CN105288585A - Application of cyclic dipeptide in preparation of drugs for treating skin injury - Google Patents
Application of cyclic dipeptide in preparation of drugs for treating skin injury Download PDFInfo
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- CN105288585A CN105288585A CN201410273124.7A CN201410273124A CN105288585A CN 105288585 A CN105288585 A CN 105288585A CN 201410273124 A CN201410273124 A CN 201410273124A CN 105288585 A CN105288585 A CN 105288585A
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Abstract
The invention provides application of cyclic dipeptide in preparation of drugs for treating skin injury. The cyclic dipeptide is cyclo-L-prolyl-L-dipeptide, and is particularly used for burns and scalds. The dipeptide has the features of small molecular weight, simple structure and the like. The cyclic dipeptide has a remarkable effect on treatment of burns and scalds, can quickly permeate injured skin tissues and enter cells in a treatment process, repairs injured cells and activates self-repairing capability, wound healing speed is accelerated, recurrence rate is low after healing, scars are shallow, and potential side effects after treatment by traditional Chinese medicines and western drugs are avoided. Moreover, the cyclic dipeptide also has effects of inhibiting inflammation and stopping pain, and improving immunity.
Description
Technical field
Biomedicine field belonging to the present invention, particularly a kind of application of Cyclic dipeptides.
Background technology
Skin trauma is the common diseases of people in daily productive life, as process can cause infecting not in time, suppurates, stays scar, even cause the sepsis of whole body, threat to life.
Burn and scald is body injury common in wartime and daily life.Along with the development of modern industrial and agricultural production technology, chemistry and electron burn are also in the trend increased.May cause a large amount of personnel's burn and scald very greatly in the disasters such as forest fire, inflammable and explosive substances combustion explosion, public place catch fire.
The pathological change of deep burn local organization, by the different levels of local damage degree, be divided into three zone of similar concentric garden shape, that is: 1. centers are coagulation necrosis band; 2. be with for blood capillary is retarded by silt around; 3. periphery is congested band.Wherein downright bad band represents this place's tissue necrosis, and increase and the expansion of capillary permeability that what the damaged tissue of be retarded by silt band and congested band mainly changed is, slow blood flow easily Microembolization occurs, and makes local tissue hypoxia and causes the impact on whole body.Therefore, to treat burn and scald, first need to stop and improve be retarded by silt band and the congested pathophysiological change of band and the impact on whole body thereof, make it recover as soon as possible and reach physiological reparation state, instead of Xiang Gengshen or worse pathological change development.
The medicine for the treatment of burn and scald conventional is clinically with the most species of Chinese medicine, and Western medicine secondly.Prescriptions of Chinese medicine take Chinese crude drug as raw material, obtain through certain processing step, but except effective ingredient, also have other composition in Chinese crude drug, these compositions are failed to understand the effect of the skin histology of damaged, there are potential risks, and after using the wound of Chinese medicine for external application to burn and scald to process, a large amount of pigmentation, after making wound healing, cicatrix is more obvious, affects attractive in appearance.Western medicine is mainly based on antiinflammatory and symptomatic treatment, and side effect is comparatively large over the course for the treatment of, though have remarkable result to control traumatic infection as silver sulfadiazine antibacterial action, has certain detrimental effect to the activity of cell, poor to the penetrance of slough.
Summary of the invention
Be used to for above-mentioned Chinese medicine and Western medicine treat the problem that there will be in the process of burned patient, inventor expects utilizing small-molecule substance in biology can direct this feature of permeates cell membranes, then acted directly on wound surface, small-molecule substance just can be very fast the histiocyte entering into damaged, thus activate the self-repairing capability of injured cell, fundamentally come to carry out treatment reparation to wound surface, doing so avoids the appearance of external used medicine to the untoward reaction of burned patient.Through long-term experimentation, inventor also have found the small-molecule substance had wound healing ability finally, and this small-molecule substance belongs to the Cyclic dipeptides in cyclic peptide, and molecular structure is simple.
The invention provides a kind of small-molecule substance to apply in the medicine preparing skin injury, the particularly application of a kind of Cyclic dipeptides in burn and scald.
Cyclic dipeptides of the present invention is ring-L-dried meat-L-third dipeptides, and relative molecular mass is 168.23, and concrete molecular structure is as follows:
Ring-L-dried meat-L-third dipeptides of the present invention can be obtained by chemosynthesis, also can obtain by extraction purification from organism.
The preparation method of the chemosynthesis of described ring-L-dried meat-L-third dipeptides, it is characterized in that synthesis step comprises condensation, deprotection, cyclisation three phases, concrete technical scheme is as follows:
1. in and condensation: get the L-PROLINE that carries out Boc amido protecting and alanine methyl ester hydrochloride containing THF (oxolane), pyridine, (Boc)
2n-tertbutyloxycarbonyl-prolyl methyl lactamine is obtained with condensation reaction in carrying out under the condition of O, DMAP (catalyst);
2. deprotection: under the effect of the saturated solution of EtoAc (ethyl acetate) and HCl, amino deprotection process is carried out to the N-tertbutyloxycarbonyl-prolyl methyl lactamine obtained in step 1, obtain prolyl methyl lactamine;
3. cyclisation: by the prolyl methyl lactamine that obtains in step 2 and methanol mixed, use NaHCO
3after regulating pH, reflux 18 hours, filters, column chromatography purification, obtains ring-L-dried meat-L-third dipeptides of white.
Synthetic route is as follows:
Ring-L-dried meat-L-of the present invention the third two peptide molecular weight is little, structure is simple, synthetic is simple, remarkable to the therapeutic effect of burn and scald, can enter cell through injured cutaneous tissue very soon over the course for the treatment of, repair damaged cell, activate self-repairing capability, healing speed is accelerated, healing relapse rate is low, cicatrix is shallow, and the potential side effect after avoiding in use medicine and western medicine.
Ring-L-dried meat-L-third dipeptides of the present invention can directly directly spread upon on treated burn and scald wound as external used medicine, and have the symptomatic treatment of targeting, side effect is little, evident in efficacy; Also can be used as oral preparations, after taking, can body's immunity be improved, strengthen the ability of the extraneous bacteriovirus infection of antagonism.
Detailed description of the invention
Being below combine specifically to test explanation of the present invention, is not limiting the scope of the invention.
The preparation method of ring-L-dried meat-L-third dipeptides described in embodiment 1 the present invention
Primary drug reagent: ALANINE, proline through Boc amido protecting
Prepare the process of ring-L-dried meat-L-third dipeptides:
(1) preparation of alanine methyl ester hydrochloride: add ALANINE 10g in the mixed liquor of proper amount of methanol and thionyl chloride, at room temperature stir 24h.TLC follows the tracks of reaction and completes, and decompression is spin-dried for solvent, obtains the alanine methyl ester hydrochloride 14.78g of white.
(2) in and condensation reaction: add in 100ml anhydrous tetrahydro furan obtain in step (1) alanine methyl ester hydrochloride, the proline 20g through Boc amido protecting, pyridine 20ml, DMAP; after all mixing, add under the protection of argon (Boc) that be dissolved in anhydrous tetrahydro furan
2o, stirred at ambient temperature 10 hours.TLC follows the tracks of reaction and completes, column chromatography purification (petroleum ether: ethyl acetate=4:1), is spin-dried for solvent and obtains yellow N-tertbutyloxycarbonyl-prolyl methyl lactamine solid 28.32g.
(3) Boc protects amino deprotection process: get the N-tertbutyloxycarbonyl-prolyl methyl lactamine obtained in step (2); add the saturated solution 2.6L of hcl ethyl acetate (HCl/EtOAc); 2h is stirred under ice-water bath; in ice-water bath, decompression evaporates solvent, obtains white prolyl methyl lactamine solid 22.31g with methanol-diethyl ether recrystallization.
(4) preparation of ring-L-dried meat-L-third dipeptides: the prolyl methyl lactamine obtained in step (3) is joined in 0.9L methanol, uses NaHCO
3adjustment pH is 7-8, reflux 18h, and filter, column chromatography purification (ethyl acetate: methanol=2:1), finally obtains white solid ring-L-dried meat-L-third dipeptides 16.45g.
The application of embodiment 2 ring-L-dried meat-L-third dipeptides in burn and scald
The object of the present embodiment is, to the application of ring-L-dried meat-L-third dipeptides described in the present invention in preparation treatment burn and scald medicine, to be described further with the result of mouse experiment burn and scald.
1, experiment material
1.1 samples: obtain sample by embodiment 1: ring-L-dried meat-L-third dipeptides
The healthy Kunming mouse of 1.2 laboratory animals: 18-22g, 180
1.3 experiment reagents: 10% sodium sulfide solution, ether, moist expose burn ointment (Shantou Mebo Pharmaceuticals Co., Ltd.)
2, to the evaluation methodology of ring-L-dried meat-L-third dipeptides treatment mice burn and scald functional effect
2.1 impacts that mouse experiment is scalded
Healthy Kunming mouse 30, be divided into 3 groups at random, often organize 10, before experiment, 24h sloughs the hair of mouse back with 10% sodium sulfide depilatory, after etherization, depilation position is dropped to the paraffin liquid 0.5mL being melted to 150 DEG C, cause III ° of scald, then divide into groups by table 1 and smear administration at scald position, 3 grouping medications are all administration sooner or later 2 times, observe and scald position healing time, scald position digital camera and take pictures, measure each group of mouse back scalding area with IPP5.1 image analysis software bag.Carry out statistical analysis by measured result, the results are shown in Table 1.
As can be seen from Table 1, ring-L-dried meat-L-third dipeptides dosage group obviously can shorten the wound healing time after scald, also scald wound area can be made obviously to reduce simultaneously, with normal saline group comparing difference, there is statistical significance (P < 0.05, P < 0.01), in the therapeutic process in coating later stage, ring-L-dried meat-L-third dipeptides at the repairing effect of scalding mice apparently higher than moist expose burn ointment group.Repeat experiment 3 times, each experimental result trend is identical with result trend in table 1.
What table 1 ring-L-dried meat-L-third dipeptides was scalded mouse experiment affects result
Note # represents and to compare with normal saline group, p<0.05
2.2 impacts that mouse experiment is burnt
Healthy Kunming mouse 30, be divided into 3 groups at random, often organize 10, before experiment, 24h sloughs the hair of mouse back with 10% sodium sulfide depilatory, after etherization, with compressed asbestos sheet one fritter, centre hollows out 3cm32cm, is placed in mice back, gets 0.3mL95% ethanol be coated in exposure place with suction pipe, ignition 20s causes eschar burn model, to divide into groups coating by table 2 afterwards, 3 grouping medications be all morning and evening administration 2 times, are coated with 60d continuously, become mildewed after observing wound healing time and healing percentage rate, the results are shown in Table 2.
Experimental result is obtained as can be seen from table 2, ring-L-dried meat-L-the third two Toplink significantly accelerates the healing rate of mice burn wound and the percentage rate that becomes mildewed after increasing mice burn-healing, statistical significance (P < 0.05) is all had with normal saline group comparing difference, significantly shorten the time of wound healing, the percentage rate that becomes mildewed significantly improves; At quickening wound healing with improve the compromised skin hair follicle performance increase percentile effect pressed on ring-L-dried meat-L-third dipeptides group that becomes mildewed and be better than moist expose burn ointment group.Repeat experiment 3 times, each experimental result trend is identical with result trend in table 2.
What table 2 ring-L-dried meat-L-third dipeptides was burnt on mouse experiment affects result
Note # represents and to compare with normal saline group, p<0.05
Embodiment 3 ring-L-dried meat-L-third dipeptides regulates the immunologic function of body
The object of the present embodiment is to be described further ring-L-dried meat-L-third effect that dipeptides is regulating body's immunity described in the present invention.
1, experiment material
Sample: by the sample that embodiment 1 is obtained: ring-L-dried meat-L-third dipeptides.
Laboratory animal: quality is the male BALB/C mice of 18 ~ 22gSPF level
Experimental technique:
Mice is divided at random normal group, model group, positive group and ring-L-dried meat-L-third dipeptides dosage group, often organizes 10.Sample is made into 0.5mg/ml by after test solution to mouse stomach, normal group and model group give normal saline, and positive group gives Radix Astragali essenc by 20mL/kg, every day ig once, continuous 14 days.In administration the 1st, 2,3,8,9,10, except normal group, all the other respectively organize ip in mice 50mL/kg adenosine cyclophosphate, totally 6 times, induction of immunity hypofunction model.
2, immunity function evaluation methodology is improved
Hypoimmunity mice Immune Organs Index by experiment: thymus index, spleen index, liver exponential sum phagocytic index, engulf coefficient, with hemolysin level in spectrophotometry mice serum.
3, enhancing immunity functional evaluation result
3.1 impacts on hypoimmunity mice Immune Organs Index
Table 3 is on the impact of hypoimmunity mice Immune Organs Index
Note * to represent that compared with normal group P < 0.05, # represents and compares P < 0.05 with model group
3.2 on hypoimmunity mice phagocytic index and the impact of engulfing coefficient
Table 4 is on hypoimmunity mice phagocytic index and the impact of engulfing coefficient
Note * to represent that compared with normal group P < 0.05, # represents and compares P < 0.05 with model group
From table 3,4, thymus index, spleen index, liver index, the phagocytic index of the mice of ring-L-dried meat-L-third dipeptides group and engulf coefficient higher than model group, have statistical significance (P < 0.05).To cyclophosphamide cause hypoimmunity mice immune organ increase and mononuclear-macrophage phagocytic function there is facilitation.
3.3 impacts on Hemolysin formation in hypoimmunity mice delayed hypersensitivity and serum
The impact that table 5 generates hypoimmunity mice delayed hypersensitivity and serum hemolysin
Note * to represent that compared with normal group P < 0.05, # represents and compares P < 0.05 with model group
As shown in Table 5, in ring-L-dried meat-L-third dipeptides mice serum, hemolysin level is higher than model group, has statistical significance (P < 0.05).Experimental result in table 5 also illustrates that ring-L-dried meat-L-the third two Toplink strengthens delayed hypersensitivity caused by hypoimmunity mice DNCB and can significantly improve the level of hemolysin in hypoimmunity mice serum.
The anti-inflammatory and analgesic effect of embodiment 4 ring-L-dried meat-L-third dipeptides
The object of the present embodiment is to be described further the anti-inflammatory and analgesic effect in the therapeutic effect of ring-L-dried meat-L-third dipeptides in burn and scald.
1, experiment material
Sample: by the sample that embodiment 1 is obtained: ring-L-dried meat-L-third dipeptides.
Laboratory animal: quality is 25 ~ 30g Kunming mouse, male and female half and half
Experiment reagent: normal saline, nabumetone
Experimental technique:
Get the mice of 30 male and female half and half, be divided into 3 groups at random: saline control group (0.1ml/10g), nabumetone matched group (250mg/kg), ring-L-dried meat-L-third dipeptides group (250mg/kg).Each group of equal per os gastric infusion.Each group every day gavage 1 time, continuous 4d, after last gavage 2h, tail vein injection Evan ' sblue50mg/kg, in mouse right ear two-sided painting dimethylbenzene 25ul/ face, after 20h, draw neck to put to death mice, cut ears along auricle baseline, round auricle is laid at the same position of ears respectively with the card punch of diameter 7.5mm, scales/electronic balance weighing, obtains weight difference, in order to represent swelling (swelling=left ear auricle weight-auris dextra auricle weight).Calculate swelling inhibition percentage as follows.
Suppression ratio (%)=(the average swelling of normal saline group-average swelling of administration group) average swelling * 100% of/normal saline group.
Table 5 ring-L-dried meat-L-third dipeptides is on the impact of mice ear degree
Note: # represents compared with normal saline group, p<0.05
Result in table 5 represents: the mice auricle edema of dimethylbenzene induction is the inflammatory model of acute non-specific, the acute inflammation that causes change comprise vasodilation, capillary permeability increases, oozes out.Viewed from result of the test, ring-L-dried meat-L-third dipeptides is respond well to suppressing the acute inflammation of mice, and result has statistical significance (p<0.05).
Can obtain from the result of the test of embodiment 2-4, ring-L-dried meat-L-third dipeptides described in the present invention has significant therapeutic effect to burn and scald, the affected part improvement reparation hair follicle of skin damage and the pathologic structure of sebaceous gland can be used in by directly outer, activate the histiocytic self-repairing capability in affected part, accelerate the healing rate of wound surface, the anti-inflammatory and analgesic effect simultaneously itself had can alleviate the misery of patient; By directly taking the immunoloregulation function strengthening patient orally, the ability of self resisting the infection of extraneous virus and bacteria can also be strengthened, reduces the probability of recurrence.
Claims (7)
1. the application of ring-L-dried meat-L-third dipeptides in the medicine of preparation treatment skin trauma.
2. the application of ring-L-dried meat-L-third dipeptides in the medicine of preparation treatment burn and scald.
3. a Cyclic dipeptides as described in claim 1, is characterized in that, during the synthetic route of described Cyclic dipeptides comprises and condensation reaction, amino deprotection, cyclisation three phases, specifically comprises following several step:
(1) in and condensation reaction: get the L-PROLINE that carries out Boc amido protecting and alanine methyl ester hydrochloride containing oxolane, pyridine, (Boc)
2in carrying out under the condition of O, DMAP and condensation reaction obtain N-tertbutyloxycarbonyl-prolyl methyl lactamine;
(2) amino deprotection: under the effect of the saturated solution of EtoAc and HCl, amino deprotection process is carried out to the N-tertbutyloxycarbonyl-prolyl methyl lactamine obtained in step (1), obtain prolyl methyl lactamine;
(3) cyclisation: by the prolyl methyl lactamine that obtains in step (2) and methanol mixed, use NaHCO
3after regulating pH, reflux 18 hours, filters, column chromatography purification, obtains ring-L-dried meat-L-third dipeptides of white.
4. an application as described in claim 1, it is characterized in that, the application of described Cyclic dipeptides in burn and scald can be that external also can be taken orally.
5. an application as described in claim 1, it is characterized in that, described Cyclic dipeptides has the effect making empyrosis wound surface accelerate healing rate.
6. an application as described in claim 1, it is characterized in that, described Cyclic dipeptides has reparation damaged cell, activates self-repairing capability.
7. an application as described in claim 1, is characterized in that, described Cyclic dipeptides reduces or desalinates the effect of wound surface cicatrix.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108771679A (en) * | 2018-03-21 | 2018-11-09 | 苏州卫生职业技术学院 | Purposes of the Cyclic dipeptides in preparing analgesic |
| CN109966296A (en) * | 2017-12-27 | 2019-07-05 | 内蒙古京新药业有限公司 | Application of the Cyclic dipeptides in preparation ulcerative colitis drug |
| CN109966295A (en) * | 2017-12-27 | 2019-07-05 | 内蒙古京新药业有限公司 | Application of the Cyclic dipeptides in preparation atrophic gastritis drug |
-
2014
- 2014-06-18 CN CN201410273124.7A patent/CN105288585A/en active Pending
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| 丁中涛等: "金铁锁根中的3 个环二肽", 《中国中药杂志》 * |
| 丁中涛等: "金铁锁根中的环肽成分", 《云南植物研究》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109966296A (en) * | 2017-12-27 | 2019-07-05 | 内蒙古京新药业有限公司 | Application of the Cyclic dipeptides in preparation ulcerative colitis drug |
| CN109966295A (en) * | 2017-12-27 | 2019-07-05 | 内蒙古京新药业有限公司 | Application of the Cyclic dipeptides in preparation atrophic gastritis drug |
| CN108771679A (en) * | 2018-03-21 | 2018-11-09 | 苏州卫生职业技术学院 | Purposes of the Cyclic dipeptides in preparing analgesic |
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