CN109966470A - Application of the Cyclic dipeptides in wound repair drug - Google Patents
Application of the Cyclic dipeptides in wound repair drug Download PDFInfo
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Abstract
The present invention relates to application of any one in ring dried meat-silk dipeptides, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, the different bright dipeptides of ring dried meat-in wound repair.Therapeutic effect through animal modeling experiment proves that the above-mentioned four kinds of Cyclic dipeptides of the present invention are excellent to wound repair therapeutic effect, and such as high to acute and chronic gastritis ulcer inhibition rate, skin ulcer healing speed is fast, has preferably antiphlogistic effects etc..
Description
Technical field
The present invention relates to field of biological pharmacy, and in particular to application of the Cyclic dipeptides in wound repair drug.
Background technique
Cyclic dipeptides also known as 2,5- dioxygen piperazidine are formed by peptide bond cyclization by two amino acid, are the smallest in nature
Cyclic peptide.Many Cyclic dipeptides be it is born in animals and plants, there are also be by fermentation either in food processing process
It is formed.It include currently antibacterial, anticancer, the effect to cardiovascular system, protection neuron to the bioactivity research of Cyclic dipeptides
And improve brain function, de-addiction and removing toxic substances.For example, existing document report ring (dried meat-silk) dipeptides has antibacterial action, especially to golden yellow
Color staphylococcus has obvious inhibiting effect；Ring (bright-dried meat) dipeptides has inhibiting effect to breast cancer, cervical carcinoma and colon cancer,
There are also immunocompetence, adjusting hormone and the effects for regulating and controlling energy generation simultaneously, also have anti-filtration venereal disease in addition to antitumor activity
Substance, antibiotic activity also have obvious inhibiting effect to staphylococcus aureus；Ring (dried meat-is different bright) dipeptides has suppression
Tumor promotion processed and anti-MRSA activity.
At present existing patent text disclose a few utilize Cyclic dipeptides made from synthetic method be used for wound repair and
The technical solution of digestive tract ulcer treats skin in preparation as CN105288585A and CN105294830 discloses the-the third dipeptides of ring dried meat
Application in the drug of skin wound, CN105311619 disclose the-the third dipeptides of ring dried meat in the drug of preparation treatment digestive tract ulcer
Application, CN105622716 discloses the treatment use that the sweet dipeptides of cyclopropyl-and the bright dipeptides of cyclopropyl-are used for acute and chronic gastritis ulcer.
CN105622717 discloses ring dried meat-phenylpropyl alcohol dipeptides, ring dried meat-dried meat dipeptides, ring dried meat-figured silk fabrics dipeptides, ring dried meat-group dipeptides, ring dried meat-junket two
Peptide and ring dried meat-sweet dipeptides are used for the application of Wound treating.CN105622718 discloses ring junket-bright dipeptides for gastric ulcer
Treatment use.There is not document to disclose Cyclic dipeptides middle ring dried meat-silk dipeptides, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, ring at present
The different bright dipeptides of dried meat-can be used for wound repair, especially effectively treat gastric ulcer and skin ulcer.
Gastric ulcer is digestive system common disease, frequently-occurring disease, is apt to occur in lesser curvature, especially more nearby with antrum lesser curvature side stomach angle
See, typical clinical manifestations are the middle Upper abdominal pain of chronic, periodicity, the postprandial timing of rhythmicity, and characteristic of pain is different, can secret anguish
Or dull pain.About 10% patient can without abdominal pain, and using spitting blood or melaena as onset symptoms, can also with belch, sour regurgitation, nausea, vomit
It spits, other symptoms of digestive tract such as hungry discomfort.Modern medicine thinks that gastric ulcer is that stomach lining invasion sex factor and stomach are glutinous
It is unbalance between film self-defense/reparation factor to cause.It is clinically treated frequently with H2-R PPI class, but recurrence rate after drug withdrawal
It is high.
Skin ulcer is clinically common disease, frequently-occurring disease, including varicose ulcer, diabetic ulcer, pressure
Ulcer etc., using lower limb, foot, buttocks and hand as predilection site.Its main cause has burn, chemical burn, skin injury infection
And caused by the reasons such as oppression.It is clinically auxiliary frequently with the physical therapies such as laser, microwave and infrared ray, biotherapy and external application
The modes such as material are treated.Although achieving certain effect, skin ulcer wound healing effect intractable for part is owed
It is good.
The present invention obtains six kinds of Cyclic dipeptides, middle ring dried meat-silk dipeptides, ring dried meat-by extracting separation from American cockroach
The different bright dipeptides of asparagine dipeptides, ring dried meat-bright dipeptides, ring dried meat-has excellent effect to the treatment of wound repair.
Summary of the invention
The present invention provides in ring dried meat-silk dipeptides, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, the different bright dipeptides of ring dried meat-
Any one application in wound repair.
The present invention provides in ring dried meat-silk dipeptides, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, the different bright dipeptides of ring dried meat-
Any one treatment acute and chronic gastritis ulcer, the application in gastric mucosa damage drug or treatment skin injury such as skin ulcer,
Application in skin injury, scytitis drug.
Separation is extracted by American cockroach the present invention also provides one kind and prepares ring (dried meat-silk) dipeptides (Pro-Ser), ring (dried meat-
Asparagine) dipeptides (Pro-Asn), ring (dried meat-is bright) dipeptides (Pro-Leu), ring (dried meat-is different bright) dipeptides (Pro-Lso), ring (dried meat-
The third) dipeptides (Pro-Ala), in ring (dried meat-figured silk fabrics) dipeptides (Pro-Val) any one Cyclic dipeptides method:
Step 1: American cockroach coarse powder is concentrated to give medicinal extract after alcohol steep；
Step 2: macroporous resin column chromatography on above-mentioned medicinal extract being eluted with water, eluent is concentrated to give water position sample；
Step 3: water intaking position sample is chromatographed through MCI column, obtains component A with water elution；By component A points for containing compared with polyamino
Sour A1 component and the A2 component containing less amino acid；
Step 4: A2 component being passed through into LC-MS LC-MS separation detection, obtains compound ring dried meat-silk dipeptides, ring dried meat-day
Winter amide dipeptides, the-the third dipeptides of ring dried meat, ring dried meat-figured silk fabrics dipeptides, the different bright dipeptides of ring dried meat-, ring dried meat-bright dipeptides.
In one embodiment of the invention, the macroporous resin column in step 2 is HP-20 macroporous resin column.
In one embodiment of the invention, the wire feeding of the MCI column in step 3 is MCI GEL CHP20P.
In one embodiment of the invention, in step 1, leaching is concentrated under reduced pressure to obtain in American cockroach coarse powder after alcohol steep
Cream.
In one embodiment of the invention, in step 2, the medicinal extract is spin-dried for ethyl alcohol, on after deionized water dissolving
Macroporous resin column chromatography column.
In one embodiment of the invention, in step 2, eluent concentration is freeze-dried the position get Shui sample again.
In one embodiment of the invention, it in step 3, is detected in conjunction with TLC, by ninhydrin as color developing agent, according to
TLC spot number divides into component A containing the more A1 component of amino acid and the A2 component less containing amino acid；Wherein by TLC
Component A of the number of spots less than or equal to 5 is as A2 component, and remaining is A1 component；Preferably, TLC number of spots is small
In the component A equal to 3 as A2 component, and remaining is A1 component.
In one embodiment of the invention, in step 3, the solvent of TLC detection is n-butanol: glacial acetic acid: water=4:
1:1。
In one embodiment of the invention, in step 4, the chromatographic column that the LC liquid phase chromatogram condition uses is selected from:
Capcell Pak C18MGll, Boston Luna Clone C18, Diamonsil C18,Boston Luna Clone；It is preferred that
Ground, the chromatographic column that the LC liquid phase chromatogram condition uses is Boston Luna Clone.
In one embodiment of the invention, in step 4, mobile phase uses mobile phase A in the LC liquid phase chromatogram condition
And Mobile phase B；The mobile phase A is 0.06-0.3% aqueous formic acid or 0.06-0.3% phosphate aqueous solution；Preferably, described
Mobile phase A is the aqueous formic acid of 0.06-0.1%；The Mobile phase B is acetonitrile or alcohols solvent；Preferably, the mobile phase
B is methanol.
In one embodiment of the invention, in step 4, the LC liquid phase chromatogram condition is using isocratic or gradient elution
Mode；Preferably, the LC liquid phase chromatogram condition is by the way of gradient elution, wherein the flowing when gradient elution
The volume ratio of phase A and the Mobile phase B is 90:10~5:95.
The present invention also provides a kind of extracted separation of American cockroach to prepare ring (dried meat-silk) dipeptides (Pro-Ser), ring (dried meat-
Asparagine) dipeptides (Pro-Asn), ring (dried meat-is bright) dipeptides (Pro-Leu), ring (dried meat-is different bright) dipeptides (Pro-Lso), ring (dried meat-
The third) dipeptides (Pro-Ala), in ring (dried meat-figured silk fabrics) dipeptides (Pro-Val) any one Cyclic dipeptides method:
Step 1: medicinal extract is concentrated under reduced pressure to obtain in American cockroach coarse powder after alcohol steep；
Step 2: the medicinal extract is spin-dried for ethyl alcohol, with macroporous resin column chromatography column upper after deionized water dissolving, is eluted with water,
Eluent concentration is freeze-dried the position get Shui sample again；
Step 3: water intaking position sample is chromatographed through MCI column, obtains component A with water elution；By ninhydrin as color developing agent,
In conjunction with TLC detection by component A points for containing the more part A1 component of amino acid and the A2 component less containing amino acid；Wherein, will
TLC number of spots less than or equal to 3 component A as A2 component, and remaining for A1 component wherein, the solvent that TLC is detected
For n-butanol: glacial acetic acid: water=4:1:1；
Step 4: A2 component is respectively obtained into compound ring dried meat-silk dipeptides, ring dried meat-asparagus fern acyl by LC-MS separation detection
The different bright dipeptides of amine dipeptides, ring dried meat-bright dipeptides, ring dried meat-, the-the third dipeptides of ring dried meat and ring dried meat-figured silk fabrics dipeptides.
In one embodiment of the invention, in above-mentioned steps 4,
LC liquid phase chromatogram condition are as follows:
Chromatographic column: Boston Luna Clone；
Mobile phase uses the gradient elution program of Table A；
Wherein, mobile phase A: 0.1% aqueous formic acid, Mobile phase B: acetonitrile
Table A
Wherein, ring dried meat-silk dipeptides retention time is 6.17 ± 0.02min, ring dried meat-asparagine dipeptides retention time is
8.25 ± 0.02min, ring dried meat the-the third dipeptides retention time are 10.38 ± 0.02min, ring dried meat-figured silk fabrics dipeptides retention time is 20.23
The different bright dipeptides retention time of ± 0.02min, ring dried meat-is 25.58 ± 0.02min, ring dried meat-bright dipeptides retention time be 27.38 ±
0.02min。
Above-mentioned Cyclic dipeptides of the invention can be both made with preparation method according to the invention, can also pass through open source literature
Synthetic method preparation.
On the basis of common knowledge of the art, above-mentioned each optimum condition, can any combination to get each preferable reality of the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: the therapeutic effect through animal model experiment proves, ring of the present invention
(dried meat-silk) dipeptides, ring (dried meat-asparagine) dipeptides, ring (dried meat-is bright) dipeptides, ring (dried meat-is different bright) dipeptides is to wound repair such as skin
The therapeutic effect of damage and gastric ulcer is excellent, better than comparative example ring (dried meat-figured silk fabrics) and ring (dried meat-the third) dipeptides group and positive control
Group.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Embodiment 1 is prepared the embodiment of six kinds of Cyclic dipeptides by American cockroach simultaneously
1) it takes American cockroach ethanol extract 400ml (about 218 grams) to be spin-dried for ethyl alcohol, is concentrated under reduced pressure into deionized water dissolving
After suitable concentration, filtered direct upper prop volume is the HP-20 macroporous resin column chromatography of 3.2L, is eluted with water, and is concentrated under reduced pressure
Freeze-drying process obtains water position (156g) to eluent again.
2) by American cockroach water elution obtained above position 35g, through MCI column that column volume is 380ml chromatography, (filler is
Mitsubishi Chemical MCI GEL CHP20P), be eluted with water, connect in each conical flask water flow divides A (32g).By component A's
Each bottle is detected with TLC, and solvent is n-butanol: glacial acetic acid: water=4:1:1, and ninhydrin colour developing is divided into the A1 more containing amino acid
Component (30g) and the A2 component (2g) less containing amino acid.Wherein, using TLC number of spots less than or equal to 3 component A as
A2 component, and remaining is A1 component.Separately merge.It is concentrated under reduced pressure.
3) combine MS mass spectrum (LC-MS) according to polarity size under following chromatographic condition A2 component (2g) obtained above
Respectively obtain 1 ring of compound (dried meat-silk) dipeptides, 2 ring of compound (dried meat-asparagine) dipeptides, 3 ring of compound (dried meat-the third) dipeptides,
4 ring of compound (dried meat-figured silk fabrics) dipeptides, 5 ring of compound (dried meat-is different bright) dipeptides, 6 ring of compound (dried meat-is bright) dipeptides.
Wherein LC chromatographic condition is as follows:
Chromatographic column: Boston Luna Clone (4.6mm × 250mm, 5 μm)；
Mobile phase A: 0.1% formic acid, Mobile phase B: acetonitrile,
Using gradient elution program, it is shown in Table A；
Flow velocity 0.4ml/min；40 DEG C of column temperature；2 μ l of sample volume；
Table A
Wherein, 1 ring dried meat of compound-silk dipeptides retention time is 6.17 ± 0.02min, 2 ring dried meat of compound-asparagine two
Peptide retention time is 8.25 ± 0.02min, 3 ring dried meat the-the third dipeptides retention time of compound is 10.38 ± 0.02min, compound 4
Ring dried meat-figured silk fabrics dipeptides retention time is 20.23 ± 0.02min, 5 ring dried meat of compound-different bright dipeptides retention time be 25.58 ±
0.02min, 6 ring dried meat of compound-bright dipeptides retention time are 27.38 ± 0.02min.
Wherein compound 1 is white powder.The ESI-MS m/z of the compound 1: positive ion mode 185 [M+H]+.Molecule
Formula: C8H12N2O3, molecular weight: 184.1H-NMR (D2O, 400MHz) δ: 1.04 (3H, d, J=7.0Hz, H-5), 2.28 (1H, m,
), H-3 3.61 (1H, d, J=4.4Hz, H-2), 4.51 (1H, m, Ser- α H).13C-NMR(D2O,100MHz)δ:172.0
(Pro-CO),165.3(Ser-CO),60.0(Ser-βCH2),59.0(Pro-αCH),56.9(Ser-αCH),45.2(Pro-δ
CH2),28.0(Pro-βCH2),21.6(Pro-γCH2).It is ring that the above spectral data, which is compareed authenticating compound 1 with document,
(dried meat-silk) dipeptides.
It is white powder that wherein compound, which is 2,.The ESI-MS m/z of the compound 2: positive ion mode 212 [M+H]+,234
[M+Na]+.Molecular formula: C9H13N3O3, molecular weight: 211.1H-NMR(D2O,400MHz)δ:4.51(1H,m,Ser-αH),1.04
(3H, d, J=7.0Hz, H-5), 2.28 (1H, m, H-3), 3.61 (1H, d, J=4.4Hz, H-2).13C-NMR(D2O,
100MHz)δ:174.2(NH2-CO),171.6(Pro-CO),166.6(Asn-CO),59.1(Pro-αCH),51.8(Asn-α
CH),45.5(Pro-δCH2),34.4(Asn-βCH2),27.6(Pro-βCH2),21.7(Pro-γCH2).The above spectral data
It is ring (dried meat-asparagine) dipeptides that authenticating compound 2 is compareed with document.
Wherein compound 3 is white powder.The ESI-MS m/z of the compound 3: positive ion mode 169 [M+H]+.Molecule
Formula: C8H12N2O2, molecular weight: 168.1H-NMR (D2O, 400MHz) δ: 1.40 (3H, d, J=6.9Hz, H-10), 1.94 (1H, m,
H-5b),2.03(2H,m,H-4a,H-5a),2.33(1H,m,H-4b),3.53(2H,m,H-3),4.21(1H,m,H-6),4.27
(1H,m,H-9)。13C-NMR(D2O,100MHz)δ:171.2(C-7),167.7(C-1),59.1(C-6),50.7(C-9),
45.0(C-3),27.8(C-5),22.2(C--4),14.3(C-10).The above spectral data is compareed authenticating compound 3 with document
For ring (dried meat-the third) dipeptides.
Wherein compound 4 is white powder.The ESI-MS m/z of the compound 4: positive ion mode 197 [M+H]+.Molecule
Formula: C10H16N2O2, molecular weight: 196.1H-NMR (D2O, 400MHz) δ: 0.95 (3H, d, J=6.9Hz, H-12), 1.11 (3H,
D, J=7.2Hz, H-11), 1.95 (2H, m, H-4,10), 2.01 (1H, m, H-4), 2.34 (1H, m, H-5), 2.51 (1H, m, H-
5), 3.55 (2H, m, H-3), 4.06 (1H, s, H-9), 4.23 (1H, t, J=7.2Hz, H-6).13C-NMR(D2O,100MHz)
δ:171.2(C-1),166.2(C-7),60.1(C-6),58.6(C-9),44.8(C-3),28.5(C-10),28.1(C-5),
21.9(C-4),17.5(C-11),15.3(C-12).It is ring (dried meat-that the above spectral data, which is compareed authenticating compound 4 with document,
Figured silk fabrics) dipeptides.
Wherein compound 5 is white powder.The ESI-MS m/z of the compound 5: positive ion mode 211 [M+H]+.Molecule
Formula: C11H18N2O2, molecular weight: 210.1H-NMR (D2O, 400MHz) δ: 0.95 (3H, t, J=7.4Hz, H-12), 1.09 (3H,
D, J=7.1Hz, H-12), 1.33 (1H, m, H-11), 1.45 (1H, m, H-11), 1.94 (2H, m, H-4), 2.05 (1H, m, H-
5a),2.19(1H,m,H-5b),2.34(1H,m,H-10),3.54(2H,m,H-3),4.09(1H,s,H-9),4.22(1H,m,
H-6)。13C-NMR(D2O,100MHz)δ:170.7(C-7),166.1(C-1),59.9(C-6),58.6(C-9),44.8(C-
3),36.6(C-10),28.1(C-5),24.0(C-11),21.8(C-4),15.9(C-13),11.1(C-12).The above wave spectrum number
It is ring (dried meat-is different bright) dipeptides according to authenticating compound 5 is compareed with document.
Wherein compound 6 is white powder.The ESI-MS m/z of the compound 6: positive ion mode 211 [M+H]+.Molecule
Formula: C11H18N2O2, molecular weight: 210.1H-NMR (D2O, 400MHz) δ: 0.98 (6H, dd, J=2.5,6.4Hz, H-12, H-
13),1.54(1H,m,H-11),1.91(2H,m,H-4),2.03(2H,m,H-10),2.32(1H,m,H-5),3.54(2H,m,
), H-3 4.15 (1H, m, H-9), 4.28 (1H, t, J=8.0Hz, H-6).13C-NMR(D2O,100MHz)δ:171.4(C-7),
167.5(C-1),58.8(C-6),53.2(C-9),45.1(C-3),38.0(C-10),27.7(C-5),24.4(C-11),22.2
(C-12),21.9(C-4),20.8(C-13).It is ring (dried meat-is bright) two that the above spectral data, which is compareed authenticating compound 6 with document,
Peptide.
The effect example of the treatment gastric ulcer of embodiment 2
1, experimental material:
1.1 samples: ring dried meat-silk, ring dried meat-asparagine, ring dried meat-bright, ring dried meat-different bright, the ring dried meat-the third, ring of embodiment 1
Dried meat-figured silk fabrics dipeptides
1.2 experimental animals: SD rat, weight: 180-200g, half male and half female, source: this western Poole-Bi Kai experiment of Shanghai
Company of Animals Ltd.；Kunming mouse, weight: 18-22g, half male and half female, source: this western Poole-Bi Kai experimental animal of Shanghai has
Limit company.
1.3 test reagents: ulcerlmin (Nanjing Bai Jingyu pharmacy responsibility Co., Ltd), ranitidine hydrochloride (Suzhou third
Co., Ltd, pharmaceutical factory), dehydrated alcohol, glacial acetic acid, yellow Jackets (Chinese medicines group).
2, experimental method
2.1 pairs of dehydrated alcohols cause mouse gastric ulcer effect
KM mouse 90, it is randomly divided into ring dried meat-silk, the ring dried meat-asparagine, ring of blank group, model group and embodiment 1
Dried meat-is bright, different bright, the ring dried meat-the third of ring dried meat-, ring dried meat-figured silk fabrics dipeptides group, (concrete condition is shown in Table positive controls (ranitidine hydrochloride)
1), each test group gives corresponding drug, and each group mouse is administered 10 days, and each administration group dosage of the Cyclic dipeptides of embodiment 1 is
15mg/kg, ranitidine hydrochloride group dosage are 75mg/kg.9th day administration after fasting for 24 hours, free water.Every group small
Mouse after last dose 3h, give 0.2ml dehydrated alcohol and carry out stomach-filling by all mouse, and animal is put to death after 1 hour, ligatures pylorus,
1% formaldehyde is fixed, and is observed and is evaluated ulcer index and inhibiting rate.With the maximum major diameter of vernier caliper measurement ulcer and perpendicular to most
The wide diameter of the maximum of big major diameter, the product of the two is ulcer index.Ulcer inhibition rate=(averaging model group ulcer index-is average
Experimental group ulcer index)/averaging model group ulcer index × 100%.
The influence of 2.2 Dichlorodiphenyl Acetates cause rat gastric ulcer model
SD rat 90, it is randomly divided into ring dried meat-silk, the ring dried meat-asparagine, ring of blank group, model group and embodiment 1
Dried meat-is bright, different bright, the ring dried meat-the third of ring dried meat-, ring dried meat-figured silk fabrics dipeptides 1-6 group, positive controls (ulcerlmin) (concrete condition is shown in Table 2), removes
Outside blank group, after remaining each rats in test groups fasting 12h, routine disinfection skin under etherization, back fixation is cutd open in mouse plate
Abdomen, exposure stomach, the glass header of an internal diameter 7.0mm long 3.0cm is placed on above taste portion, and glacial acetic acid 80 is injected into glass tube
After μ L, 1min with cotton balls exhaust glacial acetic acid, and use normal saline flushing, with omentum majus wrap up burn position, slowly stomach is sent into
In abdomen, layering suture, postoperative careful nursing.Postoperative each administration group on the 2nd gives corresponding drug, is administered once daily, continuously gives
Medicine 10d.Each administration group dosage of the Cyclic dipeptides of embodiment 1 is 10mg/kg, and ulcerlmin group dosage is 100mg/kg.In
After doomsday administration, animal is put to death, abdominal cavity ligation pylorus and cardia is opened, wins full stomach, calculate ulcer index and ulcer inhibition rate.
Ulcer index=ulcer maximum gauge × perpendicular to the wide diameter of maximum of maximum gauge；
Ulcer inhibition rate=(averaging model group ulcer index-average experiment group ulcer index)/averaging model group ulcer refers to
Number × 100%.
3, experimental result
3.1 pairs of dehydrated alcohols cause the influence of Mouse Gastric Mucous Membrane damage
As it can be seen that compared with model group, each administration group can be significantly reduced dehydrated alcohol and causes Mouse Gastric Mucous Membrane damage table 1
Ulcer index (p < 0.05), middle ring dried meat-asparagus fern inhibitory effect is best, has extremely significant sex differernce (P < 0.01), and inhibiting rate is
71.67%.After administration 10 days, the ulcer index and inhibiting rate of each Cyclic dipeptides group are controlled compared with positive drug ranitidine hydrochloride group
Therapeutic effect is significantly better than that positive controls.From table 1 it has been also found that with 1 ring dried meat of comparative example -2 ring dried meat of figured silk fabrics dipeptides and comparative example -
Third dipeptides is compared, 4 kinds of Cyclic dipeptides ring dried meat-silk dipeptides, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, ring dried meat-different of the invention
Bright dipeptides has more obvious protective effect to chronic gastric mucosa damage caused by dehydrated alcohol.
Table 1 causes the influence of mouse gastric ulcer to dehydrated alcohol
Note: compared with model group:*p<0.05；**p<0.01；
Compared with positive controls:#P < 0.05,##p<0.01
3.2 Dichlorodiphenyl Acetates cause the influence of Mouse Gastric Mucous Membrane damage
For table 2 as it can be seen that compared with model group, bursting for acetic acid induced mice gastric mucosa damage is can be significantly reduced in each administration group
Ulcer index, the effect of middle ring dried meat-Aspartame, ring dried meat-silk dipeptides, ring dried meat-bright dipeptides is obvious, have extremely significant sex differernce (P <
0.01).After administration 10 days, the ulcer index and inhibiting rate of each Cyclic dipeptides group are superior to positive controls ulcerlmin group.Table 2 can be with
Find out, compared with 2 the-the third dipeptides of ring dried meat of 1 ring dried meat of comparative example-figured silk fabrics dipeptides and comparative example, 4 kinds of Cyclic dipeptides ring dried meat-silks two of the invention
Acute gastric mucosal lesion caused by the different bright dipeptides Dichlorodiphenyl Acetate of peptide, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, ring dried meat-has
More preferably protective effect.
The influence of 2 Dichlorodiphenyl Acetate of table cause mouse gastric ulcer
Note: compared with model group:*p<0.05；**p<0.01
Compared with positive controls:#p<0.05
The studies above the result shows that: ring dried meat-silk dipeptides of the invention, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, ring
The different bright dipeptides of dried meat-all has preferable mucous membrane to acute gastric ulcer model caused by chronic gastric ulcer caused by ethyl alcohol and acetic acid and repairs
Multiple effect, compared with positive controls common drug and comparative example ring dried meat-figured silk fabrics dipeptides, the-the third dipeptides of ring dried meat, ulcer inhibition rate is high,
Function and effect are more significant.
Embodiment 3 treats skin injury effect example
1, experimental material:
1.1 samples: ring dried meat-silk, ring dried meat-asparagine, ring dried meat-bright, ring dried meat-different bright, the ring dried meat-the third, ring of embodiment 1
Dried meat-figured silk fabrics dipeptides.
1.2 experimental animals: Wistar rat, weight: 180-200g, half male and half female, source: this western Poole-Bi Kai of Shanghai
Experimental animal Co., Ltd；Kunming mouse, weight: 18-22g, half male and half female, source: this western Poole-Bi Kai experiment of Shanghai is dynamic
Object Co., Ltd.
1.3 test reagents: moist exposed burn cream (Shantou Mebo Pharmaceuticals Co., Ltd.), carrageenan (upper sea blue China's chemistry
Science and Technology Ltd.), dimethylbenzene (Jing Mao trade Co., Ltd), dexamethasone acetate (China Resources Sanjiu Medical & Pharmaceutical Co., Ltd.)
2, test method:
The influence of 2.1 pairs of Rat Models of Traumatic skin ulcer models
Wistar rat 90, be randomly divided into blank group, model group, ring dried meat-silk of embodiment 1, ring dried meat-asparagine,
(concrete condition is shown in Table for different bright, the ring dried meat-the third of ring dried meat-bright, ring dried meat-, ring dried meat-figured silk fabrics dipeptides group and positive controls (moist exposed burn cream)
3), in addition to blank group, remaining each rats in test groups is injected intraperitoneally 10% chloraldurate 0.3ml/100g, anesthetized rat, and back is net
Hair (3cm × 2cm), with punch, other 1.5cm cuts 1 roun ulcer (diameter 1.8cm, area on the right side of dorsocentral ridge column
2.54cm2), removing subcutaneous tissue is spare after hemostasis to muscular fascia.Each administration group starts to be administered in modeling next day, and 10 are administered altogether
It.The the 3rd, 7,10 day observation ulcer healing situation and surface of a wound area after medication.
2.2 form influence to experimental rat granuloma induced by implantation of cotton pellets
Wistar rat 80, it is randomly divided into ring dried meat-silk, the ring dried meat-asparagine, ring dried meat-of model group and embodiment 1
(concrete condition is shown in Table for bright, different bright, the ring dried meat-the third of ring dried meat-, ring dried meat-figured silk fabrics dipeptides group and positive controls (dexamethasone acetate group)
4).Each rats in test groups is anesthetized with ether, an osculum is cut at back, the disinfecting silk or cotton of 20mg will be weighed as with ophthalmic tweezers
Ball is subcutaneous from small notch implantation, immediately skin suture, and conventinal breeding is spare after being sterilized with iodine solution.Each administration group is opened in operation next day
Begin to be administered, successive administration 10d.After administration, cotton balls is taken out together with surrounding connective tissue, rejects peripheral adipose group
It knits, puts 50 DEG C of drying in baking oven and claim dry weight for 24 hours.Cotton balls weight before cotton balls dry weight-experiment after granuloma dry weight=experiment.
The influence of 2.3 pairs of mouse dimethylbenzene induction ear swelling models
KM mouse 80, it is randomly divided into model group, ring dried meat-silk of embodiment 1, ring dried meat-asparagine, ring dried meat-bright, ring
Different bright, the ring dried meat-the third of dried meat-, ring dried meat-figured silk fabrics dipeptides group and positive controls (moist exposed burn cream group) (concrete condition is shown in Table 5).Exist respectively
Two sides applies 100% caused by dimethylbenzene xylene inflammation liquid 0.02ml/ only before and after mouse right ear.After 30min, in mouse right ear swelling position smearing pair
The each group trial drug answered, left ear is as a comparison without processing.Animal is put to death after 4 hours, cuts ears immediately, is beaten with 8mm
Hole device takes same area auricle, weighs on assay balance.Swelling=auris dextra sheet weight-left auricle weight, swelling rate=(right
Ear weight-Zuo Erchong)/Zuo Erchong × 100%.
3, experimental result
The influence of 3.1 pairs of Rat Models of Traumatic skin ulcer models
As it can be seen that compared with model group, each administration group is substantially reduced table 3 in the 3rd, 7,10 day ulcer area of medication, is had
Statistical difference (p < 0.05, p < 0.01)；Compared with positive controls moist exposed burn cream, four kinds of Cyclic dipeptides ring dried meat-of the invention
Silk dipeptides, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, the different bright dipeptides of ring dried meat-reduce each administration group skin ulcer area,
Rat surface of a wound scar color is shallower, and healing rate is faster.With 2 ring dried meat the-the third dipeptides phase of 1 ring dried meat of comparative example-figured silk fabrics dipeptides and comparative example
Than 4 kinds of Cyclic dipeptides ring dried meat-silk dipeptides of the invention, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, the different bright dipeptides pair of ring dried meat-
Traumatic skin ulcer healing speed faster, healing effect more preferably.
Influence of the table 3 to Rat Models of Traumatic skin ulcer
Note: compared with model group:*p<0.05；**p<0.01
The influence that 3.2 pairs of experimental rat granuloma induced by implantation of cotton pellets are formed
For table 4 as it can be seen that compared with model group, each administration group of Cyclic dipeptides and dexamethasone acetate group can reduce granuloma induced by implantation of cotton pellets
Dry weight.Its middle ring dried meat-asparagus fern, ring dried meat-silk, ring dried meat-are bright and dexamethasone acetate group reduction effect is the most obvious, have extremely aobvious
It writes sex differernce (p < 0.01).Result of study shows: four kinds of Cyclic dipeptides ring dried meat-silk dipeptides, ring dried meat-asparagine two of the invention
The different bright each administration group of dipeptides of peptide, ring dried meat-bright dipeptides, ring dried meat-can inhibit granulation tissue hyperplasia, have apparent anti-inflammatory effect.With
1 ring dried meat of comparative example-figured silk fabrics dipeptides is compared with 2 the-the third dipeptides of ring dried meat of comparative example, 4 kinds of Cyclic dipeptides ring dried meat-silk dipeptides, ring dried meat-of the invention
The different bright dipeptides of asparagine dipeptides, ring dried meat-bright dipeptides, ring dried meat-becomes apparent from granulation tissue hyperplasia anti-inflammatory effect.
The influence that table 4 forms swollen hyperplasia of rat granuloma
Note: compared with model group:*p<0.05；**p<0.01
The influence of 3.3 paraxylene cause mice auricle swelling
For table 5 as it can be seen that compared with model group, each dosage group of Cyclic dipeptides and moist exposed burn cream group can obviously reduce diformazan
The right ear thickness of benzene induced mice has extremely significant sex differernce (p < 0.01).The result shows that: four kinds of Cyclic dipeptides rings of the invention
The different bright each dosage group of dipeptides of dried meat-silk dipeptides, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, ring dried meat-can substantially reduced dimethylbenzene
Mice auricle swelling rate is caused, there is certain anti-inflammatory effect.With 2 the-the third dipeptides of ring dried meat of 1 ring dried meat of comparative example-figured silk fabrics dipeptides and comparative example
It compares, 4 kinds of Cyclic dipeptides ring dried meat-silk dipeptides of the invention, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, the different bright dipeptides of ring dried meat-
It is stronger to ear thickness anti-inflammatory effect effect.
The influence of 5 paraxylene of table cause mice auricle swelling
Note: compared with model group:*p<0.05；**p<0.01
Based on the above results, four kinds of Cyclic dipeptides ring dried meat-silk dipeptides, ring dried meat-in American-cockroach-extract of the present invention
The different bright dipeptides of asparagine dipeptides, ring dried meat-bright dipeptides, ring dried meat-has effects that preferably wound healing, has and promotes to glue
Film reparation and anti-inflammatory effect.To acute gastric ulcer model and rat caused by chronic gastric ulcer model caused by ethyl alcohol, acetic acid
Traumatic skin Ulcer Models all have preferably therapeutic effect, and can obviously inhibit granulation tissue hyperplasia and mitigate dimethylbenzene
Mice auricle swelling degree is caused, there is apparent anti-inflammatory effect.Wherein, ring (dried meat-asparagus fern) dipeptides, ring (dried meat-silk) dipeptides, ring (dried meat-
It is bright) dipeptides relative to positive controls and comparative example 1 ring dried meat-figured silk fabrics dipeptides and 2 the-the third dipeptides of ring dried meat of comparative example for acute and chronic gastritis
Ulcer and skin injury therapeutic effect are obvious；Wherein, ring (dried meat-asparagus fern) dipeptides, ring (dried meat-silk) dipeptides group therapeutic effect be more
It is good.
Claims (10)
1. any one in ring dried meat-silk dipeptides, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, the different bright dipeptides of ring dried meat-is in the surface of a wound
Application in repair medicine.
2. application or such as power of the Cyclic dipeptides as described in claim 1 in treatment acute and chronic gastritis ulcer, gastric mucosa damage drug
Benefit require 1 described in Cyclic dipeptides in treatment skin injury such as skin ulcer, scytitis, the application in skin burn drug；
Wherein, skin ulcer can be varicose ulcer, diabetic ulcer, pressure ulcer.
3. a kind of prepare ring dried meat-silk dipeptides, ring dried meat-asparagine dipeptides, ring dried meat-bright dipeptides, ring by American cockroach extraction separation
The method of the different bright dipeptides of dried meat-, the-the third dipeptides of ring dried meat-figured silk fabrics dipeptides and ring dried meat:
Step 1: American cockroach coarse powder is concentrated to give medicinal extract after alcohol steep；
Step 2: macroporous resin column chromatography on above-mentioned medicinal extract being eluted with water, eluent is concentrated to give water position sample；
Step 3: water intaking position sample is chromatographed through MCI column, obtains component A with water elution；By component A points for containing compared with amino acids
A1 component and A2 component containing less amino acid；
Step 4: A2 component being passed through into LC-MS LC-MS separation detection, obtains compound ring dried meat-silk dipeptides, ring dried meat-asparagus fern acyl
Amine dipeptides, the-the third dipeptides of ring dried meat, ring dried meat-figured silk fabrics dipeptides, the different bright dipeptides of ring dried meat-, ring dried meat-bright dipeptides.
4. the preparation method of Cyclic dipeptides according to claim 3, wherein
Macroporous resin column in step 2 is HP-20 macroporous resin column；
The wire feeding of MCI column in step 3 is MCI GEL CHP20P.
5. the preparation method of Cyclic dipeptides according to claim 3, wherein
In step 1, medicinal extract is concentrated under reduced pressure to obtain in American cockroach coarse powder after alcohol steep；
In step 2, the medicinal extract is spin-dried for ethyl alcohol, with macroporous resin column chromatography column upper after deionized water dissolving；
In step 2, eluent concentration is freeze-dried the position get Shui sample again；
In step 3, detects in conjunction with TLC, by ninhydrin as color developing agent, divided into component A containing ammonia according to TLC spot number
The base more A1 component of acid and the A2 component less containing amino acid；Wherein the component A by TLC number of spots less than or equal to 5 makees
For A2 component, and remaining component A is A1 component；Preferably, the component A using TLC number of spots less than or equal to 3 is as A2 group
Point, and remaining component A is A1 component.
6. the preparation method of Cyclic dipeptides according to claim 5, wherein in step 3, the solvent of TLC detection is positive fourth
Alcohol: glacial acetic acid: water=4:1:1.
7. the preparation method of Cyclic dipeptides according to claim 3, wherein in step 4,
The chromatographic column that the LC liquid phase chromatogram condition uses is selected from: Capcell Pak C18MGll, Boston Luna Clone
C18, Diamonsil C18,Boston Luna Clone；Preferably, the chromatographic column that the LC liquid phase chromatogram condition uses for
Boston Luna Clone；
Mobile phase uses mobile phase A and Mobile phase B in the LC liquid phase chromatogram condition；
The mobile phase A is 0.06-0.3% aqueous formic acid or 0.06-0.3% phosphate aqueous solution；Preferably, the mobile phase
A is the aqueous formic acid of 0.06-0.1%；
The Mobile phase B is acetonitrile or alcohols solvent；Preferably, the Mobile phase B is methanol.
8. the preparation method of Cyclic dipeptides according to claim 7, wherein in step 4, the LC liquid phase chromatogram condition is used
Isocratic or gradient elution mode；Preferably, the LC liquid phase chromatogram condition is by the way of gradient elution, wherein the ladder
The volume ratio of the mobile phase A and the Mobile phase B is 90:10~5:95 when degree elution.
It separates 9. a kind of American cockroach is extracted while preparing ring dried meat-silk dipeptides, ring dried meat-asparagine dipeptides, ring dried meat-bright two
The method of the different bright dipeptides of peptide, ring dried meat-, the-the third dipeptides of ring dried meat-figured silk fabrics dipeptides and ring dried meat:
Step 1: medicinal extract is concentrated under reduced pressure to obtain in American cockroach coarse powder after alcohol steep；
Step 2: the medicinal extract being spin-dried for ethyl alcohol, with macroporous resin column chromatography column upper after deionized water dissolving, is eluted with water, will wash
De- liquid concentration is freeze-dried the position get Shui sample again；
Step 3: water intaking position sample is chromatographed through MCI column, obtains component A with water elution；By ninhydrin as color developing agent, in conjunction with
TLC detection is by component A points for containing the more part A1 component of amino acid and the A2 component less containing amino acid；Wherein, by TLC spot
Point number less than or equal to 3 component A as A2 component, and remaining for A1 component wherein, the solvent that TLC is detected is positive fourth
Alcohol: glacial acetic acid: water=4:1:1；
Step 4: A2 component is respectively obtained into compound ring dried meat-silk dipeptides, ring dried meat-asparagine two by LC-MS separation detection
The different bright dipeptides of peptide, ring dried meat-bright dipeptides, ring dried meat-, the-the third dipeptides of ring dried meat and ring dried meat-figured silk fabrics dipeptides.
10. the preparation method of Cyclic dipeptides according to claim 3 or 9, wherein in step 4,
LC liquid phase chromatogram condition are as follows:
Chromatographic column: Boston Luna Clone；
Mobile phase uses the gradient elution program of Table A；
Wherein, mobile phase A: 0.1% aqueous formic acid, Mobile phase B: acetonitrile
Table A
Wherein, ring dried meat-silk dipeptides retention time be 6.17 ± 0.02min, ring dried meat-asparagine dipeptides retention time be 8.25 ±
0.02min, ring dried meat the-the third dipeptides retention time are 10.38 ± 0.02min, ring dried meat-figured silk fabrics dipeptides retention time be 20.23 ±
The different bright dipeptides retention time of 0.02min, ring dried meat-is 25.58 ± 0.02min, ring dried meat-bright dipeptides retention time be 27.38 ±
0.02min。
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