CN1548445A - N-crotonoyl hydroxy protected glucosamine and its prepn and application - Google Patents
N-crotonoyl hydroxy protected glucosamine and its prepn and application Download PDFInfo
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- CN1548445A CN1548445A CNA031122744A CN03112274A CN1548445A CN 1548445 A CN1548445 A CN 1548445A CN A031122744 A CNA031122744 A CN A031122744A CN 03112274 A CN03112274 A CN 03112274A CN 1548445 A CN1548445 A CN 1548445A
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- glucosamine
- compound
- acyl group
- crotonoyl
- butenoic acid
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Abstract
The N-crotonoyl hydroxy protected glucosamine compound features its amino position connected via amido bond with maleic acid. The compound is prepared with aminoglucose derivative and maleic anhydride and through acidation reaction in solvent. The compound of the present invention has extraneous antitumor activity and has erythromycin-like skeleton or conjugate plane perpendicular to glycosyl cycle, being favorable to insertion of conjugate plane to DNA and antitumor activity.
Description
The present invention relates to the glucosamine compound that a class has the N-butenoic acid acyl group hydroxyl protection of anti-tumor activity.
In the glucide that occurring in nature exists, chitin is modal glycosaminoglycan, is one of organic compound that is only second on the earth cellulosic most abundant.Studies show that chitin and chitosan are not only nontoxic, biodegradable, and have multiple medical science function and pharmacological actions such as remarkable inhibition fungus breeding that it is nontoxic and effective biological agent is applied in medicine and sanitation and health-care field to can be used as a class.Glucosamine is the degraded product of chitin, has multiple biological activity, finds again that in recent years it also has restraining effect to cancer cells, and is very little to normal body toxicity.Cancer therapy drug attracts people's attention in recent years, and the inventor has studied the anti-tumor activity of the aminosugar compound that contains different aglucons according to the demand in market.
The purpose of this invention is to provide the compound that a kind of MALEIC ANHYDRIDE derivative links to each other with the glucosamine derivative; being about to maleic acid and the coupling of glucosamine derivative gets up; the glucosamine compound for preparing a series of N-butenoic acid acyl group hydroxyl protections; this compound has anti-tumor activity, can satisfy the demand in market.
A kind of glucosamine compound of N-butenoic acid acyl group hydroxyl protection is characterized in that the glucosamine derivative is connected with amido linkage with maleic acid at amino position.
A kind of preparation method of glucosamine compound of N-butenoic acid acyl group hydroxyl protection is characterized in that carrying out acylation reaction by glucosamine derivative and MALEIC ANHYDRIDE in the presence of solvent.
A kind of glucosamine compound of N-butenoic acid acyl group hydroxyl protection is characterized in that it is used to prepare cancer therapy drug.
Compound of the present invention has anti tumor activity in vitro, by the reaction of two kinds of materials, obtains a kind of similar daunorubicin skeleton, and promptly conjugate planes and the sugared compound that encircles vertical skeleton help the insertion of conjugate planes to DNA, make it to have anti-tumor activity.
Below by embodiment the present invention is described.
Embodiment 1
The O-that gets thorough drying is tetra-acetylated-2-glucosamine 3.47g (10mmol), be dissolved in the dry acetonitrile 50ml that crosses, and add equimolar MALEIC ANHYDRIDE, molten entirely, the stirring at room reaction is spent the night; Reaction solution is concentrated into about 30ml; add the 30ml anhydrous diethyl ether; adularescent is muddy to be generated; below 0 ℃ freezing 2 hours; there are a large amount of white solids to separate out; incline and supernatant liquor; solid is dissolved with minor amounts of acetonitrile again; anhydrous diethyl ether settles out, suction filtration, filter cake anhydrous diethyl ether washed twice; obtain a kind of white product 3-(1 ' of the present invention; 3 ', 4 ', 6 '-four-O-ethanoyl-2 '-deoxyglucose-2 '-formamyl)-vinylformic acid or claim N-butenoic acid acyl group-O-tetra-acetylated-2-glucosamine (being called for short compound (1)) 3.51g.Yield: 78.9%.Can see 3328cm from its pressing potassium bromide troche infrared spectra
-1The NH charateristic avsorption band at place; 3065cm
-1, 1610cm
-1The place is the charateristic avsorption band of carbon-carbon double bond=C-H and C=C; 1753cm
-1, 1634cm
-1The place is the C=O charateristic avsorption band; 2960cm
-1The place is-CH
3The C-H charateristic avsorption band.The proton nmr spectra of this compound (DMSO, δ) in 8.55～8.59 places are peaks of NH; 6.15～6.26 places are the C on the carbon-carbon double bond
2-H, C
3The peak of-H; 5.72～5.76,5.18～5.22,4.89～4.93,4.17～4.22,4.01～4.07,4.01～4.05 and 3.97～4.01 places are respectively the sugar ring and go up C
1', C
4', C
3', C
6', C
2', C
5' and C
6' go up the peak of hydrogen; 1.92～2.06 places are 12 hydrogen peaks of ethanoyl.Can determine that by above-mentioned infrared spectra and proton nmr spectra compound structure of the present invention is
Wherein: to compound (1) R=Ac, to compound (2) R=Bz, to compound (3) R=Bn
The used reactant O-of present embodiment is tetra-acetylated-the 2-glucosamine can change O-into tetra-acetylated-1-glucosamine.
Embodiment 2
Get the O-four benzoyls-2-glucosamine 5.96g (10mmol) of thorough drying, be dissolved among the dry acetonitrile 100ml, add equimolar MALEIC ANHYDRIDE, the stirring at room reaction is spent the night; There are a large amount of white solids to generate, suction filtration, filter cake washs three times with acetonitrile; Get product white powder 3-of the present invention (1 ', 3 ', 4 ', 6 '-four-O-benzoyl-2 '-deoxyglucose-2 '-formamyl)-vinylformic acid or claim N-butenoic acid acyl group-O-benzoyl-2-glucosamine (being called for short compound (2)) 6.17g.Yield: 89.0%, m.p.175～177 ℃.Can see 3066cm from its pressing potassium bromide troche infrared spectra
-1Place and 1601cm
-1, 1491cm
-1The ArH at place and the charateristic avsorption band of phenyl ring; 1742cm
-1, 1634cm
-1The C=O charateristic avsorption band at place; 1558cm
-1The N-H and the 1248cm at place
-1The C-O-C charateristic avsorption band at place; (DMSO δ) at 7.26～8.05 places is the peak of 20 hydrogen on the phenyl ring to its proton nmr spectra; 6.10～6.16 places are carbon-carbon double bond C
2, C
3Two hydrogen peaks; 6.21～6.23,5.82～5.85,5.78～5.81,4.84～4.89,4.63～4.66,4.47～4.50 and 4.37～4.40 places are respectively sugar ring C
1', C
4', C
3', C
2', C
6', C
6' and C
5' on the hydrogen peak.Can determine the structure of compound (2) from above-mentioned infrared spectra and proton nmr spectra.
The used reactant O-four benzoyls-2-glucosamine of present embodiment can change O-four benzoyls-1-glucosamine into.
Embodiment 3
Is solvent with O-tetrabenzyl-2-glucosamine 5.40g (10mmol) with acetonitrile (100ml), reflux, and dissolving adds equimolar MALEIC ANHYDRIDE, back flow reaction 5 hours; With the reaction solution evaporated under reduced pressure, sticky solid, with the dissolving of 20ml chloroform, add 30ml methyl alcohol ,-4 ℃ freezing 4 hours, have a large amount of white solids to separate out, suction filtration, filter cake cold methanol washed twice; Get white powder 3-(1 ', 3 ', 4 ', 6 '-four-O-benzyl-2 '-deoxyglucose-2 '-formamyl)-vinylformic acid or claim N-butenoic acid acyl group-O-benzyl-2-glucosamine (being called for short compound (3)) 5.26g.Yield: 82.5%, m.p.134～136 ℃.Can see 3288cm from its pressing potassium bromide troche infrared spectra
-1The N-H charateristic avsorption band at place; 3030cm
-1, 3066cm
-1The charateristic avsorption band of the ArH at place; 1717cm
-1, 1630cm
-1The C=O absorption peak at place; And 1248cm
-1The C-O-C charateristic avsorption band at place.Its proton nmr spectra (DMSO. δ) is N-H peaks at 9.15～9.26 places; 7.21～7.38 places are peaks of 20 hydrogen on the phenyl ring; 6.27～6.35 places are carbon-carbon double bond C
2, C
3On two hydrogen peaks; 4.52～4.73 places are benzyl (Ph-CH
2) on 8 hydrogen peaks; 4.77～4.81,3.78～3.85,3.66～3.75,3.53～3.59 is respectively sugar ring C
1' last 1 hydrogen, C
2' last 1 hydrogen, C
4', C
3', C
5' last 3 hydrogen and C
6' peak of last 2 hydrogen.Can determine the structure of compound (3) by above-mentioned infrared spectra and proton nmr spectra.
The used reactant O-tetrabenzyl-2-glucosamine of present embodiment can change O-tetrabenzyl-1-glucosamine into.
Solvent acetonitrile used in the foregoing description can change methyl alcohol, ethanol into.
The anti-tumor activity of institute of the present invention synthetic conjugate
Adopt sulphonyl rhodamine B (sulforhodamine B) protein staining method to measure the external antitumour activity of institute of the present invention synthetic compound, on people's liver cancer (BEL-7402), mouse leukemia (P388), human leukemia (HL-60) and people's lung cancer (A-549) cell strain, carried out the antitumour activity screening.The anti-tumor activity experimental result shows that the compound of benzene invention all has the effect that suppresses BEL-7402, P388, HL-60 and A-549 cell strain.Compound particularly of the present invention (2) is higher than the inhibiting rate of reference substance 5-fluorouracil to the inhibiting rate of above-mentioned four kinds of cell strains, has shown the effect that suppresses growth of tumour cell preferably.At drug level is 10
-5During mol/l, compound (2) can reach 99.3% to the inhibiting rate of BEL-7402 cell strain, can reach 91.9% to P388 cell strain inhibiting rate, and the inhibition growth effect that shows BEL-7402, P388 cell strain has potent; Can reach 82.1% to HL-60 cell strain inhibiting rate, can reach 80.6% to A-549 cell strain inhibiting rate, the inhibition growth effect that shows HL-60, A-549 cell strain has weak effect.
The cancer therapy drug of band sugar chain occupies critical role in the clinical chemotherapy, as anthracycline antibiotics Zorubicin, Hydroxydaunomycin, butterfly mycin, Etoposide, podophyllotoxin etc., the antibiotic glycosyl of anthracene nucleus class (anthracyclines) plays a decisive role stablizing the conformation of whole molecule in acceptor.The polarity of glycosyl, fixedly aglucon is to the embedding of DNA, thus blocking dna duplicates and transcribes.And anthracene nucleus helps the embedding of conjugate planes to DNA with sugar ring near normal configuration spatially; Carbonyl on the anthracene nucleus conjugate planes and hydroxyl can form hydrogen bond with the pyrimidine of DNA, also help conjugate planes chimeric to DNA.The effect essence of DNA chimeric molecule is to disturb topoisomerase (topoisomerase Top) to identification and the reparation of DNA, thereby kills or anticancer.Top is one of vital role target spot of antitumor drug research in recent years.
The anti-tumor activity that inventor's research contains the sugar compounds of different aglucons shows that the compound that the MALEIC ANHYDRIDE derivative links to each other with glucosamine has stronger anti tumor activity in vitro.Syble software by Tripos company carries out composition optimizes and calculating on SGI O2 workstation, and with the contrast of the structure of numerous anti-cancer active matters and medicine, show that the skeleton of this compounds and anthracycline antibiotics has very big similarity: (1) planar conjugate structure and approximately perpendicular with it sugar encircle; (2) distribution of hydrogen bond donor and acceptor on the conjugate planes.
The present invention is based on The above results, D-2-glucosamine or D-1-glucosamine and derivative thereof are carried out chemically modified, prepare a series of glucosamine conjugates that contain maleic acid, purpose is to improve the target of compound, searching curative effect height, the new antineoplastic compound that toxic side effect is low are in the hope of the clinical new type antineoplastic medicine that provides is provided.
Claims (4)
1, a kind of glucosamine compound of N-butenoic acid acyl group hydroxyl protection is characterized in that the glucosamine derivative is connected with amido linkage with maleic acid at amino position.
2, a kind of preparation method of glucosamine compound of N-butenoic acid acyl group hydroxyl protection is characterized in that carrying out acylation reaction by glucosamine derivative and MALEIC ANHYDRIDE in the presence of solvent.
3, preparation method as claimed in claim 2 is characterized in that described solvent is acetonitrile, methyl alcohol, ethanol.
4, a kind of glucosamine compound of N-butenoic acid acyl group hydroxyl protection is characterized in that it is used to prepare cancer therapy drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031122744A CN1310932C (en) | 2003-05-16 | 2003-05-16 | N-crotonoyl hydroxy protected glucosamine and its prepn and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031122744A CN1310932C (en) | 2003-05-16 | 2003-05-16 | N-crotonoyl hydroxy protected glucosamine and its prepn and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1548445A true CN1548445A (en) | 2004-11-24 |
| CN1310932C CN1310932C (en) | 2007-04-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB031122744A Expired - Fee Related CN1310932C (en) | 2003-05-16 | 2003-05-16 | N-crotonoyl hydroxy protected glucosamine and its prepn and application |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008007825A1 (en) * | 2006-07-10 | 2008-01-17 | Pukyong National University Industry-Academic Cooperation Foundation | Quarternized amino glucosamine compound for exerting anticancer effect |
| CN104177452A (en) * | 2013-05-27 | 2014-12-03 | 淮海工学院 | Synthetic method for (E)-2-(N-(2-deoxy-1,3,4,6-O-tetraacetyl-2-D-glucosyl))amino-3-olefine acid |
| CN107286209A (en) * | 2016-03-31 | 2017-10-24 | 中国石油化工股份有限公司 | A kind of N- glucose hydrochlorides alkali maleic amide acid monomers, preparation method and application |
-
2003
- 2003-05-16 CN CNB031122744A patent/CN1310932C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008007825A1 (en) * | 2006-07-10 | 2008-01-17 | Pukyong National University Industry-Academic Cooperation Foundation | Quarternized amino glucosamine compound for exerting anticancer effect |
| CN104177452A (en) * | 2013-05-27 | 2014-12-03 | 淮海工学院 | Synthetic method for (E)-2-(N-(2-deoxy-1,3,4,6-O-tetraacetyl-2-D-glucosyl))amino-3-olefine acid |
| CN104177452B (en) * | 2013-05-27 | 2018-05-29 | 淮海工学院 | The synthetic method of one kind (E) -2- (N- (tetra-acetylated -2-D- glucosyl groups of 2- deoxidations -1,3,4,6-O-)) amino -3- olefin(e) acids |
| CN107286209A (en) * | 2016-03-31 | 2017-10-24 | 中国石油化工股份有限公司 | A kind of N- glucose hydrochlorides alkali maleic amide acid monomers, preparation method and application |
| CN107286209B (en) * | 2016-03-31 | 2020-04-24 | 中国石油化工股份有限公司 | N-glucose hydrochloride maleic amide acid monomer, preparation method and application |
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| Publication number | Publication date |
|---|---|
| CN1310932C (en) | 2007-04-18 |
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| C06 | Publication | ||
| PB01 | Publication | ||
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| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Weifang Noted Pharmaceutical Co., Ltd. Assignor: Ocean University of China Contract fulfillment period: 2008.10.14 to 2013.10.14 contract change Contract record no.: 2008990000830 Denomination of invention: N-crotonoyl hydroxy protected glucosamine and its prepn and application Granted publication date: 20070418 License type: Exclusive license Record date: 20081017 |
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| LIC | Patent licence contract for exploitation submitted for record |
Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2008.10.14 TO 2013.10.14; CHANGE OF CONTRACT Name of requester: WEIFANG NUODA PHARMACEUTICAL CO., LTD. Effective date: 20081017 |
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| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070418 Termination date: 20110516 |