CN107987124A - A kind of dipeptide compound and its application - Google Patents

A kind of dipeptide compound and its application Download PDF

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Publication number
CN107987124A
CN107987124A CN201710992217.9A CN201710992217A CN107987124A CN 107987124 A CN107987124 A CN 107987124A CN 201710992217 A CN201710992217 A CN 201710992217A CN 107987124 A CN107987124 A CN 107987124A
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CN
China
Prior art keywords
compound
tyrosine
coo
tyrosinase
dipeptide compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201710992217.9A
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Chinese (zh)
Inventor
周彬
徐金荣
查建生
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NANJING SIBAIKE BIOCHEMICAL INDUSTRY Co Ltd
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NANJING SIBAIKE BIOCHEMICAL INDUSTRY Co Ltd
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Priority to CN201710992217.9A priority Critical patent/CN107987124A/en
Publication of CN107987124A publication Critical patent/CN107987124A/en
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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
    • A—HUMAN NECESSITIES
    • 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
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • 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
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
    • A61K2800/782—Enzyme inhibitors; Enzyme antagonists

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Dermatology (AREA)
  • Cosmetics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention discloses a kind of dipeptide compound and its application, the dipeptide compound is based on two tyrosine, the straight-chain carboxyl group of certain length can be connected, the compound morning tyrosinase has remarkable result on suppressing, cell toxicity test verifies no cytotoxicity, show that it is not stimulated under patch test, it is safe to use；Tyrosinase inhibitory activity is significantly higher than current market and generally uses whitening agent.

Description

A kind of dipeptide compound and its application
Technical field
The present invention relates to organic chemistry and Peptides Synthesis, relates in particular to a kind of dipeptide compound and its application.
Background technology
Currently used white-making ingredient can substantially be divided into plant extract class, vitamin C series, benzenediol class, song Acids and micromolecule polypeptide class, vitamin C series is using Vitamin C Ethyl Ether, L-Ascorbic Acid L-O-Phosphate as representative, by also Former melanin intermediates are oxidized easily so as to play skin whitening effect, but such product stability deficiency；Kojic acid class can make junket Propylhomoserin oxidation reaction loses activity, and suppresses the generation of melanin, except whitening function also has certain anti-corrosion effect；Benzene two Phenols is based primarily upon the principle of Reverse transcriptase tyrosinase activity so as to fulfill whitening effect.
It is carnosine and glutathione that polypeptide compound, which is most applied in cosmetics, is constantly improved with the research of polypeptide, Develop successively in recent years no less than the relevant bioactive small molecule polypeptide of beautifying skin anti-aging, such as copper victory peptide, acetyl Base hexapeptide -3, Matrixyl -3, palmityl tripeptides -5 etc., these micromolecule polypeptides are aobvious to skin tone, anti-wrinkle and other effects Write, but do not have the product that effect protrudes in whitening also at present.
When skin is subject to environmental stimuli or ultraviolet to irradiate, α-melanotropin in basal layer cell will be with Recipient on melanocyte combines, and direct stimulation melanin cell, activates Tyrosine Enzyme, starts to secrete melanin.Some Whitening agent forms source in melanin and is blocked, and stops the conduction of α-melanotropin message, avoids with being connect on melanocyte Receiver combines, to reduce melanin generation chance.Most commonly used whitening polypeptide products are nonapeptide -1 currently on the market.It has More outstanding whitening effect, and it is safe to use.
The content of the invention
Goal of the invention：The object of the present invention is to provide the dipeptide compound that a kind of Reverse transcriptase tyrosine realizes whitening； The present invention also provides the composition containing foregoing dipeptide compound, and the present invention also provides foregoing dipeptide compound to prepare tyrosine Application on enzyme inhibitor.
Technical solution：A kind of dipeptide compound of the present invention, shown in its general formula such as formula (I)：
Wherein, X is selected from H, or the straight-chain carboxyl group containing 1~20 carbon atom.
The dipeptide compound of the present invention is to form peptide bond using two tyrosine, and one of tyrosine has free ammonia Base, or amino are substituted by side chain X group.
Further, the group X is selected from H, CH3COO、CH3CH2CH2COO、CH3(CH2)12COO、CH3(CH2)14COO、 CH3(CH2)16Any one of COO.It is highly preferred that the group X is selected from CH3COO and CH3CH2CH2COO。
The compound can use the synthesis of a variety of prior arts to obtain, and as one of which preferred embodiment, use Following method obtains：
When X is H, the amino of tyrosine A is protected first, blocking group includes but not limited to tert-butyl carbonyl (Boc), any one of benzyloxycarbonyl group (Cbz), tablet held before the breast by officials methoxycarbonyl group (Fmoc)；Then with existing active ester method to tyrosine A's Carboxyl is activated, and n-hydroxysuccinimide (HOSU), o-nitrophenol (ONP) can be selected in the active ester method；Then exist It is condensed, then deprotects with tyrosine B under alkaline condition, forms the dipeptide compound.
When X is the straight-chain carboxyl group containing 1~20 carbon atom, acylation reaction first is carried out to the amino of tyrosine A, is carried out The acid of acylation reaction is consistent with the structure of X group.Then lived with existing active ester method to the carboxyl of acylated tyrosine X-A Change, n-hydroxysuccinimide (HOSU), o-nitrophenol (ONP) can be selected in the active ester method；Then in alkaline conditions It is condensed with tyrosine B, forms the dipeptide compound.
The present invention dipeptide compound include but not limited to itself, on the basis of itself physicochemical property, its Acceptable salt is also within the scope of the present invention on chemical species.
The dipeptide compound product of the present invention is white powder, is dissolved in water, after tested no cytotoxicity, is had to tyrosinase There is a significant inhibitory action, inhibition is higher than such as mandelic acid known in the art, VC ethylethers, tranexamic acid, VC Portugals The tyrosinase inhibitor products such as polyglycoside, VC phosphate magnesium, dipeptide compound of the invention is to junket under monophenolase active testing Propylhomoserin inhibition of enzyme activity effect is 50 times of VC phosphate magnesium, is 14 times of VC ethylethers.The product presses down tyrosinase activity Effect processed is 36 times of nonapeptide -1, and effect is unexpected, and in view of it, which possesses, stablizes the property such as nontoxic, non-stimulated, may replace mesh Preceding nonapeptide -1 is as the excellent whitening agent of a new generation.
Acceptable salt can be used for preparing new tyrosinase inhibitor in the compound or its chemical species, the suppression Preparation can effectively suppress tyrosinase activity, have significant whitening effect.
Embodiment
The present invention is further described with reference to specific embodiment
Embodiment 1
A kind of dipeptide compound, shown in its general formula such as formula (I)：
Wherein, X is selected from H, or the straight-chain carboxyl group containing 1~20 carbon atom；Preferably, table 1 includes wherein 6 compounds, the source of these compound X groups is easier to obtain, and has significant whitening effect.
Table 1
X group Title Molecular weight
Compound 1 H L- tyrosyls-l-tyrosine 344.364
Compound 2 CH3COO Acetyl-L- tyrosyls-l-tyrosine 386.404
Compound 3 CH3CH2CH2COO Butyryl-L- tyrosyls-l-tyrosine 414.454
Compound 4 CH3(CH2)12COO Myristoyl-L- tyrosyls-l-tyrosine 554.724
Compound 5 CH3(CH2)14COO Palmityl-L- tyrosyls-l-tyrosine 582.774
Compound 6 CH3(CH2)16COO 18 acyl-L- tyrosyls-l-tyrosine 610.824
Above compound can use the synthesis of a variety of prior arts to obtain, and preferred solution is for example：
When X is H, the amino of tyrosine A is protected first, blocking group includes but not limited to tert-butyl carbonyl (Boc), any one of benzyloxycarbonyl group (Cbz), tablet held before the breast by officials methoxycarbonyl group (Fmoc)；Then with existing active ester method to tyrosine A's Carboxyl is activated, and n-hydroxysuccinimide (HOSU), o-nitrophenol (ONP) can be selected in the active ester method；Then exist It is condensed, then deprotects with tyrosine B under alkaline condition, forms the dipeptide compound.
When X is the straight-chain carboxyl group containing 1~20 carbon atom, acylation reaction first is carried out to the amino of tyrosine A, is carried out The acid of acylation reaction is consistent with the structure of X group.Then lived with existing active ester method to the carboxyl of acylated tyrosine X-A Change, n-hydroxysuccinimide (HOSU), o-nitrophenol (ONP) can be selected in the active ester method；Then in alkaline conditions It is condensed with tyrosine B, forms the dipeptide compound.
1 cell toxicity test of test example
1. experiment material
Mouse melanin tumor cell (B16), DMEM (high sugar) culture medium, PBS, Hank balanced salt solution (HBSS), blue or green chain Mycin and hyclone (FBS), 0.25% pancreatin (containing EDTA), DMSO, CCK-8 kit.
Test group is selected from compound 1 to totally six compounds of compound 6, empty respectively by 500mg/ml and 1mg/ml dosings White control.
2. experimental procedure
The cell suspension of 100 μ L is configured in 96 orifice plates.By culture plate when incubator preculture 24 is small (37 DEG C, 5% CO2).The test substance of 10 μ L various concentrations of above-mentioned test group and blank control is separately added into culture plate.Culture plate is being trained Support case be incubated 24 it is small when.Then 10 μ L CCK solution are added to every hole, when incubation 1-4 is small in incubator, is measured with microplate reader 450nm absorbances.
Tyrosinase vigor calculation formula：
Cell viability*(%)=[A(dosing)-A(blank)]/[A(0 dosing)-A(blank)]×100
A(dosing)：The absorbance in the hole with cell, CCK solution and drug solution；
A(blank)：With culture medium and CCK solution without the absorbance in the hole of cell；
A(0 dosing)：With cell, CCK solution without the absorbance in the hole of drug solution.
* cell viability refers to cell Proliferation vigor or cytotoxicity vigor.
3. result of the test
2 cell toxicity test of table
4. experiment conclusion
From table 2 it can be seen that above-claimed cpd 1 is to 6 equal no cytotoxicity of compound.Other compound phases are for this six It differs only in the carbon atom number difference of X straight-chain carboxyl groups for compound, its chemical property is close with above-claimed cpd, and All there is no cytotoxicity through testing and verification.
2 irritation verification of test example-patch test
1. experiment prepares
Tested material：Compound 2；
Negative control：Distilled water；
Subject：Totally 30 people, male 4 people, 26 people of female, one full year of life at age 18-60, the subject for meeting following standard is arranged Remove：
(1) nursing period or pregnancy women；
(2) the extremely sensitive person of constitution；
(3) use within nearly one week antihistamine or use immunodepressant in nearly one month；
(4) nearly two months recipient sites use any anti-inflammatory drug；
(5) inflammatory dermatoses are suffered from and are not fully recovered；
(6) insulin-dependent diabetes mellitus patient；
(7) asthma for the treatment of or other chronic respiratory disease patients are being received；
There is the person that receives cancer chemotherapy in (8) six months；
(9) immune deficiency or spontaneous immunity disease patient；
(10) other clinical and experimental studies person is participated in；
(11) test zone has the skin table that the influences such as large area birthmark, scratch, day shift, mole, keloid are tested Sign.
2. test method
Suitable spot examination device is selected, to close patch test method, according to customer requirement, is diluted sample using distilled water Be added to 10%, 0.02g-0.025g in patch examination device, external application special adhesive tape is pasted on subject back, 24 it is small when after remove Tested material, dermoreaction is observed when 0.5,24,48 is small after removal, according to《Cosmetics safety technical specification》(2015 Version) in skin grade scale record its result.
3. skin adverse reaction grade scale
3. result of the test
4. conclusion (of pressure testing)
For compound 2 carry out human skin patch the results show that having no adverse reaction in 30 people.
Patch test has also separately been carried out to other compounds, has as a result shown nonirritant to application on human skin, has been had no adverse reaction.
3 tyrosine inhibitory activity of test example is tested
1. test method
L-tyrosine, the VC standard items or medicine to be measured and phosphate of various concentrations of certain volume are added into 96 orifice plates Buffer solution adds tyrosinase after being incubated in 37 DEG C, after 37 DEG C are reacted a period of time, is measured under BioTek microplate reader rapidly Absorbance.Each concentration setting three is parallel；Blank group and control are set.
2. criterion
Tyrosinase activity (single phenol enzymatic activity) inhibiting rate %=[1-Ai/Ao] × 100%
A0=(A control group-A blank groups)
Ai=(A medicine group-A blank groups)
The suppression tyrosinase activity ability under 3 concentration is measured, EC50, i.e. tyrosinase are calculated after data are fitted Sample solution concentration when maximum inhibition is 50%, EC50 is smaller, and it is stronger to suppress tyrosinase (single phenol enzymatic activity) ability.
3. result of the test
Suppression of the table 3 to tyrosinase activity (single phenol enzymatic activity)
4. conclusion (of pressure testing)
Test common several whitening agent tyrosinase activities (single phenol enzymatic activity) inhibitory action of in the market and AC-YYDE ammonia The inhibitory action of phytase activity (single phenol enzymatic activity), since EC50 is smaller, it is stronger to suppress tyrosinase (single phenol enzymatic activity) ability. It is 50 times of L-Ascorbic Acid L-O-Phosphate so it can be seen from Table 3 that AC-YY is fabulous to tyrosinase activity inhibition.
The above is only the preferred embodiment of the present invention, it should be pointed out that：For the ordinary skill people of the art For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications also should It is considered as protection scope of the present invention.

Claims (4)

  1. A kind of 1. dipeptide compound, shown in its general formula such as formula (I)：
    Wherein, X is selected from H, or the straight-chain carboxyl group containing 1~20 carbon atom.
  2. 2. polypeptide compound according to claim 1, it is characterised in that：The group X is selected from H, CH3COO、 CH3CH2CH2COO、CH3(CH2)12COO、CH3(CH2)14COO、CH3(CH2)16Any one of COO.
  3. 3. polypeptide compound according to claim 2, it is characterised in that：The group X is selected from H, CH3COO、 CH3CH2CH2COO。
  4. A kind of 4. application of dipeptide compound on tyrosinase inhibitor is prepared as claimed in claim 1.
CN201710992217.9A 2017-10-20 2017-10-20 A kind of dipeptide compound and its application Pending CN107987124A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109893463A (en) * 2019-04-24 2019-06-18 深圳市健翔生物制药有限公司 A kind of whitening peptide composition and its preparation and use
CN114315958A (en) * 2022-01-11 2022-04-12 北京志道生物科技有限公司 Compound and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102492018A (en) * 2010-07-27 2012-06-13 萧乃文 Tyrosinase polypeptide inhibitor
CN102395598B (en) * 2009-04-17 2014-07-30 利普泰股份公司 Peptides used in the treatment and/or care of the skin and/or hair and their use in cosmetic or pharmaceutical compositions
CN105362088A (en) * 2015-12-22 2016-03-02 深圳市维琪医药研发有限公司 Polypeptide composition for skin whitening and spot relieving

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102395598B (en) * 2009-04-17 2014-07-30 利普泰股份公司 Peptides used in the treatment and/or care of the skin and/or hair and their use in cosmetic or pharmaceutical compositions
CN102492018A (en) * 2010-07-27 2012-06-13 萧乃文 Tyrosinase polypeptide inhibitor
CN105362088A (en) * 2015-12-22 2016-03-02 深圳市维琪医药研发有限公司 Polypeptide composition for skin whitening and spot relieving

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PAUL G.SCOTT: "Spectroscopic study of environment-dependent changes in the conformation of the isolated carboxy-terminal telopeptide of type I collagen", 《BIOCHEMISTRY》 *
TIEN-SHENG TSENG等: "Discovery of potent cysteine-containing dipeptide inhibitors against tyrosinase: a comprehensive investigation of 20×20 dipeptides in inhibiting dopachrome formation", 《JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109893463A (en) * 2019-04-24 2019-06-18 深圳市健翔生物制药有限公司 A kind of whitening peptide composition and its preparation and use
CN114315958A (en) * 2022-01-11 2022-04-12 北京志道生物科技有限公司 Compound and application thereof
CN114315958B (en) * 2022-01-11 2023-07-25 北京志道生物科技有限公司 Compound and application thereof

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