.01M NaOH solutions after pH to 7.4, be placed in lucifuge in 4 DEG C of environment and react 6h；Finally, will
Reaction solution pours into bag filter (3.5K), is dialysed with water to after without nitrine para Toluic Acid, filtering, and reaction solution is freezed at -25 DEG C,
It is Azide heparin to obtain product, and the Azide group content of product is 8.8 ‰ (g/g), and product yield is 95%.
The infrared absorption spectroscopy of Azide heparin synthesized by the present embodiment is as shown in Figure 1.It can be seen that nitrine
Change the absworption peak that heparin occurs in that azido group at 2100, this demonstrate azido has been successfully incorporated into heparin molecule
Group.The ultra-violet absorption spectrum of Azide heparin is as shown in Figure 2 synthesized by embodiment 1.It can be seen that Azide heparin exists
The absworption peak of phenyl ring is occurred in that at 275, this demonstrate p-azidobenzoic acid has been successfully incorporated into heparin molecule.
Embodiment 2
Into the container equipped with 20ml dimethylformamides (DMF contains water), 0.955g 3- (4- phenylazides are sequentially added
Base) propionic acid, 1.916g EDC.HCl, 2.170g sulfo-NHS, adjust pH to 4.7 with 0.1M dilute hydrochloric acid solution after being sufficiently stirred for
Afterwards, it is placed in magnetic agitation in 6 DEG C of environment, lucifuge reaction 4h adds 10ml (0.05g/ml) heparin lithium (molecular weight is 20000)
The aqueous solution, is adjusted after pH to 7.4 with 0.01M NaOH solutions, is placed in lucifuge in 6 DEG C of environment and is reacted 6h；Finally, reaction solution is poured into
Bag filter (3.5K), is dialysed to after without 3- (4- azidophenyls) propionic acid with water, filtering, and reaction solution is freezed at -25 DEG C, must be produced
Thing is Azide heparin, and the azido group content of product is 5.5 ‰, and product yield is 90%.
Embodiment 3
Into the container of the dimethyl sulfoxide (DMSO) (DMSO contains water) equipped with 40ml, 0.155g4- azido fourths are sequentially added
Acid, 0.258g EDC.HCl, 0.345g sulfo-NHS, are adjusted after pH to 5.0 after being sufficiently stirred for 0.1M dilute hydrochloric acid solution,
It is placed in magnetic agitation in 10 DEG C of environment, lucifuge reaction 6h；Add 10ml (0.1g/ml) calciparine (molecular weight is 20000) water
Solution, is adjusted after pH to 7.4 with 0.01M NaOH solutions, is placed in lucifuge in 10 DEG C of environment and is reacted 6h；Finally, reaction solution is poured into
Bag (3.5K) is analysed, is dialysed with water to after without 4- azido butyric acid, is filtered, reaction solution is freezed at -30 DEG C, product i.e. nitrine is obtained
Change heparin, the azido group content of product is 2.0 ‰, and product yield is 85%.
Embodiment 4
Into the container of the anhydrous DMSO equipped with 20ml, sequentially add 0.515g 6- azidos caproic acid, 2.149gDCC,
1.201g NHS, nitrogen protection is placed in magnetic agitation in room temperature environment, lucifuge reaction 6h；Add 10ml (0.7g/ml) heparin
Calcium (molecular weight is 20000) aqueous solution, is adjusted with 0.01M NaOH solutions and continues room temperature lucifuge reaction 6h after pH to 7.6；Finally, will
Reaction solution pours into bag filter (3.5K), is dialysed with water to after without 6- azido caproic acids, filtering, and reaction solution is freezed at -30 DEG C,
It is Azide heparin to obtain product, and the azido group content of product is 1.0 ‰, and product yield is 80%.
Embodiment 5
Into the container equipped with 20ml dry DMFs, 0.25g nitrine acetic acid, 0.3g DCC, 0.44g NHS, nitrogen are sequentially added
Gas shielded, magnetic agitation at 15 DEG C, lucifuge reaction 10h；Add 10ml (0.06g/ml) heparin lithium (molecular weight is 20000) water
Solution, is adjusted after pH to 8.5 with 0.01M NaOH solutions, is continued the lucifuge in 15 DEG C of environment and is reacted 10h；Finally, reaction solution is fallen
Enter bag filter (3.5K), dialysed with water to after without nitrine acetic acid, filtered, reaction solution is freezed at -30 DEG C, product i.e. nitrine is obtained
Change heparin, the azido group content of product is 4.2 ‰, and product yield is 87%.
Above-described embodiment is the present invention preferably embodiment, but embodiments of the present invention are not limited by examples detailed above
System, it is other it is any without departing from spirit of the invention and the change made under principle, modification, replacement, combine, simplification is
Effect.
Claims (10)
1. a kind of Azide method of modifying of heparin, it is characterised in that：Comprise the following steps：
(1) azido compound containing carboxyl is carried out by activation process, the azido compound activated using activating reagent；Institute
The condition for stating activation process is：0~1~14h is reacted at room temperature；The activation process is carried out in the organic solvent for have water
Or carried out in anhydrous organic solvent；When the activation process in the organic solvent for have water, the pH that need to adjust reaction solution is 4~7；
When the activation process in anhydrous organic solvent, inert gas need to be passed through, without adjusting pH；
(2) heparin salting liquid is added into the azido compound of the activation of step (1), pH to 7~9 is adjusted, in 0~enter at room temperature
Row reaction, dialysis removes small molecule, dries, obtains Azide heparin.
2. the Azide method of modifying of heparin according to claim 1, it is characterised in that：Step (1) is described carboxylic folded
Nitrogen compound be p-azidobenzoic acid, 2- azidobenzoic acids, 3- (4- azidophenyls) propionic acid, 4- azidosalicylic acids, nitrine acetic acid,
More than one in 4- azidos butyric acid, 6- azido caproic acids.
3. the Azide method of modifying of heparin according to claim 1, it is characterised in that：Step (1) described activating reagent is
The system of 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate and N- hydroxy thiosuccinimides, 1- ethyls-
The system of (3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate and I-hydroxybenzotriazole, 1- ethyls-(3- dimethylaminos
Propyl group) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide system, N, N'- dicyclohexylcarbodiimides and N- hydroxyl ambers
The imido system of amber, the system of O- BTAs-tetramethylurea hexafluorophosphate and diethyl cyano group phosphate, hexafluoro phosphorus
It is a kind of in the system of sour BTA -1- bases-epoxide tripyrrole alkyl phosphorus and DMAP.
4. the Azide method of modifying of heparin according to claim 3, it is characterised in that：In each system, the 1- ethyls-
The mol ratio of (3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate and N- hydroxy thiosuccinimides is 1:1~1:10；
The mol ratio of the 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate and I-hydroxybenzotriazole is 1:1~
1:10；The mol ratio of 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide is 1:1
~1:10；The mol ratio of the N, N'- dicyclohexylcarbodiimide and n-hydroxysuccinimide is 1:1~1:10；The O-
The mol ratio of BTA-tetramethylurea hexafluorophosphate and diethyl cyano group phosphate is 1:1~1:10；The hexafluoro phosphorus
The mol ratio of sour BTA -1- bases-epoxide tripyrrole alkyl phosphorus and DMAP is 1:1~1:10.
5. the Azide method of modifying of heparin according to claim 1, it is characterised in that：Heparinate is described in step (2)
More than one in liquaemin, heparin lithium or calciparine.
6. the Azide method of modifying of heparin according to claim 1, it is characterised in that：Activating reagent described in step (1)
Total amount and the mol ratio of carboxylic azido compound be：1:1~10:1；
The consumption of heparinate described in step (2) is the 0.1%- of carboxylic azido compound mole dosage in step (1)
10%.
7. the Azide method of modifying of heparin according to claim 1, it is characterised in that：Heparinate described in step (2)
Molecular weight is 4000~3000000.
8. the Azide method of modifying of heparin according to claim 1, it is characterised in that：Reacted described in step (2) when
Between be 1~14h；The heparin salting liquid is the aqueous solution of heparinate.
9. the Azide heparin that a kind of Azide method of modifying by any one of claim 1~8 heparin is prepared.
10. the application of Azide heparin according to claim 1, it is characterised in that：The Azide heparin is used for modified give birth to
Thing material.
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| CN110339181A (en) * | 2019-07-02 | 2019-10-18 | 中国药科大学 | A kind of pH response type nano preparation and its preparation method and application based on click-reaction |
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| CN106986955B (en) | 2019-04-09 |
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