CN1398591A - Anticancer cantharidoid-glycosamine coupler and its prepn and application - Google Patents
Anticancer cantharidoid-glycosamine coupler and its prepn and application Download PDFInfo
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- CN1398591A CN1398591A CN 02135401 CN02135401A CN1398591A CN 1398591 A CN1398591 A CN 1398591A CN 02135401 CN02135401 CN 02135401 CN 02135401 A CN02135401 A CN 02135401A CN 1398591 A CN1398591 A CN 1398591A
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- cantharidoid
- glycosamine
- coupler
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- cantharidin
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Abstract
The anticancer canthrridoid-glycosamine coupler is obtained through the dewatering coupling reaction of glucosamine derivative and cantharidoid compound in the presence of solvent and dewatering agent at room temperature. The compound of the present invention has extraneous antineoplastic activity, and the mutual supplement of the two reactants raises the target performance and the body's absorbing rate of the compound and lowers the toxic side effect.
Description
The present invention relates to cantharidoid-glycosamine coupler and preparation method thereof and application that a class has anti-tumor activity.
Cantharidin is a kind of anti-tumor active ingredient that extracts from the Chinese medicine Mylabris, norcantharidin is because removed two Mes in the cantharidin structure, thereby cancerous cell had stronger affinity, can be in the higher concentration of the local formation of carcinoma, keep the long time, and can impel its apoptosis by the number of ways destruction of cancer cells.Though cantharidin is having certain curative effect in treatment aspect the tumor, yet human body urinary system and gastronintestinal system are had untoward reaction, as: frequent micturition, urgent micturition, hematuria and feel sick etc., and its poor selectivity, toxicity is big.
The purpose of this invention is to provide a kind of cantharidoid-glycosamine coupler, be about to class cantharidin chemical compound and the coupling of glucosamine derivant and play rice, prepare a series of class cantharidin-glucosamine conjugate, to overcome the above-mentioned shortcoming on the prior art.
A kind of anticancer cantharidoid-glycosamine coupler is characterized in that glucosamine or its derivant are connected with amido link with class Cantharidin chemical compound at amino position.
A kind of preparation method of anticancer cantharidoid-glycosamine coupler is characterized in that by glucosamine derivant and class Cantharidin chemical compound the coupling reaction of dewatering of room temperature in the presence of solvent and dehydrant.
A kind of anticancer cantharidoid-glycosamine coupler is characterized in that it as cancer therapy drug.
Chemical compound of the present invention has anti tumor activity in vitro, by the addition complementation of two kinds of reactants, has improved the targeting and the body absorption rate of chemical compound, has reduced toxic and side effects.
Below by embodiment the present invention is described.
Embodiment 1
The D-glucamine hydrochlorate of 12mmol is added in the acetonitrile solution of 60ml 50%, add equimolar triethylamine again, stirring at room, after vial becomes transparent liquid, add and wait mole 5,6-dibromo cantharidin stirred five hours in the presence of dehydrant dicyclohexylcarbodiimide (DCC).Distilling under reduced pressure is desolvated, and is the eluent column chromatography with methanol-ethyl acetate, obtains a kind of white product 2 ' of the present invention (2-deoxyglucose-2-carbamoyl)-5 '; 6 '-two bromo-7 '-oxabicyclo [2; 2,1] heptane-1 '-carboxylic acid (1) 2.32g, yield: 38.5%.mp：92-93℃。Can see 3331cm from its pressing potassium bromide troche infrared spectrum
-1, 2500-3000cm
-1, 1656cm
-1, 1723cm
-1The NH at place, OH, the characteristic absorption peak of C=O.Proton nmr spectra (the CDCl of this chemical compound
3, δ, ppm) in, 7.52-7.53 is the peak of NH, the 6.46th, the peak of COOH, 4.82-4.83 is the peak of OH, the 4.61st, the peak of sugar ring Cl position H.Infrared spectrum and proton nmr spectra can determine that institute's its structure of synthetic conjugate is as follows.
Wherein, the R of conjugate (1) is H, and the R of conjugate (2) is-COCH
3, the R of conjugate (3) is-COC
6H
6Results of elemental analyses is that C is 33.53%, and H is 4.25%, and N is 2.04%, proves that this degree of purity of production reaches 99%.
The used reactant D-glucosamine amine hydrochlorate of present embodiment can change 1,3,4 into, 6-four-O-acetyl group-D-glucamine hydrochlorate, 1,3,4,6-four-O-benzoyl-D-glucamine hydrochlorate or 1,3,4,6-four-O-benzyl-D-glucamine hydrochlorate; Another reactant 5,6-dibromo cantharidin can be used norcantharidin or 5 instead, 6-dehydrogenation cantharidin.
Embodiment 2
With 3mmol 1,3,4; 6-four-O-acetyl group-D-glucamine hydrochlorate is put into the 30ml acetonitrile, stirs, and does not dissolve; the very fast dissolving of solid after adding equimolar triethylamine is filtered, and adds equimolar 5 in filtrate; 6-dibromo cantharidin; stirring at room is 10 hours in the presence of dehydrant DCC, separates out the present invention and gets conjugate (2) 2 ' (1,3; 4; 6-four-O-acetyl group-2-deoxyglucose-2-carbamoyl)-5 ', 6 '-two bromo-7 '-oxabicyclo [2,2; 1] heptane-1 '-carboxylic acid white solid; sucking filtration, filter cake be with cold acetonitrile washing 2 times, dry product 1.00g of the present invention; yield: 48.5%, mp:196-197.Can see 3350cm from its pressing potassium bromide troche infrared spectrum
-1, 2500-3000cm
-1, 1669cm
-1, 1746cm
-1The NH at place, the characteristic absorption peak of OH and C=O.Its proton nmr spectra (CDCl
3, δ is hydrogen peak on 1 in the sugar ring carbon at 5.70-5.72 ppm), and 4.86-4.91 is the hydrogen peak on 4 in the sugar ring carbon 3, carbon, and 4.25-4.26 is the peak at the hydrogen peak on 6 in the sugar ring carbon, and 1.92-2.03 is CH
3The peak.Infrared spectrum and proton nmr spectra can determine the structure of synthetic conjugate (2).Elementary analysis proves that this degree of purity of production reaches 99%.
It is more that the sugar ring is gone up reaction site, often produces many by-products when the unprotected sugar of hydroxyl reacts when using.The glucosamine amine of reagent utilization acyl group protection can be avoided the generation of by product in the present embodiment, and its advantage is to improve the conversion ratio of product.
Embodiment 3
Get 2.5mmol 1,3,4; 6-four-O-benzoyl-D-glucamine hydrochlorate adds in the 25ml acetonitrile, stirs, and is insoluble; add equimolar triethylamine; substantially entirely molten, filter, in filtrate, add equimolar 5; 6-dibromo Norabieta cantharidin; stirring at room is 24 hours in the presence of dehydrant DCC, and the most of solvent of pressure reducing and steaming is admixed silica gel; with ethyl acetate-chloroform for the eluant column chromatography gets product 3 ' (1 of the present invention; 3,4,6-four-O-benzoyl-2-deoxyglucose-2-carbamoyl)-5 '; 6 '-two bromo-7 '-oxabicyclo [2; 2,1] heptane-1 '-carboxylic acid (3) white product 0.98g, yield: 43.5%.mp：169-170℃。Can see 3353cm from its pressing potassium bromide troche infrared spectrum
-1, 3066cm
-1, 2500-3000cm
-1, 1680cm
-1, 1731cm
-1The NH at place, ArH, the characteristic absorption peak of OH and C=O.Proton nmr spectra (the CDCl of this chemical compound
3δ, ppm) at the 7.44-7.98 place be the hydrogen peak of phenyl ring, 6.19-6.20 be the hydrogen peak of 1 in sugar ring carbon, 5.85-5.87 be the hydrogen peak of 3 in sugar ring carbon, 5.53-5.55 is the hydrogen peak of 4 in sugar ring carbon, 4.85-4.86 is the hydrogen peak of 2 in sugar ring carbon, 4.29 be the hydrogen peak of 5 in sugar ring carbon, 4.07-4.09 is the hydrogen peak of 6 in sugar ring carbon.Infrared spectrum and proton nmr spectra can determine the structure of synthetic conjugate (3).Elementary analysis proves that this degree of purity of production reaches 99%.
The present invention the anti-tumor activity of synthetic conjugate
The present invention adopts tetrazolium bromide experimental technique (mtt assay) to measure the active anticancer of institute of the present invention synthetic compound, at people's pulmonary carcinoma (PC-14), has carried out the active anticancer screening on ovarian cancer (A2780) cell strain.The anti-tumor activity experimental result show synthetic chemical compound the effect that suppresses PC-14, A2780 cell strain is all arranged.Particularly the present invention synthetic conjugate (2) suppression ratio of PC-14, A2780 cell strain is higher than the suppression ratio of reference substance 5-fluorouracil, shown the effect that suppresses growth of tumour cell preferably.When drug level is 0.15 μ mol/ml, conjugate (2) can reach 87.16% to the suppression ratio of PC-14 cell strain, can reach 93.83% to A2780 cell strain suppression ratio, and five fluorouracil (5-Fu) reach 90.73% required drug level to the suppression ratio of PC-14 cell strain is 0.77 μ mol/ml, and it is 0.77 μ mol/ml that A2780 cell strain suppression ratio is reached 94.39% required drug level.This shows that class cantharidin chemical compound links to each other with amino sugar and derivant thereof, and antitumor activity significantly improves.The modification of sugar to this compounds is described, can changes its characteristic, increase its activity.
The pernicious behavior of malignant cell is attacked transfer as blood, cell surface saccharide complex synthetic, and adhesion molecule in glycan structures and cell surface and the substrate and receptor thereof all have the ten minutes confidential relation with sugar.The glycan structures of skin covering of the surface has significant change in the malignant change of cell process, and synthetic and excretory glycoprotein of tumor cell and sugar chain structure also have similar variation, and the glycolipid in tumor cell enters body is formed also and normally marked difference.Therefore research and development directly acts on the medicine on the film water horizontal target point, certainly will help to find efficient specificity antineoplastic medicine.
D-glucosamine is present in the multiple animal body, is an important monosaccharide of higher mammal glycoprotein chains.Form the monosaccharide of sugar chain in proteoglycan, great majority also have amino, and they mainly are present in intercellular substance, surface of cell membrane, and cartilaginous tissue, corneal stroma is in aorta and some synovial bursa mucus structures.Have now found that amino sugar has multiple biological activity, particularly tumor cell is had preferably lethal effect and very little human normal cell's toxicity.In addition, many results of study show that glucoside compound also has multiple physiologically active and good pharmacological action.
The present invention is based on above-mentioned two aspect factors, use principle of hybridization, class cantharidin chemical compound and D-glucosamine or glucosamine derivant are coupled together, prepare a series of class cantharidin-glucosamine conjugate.By both addition complementations, purpose is to improve the targeting and the bioavailability thereof of chemical compound, seeks the curative effect height, and the new antitumoral compounds that toxic and side effects is low is in the hope of the clinical new type antineoplastic medicine that provides is provided.
Claims (4)
1, a kind of anticancer cantharidoid-glycosamine coupler is characterized in that glucosamine or its derivant are connected with amido link with class Cantharidin chemical compound at amino position.
2, a kind of preparation method of anticancer cantharidoid-glycosamine coupler is characterized in that by glucosamine derivant and class Cantharidin chemical compound the coupling reaction of dewatering of room temperature in the presence of solvent and dehydrant.
3, a kind of anticancer cantharidoid-glycosamine coupler is characterized in that it as cancer therapy drug.
4,, it is characterized in that the hydroxyl of described reactant glucosamine derivant is connected to acetyl or benzoyl base or benzyl as claim 2 described preparation methoies.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 02135401 CN1398591A (en) | 2002-08-02 | 2002-08-02 | Anticancer cantharidoid-glycosamine coupler and its prepn and application |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977175A (en) * | 2011-09-07 | 2013-03-20 | 四川大学 | Application of glucosamine derivatives as small molecule drug kidney-targeting modifying groups |
| CN107652335A (en) * | 2017-09-27 | 2018-02-02 | 遵义医学院 | A kind of Acegastrodine derivative preparation method and its anti-lung cancer activity application |
-
2002
- 2002-08-02 CN CN 02135401 patent/CN1398591A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102977175A (en) * | 2011-09-07 | 2013-03-20 | 四川大学 | Application of glucosamine derivatives as small molecule drug kidney-targeting modifying groups |
| CN102977175B (en) * | 2011-09-07 | 2015-12-02 | 四川大学 | Aminoglucose sugar derivatives is as the purposes of small-molecule drug kidney targeting modification group |
| CN107652335A (en) * | 2017-09-27 | 2018-02-02 | 遵义医学院 | A kind of Acegastrodine derivative preparation method and its anti-lung cancer activity application |
| CN107652335B (en) * | 2017-09-27 | 2020-02-11 | 遵义医科大学 | Preparation method of acetyl gastrodin derivative and application of acetyl gastrodin derivative in anti-liver cancer activity |
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