CN102028952B - Galactan sulfate 5-fluorouracil compound and preparation and application thereof - Google Patents
Galactan sulfate 5-fluorouracil compound and preparation and application thereof Download PDFInfo
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- CN102028952B CN102028952B CN2009100195263A CN200910019526A CN102028952B CN 102028952 B CN102028952 B CN 102028952B CN 2009100195263 A CN2009100195263 A CN 2009100195263A CN 200910019526 A CN200910019526 A CN 200910019526A CN 102028952 B CN102028952 B CN 102028952B
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Abstract
The invention relates to a red alga galactan sulfate carrier material with sustained-release effect. The carrier material is a galactan sulfate 5-fluorouracil compound obtained by compounding reaction of galactan sulfate and 5-fluorouracil, wherein the medicament carrying load of the 5-fluorouracil is 5 to 30 percent. The galactan sulfate is reacted with a chlorine acetylation reagent in an organic solvent to form chlorine acetylation polysaccharide, then active chlorine atoms are removed from the polysaccharide, and the polysaccharide is compounded with the 5-fluorouracil to form the galactan sulfate 5-fluorouracil compound. The galactan sulfate and the 5-fluorouracil are combined through a covalent chemical bond, and the 5-fluorouracil monomer is easily degraded and released in neutral buffer solution so as to achieve the sustained-release effect of the medicament and reduce the toxic or side effect. The galactan sulfate carrier of the compound is a good material with good biocompatibility and remarkable enhancement on the immune activities of cells and body fluid, and can fulfill the purpose of improving the synergistic effect of the medicament together with the 5-fluorouracil.
Description
Technical field
The invention belongs to the pharmaceutical carrier part in the chemical synthetic drug field, specifically a kind of is preparation and the application in antitumor drug of the 5-fluorouracil complex of carrier with the galactan sulfuric ester.
Background technology
Tumor is a kind of genopathy.It is phalangeal cell under the carcinogenic factor effect, change has taken place in gene, loses the normal regulation to its growth, causes the monoclonicity paraplasm and the neoplasm that forms.This neoplasm often forms local lump, thereby gains the name.At present, malignant tumor has become the commonly encountered diseases and the frequently-occurring disease of serious threat human health.Its growth can be transferred to other positions of health rapidly, also can produce harmful substance, destroys the normal organ structure, makes the body function imbalance, life-threatening.The mortality rate that the mankind cause because of malignant tumor has accounted for second of all disease death rates at present.At present tumor treatment generally has operative treatment, radiotherapy and chemotherapeutical etc., but still is main with chemotherapy.Clinical antitumor drug commonly used has kind more than 60 at present, and most of tumors are played certain curative effect.These antitumor drug are generally small-molecule drug, are characterized in that selectivity is not high, and therapeutic efficiency is low, and toxic and side effects reaches problems such as cancerous cell drug resistance greatly.5-fluorouracil (5-Fu) is a broad-spectrum antitumor drug, and other solid tumors such as digestive system tumor are had significant curative effect.But at present there are many shortcomings in the clinical 5-Fu of belonging to, should not absorb as oral, and internal metabolism is fast, the half-life short (10～20min) and toxic and side effects big etc., need heavy dose of long-time intravenous drip administration to reach intravital valid density and effect is held time.The antineoplastic agent of therefore efficient to seek to the chemical modification of 5-Fu, low toxicity, slow release becomes the task of top priority of research.
In recent years, obtained broad research with having biocompatibility and biodegradable macromolecular material antitumor drug as carrier.They discharge medicine selectively at lesions position, can greatly improve the bioavailability of medicine, reduce the toxic and side effects and the dosage of medicine effectively.Wherein utilize polysaccharide as pharmaceutical carrier, becoming the macromolecule prodrug through crosslinked or coupling is the human focus of paying close attention to.This polysaccharides compound prodrug can pass through drug diffusion, the fracture of medicine marriage chain or depolymerization, slowly discharges with certain speed, can reduce the medication number of times, improves bioavailability of medicament, thereby reduces toxic and side effects.Except because the carrier system that polysaccharide forms has good slow release or the controlled-release effect, also, have physiologically actives such as high-affinity, biodegradability, targeting property and antiinflammatory antiviral, enhance immunity because of one of basic living matter of they conducts.Now through being mainly seen in chitin and derivant thereof with medicament coupling serves as carrier mass.Cellulose, glucosan, Algin, amylopectin, carrageenan and agarose etc. also have report with the study on the synthesis of prodrug in addition.For example Larsen equals just to synthesize glucosan, Algin, agarose, glycogen and cellulose and the bonded macromolecule prodrug of naproxen in 1989, and they have good targeting property.
The galactan sulfuric ester sulfuric ester that from marine red alga, is separated to, its basic structural unit are the disaccharide unit of the β-D-galactose of 1,3 connection and the α-L-galactose of 1,4 connection-6-sulfate composition.Its basic cell structure formula is following:
Research shows that the marine red alga galactan sulfuric ester sulfuric ester with said structure has remarkable function aspect enhancing cell and the humoral immunization activity.As good immunopotentiating agent, galactan sulfuric ester sulfuric ester has its excellent biological compatibility, becomes a kind of excellent drug carrier material.The present invention utilizes acyl bond that the active hydroxyl of galactan sulfuric ester sulfuric ester is combined with 5-Fu, to obtain the prodrug complex of low toxicity and tool slow releasing function.
Summary of the invention
It is 5-Fu prodrug complex and the preparation and the application of carrier with the galactan sulfuric ester that the object of the invention is to provide a kind of.The present invention loads on 5-Fu on the galactan sulfuric ester; Prolong the release time of 5-Fu, be beneficial to the absorption of active component, improve its bioavailability; And utilize galactan sulfuric ester to have the drug effect similar with 5-Fu as carrier, reach the purpose of the cooperative effect that improves medicine.
A kind of galactan sulfuric ester 5-fluorouracil complex; It is to be carrier with the galactan sulfuric ester; The C6 position of the β of 5-30%-D galactose forms galactan sulfuric ester 5-fluorouracil complex through the covalent bond 5-fluorouracil in the galactan sulfuric ester, has slow releasing function;
Its typical structure unit is following,
Wherein, n is the positive integer of 15-1000.
Galactan sulfuric ester carrier material with slow releasing function provided by the invention is that the low-molecular-weight galactan sulfuric ester after the degraded of employing polysaccharide is a raw material; Earlier it being derived changes into the chloroacetylation polysaccharide, reacts compound obtaining under certain condition through acyl group and 5-Fu again.Concrete method for preparing is following:
(1) the synthetic chloroacetylation polysaccharide of polysaccharide and monochloroacetic acid anhydride reaction
A certain amount of galactan sulfuric ester is dissolved in the organic solution Methanamide, and 50-80 ℃ of heating fully dissolved it, makes ultimate density reach 1-50mg/mL, adds the chloroacetylation catalyst stirring and dissolving of 0.5-1 sesquialter breast polysaccharide sulfuric ester weight; In step 1) solution, divide then and add chloroacetylation reagent 3-4 time, ultimate density 10-150mg/mL, heated and stirred reaction 3-6h in 65-80 ℃ of water-bath;
Reaction adds ethanol after accomplishing in mixed reaction solution, deposition occurs; Centrifugal collecting precipitation, and with behind the absolute ethanol washing, remove the micromolecule reactant after, the solution concentration lyophilizing gets acylate, i.e. the chloroacetylation polysaccharide;
Reaction scheme is following:
(2) 5-Fu and chloroacetylation polysaccharide are connected to form complex
Take by weighing a certain amount of chloroacetylation polysaccharide and be dissolved in the organic solvent Methanamide, 60-70 ℃ of heated and stirred dissolving, ultimate density reaches 5-50mg/mL; With slowly splashing in the formamide solution that is dissolved with 5-fluorouracil in the chloroacetylation polysaccharide solution; The concentration of 5-fluorouracil in Methanamide is 5-60mg/mL;
Add a certain amount of composite reaction catalyst then, composite reaction catalyst ultimate density 10-60mg/mL after 60-80 ℃ of water-bath 24-40 hour, adds ethanol and makes deposition, sucking filtration; Deposition is with organic solvent washing 1-6 time, must the khaki powder solid behind the vacuum drying, be product.
Reaction scheme is following:
Described chloroacetylation reagent is monochloroacetic acid anhydride; Used chloroacetylation catalyst is a base catalyst, like pyridine, and 4-dimethylamino naphthyridine, N-bromosuccinimide etc.;
Catalyst system therefor is a triethylamine in the compound reaction; The used organic solvent of washing complex deposition is chloroform and/or ether.
The final weight concentration of the needed ethanol of described deposit sample in system is 85%.The described micromolecule reactant mode of removing is dialysis or ultrafiltration.The ultraviolet spectra of complex obtained the maximum absorption occurs at 258nm.
The present invention is the galactan sulfuric ester carrier material with slow releasing function, and it is that galactan sulfuric ester and 5-fluorouracil compound reaction obtain the galactan sulfate derivative, and the 5-fluorouracil carrying drug ratio is 25%.It is in organic solvent, and galactan sulfuric ester and chloroacetylation reagent reacting obtained the chloroacetylation polysaccharide before this, through taking off active chlorine atom, is composited with 5-fluorouracil then.Both combine through covalent chemical bond, and degraded discharges the monomer 5-fluorouracil easily in neutral buffered liquid, thereby reaches the slow releasing function of medicine, reduce toxic and side effects.The carrier galactan sulfuric ester of this complex is to have good biocompatibility and significant cell and the active excellent material of humoral immunization of strengthening, and can reach the purpose of the cooperative effect that improves medicine with 5-fluorouracil.
The 5-fluorouracil complex that said galactan sulfuric ester is a carrier can be used for preparing in the antitumor drug.Described tumor comprises cancers in digestive system (gastric cancer, colon cancer, hepatocarcinoma, cancer of pancreas, the esophageal carcinoma etc.), breast carcinoma, ovarian cancer, cervical cancer, chorionic epithelioma, malignant mole, bladder cancer, pulmonary carcinoma, skin carcinoma, incidence cancer.
The reactivity of 6 primary hydroxyls in the material therefor galactan sulfuric ester structure of the present invention is far longer than other non-primary hydroxyls, and especially other non-primary hydroxyls are not participated in reaction basically when carrying out chloroacetylation.Carrying out the second step compound reaction time, because 6 steric hindrances are less, and reactant 5-Fu structure is bigger, is difficult to and other hydroxyl reactions, so this composite structure is the above structure.
The present invention has easy and simple to handle, stable preparation process, advantage such as cheap for manufacturing cost.The present invention has extensive applicability to raw material, and the polysaccharide that contains more primary hydroxyl in every molecular structure chain is all applicable to the present invention.If polysaccharide can be dissolved in N, dinethylformamide or dimethyl sulfoxine can be replaced the reaction dissolvent Methanamide with them, and 5-Fu can be solvent with the dimethyl sulfoxine simultaneously.The present invention the complex favorable solubility, in Acidity of Aikalinity and the equal solubilized of neutral environment, slow release effect is obvious in external artificial simulated body fluid environment, for utilizing the exploitation slow release antitumor drug condition that facilitates better.
Description of drawings
The IR spectrogram of complex among Fig. 1 embodiment 1 (a), galactan sulfuric ester (b) and chloroacetylation polysaccharide (c).
Fig. 2 is the UV scanning collection of illustrative plates of 5-Fu among the embodiment 1 (a), 5-Fu/ galactan sulfate mixture (b), complex (c), chloroacetylation polysaccharide (d) galactan sulfuric ester (e).
Fig. 3 is the 5-Fu accumulative total release profiles of complex in external release experiment among the embodiment 2.
The specific embodiment
Embodiment 1: the preparation of complex and carrying drug ratio are measured
2g galactan sulfuric ester is joined in the there-necked flask that the 80mL Methanamide is housed, and 65 ℃ of heated and stirred make it dissolving fully.Take by weighing 1.5g catalyst 4-dimethylamino naphthyridine and join in the reactant liquor stirring and dissolving.Divide 3 batches to add in the there-necked flask 12g monochloroacetic acid anhydride, add once every separated half an hour, each 4g.After keeping 70 ℃ of reactions of bath temperature 4h, reactant liquor is poured in the ethanol, made concentration of alcohol reach 85%, deposition occurs.To precipitate collection, the molecular cut off 3 of packing into after the washing with alcohol is dialysed in the bag filter of 500KD.After tap water and distilled water were dialysed respectively one day, solution concentration is freezing, and vacuum drying got the cotton-shaped solid of brown and is required chloroacetylation polysaccharide.
Take by weighing chloroacetylation polysaccharide 0.5g and be dissolved in the 10mL Methanamide, the heated and stirred dissolving fully.Simultaneously 5-Fu 1.2g is dissolved in the 20mL Methanamide, heats 70 ℃ of dissolvings equally fully.Behind the 10min, slowly splash in the chloroacetylation polysaccharide solution formamide solution that is dissolved with 5-Fu and stirring.Add the 1.4mL catalyst of triethylamine then.Keep 75 ℃ of bath temperatures, stir and treat to pick up counting when solution is transparent, behind the reaction 40h, stopped reaction.Reactant liquor is poured in the alcoholic solution, made the whole weight concentration of ethanol in system reach 85%, deposition occurs.Deposition is collected, and washs successively 3 times with chloroform and ether.The dry end product that gets is the khaki powder solid.
Infrared and the ultraviolet detection of synthetic drug sample:
Intermediate products and final products are carried out infrared and UV scanning.Find out that from accompanying drawing sample is infrared behind the chloroacetylation goes out the peak at 1753cm
-1(C=O), 1320cm
-1(CH
2For C-CH
2-Cl) and 773cm
-1(C-Cl), show that chloroacetylation is successful.With 5-Fu compound after, sample goes out the peak at 1715-1668cm
-1(OCO and C=O/5FU) and 814 (C-F) cm
-1773cm
-1(C-Cl) peak disappears, and the compound success of 5-Fu and galactan sulfuric ester is described.Find out that from UV scanning final products have maximum absorption band at 258nm, and both simple mixing things and 5-Fu there is maximum absorption band at 265nm.
The mensuration of carrying drug ratio in the complex:
Complex hydrolyzable under alkali condition discharges 5-Fu, uses ultraviolet spectrophotometry the carrying drug ratio of complex is measured.Concrete steps are: precision is measured the 5-Fu 10mg that is dried to constant weight, is dissolved among the NaOH solution 100mL of 0.05mol/L, is mixed with the 5-Fu mother solution.Accurately take by weighing mother solution 0.25,0.50,0.75,1.00,1.25 with pipet, 1.50mL in tool plug test tube, with the NaOH solution dilution of 0.05mol/L to 5mL.With the absorbance at ultraviolet spectrometer mensuration 265nm place, do standard curve.Take by weighing the 20mg complex during working sample, be dissolved in the 0.05mol/L NaOH solution.Get the 0.05mL sample solution with the NaOH solution dilution of 0.05mol/L to 5mL, measure its absorbance with ultraviolet spectrometer at 265nm, utilize the content of the regression equation calculation 5-Fu of standard curve.
Carrying drug ratio=W
1/ W
0* 100%
In the formula: W
0Be the complex total amount; W
1Weight for 5-Fu.
Measure through carrying drug ratio, embodiment 1 prepared complex 5-Fu carrying drug ratio is 25.5%.
Experimental example 2: the external release experiment of complex
Take by weighing the 10mg complex, placing diameter is the bag filter of 1cm, and mouth sealing back is added in the fine taper bottle; The hydrochloric acid solution (0.1M), phosphate buffer (pH 7.2) and the sodium hydroxide solution (0.01M) that add 10mL; Jumping a queue and putting into temperature is the constant temperature oscillator of 100 times/min for (37.0 ± 0.5) ℃, hunting speed, and sampling at set intervals replenishes the equivalent fresh buffer simultaneously; According to working curve; Calculate the content that discharges 5-Fu in the liquid, and calculate the cumulative release rate of complex thus, draw cumulative release rate-time graph.External release result sees Fig. 2. the result shows that galactan sulfuric ester 5-FU complex has slow releasing function.Wherein slow relatively in sour environment (pH1.8) 5-Fu of simulated gastric fluid release, in neutral buffered liquid, discharge the monomer 5-fluorouracil easily, thereby reach the slow releasing function of medicine, reduce toxic and side effects.
Experimental example 3: the anti-tumor in vivo of complex is active
(body weight 20.0 ± 2.0g) is divided into 6 groups after weighing at random, 10 every group with Kunming mouse.Aseptic condition extracts the cell suspending liquid of 5-7 days tumor-bearing mice (S180 solid tumor) belly cavity tumor of inoculation, axillary fossa subcutaneous injection 0.2mL before right side of mice down.Preparation raw material galactan sulfuric ester, complex (5-Fu carrying drug ratio 17%) and polysaccharide become certain density distilled water solution with the biased sample of 5-Fu respectively.Inoculate after 24 hours each solution respectively to mouse stomach 0.2mL.Blank and positive control then every irritate stomach 0.2mL normal saline and 5-Fu, successive administration 7 days.After the drug withdrawal 24 hours, take off vertebra and put to death each Mus, dissect and peel off the tumor piece, remove fat and connective tissue, claim that tumor is heavy, calculate tumour inhibiting rate.
Tumour inhibiting rate=[(the average tumor of the average tumor weight-administration of matched group group is heavy)/average tumor of matched group is heavy] * 100%
Experimental data adopts the meansigma methods of three experimental results to represent that the t check analysis meets the requirements between group, presses down the tumor result and sees table 1.
Table 1, each sample medication and dosage are to the inhibitory action of mice S180 solid tumor
Experimental result shows, the tumour inhibiting rate of complex is not only than the height of two kinds of reactants, and is higher than the tumour inhibiting rate after both simple mixing, explains that the change of compound afterproduct structure can reach tumor killing effect very effectively.
The present invention is the red algae galactan sulfuric ester carrier material with slow releasing function, and it is that galactan sulfuric ester and 5-fluorouracil compound reaction obtain galactan sulfuric ester 5-fluorouracil complex, and the 5-fluorouracil carrying drug ratio is 5-30%.It is in organic solvent, and galactan sulfuric ester and chloroacetylation reagent reacting obtained the chloroacetylation polysaccharide before this, through taking off active chlorine atom, is composited with 5-fluorouracil then.Both combine through covalent chemical bond, and degraded discharges the monomer 5-fluorouracil easily in neutral buffered liquid, thereby reaches the slow releasing function of medicine, reduce toxic and side effects.The carrier galactan sulfuric ester of this complex is to have good biocompatibility and significant cell and the active excellent material of humoral immunization of strengthening, and can reach the purpose of the cooperative effect that improves medicine with 5-fluorouracil.
Claims (3)
1. galactan sulfuric ester 5-fluorouracil complex; It is characterized in that: it is to be carrier with the galactan sulfuric ester; The C6 position of the β of 5-30%-D galactose is through the covalent bond 5-fluorouracil in the galactan sulfuric ester; Form galactan sulfuric ester 5-fluorouracil complex, have slow releasing function; Its preparation method is:
(1) the galactan sulfuric ester is dissolved in the organic solution, 50-80 ℃ of heating fully dissolved it, makes ultimate density reach 1-50mg/mL, adds the chloroacetylation catalyst stirring and dissolving of 0.5-1 sesquialter breast polysaccharide sulfuric ester weight;
(2) in step (1) solution, divide adding chloroacetylation reagent then 3-4 time, ultimate density 10-150mg/mL, heated and stirred reaction 3-6h in 65-80 ℃ of water-bath;
(3) after reaction is accomplished, in mixed reaction solution, add ethanol, deposition occurs; Centrifugal collecting precipitation, and with behind the absolute ethanol washing is removed concentrated freeze-dried acylate, i.e. chloroacetylation polysaccharide behind the micromolecule reactant;
(4) the chloroacetylation polysaccharide is dissolved in the organic solvent, 60-70 ℃ of heated and stirred dissolving, and ultimate density reaches 5-50mg/mL; With slowly splashing in the formamide solution that is dissolved with 5-fluorouracil in the chloroacetylation polysaccharide solution; The concentration of 5-fluorouracil in Methanamide is 5-60mg/mL; The mass ratio of 5-fluorouracil and chloroacetylation polysaccharide is 3: 1-5;
(5) add composite reaction catalyst then, composite reaction catalyst ultimate density 10-60mg/mL after 60-80 ℃ of water-bath 24-40 hour, adds ethanol and makes deposition, sucking filtration; Deposition is with organic solvent washing 1-6 time, must the khaki powder solid behind the vacuum drying, be product;
Step (1) and (4) said organic solution are Methanamide; Described chloroacetylation reagent is monochloroacetic acid anhydride; The chloroacetylation catalyst is base catalyst pyridine, 4-dimethylamino naphthyridine or N-bromosuccinimide;
Catalyst system therefor is a triethylamine in the compound reaction; The used organic solvent of step (5) washing complex deposition is chloroform and/or ether.
2. the method for preparing of the said complex of claim 1 is characterized in that:
(1) the galactan sulfuric ester is dissolved in the organic solution, 50-80 ℃ of heating fully dissolved it, makes ultimate density reach 1-50mg/mL, adds the chloroacetylation catalyst stirring and dissolving of 0.5-1 sesquialter breast polysaccharide sulfuric ester weight;
(2) in step (1) solution, divide adding chloroacetylation reagent then 3-4 time, ultimate density 10-150mg/mL, heated and stirred reaction 3-6h in 65-80 ℃ of water-bath;
(3) after reaction is accomplished, in mixed reaction solution, add ethanol, deposition occurs; Centrifugal collecting precipitation, and with behind the absolute ethanol washing is removed concentrated freeze-dried acylate, i.e. chloroacetylation polysaccharide behind the micromolecule reactant;
(4) the chloroacetylation polysaccharide is dissolved in the organic solvent, 60-70 ℃ of heated and stirred dissolving, and ultimate density reaches 5-50mg/mL; With slowly splashing in the formamide solution that is dissolved with 5-fluorouracil in the chloroacetylation polysaccharide solution; The concentration of 5-fluorouracil in Methanamide is 5-60mg/mL; The mass ratio of 5-fluorouracil and chloroacetylation polysaccharide is 3: 1-5;
(5) add composite reaction catalyst then, composite reaction catalyst ultimate density 10-60mg/mL after 60-80 ℃ of water-bath 24-40 hour, adds ethanol and makes deposition, sucking filtration; Deposition is with organic solvent washing 1-6 time, must the khaki powder solid behind the vacuum drying, be product;
Step (1) and (4) said organic solution are Methanamide; Described chloroacetylation reagent is monochloroacetic acid anhydride; The chloroacetylation catalyst is base catalyst pyridine, 4-dimethylamino naphthyridine or N-bromosuccinimide;
Catalyst system therefor is a triethylamine in the compound reaction; The used organic solvent of step (5) washing complex deposition is chloroform and/or ether.
3. the application of the described complex of claim 1 is characterized in that: said galactan sulfuric ester 5-fluorouracil complex is used for preparing anti-gastric cancer, colon cancer, hepatocarcinoma, cancer of pancreas or esophageal carcinoma medicine.
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| CN101230108A (en) * | 2008-02-01 | 2008-07-30 | 中国科学院海洋研究所 | Method for preparing acetylated brown seaweed polysaccharide sulfuric ester |
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| CN101230108A (en) * | 2008-02-01 | 2008-07-30 | 中国科学院海洋研究所 | Method for preparing acetylated brown seaweed polysaccharide sulfuric ester |
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| Title |
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| 张英慧 等.溴代十六烷基吡啶法提取海带岩藻-半乳聚糖硫酸酯.《中国生化药物杂志》.2003,第24卷(第5期),219-221. * |
| 王晶 等.乙酰化海带褐藻多糖硫酸酯的制备及其抗氧化活性研究.《中国海洋药物杂志》.2008,第27卷(第1期),50-54. * |
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