CN106986955B - The Azide method of modifying and Azide heparin of a kind of heparin and application - Google Patents
The Azide method of modifying and Azide heparin of a kind of heparin and application Download PDFInfo
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- CN106986955B CN106986955B CN201710292924.7A CN201710292924A CN106986955B CN 106986955 B CN106986955 B CN 106986955B CN 201710292924 A CN201710292924 A CN 201710292924A CN 106986955 B CN106986955 B CN 106986955B
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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) being activated the azido compound containing carboxyl using activating reagent, the azido compound activated；The condition of the activation processing are as follows: 0~1~14h is reacted at room temperature；(2) heparin salting liquid is added into the azido compound of the activation of step (1), adjusts pH to 7~9, in 0~reacted at room temperature, dialysis removal small molecule is dry, obtains Azide heparin.Method of the invention is simple, successfully modifies onto heparin molecule chain azido group, has obtained Azide heparin.The Azide heparin can preferable modified biological material, heparin is introduced into biomaterial in the form of chemical bond, has 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 to heparin
Modification and modified resulting Azide heparin and the Azide heparin are used for modified biological material.
Background technique
Biomaterial has a large amount of application in clinicing aspects such as current vessel catheter, heart valve, haemodialysis, still
When biomaterial and contacting blood, one layer of plasma protein can be adsorbed rapidly；Undesirable Hemocompatible surfaces can make albumen structure
As transformation, the albumen of conformation transition can interact again with platelet membrane surface receptor, make platelet activation, and finally induce blood
Bolt.The surface anticoagulation of associated materials has great importance.Heparin is a kind of main clinical anticoagulant, and a kind of
Heparin molecule introducing material surface is the anticoagulant skill of currently used biomaterial surface by important anticoagulant material modifying agent
Art.
The method that current heparin is combined with biomaterial surface mainly includes that material surface directly coats heparin molecule (such as
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.Passing through
Heparin molecule is integrated to material surface by combination preferably to solve the above problems, and conventional method is mostly used on material
Carboxyl on carboxyl or heparin is activated, then heparin molecule is grafted to material surface with chemical bond by amidation process
(such as: application No. is 200410009002.3 disclose a kind of covalent grafting heparin on surface of polymer film method, application No. is
201310176950.5 disclosing 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 through the methods of surface treatment, such as low temperature plasma, corona discharge and chemical attack side
Method is handled, and this then further increases the synthesis technology and cost of material.
The present invention has good light reaction and thermal reaction characteristic, under the above conditions, azido group using azido group
The free radical of formation can carry out dehydrogenation substitution reaction to molecular structure corresponding on material, thus by mesh in a manner of chemical bond
Mark molecule is introduced into material surface.By using azido group it is good can response characteristic, by azido group to heparin molecule into
Row chemical modification introduces azido group in heparin molecule side group, the heparin molecule of Azide is illuminated the way by ultraviolet light
Hair azido group is decomposed to form free radical and makes heparin grafting on the surface of the material, so that the technique of heparin modified biological material is more
Simply, cost is lower.
Summary of the invention
One of the objects of the present invention is to provide a kind of Azide method of modifying of heparin, are modified to heparin, make 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 by Azide heparin obtained by the above method.
A further object of the present invention is to provide the applications of above-mentioned Azide heparin.The Azide heparin is for modified life
Object material, the especially 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, comprising the following steps:
(1) azido compound containing carboxyl is activated using activating reagent, the nitrine chemical combination activated
Object；The condition of the activation processing are as follows: 0~1~14h is reacted at room temperature；The activation processing is in the organic solvent for having water
It is carried out in middle progress or anhydrous organic solvent；When being activated in the organic solvent for having water, the pH of reaction solution need to be adjusted
It is 4~7；When being activated in anhydrous organic solvent, it need to be passed through inert gas, 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
Under reacted, dialysis removal small molecule is dry, obtains Azide heparin.
Step (1) the carboxylic azido compound is p-azidobenzoic acid, 2- azidobenzoic acid, 3- (4- phenylazide
Base) propionic acid, 4- azidosalicylic acid, nitrine acetic acid, 4- azido butyric acid, more than one in 6- azido caproic acid.
Step (1) activating reagent is 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate
(EDC.HCl) with the system of N- hydroxy thiosuccinimide (sulfo-NHS), 1- ethyl-(3- dimethylaminopropyl) carbon
The system of acyl diimmonium salt hydrochlorate (EDC.HCl) and I-hydroxybenzotriazole (HOBT), 1- ethyl-(3- dimethylaminopropyl)
The system of phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl) and n-hydroxysuccinimide (NHS), N, N'- dicyclohexylcarbodiimide
(DCC) with the system of n-hydroxysuccinimide (NHS), O- benzotriazole-tetramethylurea hexafluorophosphate (HBTU) and two
System, hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (PyBOP) and the 4- diformazan ammonia of ethyl cyano phosphate
It is a kind of in the system of yl pyridines (DMAP).
In each system, 1- ethyl-(3- dimethylaminopropyl) the phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl) and N- hydroxyl
The molar ratio of base thiosuccimide (sulfo-NHS) is 1:1~1:10；The 1- ethyl-(3- dimethylaminopropyl)
The molar ratio of phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl) and I-hydroxybenzotriazole (HOBT) are 1:1~1:10；1- ethyl-(3-
Dimethylaminopropyl) molar ratio of phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl) and n-hydroxysuccinimide (NHS) is 1:1
~1:10；The molar ratio of the N, N'- dicyclohexylcarbodiimide (DCC) and n-hydroxysuccinimide (NHS) are 1:1~1:
10；The molar ratio of the O- benzotriazole-tetramethylurea hexafluorophosphate (HBTU) and diethyl cyano phosphate be 1:1~
1:10；Hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl the phosphorus (PyBOP) and 4-dimethylaminopyridine (DMAP)
Molar ratio be 1:1~1:10.
The total amount of activating reagent described in step (1) and the molar ratio of carboxylic azido compound are as follows: 1:1~10:1.
Organic solvent described in step (1) is conventional organic solvent, such as: dimethyl sulfoxide (DMSO), dimethyl methyl
Amide (DMF) etc..
Heparinate described in step (2) be heparin sodium, 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 of reaction described in step (2) is 1~14h；
The dosage of heparinate described in step (2) is carboxylic azido compound mole dosage in step (1)
0.1%-10%.
The substance that pH is adjusted described in step (2) is NaOH solution.
The azido compound of activation described in step (1) can carry out separating-purifying, and heparin salting liquid is then added and carries out instead
It answers, Azide heparin yield can be made to improve, the azido group content in product increases.
By taking p-azidobenzoic acid as an example, the structure of the Azide heparin are as follows:
The condition of dialysis described in step (2) are as follows: the temperature of dialysis are as follows: 20~40 DEG C；Dialyzate are as follows: deionized water；With
Substance containing nitrine cannot be detected in dialyzate as dialysis terminal.
The reaction of step (2) and (1) is carried out under conditions of being protected from light.
The Azide heparin is prepared by the above method.
The Azide heparin is used for modified biological material, the especially 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
Object material and reagent highly effective reaction；
(2) heparin side introduces azido group, can increase the synthetic method of heparin modified material.
Detailed description of the invention
Fig. 1 is the infrared absorption spectrum of Azide heparin synthesized by embodiment 1；
Fig. 2 is the ultra-violet absorption spectrum of Azide heparin synthesized by embodiment 1.
Specific embodiment
The present invention is done below with reference to embodiment and attached drawing and is further described in detail, but embodiments of the present invention are unlimited
In this.
Embodiment 1
To equipped with 20ml dimethyl sulfoxide (DMSO contains water) container in, sequentially add 0.815g p-azidobenzoic acid,
0.958g EDC.HCl, 0.575g NHS are placed in 4 DEG C of environment with after the dilute hydrochloric acid solution tune pH to 4.7 of 0.1M after being sufficiently stirred
Middle magnetic agitation is protected from light and (azido group is prevented to be illuminated by the light decomposition) 4h；Heparin sodium (the molecule of 10ml (0.1g/ml) is added
Amount is placed in 4 DEG C of environment after 0.01M NaOH solution tune pH to 7.4 for 12000) aqueous solution and is protected from light 6h；Finally, will
Reaction solution pours into bag filter (3.5K), is dialysed with water to no nitrine para Toluic Acid, and reaction solution is lyophilized at -25 DEG C for filtering,
Product, that is, Azide heparin is obtained, the Azide group content of product is 8.8 ‰ (g/g), product yield 95%.
The infrared absorption spectrum of Azide heparin synthesized by the present embodiment is as shown in Figure 1.It can be seen from the figure that nitrine
Change heparin and occur the absorption peak of azido group at 2100, this demonstrate be successfully incorporated into azido in heparin molecule
Group.The ultra-violet absorption spectrum of Azide heparin synthesized by embodiment 1 is as shown in Figure 2.It can be seen from the figure that Azide heparin exists
Occurs the absorption peak of phenyl ring at 275, this demonstrate p-azidobenzoic acid has been successfully incorporated into heparin molecule.
Embodiment 2
Into the container equipped with 20ml dimethylformamide (DMF contains water), 0.955g 3- (4- phenylazide is sequentially added
Base) propionic acid, 1.916g EDC.HCl, 2.170g sulfo-NHS, the dilute hydrochloric acid solution tune pH to 4.7 of 0.1M is used after being sufficiently stirred
Afterwards, it is placed in magnetic agitation in 6 DEG C of environment, is protected from light 4h, the heparin lithium (molecular weight 20000) of 10ml (0.05g/ml) is added
Aqueous solution is placed in 6 DEG C of environment after 0.01M NaOH solution tune pH to 7.4 and is protected from light 6h；Finally, reaction solution is poured into
Bag filter (3.5K) is dialysed with water to no 3- (4- azidophenyl) propionic acid, and reaction solution is lyophilized at -25 DEG C, must produce by filtering
Object, that is, Azide heparin, the azido group content of product are 5.5 ‰, product yield 90%.
Embodiment 3
Into the container of the dimethyl sulfoxide (DMSO contains water) equipped with 40ml, 0.155g4- azido fourth is sequentially added
After the sulfo-NHS of acid, 0.258g EDC.HCl, 0.345g, the dilute hydrochloric acid solution tune pH to 5.0 that 0.1M is used after being sufficiently stirred,
It is placed in magnetic agitation in 10 DEG C of environment, is protected from light 6h；Calciparine (molecular weight 20000) water of 10ml (0.1g/ml) is added
Solution is placed in 10 DEG C of environment after 0.01M NaOH solution tune pH to 7.4 and is protected from light 6h；Finally, reaction solution is poured into
It analyses bag (3.5K), is dialysed with water to no 4- azido butyric acid, filter, reaction solution is lyophilized at -30 DEG C, obtains product i.e. nitrine
Change heparin, the azido group content of product is 2.0 ‰, product yield 85%.
Embodiment 4
To equipped with 20ml anhydrous DMSO container in, sequentially add 0.515g 6- azido caproic acid, 2.149gDCC,
1.201g NHS, nitrogen protection are placed in magnetic agitation in room temperature environment, are protected from light 6h；The heparin of 10ml (0.7g/ml) is added
Calcium (molecular weight 20000) aqueous solution is protected from light 6h with room temperature is continued after 0.01M NaOH solution tune pH to 7.6；Finally, will
Reaction solution pours into bag filter (3.5K), is dialysed with water to no 6- azido caproic acid, and reaction solution is lyophilized at -30 DEG C for filtering,
Product, that is, Azide heparin is obtained, the azido group content of product is 1.0 ‰, product yield 80%.
Embodiment 5
Into the container equipped with 20ml anhydrous DMF, 0.25g nitrine acetic acid, 0.3g DCC, 0.44g NHS, nitrogen are sequentially added
Gas shielded, magnetic agitation at 15 DEG C, is protected from light 10h；Heparin lithium (molecular weight 20000) water of 10ml (0.06g/ml) is added
Solution, after 0.01M NaOH solution tune pH to 8.5, continuation is protected from light 10h in 15 DEG C of environment；Finally, reaction solution is fallen
Enter bag filter (3.5K), dialysed with water to no nitrine acetic acid, filters, reaction solution is lyophilized at -30 DEG C, obtains product i.e. nitrine
Change heparin, the azido group content of product is 4.2 ‰, product yield 87%.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not limited by examples detailed above
System, others are any to be without departing from made changes, modifications, substitutions, combinations, simplifications under spirit of the invention and principle
Effect.
Claims (8)
1. a kind of Azide method of modifying of heparin, it is characterised in that: the following steps are included:
(1) carboxylic azido compound is activated using activating reagent, the azido compound activated；It is described
The condition of activation processing are as follows: 0 ~ 1 ~ 14h is reacted at room temperature；The activation processing is progress or nothing in the organic solvent for having water
It is carried out in the organic solvent of water；When being activated in the organic solvent for having water, the pH that need to adjust reaction solution is 4 ~ 7；When
When being activated in anhydrous organic solvent, it need to be passed through inert gas, without adjusting pH；
(2) heparin salting liquid is added into the azido compound of the activation of step (1), adjusts pH to 7 ~ 9, in 0 ~ carry out at room temperature
Reaction, dialysis removal small molecule is dry, obtains Azide heparin；
Step (1) activating reagent is 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and N- hydroxyl sulphur
For the system of succinimide, 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and I-hydroxybenzotriazole
System, 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide system, N,
The system of N'- dicyclohexylcarbodiimide and n-hydroxysuccinimide, O- benzotriazole-tetramethylurea hexafluorophosphate
With system, hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus and the 4- dimethylamino pyrrole of diethyl cyano phosphate
It is a kind of in the system of pyridine；
In each system, 1- ethyl-(3- dimethylaminopropyl) the phosphinylidyne diimmonium salt hydrochlorate and N- hydroxy succinyl
The molar ratio of imines is 1:1 ~ 1:10；1- ethyl-(3- dimethylaminopropyl) the phosphinylidyne diimmonium salt hydrochlorate and 1- hydroxyl
The molar ratio of benzotriazole is 1:1 ~ 1:10；1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and N- hydroxyl
The molar ratio of succinimide is 1:1 ~ 1:10；The N, N'- dicyclohexylcarbodiimide and n-hydroxysuccinimide rub
You are than being 1:1 ~ 1:10；The molar ratio of the O- benzotriazole-tetramethylurea hexafluorophosphate and diethyl cyano phosphate
For 1:1 ~ 1:10；Hexafluorophosphoric acid benzotriazole -1- the base-oxygroup tripyrrole alkyl phosphorus and 4-dimethylaminopyridine molar ratio
For 1:1 ~ 1:10.
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 acid, 3- (4- azidophenyl) propionic acid, 4- azidosalicylic acid, nitrine acetic acid,
More than one in 4- azido butyric acid, 6- azido caproic acid.
3. the Azide method of modifying of heparin according to claim 1, it is characterised in that: heparinate described in step (2) is
More than one in heparin sodium, heparin lithium or calciparine.
4. 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 carboxylic azido compound molar ratio are as follows: 1:1 ~ 10:1；
The dosage of heparinate described in step (2) is the 0.1%-10% of carboxylic azido compound mole dosage in step (1).
5. 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.
6. the Azide method of modifying of heparin according to claim 1, it is characterised in that: reaction described in step (2) when
Between be 1 ~ 14h；The heparin salting liquid is the aqueous solution of heparinate.
7. a kind of Azide heparin that the Azide method of modifying by any one of claim 1 ~ 6 heparin is prepared.
8. the application of Azide heparin according to claim 1, it is characterised in that: the Azide heparin is used for modification biological
Material.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107828075A (en) * | 2017-10-18 | 2018-03-23 | 华南理工大学 | A kind of medical anticoagulant high polymer material and preparation method thereof |
| 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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