CN100490901C - Tetramethylpyrazine derivatives modified silk fibroin protein fiber anti-coagulant material and its preparation method - Google Patents
Tetramethylpyrazine derivatives modified silk fibroin protein fiber anti-coagulant material and its preparation method Download PDFInfo
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- CN100490901C CN100490901C CNB2006100722041A CN200610072204A CN100490901C CN 100490901 C CN100490901 C CN 100490901C CN B2006100722041 A CNB2006100722041 A CN B2006100722041A CN 200610072204 A CN200610072204 A CN 200610072204A CN 100490901 C CN100490901 C CN 100490901C
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Abstract
Disclosed are three kinds of ligustrazine derivatives including 2,5-diacryloyl oxymethylene-3,6- dimethylpyrazine, 2-acryloyl oxymethylene-5-methyol-3,6- dimethylpyrazine, and 2- acryloyl oxymethylene-3,5,6- trimethylpyrazine, and three kinds of anticoagulation material modified from three kinds of ligustrazines and obtained on the surface of silk protein fiber by graft polymerization. The invention also provides synthesis of the ligustrazine derivatives and preparation method of the coagulation materials which comprises the steps of transforming the lateral chain of ligustrazine into a ligustrazine derivative with double bond active group and initiating graft polymerization by free radical on the surface of silk protein fiber. The anticoagulation activity of silk protein applied in the biomedical material field is improved and the application field is expanded.
Description
Technical field
The invention relates to the research of three kinds of derivative modified polymer fibroin fibers and preparation method thereof of Chinese herbal medicine effective ingredients ligustrazine, relate to biomedical materials field.
Background technology
Fibroin albumen is a natural macromolecular material, is the main component of silkworm silk.Owing to having excellent biological compatibility, it is widely used in enzyme immobilization technology, cell culture substrate, artificial skin, biomedical materials field such as medicament slow release material.But the fibroin albumen of non-modified can not satisfy directly and the requirement of blood contact environment.Chinese herbal medicine is the rarity of Chinese culture, and it uses existing history in several thousand.Clinical treatment and pharmacological research show that the effective ingredient ligustrazine of activating blood circulation to dissipate blood stasis Chinese herbal medicine Rhizoma Chuanxiong has antiplatelet aggregation, thrombolytic, multiple pharmacological effect such as blood vessel dilating and antiphlogistic antibacterial.People such as Zhang Youzhu are (referring to " development of Chinese medicine fibroin membrane and performance thereof [J] " 1999 the 8th phases of silk; author: Zhang Youzhu; Huo Jin etc. [1]) be base material with the fibroin; utilizing China to have the medical treasure-house of long history---the Chinese medicine fibroin membrane of Chinese herbal medicine preparation has good strength and elongation, flexibility, water-permeable and air permeable; can also effectively medicine be discharged from film first quick and back slow, it has the effect of the sterilization promoting muscle growth functions and the wound surface cladding material protection wound surface of conventional Chinese medicine coating wound surface concurrently.With ligustrazine derivant fibroin fiber being carried out chemical modification under the condition of no initiator does not appear in the newspapers as yet.
Summary of the invention
The present invention is directed to the following blood coagulation problem that exists with the blood contact material of some specific conditions that present clinical medicine runs into, the activating blood circulation to dissipate blood stasis Chinese herbal medicine effective ingredients carries out modification to material surface as anticoagulant method is proposed, with the fibroin albumen that is widely used in the bio-medical field is base material, three kinds of novel ligustrazine derivants are provided, and with the novel anticoagulant material that obtain of their glycerol polymerizations on the fibroin fiber surface, improve the blood compatibility of fibroin fiber, widened the range of application of fibroin albumen.
The biological activity according to ligustrazine determined of technical scheme provided by the present invention depends on the characteristics of its mother nucleus structure, select the ligustrazine side chain as with the binding site of polymer surfaces.Technical scheme is as follows:
The preparation of ligustrazine derivant modified anticoagulant fimbrin material is characterised in that: three kinds of ligustrazine derivants 2 that the ligustrazine side chain functionalitiesization obtains, 5-two propylene acyl-oxygen methylene-3,6-dimethyl pyrazine (PZOE2), 2-acryloyl-oxy methylene-5-methylol-3,6-dimethyl pyrazine (PZOHOE) and 2-acryloyl-oxy methylene-3,5,6-trimethylpyrazine (PZOE) is grafted on the fibroin fiber surface by the radical polymerization of no initiator respectively.Infrared signature is absorbed as 1731cm
-1(C=O) can be defined as ester group.
The reactions steps of the preparation method of ligustrazine derivant modified fibroin azelon is as follows:
(4) silkworm silk is come unstuck and handle with acetone extracting 12 hours after obtain fibroin fiber;
(5) 2,5-dihydroxymethyls-3,6-dimethyl pyrazine (TMPD2) and 2-methylol-3,5,6-trimethylpyrazine (TMPD1) pass through with the esterification of acryloyl chloride two keys to be introduced the side chain of ligustrazine;
Three kinds of different ligustrazine derivants that (6) will obtain respectively in the decompression system of no initiator glycerol polymerization on the fibroin fiber surface, to obtain having anticoagulant fibroin fiber.
Synthetic route is:
(1) 2,5-two propylene acyl-oxygen methylene-3,6-dimethyl pyrazine (PZOE2) synthetic
(2) 2-acryloyl-oxy methylene-5-methylol-3,6-dimethyl pyrazine (PZOHOE) synthetic
(3) 2-acryloyl-oxy methylene-3,5,6-trimethylpyrazine (PZOE) synthetic
R is respectively PZOE2, PZOHOE and PZOE
Chinese herbal medicine modified fibroin protein material is the novel anticoagulant material of a class.Its advantage is to utilize the Chinese herbal medicine toxic and side effects little, human body had characteristics such as dual regulation, under the prerequisite that does not influence the fibroin albumen biocompatibility, improve its anticoagulation function and other performance, widened the range of application of fibroin albumen in biomedical materials field.
The specific embodiment
The invention will be further described with preparation example below.
Preparation example one
(1) 2,5-two propylene acyl-oxygen methylene-3, the preparation of 6-dimethyl pyrazine (PZOE2)
Press document (referring to referring to Chinese patent, application number 200410042876.9[2]) Synthetic 2,5-dihydroxymethyl-3,6-dimethyl pyrazine (TMPD2), fusing point are 76 ~ 83 ℃.In the 100ml round-bottomed flask, 1.23g TMPD2 is dissolved in the mixed solution of 15mlDMF and 1.36ml pyridine then, the 1.2ml acryloyl chloride is dissolved in 15mlDMF, be added drop-wise in the flask downwards by constant pressure funnel, hour drip, continue reaction 24 hours, left standstill 48 hours.After the filtration, reactant liquor is poured in a large amount of ice ether, faint yellow precipitation occurred, centrifugal back collecting precipitation obtains the Chinese red material.It is clean at room temperature will to remain the ether volatilization.Obtain 2,5-two propylene acyl-oxygen methylene-3,6-dimethyl pyrazine, FTIR (KBr): 1731cm
-1(C=O, ester carbonyl group), 1489cm
-1(N=C-, pyrazine ring) is at 1172cm
-1(C-O-C)..
(2) preparation of fibroin fiber
Silkworm silk is at 1%NaHCO
3Boil in the solution and remove photoresist, for several times also with acetone extracting 12 hours, to remove the waxy substance in the silkworm silk, room temperature vacuum drying 72 hours obtains fibroin fiber with deionized water wash.
(3) chemical modification of fibroin fiber
0.067 the gram fibroin adds and contains 2,5-two propylene acyl-oxygen methylene-3, and the 6ml dioxane of 6-dimethyl pyrazine and 6ml water volume ratio are in the mixed liquor of 1:1, the vacuum condition lower seal places 85 ℃ of water-baths, reacts 3 hours.Take out fibroin fiber,, be adsorbed on 2 of surface, 5-two propylene acyl-oxygen methylene-3,6-dimethyl pyrazine, and homopolymer, room temperature vacuum drying to remove with acetone extracting 24 hours.By the control reaction condition, can obtain the fibroin fiber of different percent graftings, ATR-FTIR:1729 ~ 1732cm
-1Be the absworption peak of ester carbonyl group, 1619 ~ 1632cm
-1Be the characteristic absorption peak of amide I, 1512 ~ 1513cm
-1Be the characteristic absorption peak of amide II, 1216 ~ 1226cm
-1It is the characteristic absorption peak of amide III.
Percent grafting=[(W-W
0)/W
0] * 100%
W
0, W is respectively the weight before and after the fibroin fiber grafting.
(4) the anticoagulant property evaluation of material
Adopt the semi-automatic Blood coagulation instrument of four-way (U.S. Coag-A-Mate XM) mensuration thrombin time (TT) and partial thromboplastin time (APTT) that sample is carried out external anticoagulation function evaluation.Taking from healthy human body blood plasma organizes in contrast.Measure 0.5mg pure silk fibroin fiber respectively and have 2 of different percent graftings, 5-two propylene acyl-oxygen methylene-3, the APTT of the grafting fibroin fiber of 6-dimethyl pyrazine (PZOE2).
| Sample | Blank plasma | Pure silk fibroin fiber | PZOE2 grafting fibroin fiber (percent grafting 63.6%) | PZOE2 grafting fibroin fiber (percent grafting 149%) |
| APTT | 35.1 | 37.2 | 41.2 | 50.9 |
Preparation example two
(1) 2-acryloyl-oxy methylene-5-methylol-3, the preparation of 6-dimethyl pyrazine (PZOHOE)
1.23g TMPD2 is dissolved in the mixed solution of 15mlDMF and 0.7ml pyridine in the 100ml round-bottomed flask, the 0.7ml acryloyl chloride is dissolved in 15mlDMF, is added drop-wise to downwards in the flask by constant pressure funnel, drips in one hour, continues reaction 24 hours, leaves standstill 48 hours.After the filtration, reactant liquor is poured in a large amount of ice ether, faint yellow precipitation occurred, centrifugal back collecting precipitation obtains the Chinese red material.It is clean at room temperature will to remain the ether volatilization.Obtain 2-acryloyl-oxy methylene-5-methylol-3,6-dimethyl pyrazine, FTIR (KBr): 1735cm
-1(C=O, ester carbonyl group), 1489cm
-1(N=C-, pyrazine ring) is at 1172cm
-1(C-O-C).
(2) preparation of fibroin fiber.
Repeat the step of preparation example 1
(3) chemical modification of fibroin fiber
Preparation method is with example one, and different is that reactant is changed to 2-acryloyl-oxy methylene-5-methylol-3, and the 6-dimethyl pyrazine by the control reaction condition, obtains the fibroin fiber of different percent graftings, ATR-FTIR:1729 ~ 1732cm
-1Be the absworption peak of ester carbonyl group, 1619 ~ 1632cm
-1Be the characteristic absorption peak of amide I, 1512 ~ 1513cm
-1Be the characteristic absorption peak of amide II, 1216 ~ 1226cm
-1It is the characteristic absorption peak of amide III.
(4) the anticoagulant property evaluation of material
Experimental technique is measured 0.5mg pure silk fibroin fiber and 2-acryloyl-oxy methylene-5-methylol-3 respectively, the APTT of the grafting fibroin fiber of 6-dimethyl pyrazine (PZOHOE) with preparation example one.
| Sample | Blank plasma | Pure silk fibroin fiber | PZOHOE grafting fibroin fiber (grafting 76.1%) |
| APTT | 35.1 | 37.2 | 45.9 |
Preparation example three
(1) 2-acryloyl-oxy methylene-3,5, the preparation of 6-trimethylpyrazine (PZOE)
By document (referring to " structural modification of ligustrazine and anticoagulant property research " thereof Beijing Institute of Technology's master thesis (2004): the author: the summer is undertaken the construction of [3]) Synthetic 2-methylol-3,5,6-trimethylpyrazine (TMPD1), 70 ~ 72 ℃ of fusing points.0.91g TMPD1 is dissolved in the mixed solution of 11.5mlDMF and 0.485ml pyridine, the 0.487ml acryloyl chloride is dissolved in 11.5mlDMF, be added drop-wise to downwards in the flask by constant pressure funnel; Dripped in one hour, and continued reaction 24h, leave standstill 48h.After the filtration, reactant liquor is poured in a large amount of ice ether, faint yellow precipitation occurred, centrifugal back collecting precipitation obtains the Chinese red material.It is clean at room temperature will to remain the ether volatilization.Obtain 2-acrylic acid methyl ester. base-5-methylol-3,6-dimethyl pyrazine, FTIR (KBr): 1731cm
-1(C=O, ester carbonyl group), 1489cm
- 1(N=C-, pyrazine ring) is at 1174cm
-1(C-O-C).
(2) preparation of fibroin fiber
Repeat the step of preparation example 1.
(3) chemical modification of fibroin fiber
Preparation method is with example one, and different is that reactant is changed to 2-acryloyl-oxy methylene-3,5, and the 6-trimethylpyrazine by the control reaction condition, obtains the fibroin fiber of different percent graftings, ATR-FTIR:1729～1732cm
-1Be the absworption peak of ester carbonyl group, 1619～1632cm
-1Be the characteristic absorption peak of amide I, 1512～1513cm
-1Be the characteristic absorption peak of amide II, 1216～1226cm
-1It is the characteristic absorption peak of amide III.
(4) the anticoagulant property evaluation of material
Experimental technique is measured 0.5mg pure silk fibroin fiber and 2-acryloyl-oxy methylene-3,5 respectively, the APTT and the TT of the grafting fibroin fiber of 6-trimethylpyrazine (PZOE) with preparation example one.
| Sample | Blank plasma | Pure silk fibroin fiber | PZOE grafting fibroin fiber (percent grafting 31.7%) |
| APTT | 35.1 | 37.2 | 35.4 |
Claims (3)
1. modified fibroin azelon anticoagulant material, it is characterized in that the ligustrazine derivant glycerol polymerization is on the fibroin fiber surface, wherein ligustrazine derivant is 2,5-two propylene acyl-oxygen methylene-3,6-dimethyl pyrazine or 2-acryloyl-oxy methylene-5-methylol-3,6-dimethyl pyrazine or 2-acryloyl-oxy methylene-3,5, the 6-trimethylpyrazine, the structural formula of the fibroin fiber of modification is as follows:
2. anticoagulant material according to claim 1 is characterized in that preparation method comprises that three kinds of ligustrazine derivants are grafted on the fibroin fiber surface by the radical polymerization of no initiator respectively.
3. anticoagulant material according to claim 2 is characterized in that preparation method comprises the steps:
(1) silkworm silk is come unstuck and handle with the acetone extracting and to obtain fibroin fiber after 12 hours;
(2) 2,5-dihydroxymethyls-3,6-dimethyl pyrazine or 2-methylol-3,5,6-trimethylpyrazine pass through with the esterification of acryloyl chloride two keys to be introduced the side chain of ligustrazine; The post processing of three kinds of ligustrazine derivants is to drip in refrigerative absolute ether, until there being faint yellow precipitation to produce, and centrifugal back collecting precipitation, and at room temperature will remain the ether volatilization totally;
Three kinds of different ligustrazine derivants that (3) will obtain are in the mixed solvent of 1:1 with fibroin fiber at water and dioxane volume ratio respectively, 85 ℃ of water-baths, reaction is 3 hours in the vacuum systems of no initiator, the ligustrazine derivant glycerol polymerization is on the fibroin fiber surface, to obtain to have the fibroin fiber of anticoagulation function.
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| CN101786992A (en) * | 2010-03-10 | 2010-07-28 | 天津市汉康医药生物技术有限公司 | 2-hydroxymethyl-3,5,6-trimethylpyrazine derivatives, preparation methods and application thereof |
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| CN105017165B (en) * | 2015-07-07 | 2018-04-03 | 广州喜鹊医药有限公司 | A kind of new pyrazines derivatives and preparation method thereof and medical applications |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101786992A (en) * | 2010-03-10 | 2010-07-28 | 天津市汉康医药生物技术有限公司 | 2-hydroxymethyl-3,5,6-trimethylpyrazine derivatives, preparation methods and application thereof |
| CN101786992B (en) * | 2010-03-10 | 2012-11-07 | 天津市汉康医药生物技术有限公司 | 2-hydroxymethyl-3,5,6-trimethylpyrazine derivatives, preparation methods and application thereof |
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