CN107987105B - A kind of H can be used for dressing for skin2S donor compound, sponge dressing and preparation method - Google Patents

A kind of H can be used for dressing for skin2S donor compound, sponge dressing and preparation method Download PDF

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CN107987105B
CN107987105B CN201711192470.2A CN201711192470A CN107987105B CN 107987105 B CN107987105 B CN 107987105B CN 201711192470 A CN201711192470 A CN 201711192470A CN 107987105 B CN107987105 B CN 107987105B
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dressing
donor compound
solution
sponge
preparation
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CN107987105A (en
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赵霞
王超
龚艺谋
刘林
林园
王倩
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Wuxi Micro Chromatography Biological Science And Technology Co Ltd
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Wuxi Micro Chromatography Biological Science And Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/44—Amides thereof
    • C07F9/4461—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4465—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0036—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents

Abstract

A kind of H can be used for dressing for skin2S donor compound, sponge dressing and preparation method, are related to H2S donor compound, sponge dressing and preparation method.The first purpose of the invention is to provide a kind of H that can be used for dressing for skin2S donor compound CW-1, the compound can be specifically to dermal delivery H2S gas molecule, by-product have antibacterial action simultaneously.A second object of the present invention is to provide the dressing suitable for skin, it be include H2The sponge dressing of the calcium alginate of S donor compound CW-1.The dressing can be contacted with skin wound, can effectively deliver the H with therapeutic dose long-term and stably to wound location skin2S gas molecule, while playing antibacterial action.

Description

A kind of H can be used for dressing for skin2S donor compound, sponge dressing and preparation method
Technical field
The present invention relates to a kind of H2S donor compound, sponge dressing and preparation method.
Background technique
H2S is a kind of colourless gas molecule with rotten egg smell, for a long time by it is believed that being that one kind will cause The toxic gas of environmental pollution.However, recent study finds toxic gas molecule H2The same nitric oxide of S (NO) and carbon monoxide (CO) equally, it is a kind of important endogenous gas signaling molecule, participates in a variety of pathological processes.In the mammalian body H can be synthesized2S is mainly catalyzed cysteine generation by cystathionie-γ-lyases (CSE) and cystathionie-beta-synthetase (CBS) Xie Erlai.The H in cardiovascular system2S is mainly catalyzed and synthesized by CSE, and H in nervous system2S is mainly catalyzed and synthesized by CBS.It is raw H under the conditions of reason2The concentration of S is 1-160 μM, and 50-160 μM is reached in midbrain, reaches 10-160 μM in blood.Endogenous H2S has Multiple biological function, can regulate and control maincenter and peripheral neverous system, regulating cell metabolism, to adjust immune/inflammation anti- The function of answering, adjust cardiovascular system, inflammation, septicemia, shock, in terms of effect caused the wide of people General concern.
H2The physiological function of S mainly reduces inflammation by following several approach, and protective tissue organ escapes injury.H2S Inhibit leukocyte in the blood vessels skin, inhibit leucocyte overflow and oedema formation.H2S can replace oxygen nebulization line grain Body breathing, to weaken tissue damage caused by oxidation is pressed.H2S is able to suppress the activity of phosphodiesterase (PDEs) to diastole Vascular smooth muscle increases blood flow.H2S drives M2 type of the macrophage to anti-inflammatory by starting neutrophil apoptosis Differentiation is to reduce inflammatory reaction.H2S can inhibit the activity of transcription factor NF-kB, thus during reducing proinflammatory The generation of cell factor.H2S increases in the yield of wound site, and then passes through the healing of stimulation vascularization acceleration of wound.
Existing result of study shows H2S's promotes the function of angiogenesis and anti-inflammatory response to have wound healing There is apparent facilitation.Therefore, endogenous H is improved2The synthesis of S or the exogenous H for delivering debita spissitudo2S, which becomes, clinically to be added Effective treatment means of fast wound healing.Moreover, H2S can not need the carrier of any specificity just as gaseous signal molecule Intracellular biological targets can be reached quickly through cell membrane, to play a series of biological effect.But H2S with NO and CO is the same, and physiological function has dose dependent, and when low concentration can play physiological function and cytoprotection, and highly concentrated Then there is certain cytotoxicity when spending.Therefore, H that is lasting by carrier appropriate, controllably discharging debita spissitudo2S, can be with Make H2S becomes a kind of effective therapeutic reagent.In general, H2S carrier is in release H2After S gas molecule, it will generate useless By-product.But if a kind of bioactive molecule is connected to H simultaneously2On S carrier, H is discharged2By-product generated after S gas molecule Object will be provided with the function of bioactive molecule, achieve the effect that turn waste into wealth.
NaS and NaHS is the H being commonly used at present2S donor compound, these sulphide salts can be spontaneous in aqueous solution The H of ground quick release high concentration2S, but this delivery mode is difficult to control H2The concentration of S in aqueous solution, and H2S is in water Concentration in solution can due to gas volatilization and quickly reduce.These properties significantly limit H2The use of S clinically. Therefore, novel H is developed2S donor compound is to overcome the shortcomings of that existing donor compound has received vast concern.To current Until, it has been reported that several novel H2S donor compound, H2The release of S can be hydrolyzed, photodissociation, the active control of cellular thiols System.Wherein GYY4137 is a kind of most common donor compound, can hydrolyze in water and slowly discharge H2S, but it is this Delivery mode is excessively slow, needs the help ability fast hydrolyzing of the organic solvents such as acetone or chloroform, and complete hydrolysis then needs 71 days.The nuclear structure or thiophosphate of GYY4137 is considered as design H2Effective template of S donor compound, still There is still a need for develop new activation mechanism.Meanwhile studying H2The releasing mechanism of S and the property of by-product can preferably utilize H2S Donor compound.
Summary of the invention
The first purpose of the invention is to provide a kind of H that can be used for dressing for skin2S donor compound CW-1, the chemical combination Object can be specifically to dermal delivery H2S gas molecule, by-product have antibacterial action simultaneously.Second mesh of the invention Be to provide a kind of dressing suitable for skin, it be include H2The sponge dressing of the calcium alginate of S donor compound CW-1.It should Dressing can be contacted with skin wound, can effectively be delivered long-term and stably to wound location skin with therapeutic dose H2S gas molecule, while playing antibacterial action.
A kind of H can be used for dressing for skin of the invention2S donor compound, its chemical structural formula are as follows:
A kind of H can be used for dressing for skin of the invention2The preparation method of S donor compound, it is according to the following steps It carries out:
One, under the conditions of argon gas protection, 0 DEG C, 3- is added into the anhydrous methylene chloride solution of phenyl phosphinylidyne dichloro Hydroxypropionitrile and triethylamine obtain reaction solution after mixing；Wherein, 3- hydroxypropionitrile, triethylamine, phenyl phosphinylidyne dichloro with The molar ratio of methylene chloride is 1:1:1:18~19；
Two, reaction solution continues after 0 DEG C of reaction 15min in room temperature reaction 3h；
Three, 6- (to acetamido benzsulfamide)-L-lysine is added in the reaction system obtained after reacting to step 2 The mixed solution of methyl esters, triethylamine and anhydrous methylene chloride, the reaction was continued 3h；Wherein, 6- (to acetamido benzsulfamide)- The molar ratio of L-lysine methyl esters, triethylamine and anhydrous methylene chloride is 1.1:3:18~19；
Four, methylene chloride is added in the solution after step 3 reaction, and successively uses 2M H2SO4Washing, MgSO4It is dry, It is finally concentrated under reduced pressure, obtains crude product；Wherein, the volume ratio of the solution after methylene chloride is reacted with step 3 is 1:1；
Five, crude product is obtained into yellow oily intermediate product by chromatography, into the methanol solution of intermediate product The LiOH solution newly prepared is added, is concentrated after stirring 12h at room temperature；The volume ratio of the methanol solution of LiOH solution and intermediate product For 1:1；
Six, the solid after step 5 being concentrated, is resuspended in anhydrous methanol, through 0.2 μm of Teflon membrane filtration, then It is concentrated freeze-dried, obtain H2S donor compound CW-1, the as H that can be used for dressing for skin2S donor compound.
A kind of sponge dressing of the invention, it be include H2The sponge dressing of the calcium alginate of S donor compound CW-1.
A kind of preparation method of sponge dressing of the invention, it is followed the steps below:
Firstly, the sodium alginate aqueous solution that mass percentage is 1~2% is added in mold, made by freeze-drying For at sodium alginate sponge；
Then, sodium alginate sponge is crosslinked using the calcium chloride solution that concentration is 0.2~1.0M, by washing, Freeze-drying obtains the calcium alginate sponge of crosslinking again；
Finally, H prepared by the claim 2 that concentration is 50mM is added dropwise into the calcium alginate sponge of crosslinking2S donor chemical combination Object CW-1 solution, is freeze-dried again, obtains CA/CW-1 sponge dressing.
The H prepared by the present invention that can be used for dressing for skin2S donor compound CW-1 (lower abbreviation CW-1), can neutral and H is discharged under the conditions of faintly acid pH2S, while its by-product has antibacterial ability.The property can make it be used for dressing for skin, hurt H is specifically discharged under the subacidity pH environment of oral area position2S gaseous signal molecule promotes epithelialization and vascularization, improves simultaneously Wound infection situation, the process of accelerating wound healing.CA/CW-1 sponge dressing prepared by the present invention has high-hygroscopicity, height thoroughly Gas can largely absorb wound exudate, provide Moist healing environment for wound, and as the absorption of sepage is discharged to wound H2S.H of the present invention2S donor compound and the dressing for skin of the molecule is loaded to chronic Hard agglut wound and infected wound With unique therapeutic effect, rehabilitation can be brought to wish for patient, while prepare industry for dressing and bringing huge commercial opportunities, had very Good Social benefit and economic benefit.
CW-1 of the invention occurs protonation under the conditions of neutral or subacidity pH and forms mercaptan, and then is attacked by nucleophilic carboxyl Raw intramolecular cyclization is fired to form five-membered ring by-product while discharging H2S.H is discharged by CW-1 under detection condition of different pH2S's Situation discovery, the structure can under the conditions of faintly acid pH (pH 5 and pH 6) a large amount of H of quick release2S, H within 5 minutes2S's releases High-volume up to 90%, with the extension of time, the H of high concentration2S gas can be escaped from liquid, after 90 min H2S concentration is only remaining 50%.Under the conditions of neutral pH (pH 7.4), CW-1 slowly can constantly discharge H2S, after 90 min H2The burst size of S reaches 50%.And under the conditions of alkalescent pH (pH 8), CW-1 only discharges the H of trace2S.This H regulated and controled by pH of CW-12The release side S Formula makes it in physiological conditions being capable of controlled release H2S bioactive molecule, therefore there are specific biological applications.
The present invention is crosslinked by bivalent cation (such as calcium ion) makes sodium alginate aqueous solution become alginate.It should Gel has unique pH sensibility and coagulating effectiveness, and the differentiation and growth of energy sertoli cell.It is added in alginate dressing H2S donor compound CW-1, it is high in conjunction with alginate dressing porosity, hygroscopicity is strong, at many advantages such as colloidality is good, it can effectively inhale It receives a large amount of diffusates and forms hydrogel, provide good Moist healing environment for wound healing.It is sustainable with the absorption of sepage Discharge H2S gaseous signal molecule, thus promote the proliferation of cell, creep and angiogenesis, accelerating wound healing process, release H2Generated by-product has antibacterial action after S, will have unique curative effect for infected wound.
The present invention includes H2The sponge dressing of the calcium alginate of S donor compound CW-1 (apply by lower abbreviation CA/CW-1 sponge Material) in H2The release of S has good pH responsiveness, under the conditions of 5.0,6.0,7.4,8.0 pH, with the reduction of pH value, applies H is discharged in material2The ability of S gradually increases.Compared with free CW-1 molecule, the CW-1 that loads in CA/CW-1 sponge dressing can be with Extend H2The release time of S simultaneously increases H2The burst size of S plays long-time controllable delivery H2The purpose of S.Due to wound location PH value is acidity, therefore the CA/CW-1 dressing with pH responsiveness can be as the absorption of sepage be gradually to wound location specificity Ground discharges H2S, while good Moist healing environment and antibacterial action are provided for wound.
Detailed description of the invention
Fig. 1 is H2The synthetic route schematic diagram of S donor compound CW-1；
Fig. 2 is that CW-1 discharges H2The schematic diagram of S；
Fig. 3 is H of the CW-1 under condition of different pH2S burst size result figure；Wherein, A is the burst size under pH 6.0, and B is Burst size under pH 5.0, C are the burst size under pH 7.4, and D is the burst size under pH 8.0；
Fig. 4 is growth inhibition effect result figure of the CW-1 to E.coli；Wherein, wherein A is to test at pH 7.1, B To be tested at pH 6.0；
Fig. 5 is growth inhibition effect result figure of the CW-1 to S.aureus；Wherein, A be at pH 7.1 test, B for PH 6.0 is lower to be tested；
Fig. 6 is cytotoxicity test figure of the CW-1 to L929；Wherein, A is to test at pH 7.4, and B is at pH 6.0 Test；
Fig. 7 is the mouse wound healing process for applying CA/CW-1 sponge dressing.
Specific embodiment
Specific embodiment 1: a kind of H that can be used for dressing for skin of present embodiment2S donor compound, its chemistry Structural formula are as follows:
Specific embodiment 2: a kind of H that can be used for dressing for skin of present embodiment2The preparation method of S donor compound, It is followed the steps below:
One, under the conditions of argon gas protection, 0 DEG C, 3- is added into the anhydrous methylene chloride solution of phenyl phosphinylidyne dichloro Hydroxypropionitrile and triethylamine obtain reaction solution after mixing；Wherein, 3- hydroxypropionitrile, triethylamine, phenyl phosphinylidyne dichloro with The molar ratio of methylene chloride is 1:1:1:18~19；
Two, reaction solution continues after 0 DEG C of reaction 15min in room temperature reaction 3h；
Three, 6- (to acetamido benzsulfamide)-L-lysine is added in the reaction system obtained after reacting to step 2 The mixed solution of methyl esters, triethylamine and anhydrous methylene chloride, the reaction was continued 3h；Wherein, 6- (to acetamido benzsulfamide)- The molar ratio of L-lysine methyl esters, triethylamine and anhydrous methylene chloride is 1.1:3:18~19；
Four, methylene chloride is added in the solution after step 3 reaction, and successively uses 2M H2SO4Washing, MgSO4It is dry, It is finally concentrated under reduced pressure, obtains crude product；Wherein, the volume ratio of the solution after methylene chloride is reacted with step 3 is 1:1；
Five, crude product is obtained into yellow oily intermediate product by chromatography, into the methanol solution of intermediate product The LiOH solution newly prepared is added, is concentrated after stirring 12h at room temperature；The volume ratio of the methanol solution of LiOH solution and intermediate product For 1:1；
Six, the solid after step 5 being concentrated, is resuspended in anhydrous methanol, through 0.2 μm of Teflon membrane filtration, then It is concentrated freeze-dried, obtain H2S donor compound CW-1, the as H that can be used for dressing for skin2S donor compound.
Specific embodiment 3: present embodiment is unlike specific embodiment two: phenyl phosphinylidyne dichloro The concentration of anhydrous methylene chloride solution is 0.76M.It is other to be identical with embodiment two.
Specific embodiment 4: present embodiment is unlike specific embodiment two: the concentration of LiOH solution is 1M. It is other to be identical with embodiment two.
Specific embodiment 5: present embodiment is unlike specific embodiment two: 3- hydroxypropionitrile, triethylamine, The molar ratio of phenyl phosphinylidyne dichloro and methylene chloride is 1:1:1:18.2.It is other to be identical with embodiment two.
Specific embodiment 6: present embodiment is from 6- unlike specific embodiment two (to acetamido benzene sulfonyl Amine)-L-lysine methyl esters, triethylamine and anhydrous methylene chloride molar ratio be 1.1:3:18.2.Other and specific embodiment Two is identical.
Specific embodiment 7: a kind of sponge dressing of present embodiment, it be include H2The sea of S donor compound CW-1 The sponge dressing of calcium alginate.
Specific embodiment 8: a kind of preparation method of sponge dressing of present embodiment, it is characterised in that it be according to What following steps carried out:
Firstly, the sodium alginate aqueous solution that mass percentage is 1~2% is added in mold, made by freeze-drying For at sodium alginate sponge；
Then, sodium alginate sponge is crosslinked using the calcium chloride solution that concentration is 0.2~1.0M, by washing, Freeze-drying obtains the calcium alginate sponge of crosslinking again；
Finally, H prepared by the claim 2 that concentration is 50mM is added dropwise into the calcium alginate sponge of crosslinking2S donor chemical combination Object CW-1 solution, is freeze-dried again, obtains CA/CW-1 sponge dressing.
Specific embodiment 9: present embodiment is unlike specific embodiment eight: to the calcium alginate sea of crosslinking The H of 1/5~1/4 times of sodium alginate soln volume in silk floss2S donor compound CW-1 solution.Other and specific embodiment eight It is identical.
Specific embodiment 10: present embodiment is unlike specific embodiment eight: to the calcium alginate sea of crosslinking The H of 1/5 times of sodium alginate soln volume in silk floss2S donor compound CW-1 solution.It is other identical as specific embodiment eight.
The content of present invention is not limited only to the content of the respective embodiments described above, the group of one of them or several specific embodiments The purpose of invention also may be implemented in contract sample.
Beneficial effects of the present invention are verified by following embodiment:
Embodiment 1
Sulfa drugs with P-aminobenzene-sulfonamide structure is the artificial synthesized antimicrobial of the first kind, for clinical existing More than 80 years.Sulfanilamide structure is connected to H2One end of S donor compound, can be in release H2Generating after S gas molecule has antibacterial Active by-product.
The present embodiment devises the H based on intramolecular cyclization2S donor compound, the structure adjust molecule inner ring by pH Change the efficiency of activation, to generate the H of efficient pH control2S release.
A kind of H can be used for dressing for skin of the present embodiment2The preparation method of S donor compound, it is according to following step Suddenly it carries out:
Under the conditions of argon gas protection, 0 DEG C, to the anhydrous methylene chloride of phenyl phosphinylidyne dichloro (0.45mL, 3mmol) (CH2Cl2, 3.5mL) and 3- hydroxypropionitrile (0.2mL, 3mmol) and triethylamine (0.45mL, 3mmol) are added in solution；Reaction solution exists Continue after 0 DEG C of reaction 15min in room temperature reaction 3h；Then, 6- (to acetamido benzsulfamide)-L- is added into reaction system Lysine methyl ester (1.178g, 3.3mmol), triethylamine (1.25mL, 9mmol) and the anhydrous CH of 3.5mL2Cl2Mixed solution, after Continuous reaction 3h；After the reaction was completed, the CH of 10mL is added thereto2Cl2, and with the 2M H of 10mL2SO4Washing, MgSO4It is dry, most After be concentrated under reduced pressure；Gained crude product obtains yellow oily intermediate product by chromatography；Later, to the methanol of intermediate product The LiOH solution newly prepared is added in solution, is concentrated after stirring 12h at room temperature；Obtained solid is resuspended in anhydrous methanol, through 0.2 μm Teflon membrane filtration, then concentrated freeze-dried target product (white solid, H2S donor compound CW-1).
The H of the present embodiment2S donor compound CW-1 synthetic route chart is as shown in Figure 1.
The CW-1 of the present embodiment occurs protonation under the conditions of neutral or subacidity pH and forms mercaptan, and then by nucleophilic carboxyl Attack occurs intramolecular cyclization and forms five-membered ring by-product while discharging H2S (release H2The schematic diagram of S is as shown in Figure 2).Pass through inspection It surveys CW-1 under condition of different pH and discharges H2The case where S, finds (as shown in Figure 3), which can be in faintly acid pH (pH 5 and pH 6) a large amount of H of quick release under the conditions of2S, H within 5 minutes2The burst size of S is up to 90%, with the extension of time, the H of high concentration2S Gas can be escaped from liquid, after 90 min H2S concentration only Yus 50%.Under the conditions of neutral pH (pH 7.4), CW-1 can delay Slowly H is constantly discharged2S, after 90 min H2The burst size of S is up to 50%.And under the conditions of alkalescent pH (pH 8), CW-1 is only released Put the H of trace2S.This H regulated and controled by pH of CW-12S delivery mode makes it in physiological conditions being capable of controlled release H2S activity Molecule, therefore there are specific biological applications.
To the H of the present embodiment2The antibacterial characteristics and biocompatibility of S donor compound CW-1 are tested, specific as follows:
Select staphylococcus aureus (S.aureus) and Escherichia coli (E.coli) respectively as gram-positive bacteria with The representative of Gram-negative bacteria, to detect CW-1 release H2Antibiotic property (testing result such as Fig. 4 and Fig. 5 institute of by-product after S Show).
The growth inhibition ratio of S.aureus and E.coli is sent out by the CW-1 that micropore gradient dilution method detects various concentration Existing, after culture 18 hours, the CW-1 of 8mM can inhibit 80% E.coli bacterial growth respectively and 60% S.aureus bacterium is raw It is long.It is worth noting that, CW-1 is essentially identical to the inhibiting rate of bacterium under the conditions of pH 6.0 and pH 7.4.Although 6.0 He of pH H under the conditions of pH 7.42The release characteristics of S are different, but pass through culture in 18 hours, the H of the two2S burst size tends to be close, institute The amount of by-products of generation is close, therefore does not have significant difference to the inhibition efficiency of bacterium.Result explanation, CW-1 discharge H2S's By-product has certain antibacterial action due to sulfanilamide structure.
L929 l cell is selected to study the biocompatibility of CW-1 as model cell.It co-cultures 24 hours After find, CW-1 concentration does not have any cytotoxicity (as shown in Figure 6) to L929 in 1mM or less, this show CW-1 have it is good Good biocompatibility.
Embodiment 2
A kind of sponge dressing of the present embodiment, follows the steps below:
Firstly, the sodium alginate aqueous solution that mass concentration is 1%, 1.5% and 2% is separately added into mold appropriate, Sodium alginate sponge is prepared by freeze-drying；Then distinguished using the calcium chloride solution that concentration is 0.2M, 0.5M and 1.0M Usage ratio to select optimal sodium alginate and calcium chloride, (optimal alginic acid are crosslinked to sodium alginate sponge Sodium water solution mass concentration is 1.5%, calcium chloride solution concentration 0.2M), by washing, freeze-drying obtains crosslinking again Calcium alginate sponge (CA sponge).H is added dropwise into CA sponge2S donor compound CW-1 solution (50 mM), is freeze-dried again Obtain CA/CW-1 sponge dressing.
The present invention includes H2H in the sponge dressing of the calcium alginate of S donor compound CW-12The release of S has good PH responsiveness, with the reduction of pH value, discharges H in dressing under the conditions of 5.0,6.0,7.4,8.0 pH2The ability of S gradually increases Add.Compared with free CW-1 molecule, the CW-1 loaded in CA/CW-1 sponge dressing can extend H2Release time of S and increase H2The burst size of S plays long-time controllable delivery H2The purpose of S.Since the pH value of wound location is acidity, there is pH to ring The CA/CW-1 dressing of answering property gradually can specifically discharge H to wound location with the absorption of sepage2S, while being provided for wound Good Moist healing environment and antibacterial action.
Using the wound healing promoting ability of mouse full thickness skin damage model detection CA/CW-1 sponge dressing (such as Fig. 7 institute Show): from the point of view of the wound healing situation after detection, compared with simple CA dressing, releasable H2The CA/CW-1 dressing of S can be obvious Accelerate the speed of wound healing.It is found by Histological section, the wound location of CA/CW-1 dressing group forms thicker granulation group Knit, more keratin positive cell and higher collagen expression quantity, newly-generated corium are completely embedded with tissue, It is filled with sufficient hair follicle, and along with a large amount of Collagen fiber deposition.And CA dressing group then formed relatively thin granulation tissue layer, Less keratoprotein positive cell and less collagenous fibres.In addition, CA/CW-1 dressing group shows higher CD31 Expression illustrates H2S can promote the formation and maturation of vascularization.The above result shows that compared with CA dressing, CA/CW-1 Dressing is by discharging H in wound location2S promote the formation of wound granulation tissue, wound epithelialization, collagen deposition and Vascularization, the final healing rate for accelerating wound.

Claims (10)

1. a kind of H that can be used for dressing for skin2S donor compound, it is characterised in that its chemical structural formula are as follows:
2. preparing a kind of H that can be used for dressing for skin as described in claim 12The method of S donor compound, it is characterised in that It is followed the steps below:
One, under the conditions of argon gas protection, 0 DEG C, 3- hydroxyl is added into the anhydrous methylene chloride solution of phenyl phosphinylidyne dichloro Propionitrile and triethylamine obtain reaction solution after mixing；Wherein, 3- hydroxypropionitrile, triethylamine, phenyl phosphinylidyne dichloro and dichloro The molar ratio of methane is 1:1:1:18~19；
Two, reaction solution continues after 0 DEG C of reaction 15min in room temperature reaction 3h；
Three, be added into obtained reaction system after step 2 reaction 6- (to acetamido benzsulfamide)-L-lysine methyl esters, The mixed solution of triethylamine and anhydrous methylene chloride, the reaction was continued 3h；Wherein, 6- (to acetamido benzsulfamide)-L- relies ammonia The molar ratio of sour methyl esters, triethylamine and anhydrous methylene chloride is 1.1:3:18~19；
Four, methylene chloride is added in the solution after step 3 reaction, and successively uses 2M H2SO4Washing, MgSO4It is dry, finally It is concentrated under reduced pressure, obtains crude product；Wherein, the volume ratio of the solution after methylene chloride is reacted with step 3 is 1:1；
Five, crude product is obtained into yellow oily intermediate product by chromatography, is added into the methanol solution of intermediate product The LiOH solution newly prepared is concentrated after stirring 12h at room temperature；The volume ratio of the methanol solution of LiOH solution and intermediate product is 1: 1；
Six, the solid after step 5 being concentrated, is resuspended in anhydrous methanol, through 0.2 μm of Teflon membrane filtration, is then concentrated Freeze-drying, obtains H2S donor compound CW-1, the as H that can be used for dressing for skin2S donor compound.
3. a kind of H that can be used for dressing for skin according to claim 22The preparation method of S donor compound, feature exist In phenyl phosphinylidyne dichloro anhydrous methylene chloride solution concentration be 0.76M.
4. a kind of H that can be used for dressing for skin according to claim 22The preparation method of S donor compound, feature exist In LiOH solution concentration be 1M.
5. a kind of H that can be used for dressing for skin according to claim 22The preparation method of S donor compound, feature exist In 3- hydroxypropionitrile, triethylamine, phenyl phosphinylidyne dichloro and methylene chloride molar ratio be 1:1:1:18.2.
6. a kind of H that can be used for dressing for skin according to claim 22The preparation method of S donor compound, feature exist In 6- (to acetamido benzsulfamide)-L-lysine methyl esters, triethylamine and anhydrous methylene chloride molar ratio be 1.1:3: 18.2。
7. a kind of sponge dressing, it is characterised in that it is the H for including claim 2 preparation2The alginic acid of S donor compound CW-1 The sponge dressing of calcium.
8. a kind of preparation method of sponge dressing, it is characterised in that it is followed the steps below:
Firstly, the sodium alginate aqueous solution that mass percentage is 1~2% is added in mold, it is prepared by freeze-drying Sodium alginate sponge；
Then, sodium alginate sponge is crosslinked using the calcium chloride solution that concentration is 0.2~1.0M, by washing, again Freeze-drying obtains the calcium alginate sponge of crosslinking；
Finally, H prepared by the claim 2 that concentration is 50mM is added dropwise into the calcium alginate sponge of crosslinking2S donor compound CW- 1 solution, is freeze-dried again, obtains CA/CW-1 sponge dressing.
9. a kind of preparation method of sponge dressing according to claim 8, it is characterised in that the calcium alginate sea of crosslinking The H of 1/5~1/4 times of sodium alginate soln volume in silk floss2S donor compound CW-1 solution.
10. a kind of preparation method of sponge dressing according to claim 8, it is characterised in that the calcium alginate sea of crosslinking The H of 1/5 times of sodium alginate soln volume in silk floss2S donor compound CW-1 solution.
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