CN102442931A - Methionine-deviated peptide mimics and use in protection for mitochondrions of skin cells - Google Patents
Methionine-deviated peptide mimics and use in protection for mitochondrions of skin cells Download PDFInfo
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Abstract
The present invention relates to methionine-deviated peptide mimics and use in protection for mitochondrions of skin cells. The invention relates to a group of peptide mimics which are selected and are deviated from methionine amino acid, and to the use of the peptide mimics as protection agents for the mitochondrions of the skin cells. The invention also relates to a cosmetic composition or dermatopathology composition for preventing and treating skin diseases which are related with mitochondrion dysfunction.
Description
Technical field
The present invention relates to one group of amino acid whose peptide mimics of egg-derived propylhomoserin, and they are as the purposes of skin cells mitochondrion protecting agent through selecting.The invention still further relates to and be intended to prevent or the compsn of the skin disorder that opposing is relevant with the mitochondrial fuctionning obstacle.
Background technology
As the cytoplasmic organelles that is present in vegetable cell and the zooblast, plastosome plays crucial effects to these cells.In fact, plastosome is because of its production and store the required general energy ingredient Triphosaden (ATP) of all eukaryotic cells running and be called as " the energy power station of cell ".
In the above-mentioned production of carrying out through a series of redox chemistry reactions (being referred to as " mitochondrial respiratory chain " usually), essential ignition dope is an oxygen.Therefore; Running is absolutely necessary oxygen for cell; But contradiction is; Oxygen also is the initial and parallel source that is called as the species with reactive behavior of " active oxygen species " (oxygen-derived reactive species) (French is ERO, and English is ROS), and active oxygen species has genotoxic potential for cellular biochemical macromole (DNA, protein, lipid etc.).
Formation for this ROS that neutralizes; All cells all forms anti-oxidative defense system some enzymatics or non-enzymatic, that need some energy to move natively; And the first-selected above-mentioned just ATP that emits by mitochondrial respiratory chain of energy (Singh K.K.; FEMS Yeast Res., 2004,5:127-132).But; Between system of defense in the generation of ROS and cell is to the removing of ROS, occur when unbalance because of the amount of ROS is excessive; Therefore formed oxidative stress can cause the decline of mitochondrial function gradually, and its interruption and inner ROS of plastosome that shows as energy-producing stream of electrons especially forms (being called " ROS in the plastosome ") (Jones D.P., Chemico Biological Comm.; 2006,163:38-53).Unbalance and energy deficiency on this cell levels will be damaged the ability of the cell adapted physiological stress that it is faced.In a word this can promote cell aging phenomenon (Trifunovic A. etc., J.of Internal Medecine, 263:167-178).In addition according to confirming; These derive from mitochondrial interruption obviously relevant (Barlow-Stewart K., The Australasian Genetics Ressource Book, 2007 with the generation of diversified pathological condition or tissue disorder; The 1st～3 page, and the reference of being quoted).
As the source of ROS in the cell, plastosome remains main target.Therefore, in order to keep on all mitochondrial functions best and/or structural integrity, one of problem that many investigators pay close attention at present is to reduce to be derived from mitochondrial oxidative metabolism and promotion or protection mitochondrial function.
In the prior art with same target of being showed these years in the past, existing strategy and system below all adopting usually:
-select to carry one or more mercaptan or phenol moieties and be present in the powerful antioxidant of animal or plant circle with state of nature, like Thioctic Acid (being called as alpha-lipoic acid more), proved that it has old and feeble beneficial effect (the Palaniappan A.R. etc. of resist mitochondria; Neurochem.Res., 2007,32:1552-1558); Perhaps, it is said that it can protect mammiferous mitochondrial membrane (USP the 6th, 479 as the thioneine (ergothionein) of thiourea derivative; No. 533)
Some molecules of-use or conventional anti-oxidant protein; But it obtains modifying to obtain bigger storage inside (Kagan V.E. etc. to group or the sequence (hydrophobic cations etc.) that plastosome has strong avidity through interpolation/grafting; Adv.Drug Delivery Rev.; 2009,61:1375-1385)
-exploitation it is said the little peptide with " permeation cell property "; Said little peptide substitutes some alkalescence and die aromatischen Aminosaeuren residue (Szeto H.H. because of having the ability that penetrates mitochondrial inner membrane and in plastosome, show some cytoprotectives and chondriosome protective character subsequently; Antioxidants & Redox Signaling; 2008,3:1-15).
The present invention makes under evaluation product innovation or this same background of new product; Its purpose is to satisfy " improving mitochondrial function performance " (B.Lacroix; Nutranews, in April, 2008) these integral body needs, but main because these products or goods are topical application; Also to satisfy the needs that makeup and/or Dermatology Department use, also will satisfy the needs of following coexistence target simultaneously:
-when skin cells receives physiological the influence, keep/recover the mitochondrial efficient Metabolic activity of skin cells;
-demonstrate acceptable bioavailability at deep skin.On the one hand, admitted that this is the necessary prerequisite that realizes skin cell mitochondrial protection in the body.On the other hand, this can be used to avoided even the too early metabolism in the skin shallow-layer before can acting on epidermic cell and dermal cell.
-opposing active oxygen species is to the deleterious effect of self cell, and the ROS that produces in the burden plastochondria but not the ROS (ultraviolet radiation, pollution, oxidative environment toxin etc.) of extracellular origin.
In order to realize these targets, the applicant has studied to be endowed and has made various excited oxygens (O for example
2°
-With
1O
2) sulfide compound (Cohen S.G. and L., J.Am.Chem.Soc., 1975,97:5633-5634 and the reference of being quoted thereof) of ability of inactivation (" cancellation ").
The applicant is the special concern methionine(Met) more, and promptly wherein sulphur atom is participated in the same thioether functional (S-CH of group
3) the sulphur a-amino acid; But the more incidental characteristics of methionine(Met) are opposite with the target of seeking: be not suitable for the sulfur-bearing organic derivative smell that makeup/Dermatology Department uses; Lower dermal osmosis ability the more important thing is evidence (Caro P. etc., Rev.Esp.Geriatr.Gerontol. by the oxidative damage of ROS and Mitochondrial DNA in the plastosome of methionine(Met) food supplement generation; 2009,44:194-199; SanzA. etc., FASEB J., 2006,20:1064-1073).In addition, it is predicted that oligomerization methionine(Met) type peptide (two methionine(Met), three methionine(Met) etc.) is too high to the susceptibility of skin protein enzyme.
More than be that the applicant studies the synthetic reason to methionine(Met) institute deutero-peptide mimics the most at last.
Summary of the invention
Therefore, through further structure-activity research, to well the meeting of the combination of above-mentioned standard, the applicant is with on the minority original creation compound of selecting to be locked in the egg-derived propylhomoserin that does not have the shortcoming that methionine(Met) or oligomerization methionine(Met) demonstrated according to it.Said well meeting shows as:
-keep the excellent ability of the Metabolic activity that is exposed to the skin cells under the stressed condition, said ability is through embodying [test 1 vide infra] to keeping of ATP production level;
-extremely good even surmount cuticular skin absorption, it is embodied in the logarithmic value (" Log Kp ") [test 2 vide infra] of the permeability coefficient of said compound, and this permeability coefficient is with permeate compound such as theine etc. similar;
-ability that the plastosome oxidative stress is reduced, and the ability [test 3 vide infra] that the mitochondrial mass (being called " plastosome is biological to be taken place ") that produces identical stressed condition being made response is regulated;
The cytoprotective of-height shows that especially the V79 inoblast fastens [vide infra test 4], being characterized as of this clone: to coming from the hydrogen peroxide H of mitochondrial respiratory chain disorders
2O
2Responsive (Tatsumi T. etc., Basic Res.Cardiol., 1993,88:199-211);
-strong anti-oxidation characteristic, show to known can the influence mitochondrial oxidisability species (hydroxyl radical free radical OH °, peroxo-nitrite ion ONOO
-, singlet oxygen
1O
2) the removing ability, promptly with such as xitix or Trolox
TMDeng with reference to the similar ability of the removing ability of inhibitor [vide infra the test 5 with the test 6];
-faint the smell that discharges by these methionine(Met) verivates.
Therefore first target of the present invention provides one group of methionine(Met) deutero-peptide mimics, it is characterized in that it and is represented by following general formula (I):
R=X-C (O)-NH-, wherein X=alkyl or alkoxyl group (C
1～C
8); R '=H
Or
R '=-C (O)-OX, wherein X=alkyl (C
1～C
8); R=H.
According to preferred implementation of the present invention, formula (I) is defined as following formula (II), wherein, R ' base is merely Wasserstoffatoms, and R is that X contains 1～4 carbon atom (C for having in the group
1～C
4) alkyl or the group of alcoxyl fundamental mode group of straight or branched hydrocarbyl chain:
R=X-C (O)-NH-, wherein X=alkyl or alkoxyl group (C
1～C
4); R '=H
More advantageously, the X in the above-mentioned formula (II) contains 1～4 carbon atom (C
1～C
4) the alkyl type group of straight or branched hydrocarbyl chain.
As the limiting examples of the compound of formula (II), can specifically enumerate following compound:
-N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine
-N-propionyl group-(DL)-methionyl-4-(methylthio group) propylamine
-N-pentanoyl-(DL)-methionyl-4-(methylthio group) propylamine
-N-tert.-butoxy-(DL)-methionyl-4-(methylthio group) propylamine
According to more favourable embodiment of the present invention, above-mentioned formula (I) and formula (II) specifically are defined as N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine compound (R=CH
3-C (O)-NH-and R '=H).
According to second aspect; The invention still further relates to a kind of compsn; It is preferred for makeup or Dermatology Department's purposes; Through the skin disorder that design is used for preventing or opposing is relevant with mitochondria dysfunction, it comprises the methionine(Met) institute deutero-peptide mimics with general formula (I) that defines like preceding text as main active ingredient, and the compatible additive of any physiology.
In category of the present invention; It should be understood that " main active ingredient " be through the effect of enhanced chondriosome protective and/or enhanced to more mitochondrial must function (like the cellular energy metabolism) hormesis and can limit the skin cells plastosome physical chemistry stress or environmental stress under changing function or the active substance of structural modification.
Specifically, above-mentioned compsn through design be used for protecting skin avoids that ultraviolet radiation brings out stress (ultraviolet ray bring out stress), and said methionine(Met) verivate meets formula (II).More specifically, it is N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine compound.
Useful is that in above-mentioned compsn, the amount of the verivate of said general formula (I) accounts for the 0.1 weight %～10 weight % of said composition gross weight, is preferably 0.3 weight %～3 weight %.
Compsn of the present invention is preferred for makeup or Dermatology Department's purposes, and it is applicable to topical application, and shows as this type of and use form of ownership commonly used.Useful is that said composition can have following form: powder, emulsion, microemulsion, nanoemulsions, suspension agent, lotion, emulsifiable paste, aqueous gel or water alcogel, foam, slurries, spraying are with solution or dispersion-s or lipid vesicle dispersion-s.
Can also said composition be mixed with use (Orally administered) that is used for through the oral area approach, its form is for example tablet, capsule, capsule, sealing bottled (seal), spherical bottled (bulb), syrup, drops.
As the example additives compatible, can enumerate the compound that is selected from following substances: oil, paraffin, silicone elastomer, tensio-active agent, cosurfactant, thickening material and/or gelifying agent, wetting agent, lubricant, organic filtermedium, inorganic filter agent, filter reinforcer and photostabilizer, sanitas, tinting material, weighting agent, nacre, the photo etching that deoils (matifying agent), tighten up agent, sequestering agent, spices and composition thereof with skin physiology.
The content of these instances in compsn can be about 0.01%～20% of said composition gross weight; And in the dictionary " international cosmetic ingredient dictionary and handbook (International Cosmetic Ingredient Dictionary and Handbook) " (the 13rd edition, 2010) that " the personal care product council (PCPC; preceding CTFA) " of U.S. makeup association published, these instances have been mentioned especially.These instances can be (but being not limited to following material): organic silicone oil, natural or synthetic oil, straight chain hydrocarbon or branched-chain hydrocarbon, synthetic ester and synthetic ether, hydrocarbonylation wax, emulsifying surfactant, the Fatty Alcohol(C12-C14 and C12-C18) of straight or branched, netted homopolymer and multipolymer, natural gum, derivatived cellulose, alginic acid ester, polyvalent alcohol, sugar, TGSS C3 and other amino acid, mineral filler or organic filler, vegetable-protein, polysaccharide and composition thereof.
Compsn of the present invention can also comprise extra activeconstituents, but the interpolation of these activeconstituentss can not influence one's duty invention composition itself with effect, specifically, at least a activeconstituents is selected from: the medicament of the generation of the stimulating growth factor; Anti-saccharification or deglycation agent improve collagen protein synthesis or prevent the medicament of its degraded, and it is synthetic or prevent its degradation agents to improve elastin; Improve the medicament that synthesizes or prevent its degraded of TGSS C3 or proteoglycan, improve the medicament of Keratinocytic propagation or differentiation, improve the medicament of fibroblasts proliferation; Discoloring agent, anti-tinting material or short tinting material, inhibitor or antifree radical agent or anti-pollutant, the medicament of the barrier function of stimulation hydration and/or protection skin; Improve epidermis lipid synthetic medicament, stimulate the medicament of lipolysis, suppress steatogenesis and/or suppress the medicament that adipocyte breaks up; Water discharge agent or toxinicide, anti-inflammatory agent, penetration enhancers; Decorticating agent (desquamative agent), soothing agent and/or counter irritant, astringent matter; Act on microcirculatory medicament, act on the medicament of cellular metabolism, and the mixture of above-mentioned substance.
The content of these instances in compsn of extra activeconstituents can be the said composition gross weight about 0.001%～about 10%, and can be selected from especially: plant milk extract, silicon derivative; Yeast extract and Algae Extract, vegetable protein hydrolyzate, (acidylate or not acidylate) oligopeptides; Coffee extract, Ka Er Xining (carcinine) and verivate thereof, carnosine and verivate thereof; N-acetylcysteine and verivate thereof are such as water-soluble vitaminss such as VITMAIN B1, B2, B3, B6, B12, C, H, such as liposoluble vitamins such as vitamin A, D2, D3, E and Serlabo; Urea and verivate thereof, taurine and verivate thereof, polyphenol; Oligosaccharides and polysaccharide, lactic acid, oxyacetic acid, Hydrocerol A and Whitfield's ointment and ester thereof or salt, and the mixture of above-mentioned substance.
Another object of the present invention also relates to methionine(Met) institute deutero-peptide mimics as being used for protecting and/or the purposes of the cosmetic agent of Imidazolidinyl Urea cell mitochondrial, and said verivate has following general formula (III):
R=X-C (O)-NH-, wherein X=alkyl or alkoxyl group (C
1～C
8); R '=H or-C (O) R ", R "=O alkyl (C wherein
1～C
4), NH
2
According to preferred implementation of the present invention, its purpose is to prevent or resist the skin aging symptom through the such use of said verivate, and preferably resists photoinduced senile symptom, particularly resists the damage that ultraviolet radiation causes skin.
Last target of the present invention relates to a kind of methionine(Met) institute deutero-peptide mimics; It is used for using at skin composition; Said compsn can be used for treating the skin aging symptom, and preferred pin damage that ultraviolet radiation is caused skin, and said verivate meets following general formula (III):
R=X-C (O)-NH-, wherein X=alkyl or alkoxyl group (C
1～C
8); R '=H or-C (O) R ", R "=O alkyl (C wherein
1～C
4), NH
2
As the limiting examples of the compound of formula (III), can specifically enumerate following compound:
-N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine
-N-propionyl group-(DL)-methionyl-4-(methylthio group) propylamine
-N-pentanoyl-(DL)-methionyl-4-(methylthio group) propylamine
-N-tert.-butoxy-(DL)-methionyl-4-(methylthio group) propylamine
-N-4-(methylthio group)-butyryl radicals-L-methyl methionine
-N-ethanoyl-(DL)-methionyl-L-methionine(Met) ethyl ester
In above-mentioned latter two target of the present invention, preferentially select the verivate of following general formula (III): for example being defined as R wherein, X contains 1～4 carbon atom (C
1～C
4) alkyl type group and the R ' group that is merely Wasserstoffatoms.
More preferably, selected especially compound N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine.
Embodiment
Embodiment 1
As illustrating, below be some formulation examples of compsn of the present invention that contain the verivate of above-mentioned general formula (I):
Prescription A (emulsifiable paste)
Prescription B (gel)
Prescription C (capsule, Orally administered)
The N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine (200mg powder/capsule)
Or
N-4-(methylthio group)-butyryl radicals-L-methyl methionine (200mg powder/capsule)
Fill up the vehicle of a gelatine capsule: Microcrystalline Cellulose, Magnesium Stearate.
Embodiment 2
Pure in demonstration, hereinafter, illustrate the present invention through the following test of having mentioned in to explanation of the present invention at preceding text (test 1 is to testing 6).Should also be noted that research well afoot in the body, and PRELIMINARY RESULTS also can be illustrated the purposes of methionine(Met) institute deutero-peptide mimicses more of the present invention.
Test 1: methionine(Met) institute deutero-peptide mimics has recovery and is exposed to stressed condition (H
2O
2) cell in the evidence of ability of cell ATP level
On the fibroblast of V79 by name, carry out experimental study, seed cells in 96 orifice plates, every hole contains 5000 cells, 100 μ l substratum (containing 10% foetal calf serum).Containing some concentration at each Kong Zhongyong subsequently is that 100 μ l substratum of 7.5mM or 10mM peptide mimics of the present invention are changed original substratum.Behind the incubation 2 hours, remove the substratum in porose.Contain 50 μ l hydrogen peroxide H through interpolation then
2O
2Substratum (4ppm) and cell is stood stress.Through 8 hours incubation, measure the ATP mean concns again through the luminous measurement Law (luminometry) in the presence of resorcinolphthalein (" ATPlite 1step " test kit) and from the typical curve that high purity ATP draws.
The result representes with the mean value that obtains from three independent experiments, and is shown in the following table 1, and compared with the control.
Table 1
| Compound | ATP(×10 -7M) |
| Contrast | 4.42 |
| Contrast+H 2O 2 | 0.4 |
| The N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine 7.5mM | 5.91 |
| The N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine 7.5mM+H 2O 2 | 4.83 |
| The N-propionyl group-(DL)-methionyl-4-(methylthio group) propylamine 10mM | 5.28 |
| The N-propionyl group-(DL)-methionyl-4-(methylthio group) propylamine 10mM+H 2O 2 | 4.49 |
When compound of the present invention exists, avoided greatly that observed ATP amount declines to a great extent in contrast, this shows that compound of the present invention has the ability of the ATP production that recovers to be exposed in the cell stressed condition under.
The test 2: on people's outer planting skin, carry out to methionine(Met) institute deutero-peptide mimics through the skin Absorption Study
The working specification about skin absorption research according to describing among the OCDE criterion n ° 428 obtains permeability coefficient (Kp) value from previous refrigerated tummy tuck human skin.
In the experiment, with the outer planting placed on the Frantz of passive diffusion type device (Frantz-type cell), and through " MicroettePlus Hanson Research " system's channeling conduct.Lay the tested person product with nonocclusive mode.With after placed is on device, the peptide mimics (1% solution) among 500 μ l the present invention is placed each device, and contact totally 24 hours.Afterwards, surplus products are taken a sample and washed skin surface, extract and measure absorbed dose being used for, be used for confirming the permeability coefficient of representing with log form (Log Kp) subsequently.
Data gathering is in following table 2.
Table 2
| Compound | Kp(cm.h -1) | Log?Kp |
| Theine | 1.10 -4** | -4.0 |
| The N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine | 1.09.10 -4 | -3.96 |
| The N-propionyl group-(DL)-methionyl-4-(methylthio group) propylamine | 9.7.10 -5 | -4.0 |
| The N-pentanoyl-(DL)-methionyl-4-(methylthio group) propylamine | 3.7.10 -4*** | -3.43 |
| The N-tert.-butoxy-(DL)-methionyl-4-(methylthio group) propylamine | 4.6.10 -4*** | -3.34 |
| N-4-(methylthio group)-butyryl radicals-L-methyl methionine | 2.10 -4*** | -3.71 |
| The N-ethanoyl-(DL)-methionyl-L-methionine(Met) ethyl ester | 1.64.10 -4*** | -3.78 |
**：Mitragotri?S.，J.Controlled?Release，(2003)，86：69-92.
* *: according to forecasting software " ChemDraw ultra 11.0 editions ", supplier: CambridgeSoft Ltd.
The permeability coefficient of the The compounds of this invention that is obtained is similar with known permeability coefficient of striding stratum corneum permeate theine.
Test 3:N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine compound has the evidence of provide protection to plastosome oxidative stress and plastosome biology
Principle: realize to the measurement of oxidative stress in the plastosome cell with to the biogenous detection of plastosome through fluorescently-labeled flow cytometry below using:
-red fluorescence probe " MitoSOXTM Red " (detects at λ=580nm place hereinafter to be referred as " MitoSOX "; Supplier: Invitrogen), make and to detect the superoxide anion O that is present in the plastosome specifically
2°
-(because itself and mitochondrial strong avidity),
-green fluorescence probe "
Green FM " (detects at λ=516nm place hereinafter to be referred as " Mitogreen "; Supplier: Invitrogen), make can quantitatively determining mitochondrial quality (or the plastosome correlated measure in each cell).
In experiment, test is carried out on hamster fibroblast " V79 ", and said clone is passed through at 37 ℃ and 5%CO
2Humid atmosphere in " EMEM " perfect medium (containing 10% foetal calf serum), go down to posterity and be able to keep.In V79 cell inoculation to 96 orifice plate, every hole contains 2.5 * 10
5The substratum that individual cell and 3ml are same, and incubation 24 hours add subsequently and contain hydrogen peroxide H
2O
2Substratum (15ppm) and it is exposed under the stressed condition and continues 1 hour 30 minutes.
Through tryptic digestion, cell is contained in the EMEM perfect medium of above-mentioned " MitoSOX " (ultimate density 5 μ M) and " Mitogreen " (ultimate density 200nM) in 37 ℃ of incubations 15 minutes at 1ml, thus detection respectively:
-plastosome oxidative stress (% with positive cell representes)
The mitochondrial mass of-each cell (% with respect to the MFI (" average fluorescent strength ") that contrasts representes).
The result representes with the MV that obtains from four independent experiments, and is shown among following table 3a and the table 3b, and with compare as the pairing result of N-acetylcysteine who with reference to protectant concentration is 5mM through selecting.
Table 3a
| The % of MitoSOX positive cell | |
| Contrast | 18 |
| Contrast+H 2O 2 | 85.7 |
| N-acetylcysteine 5ppm+H 2O 2 | 15.2 |
| The N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine 7.5mM+H 2O 2 | 40.3 |
Table 3b
| MFI (% contrast) | |
| Contrast | 100 |
| Contrast+H 2O 2 | 177.3 |
| N-acetylcysteine 5ppm+H 2O 2 | 74.4 |
| The N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine 7.5mM+H 2O 2 | 123.5 |
| The N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine 10mM+H 2O 2 | 127.5 |
Under both of these case, the result is all outstanding shown in the minimizing plastosome of N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine compound stress the ability of influence.
The evidence that test 4:N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine and N-tert.-butoxy-(DL)-methionyl-4-(methylthio group) propylamine has the cytoprotective effect
This experiment is carried out on hamster fibroblast " V79 ", and this clone remains on 37 ℃ and 5%CO
2Humid atmosphere in, subsequently with every hole 0.5 * 10
4The density of individual cell seeds cells in 96 orifice plates.Subsequently with containing hydrogen peroxide H
2O
2Substratum (4ppm) and that be added with The compounds of this invention is simultaneously changed original substratum, thereby makes cellular exposure also continue 24 hours in the toxicity stress situation.After removing substratum, through " mtt assay " or 3-(4,5-dimethylthiazole-2-yl)-2, the bromide of 5-phenylbenzene tetrazolium (solution of 500 μ g/ml) also uses spectrophotometry (absorbancy at the 540nm place) to measure fibroblastic vigor.
The result representes with the MV that obtains from three independent experiments, and is shown in the following table 4, and is that the pairing result of N-acetylcysteine (recovery fully of cell viability) of 5mM compares with being elected to be with reference to the concentration of cytoprotective once more.
Table 4
| The % cell viability | |
| Contrast | 100 |
| Contrast+H 2O 2 | 54.8 |
| N-acetylcysteine 5ppm | 103.8 |
| The N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine 7.5mM+H 2O 2 | 83.5 |
| The N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine 10mM+H 2O 2 | 91.9 |
| The N-tert.-butoxy-(DL)-methionyl-4-(methylthio group) propylamine 7.5mM+H 2O 2 | 70.1 |
| The N-tert.-butoxy-(DL)-methionyl-4-(methylthio group) propylamine 10mM+H 2O 2 | 77.3 |
The protection cell that the result of table 4 is outstanding to have shown cell viability and the The compounds of this invention of the dosage that depends on The compounds of this invention avoid cytotoxicity stress ability.
Test 5:N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine and N-propionyl group-(DL)-methionyl-4-(methylthio group) propylamine has the evidence of antioxidant effect to hydroxyl radical free radical
Use Rehman A. and coll. (British J.Pharmacol. (1997); 122:1702-1706) described method is confirmed the removing speed constant of hydroxyl radical free radical [Ks (OH °)], and peptide mimics of the present invention and two kinds are compared with reference to inhibitor (N.F,USP MANNITOL and xitix (vitamins C)).
In experiment, the tested person substance dissolves in pH is 7.4 buffer medium, and, is added ribodesose OH ° of generation system (ascorbate salt/iron/EDTA) when existing in said medium.After 1 hour, reaction is stopped in 37 ℃ of incubations by means of trichoroacetic acid(TCA).After carrying out the colorimetric video picture with thiobarbituricacid, measure the pairing absorbancy of different concns at the 532nm place, calculate the relative Ks (OH °) of every kind of material subsequently.The result is shown in the following table 5.
Table 5
**：Cabelli?D.E.，J.Phys.Chem.(1983)，87：1809-1812
***：Rehman?A.，British?J.Pharmacol.(1997)，122：1702-1706
The result representes with the MV that obtains from three independent experiments, the ability force rate seminose of the outstanding removing hydroxyl radical free radical (OH) that has shown peptide mimics of the present invention obviously more efficient, and roughly similar with xitix.
Test 6:N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine compound has the evidence of antioxidant effect to the peroxo-nitrite ion
(BBRC (2001), 285:262-266) so-called " pyrogallol Red (PR) bleach test " method of description is confirmed peroxo-nitrite ion (ONOO to use Nath V.B. and coll.
-) to the restraining effect of oxidation pyrogallol Red (PR); And with N-ethanoyl of the present invention-(DL)-methionyl-4-(methylthio group) propylamine compound with reference to inhibitor; I.e. water-soluble Equivalent (6-hydroxyl-2,5,7 of " Trolox " or vitamin E; 8-tetramethyl-chroman)-and the 2-carboxylic acid, compare.
In experiment, in 96 orifice plates, with the tested person substance dissolves in pH is 7.0 buffer medium, and to the peroxo-nitrite ion ONOO of PR that wherein adds 50 μ M and 25 μ M
-(in the NaOH of 0.1M solution).After 5 minutes, measure absorbancy at the 540nm place, calculate the IC50 value (50% inhibition concentration) of every kind of material subsequently through spectrophotometry.The result is shown in the following table 6.
Table 6
| Compound | IC 50(mM) |
| Trolox | 0.083 |
| The N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine | 1.012 |
Though activity is lower than with reference to inhibitor, compound of the present invention can obviously be observed the restraining effect of peroxo-nitrite ion oxidation PR.
Claims (10)
1. a methionine(Met) deutero-peptide mimics is characterized in that, said peptide mimics is represented by following general formula (II):
Wherein,
R=X-C (O)-NH-, and X=C
1～C
4Alkyl or alkoxyl group; R '=H.
2. peptide mimics as claimed in claim 1 is characterized in that, said peptide mimics is N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine.
3. be used to prevent or the compsn of the skin disorder that opposing is relevant with mitochondria dysfunction, it is characterized in that said compsn comprises the methionine(Met) deutero-peptide mimics of general formula (II):
Wherein,
R=X-C (O)-NH-, and X=C
1～C
4Alkyl or alkoxyl group; R '=H.
4. compsn as claimed in claim 3 is characterized in that, said peptide mimics is N-ethanoyl-(DL)-methionyl-4-(methylthio group) propylamine.
5. like claim 3 or 4 described compsns, it is characterized in that the amount of said peptide mimics accounts for the 0.1 weight %～10 weight % of said composition total weight.
6. like claim 3 or 4 described compsns; It is characterized in that said compsn is suitable for being used for topical application with following form: powder, emulsion, microemulsion, nanoemulsions, suspension agent, lotion, emulsifiable paste, aqueous gel or water alcogel, foam, slurries, spraying are with solution or dispersion-s or lipid vesicle dispersion-s.
7. like claim 3 or 4 described compsns, it is characterized in that said compsn comprises the extra activeconstituents that is selected from following substances: the medicament of the generation of the stimulating growth factor; Anti-saccharification or deglycation agent improve collagen protein synthesis or prevent the medicament that collagen protein is degraded, and improve the medicament that elastin synthesizes or prevent the elastin degraded; Improve the synthetic of TGSS C3 or proteoglycan or prevent TGSS C3 or the medicament of proteoglycan degraded, improve the medicament of Keratinocytic propagation or differentiation, improve the medicament of fibroblasts proliferation; Discoloring agent, anti-tinting material or short tinting material, inhibitor or antifree radical agent or anti-pollutant, the medicament of the barrier function of stimulation hydration and/or protection skin; Improve epidermis lipid synthetic medicament, stimulate lipolysis, suppress steatogenesis and/or suppress the medicament that adipocyte breaks up, water discharge agent or toxinicide; Anti-inflammatory agent, penetration enhancers, decorticating agent; Soothing agent and/or counter irritant, astringent matter acts on microcirculatory medicament; Act on the medicament of cellular metabolism, and the mixture of above-mentioned substance.
8. like claim 3 or 4 described compsns, it is characterized in that, said compsn be used to protect skin avoids that ultraviolet ray brings out stress.
9. methionine(Met) deutero-peptide mimics is as being used to protect and/or the purposes of the cosmetic agent of Imidazolidinyl Urea cell mitochondrial, and said peptide mimics has following general formula (III):
Wherein, R=X-C (O)-NH-, and X=C
1～C
8Alkyl or alkoxyl group; R '=H or-C (O) R ", and R "=C
1～C
4O alkyl, NH
2
10. methionine(Met) deutero-peptide mimics, it is used for using at the skin composition of treatment skin aging symptom, and said peptide mimics has following general formula (III):
Wherein, R=X-C (O)-NH-, and X=C
1～C
8Alkyl or alkoxyl group; R '=H or-C (O) R ", and R "=C
1～C
4O alkyl, NH
2
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MC2573A MC200132A1 (en) | 2010-09-17 | 2010-09-17 | Peptidomimetics derived from methionine and their use in the protection of cutaneous cell mitochondria. |
| MC002573 | 2010-09-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102442931A true CN102442931A (en) | 2012-05-09 |
| CN102442931B CN102442931B (en) | 2015-06-03 |
Family
ID=43859585
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110274029.5A Expired - Fee Related CN102442931B (en) | 2010-09-17 | 2011-09-15 | Methionine-deviated peptide mimics and use in protection for mitochondrions of skin cells |
Country Status (7)
| Country | Link |
|---|---|
| CN (1) | CN102442931B (en) |
| AR (1) | AR083004A1 (en) |
| BR (1) | BRPI1104914B1 (en) |
| CO (1) | CO6640060A1 (en) |
| MC (1) | MC200132A1 (en) |
| MX (1) | MX2011009741A (en) |
| PE (1) | PE20120527A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4956173A (en) * | 1987-11-25 | 1990-09-11 | Societe Anonyme: Sanofi | Composition and use of ademetionine against ageing of the skin |
| CN101232877A (en) * | 2005-04-21 | 2008-07-30 | 格伦·A·戈尔茨坦 | N-acetylcysteine amide (NAC amide) for the treatment of diseases and conditions associated with oxidative stress |
-
2010
- 2010-09-17 MC MC2573A patent/MC200132A1/en unknown
-
2011
- 2011-09-15 CN CN201110274029.5A patent/CN102442931B/en not_active Expired - Fee Related
- 2011-09-15 MX MX2011009741A patent/MX2011009741A/en active IP Right Grant
- 2011-09-16 AR ARP110103374 patent/AR083004A1/en active IP Right Grant
- 2011-09-16 PE PE2011001659A patent/PE20120527A1/en not_active Application Discontinuation
- 2011-09-16 BR BRPI1104914-6A patent/BRPI1104914B1/en active IP Right Grant
- 2011-09-16 CO CO11120638A patent/CO6640060A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4956173A (en) * | 1987-11-25 | 1990-09-11 | Societe Anonyme: Sanofi | Composition and use of ademetionine against ageing of the skin |
| CN101232877A (en) * | 2005-04-21 | 2008-07-30 | 格伦·A·戈尔茨坦 | N-acetylcysteine amide (NAC amide) for the treatment of diseases and conditions associated with oxidative stress |
Non-Patent Citations (3)
| Title |
|---|
| FRED NAIDER ET AL.: "Utilization of Methionine-containing Peptides and Their Derivatives by a Methionine-requiring Auxotroph of Saccharomyces cerevisiae", 《J.BIOL.CHEM.》 * |
| KENJI OKAMOTO ET AL.: "Studies on Peptides. CXV. Synthesis of Hylambatin, a New Frog Skin Peptide of the Kassinin Family", 《CHEM. PHARM. BULL.》 * |
| SOICHI ARAI ET AL.: "Bioavailability of L-methionine oligomers in rats", 《AGRICULTURAL AND BIOLOGICAL CHEMISTRY》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI1104914A2 (en) | 2013-03-19 |
| MC200132A1 (en) | 2011-03-30 |
| CN102442931B (en) | 2015-06-03 |
| PE20120527A1 (en) | 2012-05-17 |
| AR083004A1 (en) | 2013-01-23 |
| MX2011009741A (en) | 2012-06-22 |
| CO6640060A1 (en) | 2013-03-22 |
| BRPI1104914B1 (en) | 2019-06-18 |
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