CN106317261A - Beta-cyclodextrin based star-shaped polymer and preparation method thereof - Google Patents
Beta-cyclodextrin based star-shaped polymer and preparation method thereof Download PDFInfo
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- CN106317261A CN106317261A CN201610822180.0A CN201610822180A CN106317261A CN 106317261 A CN106317261 A CN 106317261A CN 201610822180 A CN201610822180 A CN 201610822180A CN 106317261 A CN106317261 A CN 106317261A
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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
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
Abstract
The invention discloses a beta-cyclodextrin based star-shaped polymer and a preparation method thereof. The structural formula of the beta-cyclodextrin based star-shaped polymer is as shown in the specification, wherein x and y respectively represent degree of polymerization of monomers and each range from 30 to 80. Beta-cyclodextrin with polypeptide branch can form clathrate compound with related molecular drug to improve solubility and bioavailability of the molecular drug. As polypeptide with good biocompatibility and biodegradability cannot accumulate in the body, the material itself or degradation products have no toxic or side effect to the body.
Description
One, technical field
The present invention relates to a kind of star-shape polymer and preparation method thereof, a kind of based on beta-schardinger dextrin-starlike
Polymer and preparation method thereof.
Two, background technology
Beta-schardinger dextrin-(β-Cyclodextrin, β-CD) is that amylose is raw under cyclodextrin glycosyltransferase effect
D-Glucose oligomeric cyclic thing that become, that connected by α-Isosorbide-5-Nitrae glycosidic bond.Its structure is similar to truncated cones cavity, and outside is hydrophilic
Property hydroxyl, inner side is hydrophobic cavity.Cavity inside can utilize the non-binding effects such as hydrophobic interaction, hydrogen bond, Van der Waals force etc. to know
The other suitable guest molecule of size shape, such as hydrophobic small molecules (such as anticancer, antiviral drugs etc.), protein, oligonucleotide
Deng, form host-gust inclusion complexes, strengthen reactivity and the dissolubility of guest molecule.β-CD is due to its low price, easily obtain
Advantage must be waited, have a wide range of applications in the field such as medicine, chemistry, food, catalysis., β-CD is in actual application
There is some limitation, such as in water, dissolubility is low, and there may be hepatotoxicity etc..Therefore, β-CD is carried out structure
Transformation, increases its water solublity or reduces the research topic that its hepatotoxicity becomes popular.
Trotta etc. utilize carbonyl dimidazoles (CDI) activating carboxy acid's molecule to generate alkoxy carbonyl group diimidazole；Then will generate
Alkoxy carbonyl group diimidazole as acylting agent and beta-schardinger dextrin-react generation beta-schardinger dextrin-carbonic ester.Utilize its catalytic
Can, can be as surfactant or chiral resolving agent；Zhang etc. report a kind of multifunctional nano based on beta-schardinger dextrin-and carry
Body, it is contained, by Polyethylene Glycol (PEG) and side chain, the hydrophilic diblock copolymer (PEG-β-PCD) that beta-schardinger dextrin-forms.
This polymer can wrap the hydrophobic drug carrying the different structures such as coumarin, ibuprofen, indomethacin, dexamethasone, and can realize
Slow releasing function；Xu etc. are prepared for a kind of water solublity by the polymine (PEI, 600Da) of beta-schardinger dextrin-crosslinking low-molecular-weight
Cationic polymer PEI-CD, this polymer can bag carrying anti-tumor drug adriamycin (DOX) and have medicative simultaneously
PEI-CD/DOX/pDNA complex, it is possible to achieve medicine-gene association treatment tumor；Zhang et al. is prepared for a kind of novel parent
The diblock polymer that aqueous PCD and poly-different acrylamide (PNIPAM) are constituted.Under given conditions, this polymer formed from
Assembly can wrap load indomethacin, and drug release presents the control-release function of " switch " along with the change of temperature；The profits such as Zhao
With the difunctional of epoxychloropropane, cyclodextrin is received on the strand of chitosan, synthesized the cyclodextrin dissolving in diluted acid
Grafted chitosan.The water solublity of modified beta-schardinger dextrin-is greatly improved, and hemolysis step-down, the toxicity of medicine reduces,
Improve the availability of medicine；Binkowski etc. using the beta-schardinger dextrin-of sulfonylation as intermediate, synthesis is single-(6-N-alkyl-
N, N-Dimethyl Ammonium-6-deoxygenates)-beta-schardinger dextrin-, modified beta-schardinger dextrin-can operate with biomembrane separation field.
Three, summary of the invention
It is desirable to provide a kind of star-shape polymer based on beta-schardinger dextrin-and preparation method thereof.The starlike polymerization of the present invention
Thing can be effectively improved the water solublity of β-CD and reduce β-CD hepatotoxicity that may be present；Beta-schardinger dextrin-in star-shape polymer
Hydrophobic cavity can pass through clathration carrying medicament based on Host-guest Recognition, increase dissolubility and the biology profit of drug molecule
Expenditure, thus improve the curative effect of medicine.
Present invention star-shape polymer based on beta-schardinger dextrin-, its structural formula is as follows:
Wherein x, y represent the degree of polymerization of monomer, and x is 30～80, and y is 30～80.
The preparation method of present invention star-shape polymer based on beta-schardinger dextrin-, one is to have amino (-NH2) beta-schardinger dextrin-
Ring-opening polymerisation initiator (β-CD-6-NH2) preparation: first pass through 6-position hydroxyl (6-OH) and the paratoluensulfonyl chloride of β-CD
(TsCl) the 6-position p-toluenesulfonic esters (β-CD-6-OTs) of β-CD is prepared in reaction；Then p-toluenesulfonic esters is replaced with ethylenediamine
Base (-OTs) obtains the beta-schardinger dextrin-(β-CD-6-NH with 6-position Amino End Group afterwards2).Two is the preparation of star-shape polymer: drawing
Send out agent β-CD-6-NH2In the presence of carry out 5-benzyl ester-Pidolidone-N-carboxyanhydrides (Glu-NCA) and Nε-benzyloxy carbonyl
The ring-opening polymerisation of base-1B-N-carboxyanhydrides (Lys-NCA), prepares with beta-schardinger dextrin-(β-CD) as core, mixed
Poly-polypeptide is the star-shape polymer of support arm.
The preparation method of the present invention star-shape polymer with regular topological structure based on beta-schardinger dextrin-, including walking as follows
Rapid:
1, initiator β-CD-6-NH2Preparation
β-CD is dissolved in the NaOH solution of 1～5mol/L, adds TsCl, stirring reaction 5h under condition of ice bath, filter
Removing unreacted reactant, the hydrochloric acid of filtrate 1.0mol/L adjusts pH to 6～7, is subsequently placed at cooling crystallization in frozen water, filters, filter cake
With distilled water wash, obtain β-CD-6-OTs after drying；Owing to β-CD dissolubility in water is less, thus the most anti-
Should be to carry out in alkaline solution；
The mol ratio of β-CD and TsCl is 1.5～3.0:1；
β-CD-6-OTs is dissolved in organic basic solvent, at N2Protection, stirring reaction 10h, reaction knot under the conditions of 70 DEG C
After bundle, reactant liquor is added drop-wise in excessive propanone, after filtration, obtains thick product (white precipitate)；Thick for gained product is steamed with a small amount of
Distilled water is dissolved, and again drops in excessive propanone, filters and use washing with acetone filter cake, the most i.e. obtains initiator β-CD-6-
NH2；
Described organic basic solvent is ethylenediamine.
2, ring-opening polymerisation
By initiator β-CD-6-NH2Dissolve in organic solvent, under room temperature, airtight condition, in nitrogen with polymerization monomer
Stirring reaction 48h in atmosphere, reaction terminates to add in backward reactant liquor precipitant, obtains white precipitate.This white precipitate need not
Separating-purifying, is directly used in next step reaction.
Described polymerization monomer is Glu-NCA and Lys-NCA；The mol ratio of two kinds of monomers is 0.98～1.05:1.
The quality of described initiator is 1:80～200 with the ratio being polymerized monomer gross mass.
Described organic solvent is N, N-diformamide (DMF) or dimethyl sulfoxide etc..
3, deprotection
Trifluoroacetic acid (TFA) and the HOAc solution (v/v=1:1) of 33wt.%HBr is added in reaction bulb, de-under room temperature
Protection reaction 1～2h, reaction terminates to add in backward reactant liquor precipitant, obtains yellow oil；Remove supernatant, by yellow
Grease is completely dissolved with a small amount of distilled water, with saturated sodium bicarbonate solution tune pH value to 7～8, and (the cutting of bag filter of dialysis subsequently
Staying molecular weight MWCO is 3500Da) 48h, obtain white solid after lyophilizing, be target product.
Described lyophilizing be prior to-20 DEG C at pre-lyophilizing 4h, then in-60 DEG C, lyophilizing 36h under vacuum 25Pa.
Described in step 2,3 preparation process, precipitant is absolute ether, ethanol, methanol or acetone and other organic solvent；Precipitation
Volume is reactant liquor volume 8～10 times of agent interpolation.
Use gel permeation chromatography (GPC), nuclear magnetic resonance, NMR (1, etc. H-NMR) target product and intermediate are characterized.
Syntheti c route of the present invention is schematically as follows:
The present invention is to utilize ring-opening polymerisation (ROP) NCA based on natural amino acid system on existing Research foundation first
Standby containing polypeptide support arm, the beta-schardinger dextrin-star-shape polymer with ordered structure.Have an advantage in that polypeptide is safe to the human body nontoxic, nothing
Challeng and good biocompatibility；β-CD also reduces its toxicity after modifying；Polypeptide itself or degraded are produced
Thing can be absorbed by the body or excreted by metabolic cycles；The hydrophobic cavity of beta-schardinger dextrin-can be by knowing based on Subjective and Objective
Other clathration carrying medicament, increases dissolubility and the bioavailability of drug molecule, improves the curative effect of medicine.
Four, accompanying drawing explanation
Fig. 1 be β-CD-6-OTs nuclear magnetic resonance map (1H-NMR)。
Fig. 2 is β-CD-6-NH2Nuclear magnetic resonance map (1H-NMR)。
Fig. 3 is the gel permeation chromatography figure (GPC) of star-shape polymer of the present invention.
Fig. 4 be star-shape polymer of the present invention nuclear magnetic resonance map (1H-NMR)。
Five, detailed description of the invention
Embodiment 1:
1, the preparation of intermediate β-CD-6-OTs
In the round-bottomed flask of 250mL add beta-schardinger dextrin-(5.0g, 4.4mmol), sodium hydroxide (1.8g, 45mmol) and
100mL distilled water, is stirred well to be completely dissolved；Under condition of ice bath, addition p-methyl benzene sulfonic chloride (TsCl, 1.68g,
8.8mmol), stirring reaction 5h, filter, the hydrochloric acid of filtrate 1.0mol/L adjust pH value to behind 6～7 in frozen water crystallize；Filter,
Filter cake distillation washing twice, i.e. obtains intermediate β-CD-6-OTs (1.07g, 18.9%) after drying (vacuum drying).1H-
NMR(DMSO-d6, 400MHz, δ): 7.67 (d, J=7.5Hz, 2H), 7.36 (s, 2H), 4.77 (dd, J=42.5,15.0Hz,
7H), 4.37 (s, 7H), 4.29 (d, J=15.2Hz, 7H), 4.17 (dd, J=14.4,8.9Hz, 14H), 3.81-3.00 (m,
34H), 2.38 (s, 3H).
2, initiator β-CD-6-NH2Preparation
Accurately weigh β-CD-6-OTs (0.98g, 0.82mmol) to be dissolved in 10mL ethylenediamine, at N2Protection, 70 DEG C of conditions
Lower stirring reaction 10h；After reaction terminates, under stirring condition, reactant liquor is added dropwise in excessive propanone, obtains thick after filtration
Product (white precipitate)；Gained white precipitate is all dissolved with a small amount of distilled water, is then added in excessive propanone, filter, filter
Cake washing with acetone 2 times, the most i.e. obtains initiator β-CD-6-NH2(0.71g, 72.64%).
1H-NMR(D2O, 400MHz, δ ppm): 4.89-4.94 (d, J=8.9Hz, 7H, H-1), 3.77-3.85 (dd, J=
12.0Hz, 7.0Hz, 7H, H-6sub), 3.65-3.77 (m, 21H, H-2,3,5), 3.46-3.52 (dd, J=10.0Hz,
3.4Hz, 7H, H-4), 4.28-4.32 (m, 1H, H-6sub), 4.15-4.20 (dd, J=12.0Hz, 7.0Hz, 7H, H-6sub),
2.80-2.86(m,2H,H-7),2.64-2.70(m,2H,H-8)。
3, the preparation of star-shape polymer
Take initiator β-CD-6-NH2(2mg, 1.7mmol), Glu-NCA (100mg, 0.38mmol) and Lys-NCA
(116mg, 0.38mmol) is dissolved in 3mL DMF, under room temperature, airtight condition, and stirring reaction 48h, reaction in nitrogen atmosphere
Terminate backward reactant liquor adds precipitant absolute ether, obtain white precipitate；3mL trifluoro second is added in gained white precipitate
Acid (TFA) and 33wt.%HBr/HOAc (v/v=1:1), deprotection 1～2h under room temperature, then obtain yellow by absolute ether precipitation
Grease, removes supernatant, yellow oil is completely dissolved with a small amount of distilled water, saturated sodium bicarbonate adjust pH value to 7～8,
Solution loads bag filter (molecular cut off MWCO is 3500Da) dialysis 48h, and (pre-freeze temperature is-20 DEG C, and the time is in lyophilizing
4h；-60 DEG C, lyophilizing 36h under vacuum 25Pa) after i.e. obtain target product (40.2mg, yield 18.6%).
1H-NMR(DMSO-d6, 400MHz, δ ppm) and 7.45-7.07 (m, 10H), 4.98 (t, J=32.7Hz, 4H), 4.23
(s, 2H), 3.61 (s, 1H), 2.93 (s, 2H), 2.37 (s, 1H), 2.16 (s, 2H), 2.01 (s, 2H), 1.84 (d, J=
58.9Hz, 2H), 1.59 (s, 2H).
Embodiment 2:
1, the preparation of intermediate β-CD-6-OTs
Take the single necked round bottom flask of 250mL, be initially charged beta-schardinger dextrin-(10g, 8.8mmol), be then injected into 1mol/L's
NaOH solution 100mL, ultrasonic vibration is to being completely dissolved.Reactant liquor is cooled down in ice-water bath 30min, is added dropwise over methylbenzene
Sulfonic acid chloride (TsCl, 3.80g, 20.0mmol), reacts 5h under the conditions of magnetic agitation；After reaction terminates, it is centrifuged off unreacted reactant,
The hydrochloric acid of filtrate 1.0mol/L adjust pH value to 6～7, crystallisation by cooling in frozen water, the filter cake obtained after filtration successively with ethanol,
Water washs, and the most i.e. obtains object β-CD-6-OTs (1.42g, yield 12.5%).
2, initiator β-CD-6-NH2Preparation
Accurately weigh β-CD-6-OTs (1.20g, 1.0mmol) to be dissolved in 15mL ethylenediamine, at N2Protection, under the conditions of 70 DEG C
Stirring reaction 10h；After reaction terminates, under stirring condition, reactant liquor is added dropwise in excess ethyl alcohol, is slightly produced after filtration
Product (white precipitate)；Gained white precipitate is all dissolved with a small amount of distilled water, is then added in excess ethyl alcohol, filtration, filter cake
By washing with alcohol 2 times, the most i.e. obtain initiator β-CD-6-NH2(0.86g, 73.1%).
3, the preparation of star-shape polymer
Take initiator β-CD-6-NH2(1.5mg, 1.28mmol), Glu-NCA (100mg, 0.38mmol) and Lys-NCA
(116mg, 0.38mmol) is dissolved in 3mL DMF, under room temperature, airtight condition, and stirring reaction 36h, reaction in nitrogen atmosphere
Terminate backward reactant liquor adds precipitant absolute ether, obtain white precipitate；This white precipitate is without separating, the most wherein
Add 3mL trifluoroacetic acid (TFA) and 33wt.%HBr/HOAc (v/v=1:1), deprotection 1～2h under room temperature, then use anhydrous second
Ether precipitation obtains yellow oil.Removing supernatant, after being completely dissolved with a small amount of distilled water, saturated sodium bicarbonate solution adjusts pH value
To 7～8, solution loading bag filter (molecular cut off MWCO is 3500Da) dialysis 48h, (pre-freeze temperature is-20 in lyophilizing
DEG C, the time is 4h；-60 DEG C, lyophilizing 36h under vacuum 25Pa) after i.e. obtain target product (33.5mg, yield 15.4%).
Claims (9)
1. a star-shape polymer based on beta-schardinger dextrin-, it is characterised in that its structural formula is as follows:
Wherein x, y represent the degree of polymerization of monomer, and x is 30～80, and y is 30～80.
2. the preparation method of the star-shape polymer based on beta-schardinger dextrin-described in a claim 1, it is characterised in that include as
Lower step:
(1) ring-opening polymerisation
By initiator β-CD-6-NH2Dissolve in organic solvent, under room temperature, airtight condition, in nitrogen atmosphere with polymerization monomer
Middle stirring reaction 48h, reaction terminates to add in backward reactant liquor precipitant, obtains white precipitate；
Described polymerization monomer is Glu-NCA and Lys-NCA；
(2) deprotection
Trifluoroacetic acid and the HOAc solution of 33wt.%HBr, deprotection reaction 1～2h under room temperature, reaction knot is added in reaction bulb
Shu Houxiang reactant liquor adds precipitant, obtains yellow oil；Remove supernatant, yellow oil is complete with a small amount of distilled water
CL, adjusts pH value to 7～8 with saturated sodium bicarbonate solution, and dialyse 48h subsequently, obtains white solid, be target after lyophilizing
Product.
Preparation method the most according to claim 2, it is characterised in that:
In step (1), the mol ratio of polymerization monomer Glu-NCA and Lys-NCA is 0.98～1.05:1.
Preparation method the most according to claim 2, it is characterised in that:
Described in step (1), the quality of initiator is 1:80～200 with the ratio being polymerized monomer gross mass.
Preparation method the most according to claim 2, it is characterised in that:
Described in step (1), organic solvent is N, N-diformamide or dimethyl sulfoxide.
Preparation method the most according to claim 2, it is characterised in that:
During step (2) dialysis, the molecular cut off MWCO of bag filter is 3500Da.
Preparation method the most according to claim 2, it is characterised in that:
The pre-lyophilizing 4h at being prior to-20 DEG C of lyophilizing described in step (2), then in-60 DEG C, lyophilizing 36h under vacuum 25Pa.
Preparation method the most according to claim 2, it is characterised in that:
Precipitant described in preparation process is absolute ether, ethanol, methanol or acetone.
9. according to the preparation method described in claim 2 or 8, it is characterised in that:
Volume is reactant liquor volume 8～10 times of precipitant interpolation.
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Cited By (3)
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| CN110283321A (en) * | 2019-06-20 | 2019-09-27 | 常州大学 | It is a kind of can self-contained hole configurations polymer preparation method |
| CN113748902A (en) * | 2021-10-09 | 2021-12-07 | 安徽南北现代林业科技有限公司 | Method for removing overwintering aphids of goldenrain tree |
| CN114316279A (en) * | 2020-10-09 | 2022-04-12 | 南京大学 | Star-shaped polymer taking cyclodextrin as core and protein/polypeptide conjugate thereof |
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| CN114316279A (en) * | 2020-10-09 | 2022-04-12 | 南京大学 | Star-shaped polymer taking cyclodextrin as core and protein/polypeptide conjugate thereof |
| CN114316279B (en) * | 2020-10-09 | 2023-09-22 | 南京大学 | Star polymer with cyclodextrin as core and protein/polypeptide conjugate thereof |
| CN113748902A (en) * | 2021-10-09 | 2021-12-07 | 安徽南北现代林业科技有限公司 | Method for removing overwintering aphids of goldenrain tree |
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