CN108017690A - Artificial transmembrane channel of column [5] aromatic hydrocarbons with antibacterial activity and its preparation method and application - Google Patents
Artificial transmembrane channel of column [5] aromatic hydrocarbons with antibacterial activity and its preparation method and application Download PDFInfo
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- CN108017690A CN108017690A CN201710707669.8A CN201710707669A CN108017690A CN 108017690 A CN108017690 A CN 108017690A CN 201710707669 A CN201710707669 A CN 201710707669A CN 108017690 A CN108017690 A CN 108017690A
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- aromatic hydrocarbons
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- 150000004945 aromatic hydrocarbons Chemical class 0.000 title claims abstract description 38
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 241000894006 Bacteria Species 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 33
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 14
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 230000004048 modification Effects 0.000 claims description 9
- 238000012986 modification Methods 0.000 claims description 9
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 9
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 9
- 229960005055 sodium ascorbate Drugs 0.000 claims description 9
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 229920001184 polypeptide Polymers 0.000 claims description 8
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 5
- 244000063299 Bacillus subtilis Species 0.000 claims description 4
- 235000014469 Bacillus subtilis Nutrition 0.000 claims description 4
- 241000191940 Staphylococcus Species 0.000 claims description 4
- 241000191967 Staphylococcus aureus Species 0.000 claims description 4
- -1 arene compounds Chemical class 0.000 claims description 4
- 210000002615 epidermis Anatomy 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000010949 copper Substances 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
- 230000001988 toxicity Effects 0.000 abstract description 6
- 231100000419 toxicity Toxicity 0.000 abstract description 6
- 230000003115 biocidal effect Effects 0.000 abstract description 5
- 230000002949 hemolytic effect Effects 0.000 abstract description 5
- 241001465754 Metazoa Species 0.000 abstract description 4
- 102000004310 Ion Channels Human genes 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 230000000845 anti-microbial effect Effects 0.000 abstract description 2
- 229940000406 drug candidate Drugs 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 108091006146 Channels Proteins 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 229910052927 chalcanthite Inorganic materials 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 210000003743 erythrocyte Anatomy 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BQVUABVGYYSDCJ-UHFFFAOYSA-N Nalpha-L-Leucyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)CC(C)C)C(O)=O)=CNC2=C1 BQVUABVGYYSDCJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- CELJCNRXKZPTCX-XPUUQOCRSA-N Val-Gly-Ala Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O CELJCNRXKZPTCX-XPUUQOCRSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 108010038745 tryptophylglycine Proteins 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- FPFOYSCDUWTZBF-IHPCNDPISA-N Leu-Trp-Leu Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H]([NH3+])CC(C)C)C(=O)N[C@@H](CC(C)C)C([O-])=O)=CNC2=C1 FPFOYSCDUWTZBF-IHPCNDPISA-N 0.000 description 3
- 239000000232 Lipid Bilayer Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000003385 bacteriostatic effect Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 206010018910 Haemolysis Diseases 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- YTZYHKOSHOXTHA-TUSQITKMSA-N Trp-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=3C4=CC=CC=C4NC=3)CC(C)C)C(O)=O)=CNC2=C1 YTZYHKOSHOXTHA-TUSQITKMSA-N 0.000 description 2
- WHNSHJJNWNSTSU-BZSNNMDCSA-N Val-Val-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 WHNSHJJNWNSTSU-BZSNNMDCSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 108010000434 glycyl-alanyl-leucine Proteins 0.000 description 2
- 108010027668 glycyl-alanyl-valine Proteins 0.000 description 2
- 230000008588 hemolysis Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 125000003345 AMP group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 102000044503 Antimicrobial Peptides Human genes 0.000 description 1
- 108700042778 Antimicrobial Peptides Proteins 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 108010026389 Gramicidin Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- ZLMFVXMJFIWIRE-FHWLQOOXSA-N Val-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](C(C)C)N ZLMFVXMJFIWIRE-FHWLQOOXSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 229920006227 ethylene-grafted-maleic anhydride Polymers 0.000 description 1
- 210000004709 eyebrow Anatomy 0.000 description 1
- 210000000720 eyelash Anatomy 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 108010046845 tryptones Proteins 0.000 description 1
- ZWCXYZRRTRDGQE-LUPIJMBPSA-N valyl gramicidin a Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC=3C4=CC=CC=C4NC=3)NC(=O)[C@@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](C(C)C)NC(=O)[C@H](C)NC(=O)[C@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H](NC=O)C(C)C)CC(C)C)C(=O)NCCO)=CNC2=C1 ZWCXYZRRTRDGQE-LUPIJMBPSA-N 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
The invention discloses a kind of artificial transmembrane channel of column [5] aromatic hydrocarbons with antibacterial activity and its preparation method and application, belong to the synthesis technical field with antibacterial active compounds.Technical scheme main points are：The artificial transmembrane channel of column [5] aromatic hydrocarbons with antibacterial activity, its general structure are：
Description
Technical field
The invention belongs to the synthesis technical field with antibacterial active compounds, and in particular to a kind of with antibacterial activity
Artificial transmembrane channel of column [5] aromatic hydrocarbons and its preparation method and application.
Background technology
The pathogenic bacterial infection disease as caused by bacterium, virus, fungi etc. causes the health of the mankind and animal serious
Threaten.So far, traditional antibiotic is still the prefered method for treating this kind of infectious diseases.However, with antibiotic
Use, people gradually have found that antibiotic easily remains, produces the problems such as allergic reaction and pollution environment.It is particularly in recent years, more
The serious threat faced as human society that increases sharply of drug resistance pathogen, exploitation antibacterial agent, which becomes, compels
The task of the eyebrows and eyelashes.
Antibacterial peptide (Antimicrobial peptides, AMPs) is the one kind being widely present in living nature by biological machine
The active peptide that body produces, it is a kind of polypeptide active thing that animal immune system of defense generates for confrontation external source pathogen
Matter, plays an important roll in terms of body's immunity is adjusted.The polypeptide that antibacterial peptide is generally made of 12-80 amino acid
Matter, to bacterium, fungi etc. have wide spectrum antibacterial activity, and have the characteristics that stability by force, non-immunogenicity.Resist with tradition
The a certain particular step that raw element is typically applied to biosynthesis is different, and mainstream research thinks that the sterilization mechanism of antibacterial peptide is main at present
Be the cell membrane by acting on bacterium, destroy its integrality and produce perforated phenomenon, cause cellular content outflow it is extracellular and
Death, this unique mechanism of action make bacterium be difficult to produce drug resistance.Although antibacterial peptide has, antibacterial activity is strong, has a broad antifungal spectrum
The advantages that, but antibacterial peptide equally can influence mammalian cell (such as：Erythrocyte etc.), so as to cause hemolytic toxicity.So
Into clinical practice antibacterial peptide (such as：Gramicidin A etc.) mainly as external used medicine, with superficial skin infection and angle
The treatment of the diseases such as film inflammation.Therefore, how to develop can whole body application antibacterial peptide be that vast pharmaceutical chemists are urgently to be resolved hurrily
Problem.
Artificial transmembrane channel is one kind by artificial synthesized obtained organic molecule, by reasonably designing, this quasi-molecule
The nano pore through lipid bilayer can be formed on phospholipid bilayer, and can be realized to zwitterion and polar substances
Cross-film conveying.Since artificial transmembrane channel is similar with the mechanism of action of antibacterial peptide, cross-film can be formed on lipid bilayer and led to
Road.But artificial transmembrane channel will stablize nano level duct and could realize cross-film conveying function, institute by being formed in lipid bilayer
It is often extremely complex with its structure.How efficiently to construct artificial transmembrane channel is current Research Challenges.Artificial transmembrane channel
The features such as high stability, high transfer efficiency and structure diversity for having.So in recent years, on artificial transmembrane channel anti-
Research in terms of the bioactivity such as bacterium, anticancer attracts attention.So far, although indivedual manually transmembrane channel performances
Go out the antibacterial activity of similar antibacterial peptide, but all suffer from the problem of same：(1) antibacterial activity is not high；(2) hemolytic toxicity is difficult to disappear
Remove.
In conclusion the preparation method step at present on artificial transmembrane channel is tediously long, artificial cross-film can be efficiently prepared
Method be rarely reported.Also, the artificial transmembrane channel at the same time with high antibacterial activity and Low haemolysis toxicity has not been reported.
The content of the invention
The technical problem to be solved by the present invention is to provide a kind of artificial transmembrane channel of column [5] aromatic hydrocarbons with antibacterial activity
And preparation method thereof, the artificial transmembrane channel of column made from this method [5] aromatic hydrocarbons, which can be used in preparing, to be treated or prevented because of bacterium
The medicine of disease caused by (such as bacillus subtilis, staphylococcus aureus, staphylococcus epidermis).
The present invention adopts the following technical scheme that there is column [5] the aromatic hydrocarbons people of antibacterial activity to solve above-mentioned technical problem
Work transmembrane channel, it is characterised in that its general structure is：
Wherein R is peptide side chain, and the polypeptide sequence of the peptide side chain is：
Val-Gly-Ala-D-Leu-Trp-D-Leu-Trp-Gly-COOH；
Val-Gly-Ala-D-Val-Trp-D-Leu-Trp-D-Leu-Trp-Gly-COOH；
Val-Gly-Ala-D-Val-Val-D-Val-Trp-D-Leu-Trp-D-Leu-Trp-Gly-COOH；
Val-Gly-Ala-D-Leu-Ala-D-Val-Val-D-Val-Trp-D-Leu-Trp-D-Leu-Trp-Gly-
COOH；
Val-Gly-Ala-D-Leu-Ala-D-Val-Val-D-Val-Trp-D-Leu-Trp-D-Leu-Trp-D-Leu-
Trp-Gly-COOH。
The preparation method of column [5] aromatic hydrocarbons artificial transmembrane channel of the present invention with antibacterial activity, its feature exist
In concretely comprising the following steps：Polypeptide compounds, the catalyst five that double alkynyl-modified column [5] arene compounds, nitrine are modified
Brochanite and sodium ascorbate are added sequentially in reaction vessel, add DMSO dissolvings, in room temperature reaction 12h, TLC monitoring
Raw material filtering after the reaction was complete, it is dry, column chromatography purify to obtain column [5] aromatic hydrocarbons of target product with antibacterial activity manually across
Membrane channels, the reaction equation in preparation process are：
Further preferably, described double alkynyl-modified column [5] arene compounds, nitrine modification polypeptide compounds,
The molar ratio of catalyst cupric sulfate pentahydrate and sodium ascorbate is 8:25:0.8:4.
Column [5] aromatic hydrocarbons artificial transmembrane channel of the present invention with antibacterial activity is preparing treatment or prevention because thin
The application in disease medicine caused by bacterium, wherein bacterium are bacillus subtilis, staphylococcus aureus or staphylococcus epidermis.
The present invention is by the way that " Click Chemistry " are chemically modified column [5] aromatic hydrocarbons, by with β helical conformations
Peptide side chain is incorporated into column [5] aromatic hydrocarbons skeleton, has efficiently constructed a kind of artificial transmembrane channel of unimolecule with tubular structure,
Such compound can efficiently be embedded into bacterial cell membrane, change membrane passage, so as to inhibit bacteria growth；Should
Class compound has excellent anti-microbial property, can preferably be applied to because of bacterium (such as bacillus subtilis, Staphylococcus aureus
Bacterium, staphylococcus epidermis etc.) caused by animals and plants disease prevention, and the hemolytic toxicity of such compound is very low, can conduct
The drug candidate of the ion channel class antibiotic of whole body application.
Embodiment
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
(1) preparation of column [4] aromatic hydrocarbons [1] quinone
Column [5] aromatic hydrocarbons (3g, 4mmol) is dissolved in dichloromethane (50mL), adds ammonium ceric nitrate (2.19g, 4mmol),
30min is stirred at room temperature, adds water to extract, then uses anhydrous Na2SO4Dry, filtering, filtrate is spin-dried for.Column chromatography for separation (ethyl acetate：
Petroleum ether) after obtain solid 1.44g, yield 50%.
1H NMR(DMSO-d6,600MHz)δ:8.22(s,2H),6.84(s,2H),6.83(s,2H),6.79(s,2H),
6.78(s,2H),6.54(s,2H),3.71(s,6H),3.68(s,6H),3.65(s,12H),3.63(s,6H),3.55(s,
4H).HRMS:Calcd for C43H44NaO10[M+Na]+:743.2832.Found:743.2867。
(2) preparation of dihydroxy pilum [5] aromatic hydrocarbons
Column [4] aromatic hydrocarbons [1] quinone (0.5g, 0.693mmol), sodium borohydride (0.13g, 3.448mmol) are dissolved in tetrahydrochysene furan
In muttering, it is stirred at room temperature.Question response is complete, is extracted with ethyl acetate, and organic phase is washed with saturated nacl aqueous solution, adds anhydrous
Na2SO4Dry, filtering, filtrate is spin-dried for.Column chromatography for separation obtains 0.27g light yellow solids, yield 54%.
1H NMR(DMSO-d6,600MHz)δ:8.23(s,2H),6.85(s,2H),6.84(s,2H),6.80(s,4H),
3.72(s,6H),3.69(s,6H),3.66(s,12H),3.64(s,2H),3.56(s,2H).ESI-HRMS for
C43H46NaO10[M+Na]+calcd:745.2989,found:745.2997。
(3) preparation of diine pilum [5] aromatic hydrocarbons
Weigh Compound 2-19 (0.1g, 0.139mmol) and potassium carbonate (0.3g, 0.694mmol) add second in flask
Nitrile (2.5mL), propargyl bromide (0.12mL, 1.108mmol), react 2h.Question response is complete, filters, and filtrate is spin-dried for.Column chromatography for separation
(ethyl acetate：Petroleum ether) obtain 0.06g red solid compound 2-20, yield 52%.
1H NMR(DMSO-d6,600MHz)δ:6.87(s,2H),6.82(s,2H),6.79(s,4H),6.78(s,2H),
4.66(s,2H),3.70-3.66(m,34H),3.31(s,2H).ESI-HRMS for C49H50O10[M+Na]+calcd:
821.3302,found:821.3261。
Embodiment 2
The preparation of column [5] aromatic hydrocarbons of double octapeptide side chain modifications
The octapeptide (48mg, 0.05mmol, 3equiv) that nitrine is modified is dissolved in DMSO (3mL), adds diine pilum [5]
Aromatic hydrocarbons (13mg, 0.016mmol), adds sodium ascorbate (1.5mg, 0.008mmol, 0.5equiv) and CuSO4·5H2O
(0.4mg,1.6μmol,0.1equiv).After stirring 12h, it is spin-dried for.Gained crude product finally obtains 30mg through HPLC separating-purifyings
White solid, yield 67%.
1H NMR(DMSO-d6,600MHz)δ:12.55(s,2H),10.76(s,4H),8.87-7.96(m,20H),7.61
(t, J=6.0Hz, 4H), 7.30 (t, J=6.0Hz, 4H), 7.13-6.92 (m, 14H), 6.78 (d, J=6.0Hz, 4H), 6.75
(d, J=6.0Hz, 4H), 5.29-4.97 (m, 9H), 4.55-3.79 (m, 22H), 3.51 (d, J=6.0Hz, 8H), 3.20-
2.87(m,11H),2.02-1.97(m,3H),1.47-1.44(m,5H),1.24-1.06(m,27H),0.88(m,12H),
0.69-0.59(m,25H).
ESI-HRMS for C145H180N26O30[M+2H]2+calcd:1384.1769,found:1384.1838。
Embodiment 3
The preparation of column [5] aromatic hydrocarbons of double decapeptide side chain modifications
The decapeptide (64mg, 0.05mmol, 3equiv) that nitrine is modified is dissolved in DMSO (3mL), adds diine pilum [5]
Aromatic hydrocarbons (13mg, 0.016mmol), adds sodium ascorbate (1.5mg, 0.008mmol, 0.5equiv) and CuSO4·5H2O
(0.4mg,1.6μmol,0.1equiv).After stirring 12h, it is spin-dried for.Gained crude product finally obtains 32mg through HPLC separating-purifyings
White solid, yield 59%.
1H NMR(DMSO-d6,600MHz)δ:10.76(s,2H),10.72(s,2H),10.71(s,2H),8.48(d,
2H),8.38(t,2H),8.34-8.31(m,4H),8.18(s,2H),8.15(d,4H),8.04(d,2H),7.99(d,2H),
7.92(d,2H),7.83(d,2H),7.59(q,6H),7.30-7.27(m,6H),7.12(s,2H),7.08(s,4H),7.02-
6.99(m,8H),6.96-6.91(m,6H),6.78(d,4H),6.75(d,4H),5.32(t,2H),5.28-5.19(m,4H),
5.02-4.96(m,4H),4.60-4.52(m,6H),4.40-4.35(m,2H),4.25-4.15(m,8H),3.80(d,4H),
3.66-3.65(m,24H),3.51(d,6H),3.21-3.18(m,4H),3.09-3.07(m,4H),2.93-2.86(m,6H),
2.02-1.96(m,6H),1.82-1.77(m,2H),1.48-1.43(m,2H),1.30-1.28(m,4H),1.16(d,6H),
1.08-1.04(m,6H),1.01-0.97(m,2H),0.93-0.90(m,2H),0.87(d,12H),0.63(d,6H),0.58-
0.56(m,16H),0.53(d,10H).HRMS:calcd for C177H220N32O34[M+2H]2+1669.3252,found
1669.3451。
Embodiment 4
The preparation of column [5] aromatic hydrocarbons of double dodecapeptide side chain modifications
The dodecapeptide (74mg, 0.05mmol, 3equiv) that nitrine is modified is dissolved in DMSO (3mL), adds diine pilum
[5] aromatic hydrocarbons (13mg, 0.016mmol), adds sodium ascorbate (1.5mg, 0.008mmol, 0.5equiv) and CuSO4·5H2O
(0.4mg,1.6μmol,0.1equiv).After stirring 12h, it is spin-dried for.Gained crude product finally obtains 41mg through HPLC separating-purifyings
White solid, yield 68%.
1H NMR(DMSO-d6,600MHz)δ:10.79(s,2H),10.76(s,2H),10.71(s,2H),8.51(d,
2H),8.42(t,2H),8.36-8.33(m,4H),8.20(br,6H),8.07-8.06(m,2H),8.00-7.89(m,8H),
7.81(d,2H),7.59(d,4H),7.55(d,2H),7.30-7.26(m,6H),7.12(s,2H),7.08(s,4H),7.04-
6.99(m,8H),6.96-6.90(m,6H),6.78(d,4H),6.75(d,4H),5.33-5.21(m,6H),5.02-4.97(m,
4H),4.59-4.52(m,6H),4.41-4.39(m,2H),4.32-4.30(m,4H),4.23(br,4H),4.18-4.15(m,
4H),3.80(d,4H),3.67-3.66(m,24H),3.52(d,6H),3.19(d,2H),3.10-3.08(m,4H),2.92-
2.86(m,6H),2.03-1.98(m,8H),1.80-1.75(m,2H),1.29-1.27(m,2H),1.17(d,6H),1.10-
1.04(m,10H),0.98-0.94(m,2H),0.88(br,12H),0.85-0.83(m,4H),0.80-0.78(m,24H),
0.62(d,6H),0.57-0.53(m,22H),0.50(d,6H).HRMS:calcd for C197H256N36O38[M+2H]2+
1867.9637,found 1867.9733。
Embodiment 5
The preparation of column [5] aromatic hydrocarbons of double tetradecapeptide side chain modifications
The tetradecapeptide (83mg, 0.05mmol, 3equiv) that nitrine is modified is dissolved in DMSO (3mL), adds diine pilum
[5] aromatic hydrocarbons (13mg, 0.016mmol), adds sodium ascorbate (1.5mg, 0.008mmol, 0.5equiv) and CuSO4·5H2O
(0.4mg,1.6μmol,0.1equiv).After stirring 12h, it is spin-dried for.Gained crude product finally obtains 38mg through HPLC separating-purifyings
White solid, yield 57%.
1H NMR(DMSO-d6,600MHz)δ:12.56(br,2H),10.76(br,4H),10.68(s,2H),8.51(d,
2H),8.37(br,4H),8.32(br,2H),8.19(s,2H),8.18-8.15(m,4H),8.04(br,2H),7.95-7.91
(m,8H),7.81(br,2H),7.73(br,2H),7.58(d,4H),7.54(d,2H),7.30-7.26(m,6H),7.11(s,
2H),7.08(s,4H),7.04-6.99(m,8H),6.96-6.89(m,6H),6.78(d,4H),6.75(d,4H),5.33-
5.21(m,4H),5.02-4.97(m,4H),4.55-4.53(m,6H),4.31-4.17(m,18H),3.79-3.75(m,6H),
3.70-3.64(m,30H),3.52(d,6H),3.21-3.16(m,2H),3.09(br,4H),2.90-2.88(m,6H),2.03-
1.94(m,8H),1.81(br,2H),1.57-1.52(m,2H),1.46-1.44(m,4H),1.22(s,4H),1.20(d,6H),
1.16(d,6H),1.09(br,8H),0.96(br,2H),0.89(d,12H),0.84(d,8H),0.81-0.77(m,28H),
0.63(d,6H),0.57-0.52(m,28H).HRMS:calcd for C215H288N40O42[M+2H]2+2052.0849,found
2052.1042。
Embodiment 6
The preparation of column [5] aromatic hydrocarbons of double ten hexapeptides side chain modifications
Ten hexapeptides (97mg, 0.05mmol, 3equiv) that nitrine is modified are dissolved in DMSO (3mL), add diine pilum
[5] aromatic hydrocarbons (13mg, 0.016mmol), adds sodium ascorbate (1.5mg, 0.008mmol, 0.5equiv) and CuSO4·5H2O
(0.4mg,1.6μmol,0.1equiv).After stirring 12h, it is spin-dried for.Gained crude product finally obtains 46mg through HPLC separating-purifyings
White solid, yield 61%.
1H NMR(DMSO-d6,600MHz)δ:12.55(br,2H),10.76(br,6H),10.69(s,2H),8.51(d,
2H),8.37(br,6H),8.19-8.14(m,10H),7.99-7.93(m,12H),7.77-7.74(m,4H),7.58-7.52
(m,8H),7.29-7.27(m,8H),7.11(s,2H),7.08(s,6H),7.03-7.00(m,10H),6.95-6.89(m,
8H),6.78(br,4H),6.75(d,4H),5.33-5.21(m,4H),5.03-4.97(m,4H),4.2(br,8H),4.30-
4.15(m,20H),3.79-3.75(m,6H),3.70-3.64(m,30H),3.52(d,6H),3.25-3.21(m,2H),3.17-
3.12(m,6H),2.90(br,8H),2.03-1.97(m,6H),1.81-1.77(m,2H),1.56-1.52(m,2H),1.46
(br,4H),1.22-1.12(m,28H),0.89-0.77(m,52H),0.63-0.51(m,46H).HRMS:calcd for
C249H329KN46O46[M+H+K]2+2370.2262,found 2370.2216。
Embodiment 7
The bacteriostatic activity of bacterium is tested
(1) preparation of fluid nutrient medium
Weighed respectively with electronic balance 0.2515g yeast extracts, 0.5020g tryptones and 0.5030g NaCl in
In vial, redistilled water 50mL is added to being completely dissolved, pH=7.51 is adjusted with NaOH.With the shifting equipped with 500 μ L pipette tips
Liquid is robbed pipettes 10mL nutrient solutions into test tube respectively.
(2) activation of strain and the preparation of bacterium solution
Two days before the test, four kinds are inoculated in on examination inclined-plane, putting 28 DEG C of constant temperature incubation 48h respectively for trying bacterium, every
Lawn is washed down with the sterile saline 2mL of 0.85wt% in inclined-plane, shakes up spare.
(3) bed board
One 96 orifice plates are taken, take appropriate amount of fluid culture medium to be added thereto with liquid-transfering gun, jiggling makes to be uniformly mixed, and adds
200 μ L bacterium solutions, are separately added into the sample liquid of the pure DMSO and various concentrations of 2.5 μ L.
(4) measuring method
After (37 DEG C) concussion 12h, absorbance measurement is subjected to microplate reader in constant temperature oscillator for ready 96 orifice plate.
Three repetitions are set every time, and similarity condition is done three times.
Survival probability of bacteria (%)=(ODsample+bac-ODbroth only)/(ODDMSO+bac-ODbroth only) × 100%.
Embodiment 8
The hemolytic toxicity of erythrocyte is tested
(1) preparation of red blood cell suspension
Fresh SD rat bloods are taken, rat erythrocyte is separated by leaving heart 5min 3500.That isolates is blood red
Cell is washed till supernatant with PBS buffer and clarifies, and it is spare to be then re-dispersed into PBS buffer (1%, v/v).
(2) bed board
One 96 orifice plates are taken, 200 μ L red blood cell suspensions are added in each hole, then add triplicate 2.5 μ L samples
The DMSO solution of product molecule or pure DMSO.Weak vibrations 96 orifice plate, and cultivate 30min under the conditions of 37 DEG C.
(3) measuring method
Above-mentioned 96 orifice plate is left into heart 10min 3500, takes the supernatant of equivalent (50 μ L) to be added to newly in each hole
96 orifice plates in, be then diluted to 100 μ L with PBS buffer.Then 96 orifice plate is carried out under 562nm using microplate reader
Measurement.
Hemolysis rate (%)=(Asample-ADMSO)/(Atriton X-100-ADMSO) × 100%.
The numbering of 1 typical compound of table, chemical constitution, yield
Table 2 is typical compound to the bacteriostatic activity test result of representative bacterium, compound number 1-5 in table 2
With it is corresponding in table 1.
Bacteriostatic activity of 2 typical compound of table to representative bacterium
Basic principle, main features and advantages embodiment above describes the present invention, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe the original of the present invention
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, these changes and improvements are each fallen within
In the scope of protection of the invention.
SEQUENCE LISTING
<110>He'nan Normal University
<120>Artificial transmembrane channel of column [5] aromatic hydrocarbons with antibacterial activity and its preparation method and application
<130> 2017
<160> 5
<170> PatentIn version 3.3
<210> 1
<211> 8
<212> RNA
<213>Artificial sequence（Artificial sequence）
<400> 1
Val Gly Ala Leu Trp Leu Trp Gly
<210> 2
<211> 10
<212> RNA
<213>Artificial sequence（Artificial sequence）
<400> 1
Val Gly Ala Val Trp Leu Trp Leu Trp Gly
<210> 3
<211> 12
<212> RNA
<213>Artificial sequence（Artificial sequence）
<400> 1
Val Gly Ala Val Val Val Trp Leu Trp Leu Trp Gly
<210> 4
<211> 14
<212> RNA
<213>Artificial sequence（Artificial sequence）
<400> 1
Val Gly Ala Leu Ala Val Val Val Trp Leu Trp Leu Trp Gly
<210> 5
<211> 16
<212> RNA
<213>Artificial sequence（Artificial sequence）
<400> 1
Val Gly Ala Leu Ala Val Val Val Trp Leu Trp Leu Trp Leu Trp Gly
Claims (5)
1. the artificial transmembrane channel of column [5] aromatic hydrocarbons with antibacterial activity, it is characterised in that its general structure is：
Wherein R is peptide side chain, and the polypeptide sequence of the peptide side chain is：
Val-Gly-Ala-D-Leu-Trp-D-Leu-Trp-Gly-COOH；
Val-Gly-Ala-D-Val-Trp-D-Leu-Trp-D-Leu-Trp-Gly-COOH；
Val-Gly-Ala-D-Val-Val-D-Val-Trp-D-Leu-Trp-D-Leu-Trp-Gly-COOH；
Val-Gly-Ala-D-Leu-Ala-D-Val-Val-D-Val-Trp-D-Leu-Trp-D-Leu-Trp-Gly-COOH；
Val-Gly-Ala-D-Leu-Ala-D-Val-Val-D-Val-Trp-D-Leu-Trp-D-Leu-Trp-D-Leu-Trp-
Gly-COOH。
2. a kind of preparation method of the artificial transmembrane channel of column [5] aromatic hydrocarbons with antibacterial activity described in claim 1, it is special
Sign is to concretely comprise the following steps：By double alkynyl-modified column [5] arene compounds, the polypeptide compounds of nitrine modification, catalysis
Agent cupric sulfate pentahydrate and sodium ascorbate are added sequentially in reaction vessel, are added DMSO dissolvings, are supervised in room temperature reaction to TLC
Raw material filtering after the reaction was complete is controlled, dry, column chromatography purifies to obtain column [5] aromatic hydrocarbons of target product with antibacterial activity artificial
Transmembrane channel, the reaction equation in preparation process are：
3. the preparation method of column [5] the aromatic hydrocarbons artificial transmembrane channel according to claim 2 with antibacterial activity, it is special
Sign is：Described double alkynyl-modified column [5] arene compounds, polypeptide compounds, the five water sulphur of catalyst of nitrine modification
The molar ratio of sour copper and sodium ascorbate is 8:25:0.8:4.
4. the artificial transmembrane channel of column [5] aromatic hydrocarbons with antibacterial activity described in claim 1 prepare treat or prevent because
The application in disease medicine caused by bacterium.
5. column [5] the aromatic hydrocarbons artificial transmembrane channel according to claim 4 with antibacterial activity is preparing treatment or pre-
Application in the anti-disease medicine because caused by bacterium, it is characterised in that：The bacterium is bacillus subtilis, Staphylococcus aureus
Bacterium or staphylococcus epidermis.
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