CN101245103A - Process for producing cantharidin artificial antigen - Google Patents
Process for producing cantharidin artificial antigen Download PDFInfo
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- CN101245103A CN101245103A CNA2008100694888A CN200810069488A CN101245103A CN 101245103 A CN101245103 A CN 101245103A CN A2008100694888 A CNA2008100694888 A CN A2008100694888A CN 200810069488 A CN200810069488 A CN 200810069488A CN 101245103 A CN101245103 A CN 101245103A
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- propyloic
- blister beetle
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Abstract
The invention discloses a preparation method of a cantharidin artificial antigen. The preparation method includes a plurality of steps of the condensation reaction of a natural cantharidin and a Beta-alanine, the crystallization and purification of an intermediate product and the coupling of the intermediate product and a bovine serum albumin (BSA) or an ovalbumin (OVA). The steps of the preparation method are simple and reasonable, the product is special and novel; and the preparation method can also be used for the preparation of a cantharidin complete antigen and the artificial synthesis of a cantharidin target-positioning anti-tumor drug.
Description
Technical field
The invention belongs to the antigenic method of small organic molecule artificial preparation, specifically, relate to a kind of preparation method of cantharidin artificial antigen.
Background technology
Cantharidin (canthariding) is a kind of small molecules toxic substance of part Coleoptera Meloidae insect (being commonly called as Chinese blister beetle) synthesis secretion, and its chemical structure is terpenoid (C
10H
12O
4).Tradition Chinese materia medica and modern clinical application research find that Cantharidin has unique curative effect aspect treatment cancer and some difficult and complicated cases.Cantharidin and derivative etc. thereof have extremely strong affinity and specialization to " Cantharidin the is conjugated protein "-phosphoprotein phosphatase 2A in the tumour cell, to treatment primary hepatocarcinoma (Zheng Yinglan etc., 2005 evident in efficacy; Li Qi etc., 2006), also be used to diseases such as treatment or adjuvant treatment of breast cancer, esophagus cancer, lung cancer, carcinoma of gastric cardia, intestinal cancer, liver cirrhosis, chronic hepatitis and neurodermatitis, can be used for treating mange simultaneously, the scrofula that disappears disease etc., be to use more ideal broad-spectrum anti-cancer drug and external preparation for skin medicine a few days ago.In addition, the interleukin-II that Cantharidin can also stimulate splenic lymphocyte to produce increases 2-5 doubly, and the interleukin-I that scavenger cell produces increases 1.5-2 doubly, thus the enhance immunity function, can be used as the adjuvant drug (Zhang Junping etc., 1992) of anticancer chemicotherapy.The medical mechanism research of Chinese blister beetle and the development and use of resource thereof are subject to people's attention day by day.In China, the cancer therapy drug that with the Cantharidin is main component has had more than 10 kinds, as strange peaceful sheet (disodium cantharidinate sheet), strange injection for curing, DELISHENG ZHUSHEYE, Ai Kang injection liquid (disodium cantharidinate+vitamin B6), Yi Erkang injection liquid (Disodium Norcantharidate injection liquid), methyl Cantharidin sheet, Norcantharidin sheet, N-methylcantharidimide sheet, cantharides capsule etc.Wherein, cantharides capsule has good therapeutic action to some malignant tumours, and this medicine both can improve patient's immunological competence, activates cancer suppressor gene, again can kill cancer cell, dual function is arranged, and national Bureau of Drugs Supervision was chosen as general curing cancer drug with it in 2002.It simultaneously also is national Chinese medicine protection kind.
Therefore the biological activity small molecules can not directly adopt immunization method to detect owing to do not possess complete antigen.At present, mainly use methods such as gas-chromatography, liquid chromatography for the detection of small molecule bioactive material, the Analysis and Identification of Cantharidin is at present mainly with methods such as gas-chromatographies.These methods all can only detect the Cantharidin of unbound state, and need special equipment.The aspects such as seed selection that the Cantharidin insect was identified, produced to the Cantharidin composition in the biosynthesizing research of Cantharidin, medicine usually need fast and convenient method, also need sometimes the Cantharidin in the histocyte is carried out in situ detection.Adopt immunological method to detect then to have fast, sensitive, particularly can carry out the advantage of in situ detection, but the preparation of cantharidin artificial antigen does not see that so far the document record is arranged.
Summary of the invention
The object of the present invention is to provide a kind of is antigenic determinant with natural Cantharidin, with the Beta-alanine is connecting arm, with Cantharidin and bovine serum albumin (BSA) or oralbumin (OVA) through condensation, coupling, crystallization and the preparation method of the artificial complete antigen of Cantharidin.
Technical scheme of the present invention is as follows: make natural Cantharidin and Beta-alanine carry out condensation reaction, with the extraction crystallization purifying of intermediate product, intermediate product makes with steps such as carrier protein couplets again has immunogenic complete antigen.
The present invention is achieved in that
Step 1, imido preparation of N-propyloic Chinese blister beetle and purifying,
(1) in the twoport flask, adds natural Cantharidin crystallization and Beta-alanine, mol ratio is 1: 1.1～1: 1.4, adding 10ml～20ml Glacial acetic acid makes it substance dissolves after the above-mentioned reaction, promote the reaction of natural Cantharidin crystallization and Beta-alanine, load onto prolong, thermometer, 35～40 ℃ of water-baths 4～6 hours.Boil off glacial acetic acid then, add 10ml～20ml triethylamine, make it to install substance dissolves after the above-mentioned reaction additional the hygroscopic desiccation ball simultaneously, be warmed up to 135 ℃～140 ℃ reactions 4～6 hours on a small quantity as catalyzer and reactant.Reaction process is as follows:
(2) after reaction finishes, boiling off triethylamine, is pH 1～2 with dilute hydrochloric acid acid adjustment basicity, subsequently, uses ethyl acetate extraction, can according to circumstances extract repeatedly, keeps the yellow-green colour water, concentrates near doing; Use washed with methanol, filter, filtrate concentrates near doing, and uses re-crystallizing in ethyl acetate at last, must make with extra care its structural formula of N-propyloic Chinese blister beetle imide crystallization and be
(3) getting the crystallization of N-propyloic Chinese blister beetle imide is dissolved in the methylene dichloride, add N-hydroxy-succinamide (NHS), N successively, N-dicyclohexylcarbodiimide (DCC), mol ratio is 1: 2: 2, stirring reaction carries out reduction vaporization under the room temperature of mixing back after 18～24 hours, and the gained enriched material carries out recrystallization with methylene dichloride.Crystallization is dissolved in a small amount of pyridine dissolves the formation pyridine solution fully with crystallization; Get BSA (bovine serum albumin) or OVA (oralbumin) is dissolved in the phosphoric acid buffer of 0.03mol/L, wherein BSA or OVA and the imido mol ratio of N-propyloic Chinese blister beetle are 1: 20～1: 30; N-propyloic Chinese blister beetle imide pyridine solution is mixed with BSA or OVA phosphoric acid buffer, and mixed solution is dialysed after 12～24 hours at 4 ℃ of following stirring reactions, lyophilize, gets the artificial complete antigen of Cantharidin.
Step 2, the imido detection of N-propyloic Chinese blister beetle:
(1) the ultraviolet waves spectrum analysis is identified
As solvent, Beta-alanine and condensation product are made ultraviolet full wavelength scanner (Cantharidin is water insoluble) with distilled water, draw the ultraviolet absorpting spectrum of condensation product and Beta-alanine.After measured, the λ max of Beta-alanine (Ala) is 214nm, and the λ max of condensation product (product) is 245.5nm, and promptly Beta-alanine at introducing Chinese blister beetle acyl group post-absorption ripple tangible red shift has taken place.
(2) nucleus magnetic resonance checking
Carbon spectrum (D with BrukerAvance500NMR nmr determination condenses
2O is a solvent, 500MHz, normal temperature), can draw the carbon of 8 kinds of different chemical environment from the 13C-NMR collection of illustrative plates of condensation product, its δ (ppm) is respectively: 8.449 (q ,-CH
3); 11.579 (t ,-CH
2-); 23.286 (t ,-CH
2-); 35.910 (t ,-CH
2-); 46.787 (d,
); 54.245 (s,
); 163.782 (s,
); 183.959 (s ,-COOH).Substantially meet with the predictor of N-propyloic Chinese blister beetle imide structure each carbon of 13C-NMR in the simulation of ChemDraw programcomputer.This shows that this condensation product is N-propyloic Chinese blister beetle imide.
Beneficial effect: the present invention has that method is reasonable, simple and practical, security is good, the antigen finished product stable in properties of preparation, advantage such as immunity is strong.The present invention also can be used for the preparation and the localized application of Cantharidin target of Cantharidin antibody.
Description of drawings
Fig. 1 is the ultraviolet absorpting spectrum of condensation product and Beta-alanine;
Fig. 2 is the 13C-NMR collection of illustrative plates of condensation product.
Embodiment
Embodiment one,
(1) in the twoport flask, adds natural Cantharidin crystallization 70.6mg and Beta-alanine 37.6mg, add the Glacial acetic acid of 10ml then, load onto prolong, thermometer, 35 ℃ of water-baths 6 hours.Boil off glacial acetic acid, add triethylamine 20ml, be warming up to 135 ℃ of reactions 5 hours.
(2) after reaction finishes, boil off triethylamine, transfer pH to 1.5 with dilute hydrochloric acid, subsequently, with ethyl acetate extraction once, keep the yellow-green colour water, concentrate near doing, use washed with methanol, filter, filtrate concentrates near doing, and uses re-crystallizing in ethyl acetate at last, must make with extra care N-propyloic Chinese blister beetle imide xln.
(3) get N-propyloic Chinese blister beetle imide 95.8mg and be dissolved in the methylene dichloride, add NHS82.8mg, DCC 148.5mg successively, mix to stir after 20 hours under the room temperature of back and carry out reduction vaporization, enriched material is carried out recrystallization with methylene dichloride.Crystallization is dissolved in 2 milliliters of pyridines and forms pyridine solution; Get in the phosphoric acid buffer that BSA 792mg is dissolved in 20ml 0.03mol/L, N-propyloic Chinese blister beetle imide pyridine solution mixed with the BSA phosphoric acid buffer, dialyse after 24 hours at 4 ℃ of following stirring reactions, lyophilize, the artificial complete antigen of Cantharidin.
As solvent, Beta-alanine and condensation product are made ultraviolet full wavelength scanner (Cantharidin is water insoluble) with distilled water, draw the ultraviolet absorpting spectrum of condensation product and Beta-alanine.After measured, the λ max of (referring to Fig. 1) Beta-alanine (Ala) is 214nm, and the λ max of condensation product (product) is 245.5nm, and promptly Beta-alanine at introducing Chinese blister beetle acyl group post-absorption ripple tangible red shift has taken place.
Carbon spectrum (D with Bruker Avance500NMR nmr determination condenses
2O is a solvent, 500MHz, normal temperature), (referring to Fig. 2) can draw the carbon of 8 kinds of different chemical environment from the 13C-NMR collection of illustrative plates of condensation product, and its δ (ppm) is respectively: 8.449 (q ,-CH
3); 11.579 (t ,-CH
2-); 23.286 (t ,-CH
2-); 35.910 (t ,-CH
2-); 46.787 (d,
); 54.245 (s,
); 163.782 (s,
); 183.959 (s ,-COOH).Substantially meet with the predictor of N-propyloic Chinese blister beetle imide structure each carbon of 13C-NMR in the simulation of ChemDraw programcomputer.This shows that this condensation product is N-propyloic Chinese blister beetle imide.
Embodiment two,
(1) in the twoport flask, adds Cantharidin crystallization 75.2mg and Beta-alanine 37.6mg, add the Glacial acetic acid of 20ml then, load onto prolong, thermometer, 40 ℃ of water-baths 4.5 hours.Boil off glacial acetic acid, add triethylamine 10ml, be warming up to 135 ℃ of reactions 6 hours.
(2) after reaction finishes, boil off triethylamine, transfer pH to 2.0 with dilute hydrochloric acid, subsequently, with ethyl acetate extraction three times, keep the yellow-green colour water, concentrate near doing, use washed with methanol, filter, filtrate concentrates near doing, and uses re-crystallizing in ethyl acetate at last, must make with extra care N-propyloic Chinese blister beetle imide xln.
(3) get N-propyloic Chinese blister beetle imide crystallization 95.8mg and be dissolved in the methylene dichloride, add NHS82.8mg, DCC 148.5mg successively, the stirring at room reaction was carried out reduction vaporization after 24 hours, and enriched material is carried out recrystallization with methylene dichloride.Crystallization is dissolved in a small amount of pyridine and forms pyridine solution; Getting oralbumin (OVA) 365mg is dissolved among the phosphoric acid buffer 20ml of 0.03mol/L, N-propyloic Chinese blister beetle imide pyridine solution is mixed with the OVA phosphoric acid buffer, dialyse after 16 hours at 4 ℃ of following stirring reactions, lyophilize, the artificial complete antigen of Cantharidin.
As solvent, Beta-alanine and condensation product are made ultraviolet full wavelength scanner (Cantharidin is water insoluble) with distilled water, draw the ultraviolet absorpting spectrum of condensation product and Beta-alanine.After measured, the λ max of (referring to Fig. 1) Beta-alanine (Ala) is 214nm, and the λ max of condensation product (product) is 245.5nm, and promptly Beta-alanine at introducing Chinese blister beetle acyl group post-absorption ripple tangible red shift has taken place.
Carbon spectrum (D with Bruker Avance500NMR nmr determination condenses
2O is a solvent, 500MHz, normal temperature), (referring to Fig. 2) can draw the carbon of 8 kinds of different chemical environment from the 13C-NMR collection of illustrative plates of condensation product, and its δ (ppm) is respectively: 8.449 (q ,-CH
3); 11.579 (t ,-CH
2-); 23.286 (t ,-CH
2-); 35.910 (t ,-CH
2-); 46.787 (d,
); 54.245 (s,
); 163.782 (s,
); 183.959 (s ,-COOH).Substantially meet with the predictor of N-propyloic Chinese blister beetle imide structure each carbon of 13C-NMR in the simulation of ChemDraw programcomputer.This shows that this condensation product is N-propyloic Chinese blister beetle imide.
Embodiment three,
(1) in the twoport flask, adds Cantharidin crystallization 68.6mg and Beta-alanine 40.5mg, add the Glacial acetic acid of 15ml then, load onto prolong, thermometer, 40 ℃ of water-baths 5 hours.Boil off glacial acetic acid, add triethylamine 15ml, be warming up to 140 ℃ of reactions 4 hours.
(2) after reaction finishes, boil off triethylamine, transfer pH to 2.0 with dilute hydrochloric acid, subsequently, with ethyl acetate extraction five times, keep the yellow-green colour water, concentrate near doing, use washed with methanol, filter, filtrate concentrates near doing, and uses re-crystallizing in ethyl acetate at last, must make with extra care N-propyloic Chinese blister beetle imide xln.
(3) get N-propyloic Chinese blister beetle imide crystallization 95.8mg and be dissolved in the methylene dichloride, add NHS82.8mg, DCC 148.5mg successively, the stirring at room reaction was carried out reduction vaporization after 18 hours, and enriched material is carried out recrystallization with methylene dichloride.Crystallization is dissolved in a small amount of pyridine and forms pyridine solution; Getting oralbumin (OVA) 400mg is dissolved among the phosphoric acid buffer 20ml of 0.03mol/L, N-propyloic Chinese blister beetle imide pyridine solution is mixed with the OVA phosphoric acid buffer, dialyse after 16 hours at 4 ℃ of following stirring reactions, lyophilize, cantharidin artificial antigen.
As solvent, Beta-alanine and condensation product are made ultraviolet full wavelength scanner (Cantharidin is water insoluble) with distilled water, draw the ultraviolet absorpting spectrum of condensation product and Beta-alanine.After measured, the λ max of (referring to Fig. 1) Beta-alanine (Ala) is 214nm, and the λ max of condensation product (product) is 245.5nm, and promptly Beta-alanine at introducing Chinese blister beetle acyl group post-absorption ripple tangible red shift has taken place.
Carbon spectrum (D with Bruker Avance500NMR nmr determination condenses
2O is a solvent, 500MHz, normal temperature), (referring to Fig. 2) can draw the carbon of 8 kinds of different chemical environment from the 13C-NMR collection of illustrative plates of condensation product, and its δ (ppm) is respectively: 8.449 (q ,-CH
3); 11.579 (t ,-CH
2-); 23.286 (t ,-CH
2-); 35.910 (t ,-CH
2-); 46.787 (d,
); 54.245 (s,
); 163.782 (s,
); 183.959 (s ,-COOH).Substantially meet with the predictor of N-propyloic Chinese blister beetle imide structure each carbon of 13C-NMR in the simulation of ChemDraw programcomputer.This shows that this condensation product is N-propyloic Chinese blister beetle imide.
Embodiment four,
(1) in the twoport flask, adds Cantharidin crystallization 68.6mg and Beta-alanine 43.6mg, add the Glacial acetic acid of 15ml then, load onto prolong, thermometer, 38 ℃ of water-baths 6 hours.Boil off glacial acetic acid, add triethylamine 20ml, be warming up to 138 ℃ of reactions 5 hours.
(2) after reaction finishes, boil off triethylamine, transfer pH to 1.8 with dilute hydrochloric acid, subsequently, with ethyl acetate extraction three times, keep the yellow-green colour water, concentrate near doing, use washed with methanol, filter, filtrate concentrates near doing, and uses re-crystallizing in ethyl acetate at last, must make with extra care N-propyloic Chinese blister beetle imide xln.
(3) get N-propyloic Chinese blister beetle imide crystallization 95.8mg and be dissolved in the methylene dichloride, add NHS82.8mg, DCC 148.5mg successively, the stirring at room reaction was carried out reduction vaporization after 22 hours.Enriched material is carried out recrystallization with methylene dichloride.Crystallization is dissolved in a small amount of pyridine and forms pyridine solution; Get BSA 820mg and be dissolved among the 0.03mol/L phosphoric acid buffer 20ml, N-propyloic Chinese blister beetle imide pyridine solution is mixed with the BSA phosphoric acid buffer, dialyse after 18 hours at 4 ℃ of following stirring reactions, lyophilize, the artificial complete antigen of Cantharidin.
As solvent, Beta-alanine and condensation product are made ultraviolet full wavelength scanner (Cantharidin is water insoluble) with distilled water, draw the ultraviolet absorpting spectrum of condensation product and Beta-alanine.After measured, the λ max of (referring to Fig. 1) Beta-alanine (Ala) is 214nm, and the λ max of condensation product (product) is 245.5nm, and promptly Beta-alanine at introducing Chinese blister beetle acyl group post-absorption ripple tangible red shift has taken place.
Carbon spectrum (D with BrukerAvance500NMR nmr determination condenses
2O is a solvent, 500MHz, normal temperature), (referring to Fig. 2) can draw the carbon of 8 kinds of different chemical environment from the 13C-NMR collection of illustrative plates of condensation product, and its δ (ppm) is respectively: 8.449 (q ,-CH
3); 11.579 (t ,-CH
2-); 23.286 (t ,-CH
2-); 35.910 (t ,-CH
2-); 46.787 (d,
); 54.245 (s,
); 163.782 (s,
); 183.959 (s ,-COOH).Substantially meet with the predictor of N-propyloic Chinese blister beetle imide structure each carbon of 13C-NMR in the simulation of ChemDraw programcomputer.This shows that this condensation product is N-propyloic Chinese blister beetle imide.
Claims (3)
1, a kind of preparation method of cantharidin artificial antigen is characterized in that: comprise the steps:
Step 1, imido preparation of N-propyloic Chinese blister beetle and purifying
(1) in flask, adds natural Cantharidin crystallization and Beta-alanine, the mol ratio of the two is 1: 1.1～1: 1.4, the Glacial acetic acid that adds 10ml～20ml then, 35～40 ℃ of water-baths 4～6 hours, boil off glacial acetic acid, add 10ml～20ml triethylamine, install the hygroscopic desiccation ball additional, heat to 135 ℃～140 ℃, reacted 4～6 hours;
(2) after reaction finishes, boil off triethylamine, transferring the reaction product potential of hydrogen with dilute hydrochloric acid is pH 1～2, subsequently, use ethyl acetate extraction, keep the yellow-green colour water, concentrate near doing, filter with washed with methanol, filtrate concentrates near doing, use re-crystallizing in ethyl acetate at last, must make with extra care the crystallization of N-propyloic Chinese blister beetle imide, its structural formula is
Step 2, the artificial complete antigen preparation of Cantharidin
(1) getting the crystallization of N-propyloic Chinese blister beetle imide is dissolved in the methylene dichloride, add NHS, DCC then, the crystallization of N-propyloic Chinese blister beetle imide: the mol ratio of NHS: DCC is 1: 2: 2, mix under the room temperature of back and stirred 18～24 hours, carry out reduction vaporization then, evaporate and residue obtainedly carry out recrystallization with methylene dichloride;
(2) crystallization is dissolved in to dissolve fully in the pyridine and forms pyridine solution; Get in the phosphoric acid buffer that BSA or OVA be dissolved in 0.03mol/L, N-propyloic Chinese blister beetle imide pyridine solution is mixed with BSA or OVA phosphoric acid buffer, wherein BSA or OVA and the imido mol ratio of N-propyloic Chinese blister beetle are 1: 20～1: 30; Dialyse after 12～24 hours at 4 ℃ of following stirring reactions, lyophilize, obtain the artificial complete antigen xln of colourless Cantharidin.
2, according to the preparation method of the described cantharidin artificial antigen of claim 1, it is characterized in that: the optimum molar ratio of natural Cantharidin crystallization and Beta-alanine reaction is 1: 1.2 in the described step 1.
3, according to the preparation method of the described cantharidin artificial antigen of claim 1, it is characterized in that: BSA or OVA and the imido optimum molar ratio of N-propyloic Chinese blister beetle are 1: 25 in the described step 2.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008100694888A CN101245103A (en) | 2008-03-20 | 2008-03-20 | Process for producing cantharidin artificial antigen |
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|---|---|---|---|
| CNA2008100694888A CN101245103A (en) | 2008-03-20 | 2008-03-20 | Process for producing cantharidin artificial antigen |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102372774A (en) * | 2010-08-18 | 2012-03-14 | 中国人民解放军军事医学科学院卫生学环境医学研究所 | Synthesis method for atrazine artificial complete antigen |
| CN105601650A (en) * | 2016-03-18 | 2016-05-25 | 齐鲁工业大学 | Structure, preparation method and use of diethylenetriamine-based cantharidimide dimer derivative |
| CN105777782A (en) * | 2016-03-18 | 2016-07-20 | 齐鲁工业大学 | Two crystal structures of cantharidimide dipolymer derivative, preparation method and application |
-
2008
- 2008-03-20 CN CNA2008100694888A patent/CN101245103A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102372774A (en) * | 2010-08-18 | 2012-03-14 | 中国人民解放军军事医学科学院卫生学环境医学研究所 | Synthesis method for atrazine artificial complete antigen |
| CN105601650A (en) * | 2016-03-18 | 2016-05-25 | 齐鲁工业大学 | Structure, preparation method and use of diethylenetriamine-based cantharidimide dimer derivative |
| CN105777782A (en) * | 2016-03-18 | 2016-07-20 | 齐鲁工业大学 | Two crystal structures of cantharidimide dipolymer derivative, preparation method and application |
| CN105601650B (en) * | 2016-03-18 | 2017-12-19 | 齐鲁工业大学 | Structure, the preparation and use of diethylenetriamine base Chinese blister beetle acid imide dimer derivate |
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Application publication date: 20080820 |