CN110698538A - Cyclic peptide compound based on tyrosine coupling and preparation and application thereof - Google Patents
Cyclic peptide compound based on tyrosine coupling and preparation and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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Abstract
The invention relates to a tyrosine coupling-based cyclic peptide compound and a preparation method and application thereof. The preparation method of the cyclic peptide compound comprises the following steps: dissolving a compound shown in a formula (I) in water, adding an oxidant, a copper catalyst, an additive and a surfactant, reacting completely at normal temperature, and separating and purifying reaction liquid to obtain a cyclic peptide compound shown in a formula (II); the invention has the following beneficial effects: (1) the invention provides a cyclic peptide compound based on tyrosine coupling,can be used as a rubiyannin medicine mother ring for preparing a cyclic peptide compound based on tyrosine coupling; (2) the method for preparing the parent ring of the Yangning medicament can synthesize the original 9-step reaction into one step, and has the characteristics of simplicity, high efficiency, convenience and the like.
Description
(I) technical field
The invention relates to a tyrosine coupling-based cyclic peptide compound and preparation and application thereof.
(II) background of the invention
Cyclic peptides refer to compounds formed with amino acid peptide bonds, and this concept is expanded to a class of compounds formed with amide bonds in phytochemistry, and thus is expanded to include organic amines and macrocyclic alkaloids, and is divided into cyclic peptides and linear peptides according to whether or not ring formation is performed. The reported cyclic peptide compounds have various biological activities, including biological activities of resisting tumor, resisting HIV, resisting bacteria, resisting malaria, improving sleep, inhibiting platelet aggregation, lowering blood pressure, inhibiting tyrosinase, inhibiting cyclooxygenase, inhibiting lipid peroxidase, inhibiting estrogen-like activity, and inhibiting immunity.
Tyrosine, a nonessential amino acid, chemically known as 2-amino-3-p-hydroxyphenylpropionic acid, is an aromatic polar alpha-amino acid containing a phenolic hydroxyl group and is produced in humans and animals by hydroxylation of phenylalanine. It is involved in the production of dopamine, norepinephrine and epinephrine, and has the effects of regulating mood and stimulating nervous system. In addition, it can also promote metabolism and treat chronic fatigue. The increase and decrease of tyrosine can cause the formation of various diseases such as hypertyrosinemia and copper phenylhematuria. At present, tyrosine health care products are widely applied to the treatment of allergy, headache, Parkinson's disease and drug withdrawal reaction.
Lubiyangning is a highly effective anti-tumor natural product, and the activity of lubiyangning depends on glycosylation of fused tyrosine residues. Lubiyangning is a special compound of this family, and is a hexapeptide macrocycle consisting of two alanine amino acids (L-Ala, D-Ala), three modified tyrosine residues, two of which form a fused tyrosine. The tyrosine parent nucleus fused by two residues is an important structure of the lubiyangning compound, so that the synthesis of the drug parent nucleus has important significance.
Disclosure of the invention
The invention aims to provide a tyrosine coupling-based cyclic peptide compound, a preparation method thereof and application thereof as a tyrosine parent nucleus in preparation of lubiyangning medicaments.
The technical scheme adopted by the invention is as follows:
a tyrosine-based coupled cyclic peptide compound has a structure shown in a formula (II):
in the formula (II), R1 is hydrogen, acetyl, tert-butyloxycarbonyl, fluorenylmethoxycarbonyl chloride, amino acid or polypeptide chain; r2 is hydrogen, C1-C10 alkyl, substituted aryl, amino acid or polypeptide chain.
Preferably, the cyclic peptide compound is one of the following:
the present invention also relates to a method for preparing the cyclic peptide compound, the method comprising: dissolving a compound shown in a formula (I) in water, adding an oxidant, a copper catalyst, an additive and a surfactant, reacting completely at normal temperature, and separating and purifying reaction liquid to obtain a cyclic peptide compound shown in a formula (II); the additive is one of the following: silver acetate, silver trifluoroacetate, silver carbonate; the oxidant is one of the following: potassium persulfate or manganese dioxide, iodobenzene diacetate, benzoquinone, ferric trichloride; the copper catalyst is one of the following: copper acetate, copper chloride or copper diacetyl;
in the formulae (I), (II), R1Is hydrogen, acetyl, tert-butyloxycarbonyl or fluorenylmethoxycarbonylcarbonyl chloride; r2Hydrogen, C1-C10 alkyl and substituted aryl.
The separation and purification method comprises the following steps: adding a saturated NaCl aqueous solution into the reaction solution, extracting with dichloromethane, taking an organic layer, drying with magnesium sulfate, filtering, and rotationally evaporating at normal temperature to remove the solvent to obtain a crude product, and performing silica gel column chromatography on the crude product, wherein the volume ratio of the crude product to the solvent is 1: 3, using a solution of ethyl acetate and petroleum ether as a mobile phase, tracking and collecting an eluent with Rf value of 0.3-0.5 by TLC, decompressing and removing the solvent from the collected eluent, and drying to obtain the cyclic peptide compound shown in the formula (II).
Preferably, the amount ratio of the oxidant, the additive, the copper catalyst and the compound (I) is 1-5: 1-5: 0.1-2: 1.
the catalyst is preferably copper acetate; the oxidant is preferably potassium persulfate; the additive is preferably silver acetate; the surfactant is preferably polyethylene glycol octyl phenyl ether, and the initial concentration of the surfactant in the reaction liquid is 1-5 wt%, preferably 2 wt%.
The invention also relates to application of the cyclopeptide compound in preparation of lubiyangning medicaments. Specifically, the cyclic peptide compound is a compound shown as a formula (II-6).
The invention also relates to application of the cyclic peptide compound in preparing a skin care product additive. Specifically, the compound is a compound represented by one of formulas (II-1) to (II-5). When used in skin care products, the polypeptides act as messengers, triggering collagen synthesis, thereby increasing skin firmness. When collagen breaks down, the polypeptide acts like an alarm system, informing the body to make more collagen to help replace what is naturally lost with age. Therefore, the direct application of a product containing a polypeptide to the skin can serve as a fake alarm, enticing our skin to think that it loses collagen and needs to produce more. In addition, polypeptides help to stably transport trace elements (e.g., copper and manganese) to enzymatic reactions, which are essential for promoting collagen and elastin synthesis, new blood vessel growth, and wound healing.
The invention has the following beneficial effects: (1) the invention provides a cyclic peptide compound based on tyrosine coupling, which can be used as a rubiyangnin medicine mother ring for preparing a cyclic peptide compound based on tyrosine coupling; (2) the method for preparing the parent ring of the Yangning medicament can synthesize the original 9-step reaction into one step, and has the characteristics of simplicity, high efficiency, convenience and the like.
(IV) description of the drawings
FIG. 1 is a mass spectrum of compound (II-1);
FIG. 2 is a mass spectrum of compound (II-6).
(V) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
example 1: preparation of acetyl-tyrosine ethyl ester cyclic peptide
Adding 1mmol of acetyl-tyrosine ethyl ester into 10ml of water (containing 2% of polyethylene glycol octyl phenyl ether), adding 0.1mmol of copper acetate, 2.0mmol of potassium persulfate and 2.0mmol of silver acetate, reacting at normal temperature for 12 hours, adding a saturated NaCl aqueous solution into a reaction solution after the reaction is finished, extracting with dichloromethane, taking an organic layer, drying with anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness to obtain a crude compound. And (3) performing silica gel column chromatography on the coupling acetyl-tyrosine ethyl ester compound crude product to obtain a pure compound shown as a formula II-1, wherein a mass spectrogram is shown in figure 1. (LCMS (ESI +): Calculatedfor C23H25NO6: [ M + H ] +413.45, found 413.21.)
Example 2: preparation of Fmoc-tyrosine ethyl ester cyclic peptide
Adding 1mmol of fluorenylmethoxycarbonyl tyrosine-tyrosine ethyl ester into 10ml of water (containing 2% of polyethylene glycol octyl phenyl ether), adding 0.1mmol of copper acetate, 2.0mmol of potassium persulfate and 2.0mmol of silver acetate, reacting at normal temperature for 12 hours, adding a saturated NaCl aqueous solution into a reaction solution after the reaction is finished, extracting with dichloromethane, drying an organic layer by anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness to obtain a crude compound. And (3) performing silica gel column chromatography on the coupling acetyl-tyrosine ethyl ester compound crude product to obtain a compound pure product shown in the formula II-2. (LCMS (ESI +): scaled for C16H19NO6: [ M + H ] +593.12, found 593.42.)
Example 3: preparation of acetyl-tyrosine-glycine-tyrosine
Adding 1mmol of Fmoc-tyrosine ethyl ester into 4ml of water (containing 2% of polyethylene glycol octyl phenyl ether), adding 0.1mmol of copper acetate and 2.0mmol of ferric trichloride, reacting at normal temperature for 12 hours, adding saturated NaCl aqueous solution into the reaction solution after the reaction is finished, extracting with dichloromethane, taking an organic layer, drying with anhydrous sodium sulfate, filtering, and evaporating to dryness under reduced pressure to obtain a crude compound. And (3) performing silica gel column chromatography on the coupling acetyl-tyrosine ethyl ester compound crude product to obtain a compound pure product shown in the formula II-3. (LCMS (ESI +): scaled for C29H27NO7: [ M + H ] +442.12, found442.42.)
Example 4: preparation of acetyl-tyrosine-alanine-tyrosine cyclic peptides
Adding 1mmol of acetyl-tyrosine-alanine-tyrosine into 10ml of water (containing 2% of polyethylene glycol octyl phenyl ether), adding 0.1mmol of copper acetate, 2.0mmol of potassium persulfate and 2.0mmol of silver acetate, reacting at normal temperature for 12 hours, adding saturated NaCl aqueous solution into reaction liquid after the reaction is finished, extracting with dichloromethane, taking an organic layer, drying with anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness to obtain a crude compound. And (3) performing silica gel column chromatography on the acetyl-tyrosine-alanine-tyrosine cyclic peptide crude product to obtain a pure compound shown in the formula II-4. (LCMS ESI)+):Calculated for C31H30N2O8:[M+H]+456.12，found 456.42.)
Example 5: preparation of acetyl-tyrosine-glycine-alanine-tyrosine cyclic peptide
Adding 1mmol of acetyl-tyrosine-glycine-alanine into 10ml of water (containing 2% of polyethylene glycol octyl phenyl ether), adding 0.1mmol of copper acetate, 2.0mmol of potassium persulfate and 2.0mmol of silver acetate, reacting at normal temperature for 12 hours, adding saturated NaCl aqueous solution into reaction liquid after the reaction is finished, extracting with dichloromethane, taking an organic layer, drying with anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness to obtain a crude compound. And (3) performing silica gel column chromatography on the acetyl-tyrosine-glycine-alanine cyclopeptide compound crude product to obtain a compound pure product shown in the formula II-5. (LCMS ESI)+): Calculated for C25H28N4O8:[M+H]+513.12，found 513.42.)
Example 6: synthetic lubiyangning medicine mother ring
Adding 1mmol I-6 into 10ml water (containing 2% polyethylene glycol octyl phenyl ether), adding 0.1mmol copper acetate, 2.0mmol potassium persulfate and 2.0mmol silver acetate, reacting at normal temperature for 12 hours, adding saturated NaCl aqueous solution into the reaction solution after the reaction is finished, extracting with dichloromethane, taking the organic layer, drying with anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness to obtain the crude compound. And (3) performing silica gel column chromatography on the crude product of the acetyl-tyrosine-glycine-alanine cyclopeptide compound to obtain a pure compound (mass spectrum is shown in figure 2) shown as a formula II-6, wherein the compound is an important parent nucleus of the lubiyangning medicaments. (LCMS ESI)+):Calculated for C25H28N4O8:[M+H]+ 519.12，found 519.42.)。
Claims (9)
1. A tyrosine-based coupled cyclic peptide compound has a structure shown in a formula (II):
in the formula (II), R1Is hydrogen, acetyl, tert-butyloxycarbonyl, fluorenylmethoxycarbonylcarbonyl chloride, an amino acid, a polypeptide chain; r2Hydrogen, C1-C10 alkyl, substituted aryl, amino acid and polypeptide chain.
2. The cyclic peptide compound of claim 1, wherein the cyclic peptide compound is one of:
3. a process for preparing a cyclic peptide compound of claim 1, said process comprising: dissolving a compound shown in a formula (I) in water, adding an oxidant, a copper catalyst, an additive and a surfactant, reacting completely at normal temperature, and separating and purifying reaction liquid to obtain a cyclic peptide compound shown in a formula (II); the additive is one of the following: silver acetate, silver trifluoroacetate, silver carbonate; the oxidant is one of the following: potassium persulfate or manganese dioxide, iodobenzene diacetate, benzoquinone, ferric trichloride; the copper catalyst is one of the following: copper acetate, copper chloride or copper diacetyl;
in the formulae (I), (II), R1Is hydrogen, acetyl, tert-butyloxycarbonyl or fluorenylmethoxycarbonylcarbonyl chloride; r2Hydrogen, C1-C10 alkyl and substituted aryl.
4. The method according to claim 3, wherein the separation and purification method comprises: adding a saturated NaCl aqueous solution into the reaction solution, extracting with dichloromethane, taking an organic layer, drying with magnesium sulfate, filtering, and rotationally evaporating at normal temperature to remove the solvent to obtain a crude product, and performing silica gel column chromatography on the crude product, wherein the volume ratio of the crude product to the solvent is 1: 3, using a solution of ethyl acetate and petroleum ether as a mobile phase, tracking and collecting an eluent with Rf value of 0.3-0.5 by TLC, decompressing and removing the solvent from the collected eluent, and drying to obtain the cyclic peptide compound shown in the formula (II).
5. The method according to claim 3, wherein the amount of the oxidizing agent, the additive, the copper catalyst and the compound (I) is 1 to 5: 1-5: 0.1-2: 1.
6. use of the cyclic peptide compound of claim 1 for the preparation of lubiyangning drugs.
7. The use according to claim 6, wherein the cyclic peptide compound is of formula (II-6):
8. use of a cyclic peptide compound according to claim 1 for the preparation of a skin care additive.
9. Use according to claim 6, characterized in that the cyclic peptide compound is one of the following:
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110982806A (en) * | 2019-08-30 | 2020-04-10 | 浙江工业大学 | Protein aryl derivative and preparation method thereof |
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| CN108191887A (en) * | 2018-02-02 | 2018-06-22 | 黑龙江大学 | A kind of synthetic method of dibenzo spiral shell [4,5] dodecane ketone derivatives |
| CN109942452A (en) * | 2019-03-01 | 2019-06-28 | 浙江工业大学 | A kind of Olefination derivative of tyrosine and its preparation and application |
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Patent Citations (5)
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| JP2000128766A (en) * | 1998-10-26 | 2000-05-09 | Saburo Uchikuga | Skin-whitening cosmetic |
| WO2001025212A2 (en) * | 1999-10-01 | 2001-04-12 | Morphochem Ag | Cyclic biphenyls, method for the production thereof, and their use as medicaments |
| CN106916053A (en) * | 2017-02-20 | 2017-07-04 | 浙江泰达作物科技有限公司 | A kind of 2,4 disubstituted phenol prepares the green production process of '-biphenyl diphenol |
| CN108191887A (en) * | 2018-02-02 | 2018-06-22 | 黑龙江大学 | A kind of synthetic method of dibenzo spiral shell [4,5] dodecane ketone derivatives |
| CN109942452A (en) * | 2019-03-01 | 2019-06-28 | 浙江工业大学 | A kind of Olefination derivative of tyrosine and its preparation and application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110982806A (en) * | 2019-08-30 | 2020-04-10 | 浙江工业大学 | Protein aryl derivative and preparation method thereof |
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