CN109912477A - A kind of selenomethionine oxide and preparation method thereof and the application in synthesis polypeptide intramolecular disulfide bond - Google Patents
A kind of selenomethionine oxide and preparation method thereof and the application in synthesis polypeptide intramolecular disulfide bond Download PDFInfo
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- CN109912477A CN109912477A CN201910170189.1A CN201910170189A CN109912477A CN 109912477 A CN109912477 A CN 109912477A CN 201910170189 A CN201910170189 A CN 201910170189A CN 109912477 A CN109912477 A CN 109912477A
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- selenomethionine
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Abstract
Application the invention discloses a kind of selenomethionine oxide and preparation method thereof and in synthesis polypeptide intramolecular disulfide bond.Selenomethionine oxide has the structure as shown in formula (I).The present invention reacts selenomethionine oxide with reduced form polypeptide solution when applying at room temperature, and mixing, which can react, to be terminated, and high performance liquid chromatography separation reaction product is utilized.When selenomethionine oxide of the present invention is as oxidant synthesis polypeptide intramolecular disulfide bond, have yield high, reaction is fast, and raw material is cheap, and post-processing is simple and is suitable for the advantages of not having to reaction medium.The Atom economy that disulfide bond synthesizes in peptide molecule is set to be greatly improved.
Description
Technical field
The present invention relates to a kind of small organic molecule oxidant, specifically a kind of selenomethionine oxide and its system
Preparation Method and the application in synthesis polypeptide intramolecular disulfide bond.
Background technique
Disulfide bond can maintain the two-dimensional structure of polypeptide in peptide molecule, improve polypeptide pharmaceutical activity, selectivity and
Hydrolytic Resistance.Currently, the polypeptide drug containing intramolecular disulfide bond has been used clinically for the treatment of various diseases.Together
When, largely containing intramolecular disulfide bond, the polypeptide with pharmaceutical activity is in the clinical research in each stage.Therefore, it synthesizes
Disulfide bond is the important step of such polypeptide drugs synthesis in peptide molecule.Also, the conjunction of polypeptide drug intramolecular disulfide bond
At being an important reaction in fine organic chemical industry and pharmaceutical chemistry.It in the liquid phase, is current by the method for homogeneous oxidizing
The common method of synthesis polypeptide intramolecular disulfide bond.Oxidant used include: iodine, thallium trifluoroacetate (III), oxygen, DMSO,
Oxidized form of glutathione, K2[Pt(CN)4Cl2] and [Pt (en)2Cl2]Cl2And Ellman ' s reagent etc..But these oxidants
In synthesis polypeptide intramolecular disulfide bond, some meetings occur secondary anti-with methionine, tyrosine, the trp residue in polypeptide chain
Answer, some meetings make polypeptide generate the by-product of dimer or polymer, cause yield to reduce, some oxidants can generate toxicity compared with
Big by-product, the reaction medium that some oxidants are applicable in it is limited (Eur. J. Org. Chem., 2014, 3519–
3530).These synthetic methods greatly limit the Atom economy that disulfide bond synthesizes in peptide molecule.
Therefore, if can develop, a kind of applicable reaction medium is extensive, and yield is high, and reaction is fast, cheap oxidant, then
The cost payout for carrying out synthetic drug intramolecular disulfide bond using such oxidant can be substantially reduced, the atom warp of synthetic reaction is improved
Ji property.
Summary of the invention
An object of the present invention is to provide a kind of selenomethionine oxide and its in synthesis polypeptide intramolecular disulfide bond
In application, to solve the problems, such as that disulfide bond synthetic yield and Atom economy are low in existing peptide molecule.
The second object of the present invention is to provide the preparation method of above-mentioned selenomethionine oxide.
An object of the present invention is achieved in that
The selenomethionine oxide of one kind structure as shown in formula (I):
(I).
Application of the above-mentioned selenomethionine oxide as oxidant in synthesis polypeptide intramolecular disulfide bond.
The application is specially to react selenomethionine oxide at room temperature with reduced form polypeptide solution, is mixed
Can react terminates, and utilizes high performance liquid chromatography separation reaction product.
The selenomethionine oxide and reduced form polypeptide dosage molar ratio are 1 ~ 1.2: 1.
The reduced form polypeptide solution is using the polypeptide of the sulfydryl containing there are two as solute, with hydrochloric acid solution, water, water and acetonitrile
One of mixed liquor, hydrochloric acid solution and the mixed liquor of acetonitrile be made of solvent.
The volume ratio of water and acetonitrile is 1 ~ 5: 1 in the mixed liquor of the water and acetonitrile；The hydrochloric acid solution and acetonitrile it is mixed
The concentration of hydrochloric acid solution in liquid is closed as 0.1 ~ 1.0 mol/L, the volume ratio of hydrochloric acid solution and acetonitrile is 1 ~ 5: 1.
The reduced form polypeptide is reduced form oxytocins, reduced form arginine vasopressin, reduced form growth hormone release inhibiting hormone or reduction
Type polypeptide 1；Wherein, the amino acid sequence of the reduced form oxytocins are as follows: CYIQNCPLG-NH2, reduced form arginine vasopressin
Amino acid sequence are as follows: CYFQNCPRG-NH2, the amino acid sequence of reduced form growth hormone release inhibiting hormone are as follows: and AGCKNFFWKTFTSC-OH,
The amino acid sequence of reduced form polypeptide 1 are as follows: CGYCHKLHQMK-NH2。
The second object of the present invention is to what is be achieved: a kind of preparation method of above-mentioned selenomethionine oxide, including
Following steps:
A) selenomethionine is weighed in the round-bottomed flask with lesser trochanter, and deionized water is added in the side Bian Chaosheng, makes seleno egg ammonia
Acid dissolution obtains selenomethionine solution；
B) after progress magnetic agitation makes selenomethionine solution be cooled to 0 DEG C in ice-water bath, pair that mass concentration is 30% is added
Oxygen water reacts 10 ~ 30 minutes；
C) reaction solution is freeze-dried to get the selenomethionine oxide.
In the above method, the selenomethionine: dioxygen water consumption=0.5g: 400 ~ 600 μ L.
Selenomethionine oxide of the invention can be applied in the preparation of the polypeptide drugs containing intramolecular disulfide bond, fit
Synthesis for disulfide bond in the peptide molecule of different structure.Oxidant of the invention compared with existing several typical reagents,
It is suitable for different reaction mediums, the reaction time is short (mixing can end of reaction).The reaction rate especially in acid medium
Fastly, the methionine not aoxidized in polypeptide is residual.
The purification processes of product polypeptide of the present invention are simple, by liquid phase analysis, i.e., the purpose of reachable separation target product.
Therefore, when selenomethionine oxide is as oxidant synthesis polypeptide intramolecular disulfide bond, have yield high, reaction is fast, raw material
Cheaply, post-processing is simple and is suitable for the advantages of not having to reaction medium.Make the Atom economy that disulfide bond synthesizes in peptide molecule
It is greatly improved.
Detailed description of the invention
Fig. 1 is the chromatogram of 1 gained oxidized form oxytocins of the embodiment of the present invention.
Fig. 2 is the chromatogram of 8 gained oxidized form arginine vasopressin of the embodiment of the present invention.
Fig. 3 is the chromatogram of 9 gained oxidized form growth hormone release inhibiting hormone of the embodiment of the present invention.
Fig. 4 is the chromatogram of 10 gained oxidized form polypeptide 1 of the embodiment of the present invention.
Fig. 5 is the mass spectrogram of 1 gained oxidized form oxytocins of the embodiment of the present invention.
Fig. 6 is the mass spectrogram of 8 gained oxidized form arginine vasopressin of the embodiment of the present invention.
Fig. 7 is the mass spectrogram of 9 gained oxidized form growth hormone release inhibiting hormone of the embodiment of the present invention.
Fig. 8 is the mass spectrogram of 10 gained oxidized form polypeptide 1 of the embodiment of the present invention.
Specific embodiment
Oxidant (i.e. selenomethionine oxide) of the invention can be closed with a variety of reduced form polypeptides reactives containing sulfydryl
At disulfide bond in peptide molecule.
Selenomethionine oxide and the reduced form polypeptide containing sulfydryl pass through following scheme synthesis polypeptide intramolecular disulfide
Key: selenomethionine oxide reacts at room temperature with reduced form polypeptide solution, and mixing i.e. reaction terminates, and then, utilizes
High performance liquid chromatography separation reaction product, and reaction product is identified by mass spectrum.
Selenomethionine oxide used in following embodiment is obtained by the following method: weighing the seleno egg ammonia of 0.5g
In 50 mL, in lesser trochanter round-bottomed flask, 25mL water is added, ultrasound, dissolves selenomethionine when being added in acid.?
After magnetic agitation is cooled to 0 DEG C in ice-water bath, the hydrogen peroxide that the mass concentration of 500 μ L of addition is 30%, reaction 10 ~ 30 minutes, then
Reaction solution is freeze-dried to get selenomethionine oxide is arrived.
Embodiment 1
10 × 10-3In mol/L hydrochloric acid solution, selenomethionine oxide is reacted with reduced form oxytocins.With 10 × 10- 3The molten liquid compound concentration respectively of mol/L hydrochloric acid is 2.0 × 10-3The reduced form oxytocins solution of mol/L and 2.0 × 10-3Mol/L's
Each 1mL of selenomethionine oxide solution, reaction can terminate after mixing, solution liquid-phase chromatographic analysis oxidized form oxytocins,
Use mass spectroscopy.The yield of oxidized form oxytocins is 99%.
Embodiment 2
50 × 10-3In mol/L hydrochloric acid solution, selenomethionine oxide is reacted with reduced form oxytocins.With 50 × 10- 3The molten liquid compound concentration respectively of mol/L hydrochloric acid is 2.0 × 10-3The reduced form oxytocins solution of mol/L and 2.0 × 10-3Mol/L's
Each 1mL of selenomethionine oxide solution, reaction can terminate after mixing, solution liquid-phase chromatographic analysis oxidized form oxytocins,
Use mass spectroscopy.The yield of oxidized form oxytocins is 99%.
Embodiment 3
In 0.1 mol/L hydrochloric acid solution, selenomethionine oxide is reacted with reduced form oxytocins.With 0.1 mol/L hydrochloric acid
Molten liquid compound concentration respectively is 2.0 × 10-3The reduced form oxytocins solution of mol/L and 2.0 × 10-3The selenomethionine of mol/L
Each 1mL of oxide solution, reaction can terminate after mixing, and solution liquid-phase chromatographic analysis oxidized form oxytocins uses mass spectroscopy.
The yield of oxidized form oxytocins is 99%.
Embodiment 4
In 1.0 mol/L hydrochloric acid solutions, selenomethionine oxide is reacted with reduced form oxytocins.With 1.0 mol/L hydrochloric acid
Molten liquid compound concentration respectively is 2.0 × 10-3The reduced form oxytocins solution of mol/L and 2.0 × 10-3The selenomethionine of mol/L
Each 1mL of oxide solution, reaction can terminate after mixing, and solution liquid-phase chromatographic analysis oxidized form oxytocins uses mass spectroscopy.
The yield of oxidized form oxytocins is 98%.
Embodiment 5
In water, selenomethionine oxide is reacted with reduced form oxytocins.It is 2.0 × 10 with water difference compound concentration-3mol/
The reduced form oxytocins solution of L and 2.0 × 10-3Each 1mL of selenomethionine oxide solution of mol/L, reaction can after mixing
Terminate, solution liquid-phase chromatographic analysis oxidized form oxytocins uses mass spectroscopy.The yield of oxidized form oxytocins is 98%.
Embodiment 6
(the 1:1 in water and acetonitrile mixed solutionv/v) in, selenomethionine oxide is reacted with reduced form oxytocins.With water and
Acetonitrile mixed solution compound concentration is 2.0 × 10-3The reduced form oxytocins solution of mol/L and 2.0 × 10-3The seleno egg of mol/L
Each 1mL of propylhomoserin oxide solution, reaction can terminate after mixing, and solution liquid-phase chromatographic analysis oxidized form oxytocins uses mass spectrum
Measurement.The yield of oxidized form oxytocins is 97%.
Embodiment 7
(the 1:1 in 1.0 mol/L hydrochloric acid and acetonitrile mixed solutionv/v) in, selenomethionine oxide and reduced form oxytocins
Reaction.It is 2.0 × 10 with 1.0 mol/L hydrochloric acid and acetonitrile mixed solution compound concentration-3The reduced form oxytocins solution of mol/L and
2.0×10-3Each 1mL of selenomethionine oxide solution of mol/L, reaction can terminate after mixing, solution liquid chromatogram point
Oxidized form oxytocins is analysed, mass spectroscopy is used.The yield of oxidized form oxytocins is 97%.
Embodiment 8
It is 2.0 × 10 with water difference compound concentration-3The reduced form arginine vasopressin solution of mol/L and 2.0 × 10-3Mol/L's
Each 1mL of selenomethionine oxide solution, reaction can terminate after mixing, solution liquid-phase chromatographic analysis arginine vasopressin,
Use mass spectroscopy.The yield of oxidized form arginine vasopressin is 88%.
Embodiment 9
It is 2.0 × 10 with water difference compound concentration-3The reduced form growth hormone release inhibiting hormone solution of mol/L and 2.0 × 10-3The seleno of mol/L
Each 1mL of methionine oxidation object solution, reaction can terminate after mixing, and solution liquid-phase chromatographic analysis growth hormone release inhibiting hormone is surveyed with mass spectrum
It is fixed.The yield of oxidized form growth hormone release inhibiting hormone is 95%.
Embodiment 10
It is 2.0 × 10 with water difference compound concentration-31 solution of reduced form polypeptide of mol/L and 2.0 × 10-3The seleno egg of mol/L
Each 1mL of propylhomoserin oxide solution, reaction can terminate after mixing, and solution liquid-phase chromatographic analysis polypeptide 1 uses mass spectroscopy.Oxygen
The yield of change type polypeptide 1 is 99%.
Comparative example 1
It is 10 × 10 with water difference compound concentration-3The reduced form oxytocins solution of mol/L and 2.0 × 10-3[the Pt of mol/L
(en)2Cl2]Cl2Each 1mL of solution, mixing, 10 h of room temperature concussion reaction.Solution liquid-phase chromatographic analysis oxytocins.Oxidized form is urged
The yield for producing element is 85%.Reaction yield is higher, but the reaction time is up to 10h.
Comparative example 2
It is 10 × 10 with water difference compound concentration-31 solution of reduced form polypeptide of mol/L and 2.0 × 10-3The K of mol/L2[Pt
(CN)4Cl2] each 1mL of solution, mixing, 2 h of room temperature concussion reaction.Solution liquid-phase chromatographic analysis oxidized form polypeptide 1.It is generating
While disulfide bond, the methionine 30% in polypeptide is oxidized to methionine sulfoxide, keeps product impure, the yield of oxidized form polypeptide 1
It is 70%.
Comparative example 3
The ratio of 1:1 is added acetonitrile and obtains mixed solution the NaAc_HAc buffer solution of pH=4.65 by volume, mixes molten
It is spare that liquid leads to nitrogen 1h；In the reaction flask of 2 mL, preparing 1 mL concentration with the mixed solution of preparation is 1.0 × 10-3 mol/L
1 solution of reduced form polypeptide, this solution reacts with the oxygen in air, and magnetic agitation reacts 36 h, and reaction terminates.Oxidized form is more
The yield of peptide 1 is 50%.
Comparative example 4
It is spare that acetonitrile leads to 1 h of nitrogen；In the reaction flask of 5 mL, preparing 1 mL concentration is 1.0 × 10-3 The reduced form of mol/L is more
50 μ L triethylamines are added in 1 solution of peptide, and the acetonitrile solution that 2 mL contain 10 mg iodine is then added, and react 6 h, and reaction terminates, goes
Except excessive elemental iodine, the yield for analyzing oxidized form polypeptide 1 is 65%.
Above embodiments and experimental data show that selenomethionine oxide of the invention can be used in the more of different structure
The synthesis of disulfide bond in peptide molecule.Oxidant of the invention is compared with existing several typical reagents, suitable for different reactions
Medium, reaction time are short (mixing can end of reaction).Especially reaction rate is fast in acid medium, does not aoxidize the egg in polypeptide
Histidine residue；With traditional oxidant such as iodine, oxygen, DMSO is compared, this selenomethionine oxide oxidizing agent also has yield
High advantage, when synthesizing oxidized form polypeptide 1, using oxygen as oxidant, yield only has 50%；And using elemental iodine as
Purity is 65% when oxidant.After synthesis polypeptide intramolecular disulfide bond, the purification processes of polypeptide are simple, and those skilled in the art
It is known when using DMSO as oxidant, the purification of polypeptide needs to carry out multiple freeze-drying process after reaction, and DMSO is gone back
It originally was the very big dimethyl sulfide of toxicity, and selenomethionine oxide oxidizing agent leads to after synthesis polypeptide intramolecular disulfide bond
Cross liquid phase analysis, i.e., the purpose of reachable separation target product.Therefore, selenomethionine oxide is as oxidant synthesis polypeptide
When intramolecular disulfide bond, have yield high, reaction is fast, and raw material is cheap, and post-processing is simple and suitable for not having to the excellent of reaction medium
Point.The Atom economy that disulfide bond synthesizes in peptide molecule is set to be greatly improved.
Claims (9)
1. a kind of selenomethionine oxide of the structure as shown in formula (I):
(I).
2. a kind of preparation method of selenomethionine oxide described in claim 1, characterized in that the following steps are included:
A) selenomethionine is weighed in the round-bottomed flask with lesser trochanter, and deionized water is added in the side Bian Chaosheng, makes seleno egg ammonia
Acid dissolution obtains selenomethionine solution；
B) after progress magnetic agitation makes selenomethionine solution be cooled to 0 DEG C in ice-water bath, pair that mass concentration is 30% is added
Oxygen water reacts 10 ~ 30 minutes；
C) reaction solution is freeze-dried to get the selenomethionine oxide.
3. the preparation method of selenomethionine oxide according to claim 2, characterized in that the selenomethionine:
Dioxygen water consumption=0.5g: 400 ~ 600 μ L.
4. application of the selenomethionine oxide as oxidant in synthesis polypeptide intramolecular disulfide bond described in claim 1.
5. application according to claim 4, characterized in that by selenomethionine oxide and reduced form polypeptide solution in room
It is reacted under the conditions of temperature, mixing, which can react, to be terminated, and high performance liquid chromatography separation reaction product is utilized.
6. application according to claim 5, characterized in that the selenomethionine oxide rubs with reduced form polypeptide dosage
You are than being 1 ~ 1.2: 1.
7. application according to claim 5, characterized in that the reduced form polypeptide solution is containing there are two the more of sulfydryl
Peptide is solute, with one of mixed liquor of the mixed liquor of hydrochloric acid solution, water, water and acetonitrile, hydrochloric acid solution and acetonitrile for solvent
It is made.
8. application according to claim 7, characterized in that the volume ratio of water and acetonitrile in the mixed liquor of the water and acetonitrile
It is 1 ~ 5: 1；In the mixed liquor of the hydrochloric acid solution and acetonitrile the concentration of hydrochloric acid solution be 0.1 ~ 1.0 mol/L, hydrochloric acid solution and
The volume ratio of acetonitrile is 1 ~ 5: 1.
9. application according to claim 5, characterized in that the reduced form polypeptide is reduced form oxytocins, reduced form essence
Propylhomoserin pitressin, reduced form growth hormone release inhibiting hormone or reduced form polypeptide 1；Wherein, the amino acid sequence of the reduced form oxytocins are as follows:
CYIQNCPLG-NH2, the amino acid sequence of reduced form arginine vasopressin are as follows: CYFQNCPRG-NH2, reduced form growth hormone release inhibiting hormone
Amino acid sequence are as follows: AGCKNFFWKTFTSC-OH, the amino acid sequence of reduced form polypeptide 1 are as follows: CGYCHKLHQMK-NH2。
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2015160825A (en) * | 2014-02-27 | 2015-09-07 | 学校法人東海大学 | Method for producing relaxin |
| CN105085603A (en) * | 2015-08-26 | 2015-11-25 | 河北大学 | Reusable load type platinum complex oxidizing agents, and preparation method and application thereof |
| US20160090397A1 (en) * | 2014-09-30 | 2016-03-31 | Northeastern University | Se-Adenosyl-L-Selenohomocysteine Selenoxide As A Modulator Of Methyltransferase And Other Activities |
| CN106866744A (en) * | 2017-02-20 | 2017-06-20 | 河北大学 | A kind of tetravalence platinum complex oxidant and its preparation method and application |
| CN107892710A (en) * | 2017-10-10 | 2018-04-10 | 河北大学 | A kind of load type platinum complex oxidant for being easily recycled recycling and its preparation method and application |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015160825A (en) * | 2014-02-27 | 2015-09-07 | 学校法人東海大学 | Method for producing relaxin |
| US20160090397A1 (en) * | 2014-09-30 | 2016-03-31 | Northeastern University | Se-Adenosyl-L-Selenohomocysteine Selenoxide As A Modulator Of Methyltransferase And Other Activities |
| CN105085603A (en) * | 2015-08-26 | 2015-11-25 | 河北大学 | Reusable load type platinum complex oxidizing agents, and preparation method and application thereof |
| CN106866744A (en) * | 2017-02-20 | 2017-06-20 | 河北大学 | A kind of tetravalence platinum complex oxidant and its preparation method and application |
| CN107892710A (en) * | 2017-10-10 | 2018-04-10 | 河北大学 | A kind of load type platinum complex oxidant for being easily recycled recycling and its preparation method and application |
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