CN101891834A - Polysaccharide sulfate fragment (PSC), preparation method and application thereof - Google Patents
Polysaccharide sulfate fragment (PSC), preparation method and application thereof Download PDFInfo
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- CN101891834A CN101891834A CN 201010231317 CN201010231317A CN101891834A CN 101891834 A CN101891834 A CN 101891834A CN 201010231317 CN201010231317 CN 201010231317 CN 201010231317 A CN201010231317 A CN 201010231317A CN 101891834 A CN101891834 A CN 101891834A
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- 239000005017 polysaccharide Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 24
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- 238000006243 chemical reaction Methods 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
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- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 4
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- 230000035484 reaction time Effects 0.000 claims description 4
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- 108010037536 heparanase Proteins 0.000 abstract description 6
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- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 abstract description 2
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Abstract
The invention relates to a polysaccharide sulfate fragment (PSC) with a structural general formula I, a preparation method and application thereof in resisting angiogenesis and heparanase medicaments, wherein n is 12-36; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 can be same or different and are H, SO3N1 or SO3H; and the substituted quantity of sulfuric acid is 2.5-3.
Description
Technical field
The present invention relates to polysaccharide sulfate fragment (PSC), the application of its preparation method and angiogenesis inhibitor thereof and anti-heparitinase medicine.
Background introduction
The Invasion and Metastasis of tumour is to cause the tumour patient main causes of death, and seeking triggering tumor cell invasion and attack and the factor that shifts and effectively blocking is one of important method of treatment tumour.Tumour cell to realize invasion and attack and shift at first to pass through by extracellular matrix (extracellular matrix, ECM) and basilar membrane (basement menbrane, BM) barrier of Zu Chenging.This barrier is mainly by IV collagen (collagen IV), glutinous albumen (laminin) and Suleparoid protein-polysaccharide (the heparan sulfate proteogycans of connecting of layer, formation such as HSPGs), and heparitinase (heparanase, Hpa) can shear Suleparoid on the HSPGs (heparansulfate, HS) a kind of endo-glycosidase of side chain for unique one that is proved to be in Mammals, to find so far.Since heparitinase the invasion and attack of tumour with shift in the vital role of playing the part of, therefore be the focus that the oncotherapy of target spot becomes oncotherapy research at present with the heparitinase.
Because the vital role that heparitinase is played the part of in the Invasion and Metastasis of tumour, the research of its inhibitor and screening have become the human new direction of seeking the cancer therapy potential drug.Research to heparanase inhibitors has now obtained bigger progress, mainly contain natural product, micromolecular inhibitor and antibody etc. after natural product and the chemically modified, according to existing ten heparanase inhibitors that grinding of retrieval, and existing 1 drug candidate (PI-88) to enter the second phase clinical, be a new direction that should be noted that.
Wherein Yan Jiu natural product and the natural product after the chemically modified thereof are maximum.As far back as 1987, Matia etc. have prepared various low sulfurations or low-molecular-weight heparin, discover that the carboxyl on oxygen sulfuric ester on these heparin glycosamine residues and nitrogen sulfate group, the uronic acid residue all is the integral part that the heparan enzymic activity is suppressed, these heparin can suppress the transfer of melanoma cells etc.Borgenstrom etc. separate transfer and the human breast carcinoma MDA-MB-231 cell strain that two kinds of polysaccharide oxygen sulfuric esters obtaining and nitrogen oxygen polysaccharide sulfate are used to suppress mouse melanoma b16-BL6 cell from bacterium E.coli K5 (K5PS).The heparin that Borsig etc. have also studied after a kind of the modification has effect of sticking that suppresses the selectin mediation and the activity that suppresses heparitinase simultaneously.
The honest and just beautiful jade of Qingdao Marine University etc. has been reported a kind of oligosaccharides that derives from the ocean, and (oligomannurarate sulfate is JG3) as heparanase inhibitors for the sulfuric acid mannuronic acid of oligomerization.JG3 in vivo with external vasculogenesis and the metastases of all suppressing.The interaction of it and heparitinase is subjected to the competition of low-molecular-weight heparin (4000Da), but is not subjected to the influence of other mucopolysaccharide.In addition, this compound can also suppress the release of Prostatropin (bFGF) from extracellular matrix and vasculogenesis subsequently.Shiozawa etc. separate from fungi (Talaromyce trachyspermusSANK 12191) culture and obtain new metabolite trachyspic acid, and molecular formula is C
20H
28O
9, it is 36 μ mol/l to the IC50 of heparitinase.In addition, Parish etc. find phosphomannose pentose vitriol (phosphomannopentaose sulfate, PI-88) have the structure similar with these sulfated oligosaccharide classes of Fructus Hordei Germinatus hexose vitriol (maltohexaose sulfate) to HS, may disturb the identification of many angiogenesis factors and HS, suppress the cutting of heparitinase simultaneously HS.
In addition, Parish etc. find to survey in the live system for two kinds in heparan enzymic activity and angiogenic growth, and high Sulfated length is that the linear polysaccharide more than 5 just has above two kinds of inhibition activity.Wherein PI-88 and Fructus Hordei Germinatus hexose vitriol just have these activity, and (P-6-Man-α-(1 → 3)-Man-α-(1 → 3)-Man-α-(1 → 3)-Man-α-(1 → 2)-Man) is to prepare from the exo polysaccharides of diploid yeast Pichia holstii to PI-88.It has hypotoxic characteristics, have anti-angiogenic hyperplasia simultaneously concurrently and prevent the dual-use function that cancer cells spreads, it can either suppress vasculogenesis, can suppress again that vascular endothelial growth factor (VEGF), fibroblast somatomedin 1 and 2 (FGF-1 and 2) and heparinase (heparanase) are this to promote the activity of the factors with various tumours such as metastases involved enzyme.It suppresses rat height adenocarcinoma infiltrating and is grown to 50%, and suppressing the lymphatic cancer transfer is 40%, and suppressing the haematogenous metastasis of cancer is 90%, reduces tumor neogenetic blood vessels and forms 30%.As medicine, this compound is researched and developed successfully by Australian Progen company in nineteen ninety, and by the nontoxic test of Britain's human body fs.At present, the U.S. and each big city of Australia are carrying out being the second phase clinical trial of main clinical application with melanoma, lung cancer and multiple marrow cancer etc.In September, 2007, Progen announces that PI-88250mg merges many Xi Tasai treatment IIIB/IV nonsmall-cell lung cancers and do not reach main treatment terminal point, fail to improve significantly the disease free survival rate with single comparing with many Xi Tasai, do not reach simultaneously the second treatment terminal point yet, prolongation progress time, reactivity, total lifetime and quality of life, but the trend that as seen PI-88 administration group is survived and improved.To be in the III phase at present clinical for PI-88 primary hepatocarcinoma postoperative prevention of recurrence in addition.
Summary of the invention
The invention provides a kind of general formula is a kind of polysaccharide sulfate fragment (PSC) of I:
Wherein:
n＝12～36；
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 can be identical or different, is H or SO3Na or SO3H; The amount that activity hydroxy on each glucose unit is replaced by sulfuric acid is 2.5～3.The preferred amount that replaces is 2.6.
Sulfated polysaccharide fragment PSC of the present invention is the straight chain linear structure, preferred unbranched straight chain linear structure.
The present invention also provides a kind of preparation method of polysaccharide sulfate fragment (PSC): through sulphuric acid hydrolysis reaction degraded, separation and purification obtains molecular weight 5000～10000 polysaccharide segments, passes through sulfonation reaction again, obtains polysaccharide sulfate fragment (PSC) with yeast glucan.
Sulphuric acid hydrolysis temperature of reaction among the above-mentioned preparation method is at 65-85 ℃, and sulfuric acid concentration is at 1～1.5M, and the reaction times is 6～8 hours.
Sulfonation reaction among the above-mentioned preparation method is polysaccharide segment and chlorsulfonic acid reaction, and wherein solvent is methane amide or pyridine, and temperature of reaction is 80～120 ℃, and the reaction times is 2.5～5 hours.
The present invention also provides the purposes of above-mentioned polysaccharide sulfate fragment (PSC) in the active medicine of preparation inhibition heparitinase.The active medicine of inhibition heparitinase of the present invention can be used to comprise treatment and prevention noumenal tumour and neoplastic hematologic disorder and transfer and recurrence.
The present invention also provides the application of above-mentioned polysaccharide sulfate fragment (PSC) in the preparation anti-angiogenic medicaments.Anti-angiogenic medicaments of the present invention comprises vasculogenesis, the hyperplasia retinal diseases that treatment is relevant with tumor growth.
Description of drawings
Fig. 1 polysaccharide sulfate fragment (PSC) carbon-13 nmr spectra
Embodiment
The present invention is described further by the following examples, but the protection domain that it can not be construed as limiting the invention.
There are not specifically described extraction, separation method to be the method that those of ordinary skills know among the present invention, those of ordinary skills can adopt the method for pharmacopeia regulation or the method for other working specifications qualification to operate in conjunction with the specification sheets of institute's use instrument according to the prompting of specification sheets, can realize the present invention.
Embodiment 1
Take by weighing the 5g yeast glucan, add 1M sulfuric acid 500ml, 70 ℃ of water-baths 6 hours, reaction solution is neutralized to PH=7 with barium carbonate, filter and remove precipitation, get supernatant, revolve inspissation and contract, add 95% ethanol alcohol precipitation, make the ethanol final concentration reach 70%, centrifugal removal precipitation, supernatant liquor uses dialysis tubing, distill water dialysis 24 hours.The dialyzed solution lyophilize.The 4ml chlorsulfonic acid is bathed at cryosel and is added anhydrous pyridine 20ml, makes esterifying reagent, adds lyophilized powder, reacts 3 hours down at 100 ℃.Reaction solution is used dialysis tubing after being neutralized to PH7.5 with NaOH, distill water dialysis desalination in 24 hours, use the DE-52 ion-exchange chromatography then, as moving phase, collect elution peak with 1.5M NaCl solution, through the desalination of G-25 molecular sieve column, obtain the component polysaccharide sulfate fragment (PSC) again.
Embodiment 2
The structure of polysaccharide sulfate fragment (PSC), by carbon-13 nmr spectra hydrogen spectrum, molecular sieve gel exclusion chromatography determining molecular weight and elemental analysis method are identified.Polysaccharide sulfate fragment (PSC) is dissolved in D
2O uses the 300Hz nuclear magnetic resonance analyser, measures carbon spectrum hydrogen spectrum, and correlated results is seen Fig. 1.Molecular sieve gel exclusion chromatography determining molecular weight, chromatographic condition are two polysaccharide special gel chromatographic column series connection (the molecular weight separating ranges is 4,000,000-100 dalton), and moving phase is 0.1mol/LNaNO
3Solution, 45 ℃ of column temperatures, flow velocity are per minute 0.4ml, differential refraction detector, number of theoretical plate calculates (being not less than) by glucose peaks.Dextran series standard product: Mw is 39.3 * 10
4, 21 * 10
4, 4.88 * 10
4, 2.17 * 10
4, 1 * 10
46 * 10
3, 0.18 * 10
3, test-results shows that number-average molecular weight is 0.8 * 10
4G/mol, weight-average molecular weight is 0.9 * 10
4G/mol.Results of elemental analyses sees Table 1.Comprehensive carbon-13 nmr spectra hydrogen spectrum, molecular sieve gel exclusion chromatography determining molecular weight and results of elemental analyses infer that sulfated polysaccharide PSC has the structure of general formula (I), wherein: n=12～36; R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11Can be identical or different, be H or SO
3Na or SO
3H.This polysaccharide sulfate fragment (PSC), the amount that the activity hydroxy on each glucose unit is replaced by sulfuric acid are that the sulfuric acid substitution value is 2.6.
Table 1. polysaccharide sulfate fragment (PSC) results of elemental analyses
| Test value for the first time | Test value for the second time | |
| C(％) | 14.16 | 14.15 |
| H(％) | 2.02 | 2.18 |
| S(％) | 14.39 | 14.22 |
Embodiment 3
The heparitinase of polysaccharide sulfate fragment (PSC) suppresses determination of activity
Test method: 96 orifice plates add the polysaccharide sulfate fragment (PSC) aqueous solution or positive control drug suramin, heparinase (3 * 10 respectively
-6The IU/ hole), substrate (semi-annular jade pendant reaches heparin 100 μ M), with 40mM sodium-acetate buffer (PH=5.0), hatched 24 hours for 37 ℃, add 100 μ l 1.69mM WST, 0.1NaOH solution termination reaction, and 60 ℃ of colour developings 1 hour, detect the 584nm OD of place value with microplate reader, according to GraphPad Prism 5 computed in software polysaccharide sulfate fragment (PSC) samples to heparin enzyme inhibition activity IC
50=0.4 μ g/ml, Suramin IC
50=8 μ g/ml.Polysaccharide sulfate fragment (PSC) is 20 times of Suramin to the heparin enzyme inhibition activity.
Embodiment 4
BFGF induces the experiment migration experiment of HUVEC migration: get and be in one bottle in HUVEC cell in good condition exponential phase of growth, add 0.25% tryptic digestive juice, digestion comes off attached cell, HUVEC cell (being suspended from 1640 substratum that contain 1%FBS) with 1.8 * 104 cells/180 μ l is inoculated in inner room, and add the 20ul different concns medicine.Add training liquid and the bFGF (60ng/ml) that 600ul contains 1%FBS among the mistress and hatch 6h for 37 ℃, abandon Kong Zhongpei liquid.4% Paraformaldehyde 96 fixed cell 10min.0.1% violet staining 10min, PBS rinses excess dyestuff.Wipe the cell that does not move on the inner room upper strata gently with cotton swab.In the microscopically observation of taking pictures, get five visuals field at random, average, according to following formula computation migration inhibiting rate: migration inhibiting rate=(number of cells control-number of cells treated)/number of cells control * 100%.The results are shown in Table 2, polysaccharide sulfate fragment (PSC) IC
50=18.3ng/ml, SuraminIC
50=50 μ g/ml, the inhibition effect of sulfated polysaccharide fragment PSC is near 3000 times of Suramin.
Table 2 bFGF induces the experimental result of HUVEC migration
Claims (10)
1. general formula is a kind of polysaccharide sulfate fragment (PSC) of I:
Wherein:
n＝12～36；
R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11Can be identical or different, be H or SO
3Na or SO
3H; The amount that activity hydroxy on each glucose unit is replaced by sulfuric acid is 2.5～3.
2. according to the polysaccharide sulfate fragment (PSC) of claim 1, it is characterized in that the amount that the activity hydroxy on each glucose unit is replaced by sulfuric acid is 2.6.
3. according to the polysaccharide sulfate fragment (PSC) of claim 1 or 2, it is characterized in that this fragment is the straight chain linear structure.
4. the preparation method of the polysaccharide sulfate fragment (PSC) of any one among the claim 1-3, it is characterized in that yeast glucan through sulphuric acid hydrolysis reaction degraded, separation and purification obtains molecular weight 5000～10000 polysaccharide segments, passes through sulfonation reaction again, obtains polysaccharide sulfate fragment (PSC).
5. preparation method according to claim 4 is characterized in that described sulphuric acid hydrolysis temperature of reaction at 65-85 ℃, and sulfuric acid concentration is at 1～1.5M, and the reaction times is 6～8 hours.
6. preparation method according to claim 4 is characterized in that described sulfonation reaction is polysaccharide segment and chlorsulfonic acid reaction, and wherein solvent is methane amide or pyridine, and temperature of reaction is 80～120 ℃, and the reaction times is 2.5～5 hours.
7. any one described polysaccharide sulfate fragment (PSC) is preparing the purposes that suppresses in the active medicine of heparitinase among the claim 1-3.
8. according to the described purposes of claim 7, it is characterized in that comprising treatment and prevention noumenal tumour and neoplastic hematologic disorder and transfer and recurrence.
9. the application of any one described polysaccharide sulfate fragment (PSC) in the preparation anti-angiogenic medicaments among the claim 1-3.
10. according to the described purposes of claim 9, it is characterized in that the vasculogenesis, the hyperplasia retinal diseases that comprise that treatment is relevant with tumor growth.
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| CN104072543A (en) * | 2014-04-22 | 2014-10-01 | 浙江海洋学院 | Galactofuranose as well as preparation method and application thereof |
| US20240108648A1 (en) * | 2022-09-29 | 2024-04-04 | Adora Animal Health Corporation | Storage stable formulations of sulfated glycosaminoglycans and fragments derived therefrom for the treatment of pain and other medical conditions |
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| US20020183282A1 (en) * | 1999-06-16 | 2002-12-05 | Latifa Dahricorreia | Pharmaceutical compositions with wound healing or anti-complementary activity comprising a dextran derivative |
| US20040242801A1 (en) * | 2001-11-29 | 2004-12-02 | Organes, Tissus: Regeneration, Reparation, Remplacement - Otr3, A Corporation Of France | Method for the sulfonation of compounds comprising free hydroxyl (OH) groups or primary or secondary groups |
| CN1844161A (en) * | 2006-04-30 | 2006-10-11 | 华南理工大学 | Beta-1,4-glucan-6,2,3-sulfate and its preparation method and use |
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| CN1206717A (en) * | 1998-07-28 | 1999-02-03 | 中国科学院昆明植物研究所 | Beta-D-(1-4)-dextran sulfate compound |
| US20020183282A1 (en) * | 1999-06-16 | 2002-12-05 | Latifa Dahricorreia | Pharmaceutical compositions with wound healing or anti-complementary activity comprising a dextran derivative |
| US20040242801A1 (en) * | 2001-11-29 | 2004-12-02 | Organes, Tissus: Regeneration, Reparation, Remplacement - Otr3, A Corporation Of France | Method for the sulfonation of compounds comprising free hydroxyl (OH) groups or primary or secondary groups |
| JP2006273758A (en) * | 2005-03-29 | 2006-10-12 | Saga Prefecture | Neutrophil activator |
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| CN104072543A (en) * | 2014-04-22 | 2014-10-01 | 浙江海洋学院 | Galactofuranose as well as preparation method and application thereof |
| US20240108648A1 (en) * | 2022-09-29 | 2024-04-04 | Adora Animal Health Corporation | Storage stable formulations of sulfated glycosaminoglycans and fragments derived therefrom for the treatment of pain and other medical conditions |
| US12059430B2 (en) * | 2022-09-29 | 2024-08-13 | Adora Animal Health Corporation | Storage stable formulations of sulfated glycosaminoglycans and fragments derived therefrom for the treatment of pain and other medical conditions |
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