CN115536608A - Oxazine compound and preparation method and application thereof - Google Patents
Oxazine compound and preparation method and application thereof Download PDFInfo
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- CN115536608A CN115536608A CN202211109688.8A CN202211109688A CN115536608A CN 115536608 A CN115536608 A CN 115536608A CN 202211109688 A CN202211109688 A CN 202211109688A CN 115536608 A CN115536608 A CN 115536608A
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- -1 Oxazine compound Chemical class 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- 150000001875 compounds Chemical class 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 26
- 238000010992 reflux Methods 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 239000011593 sulfur Substances 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052711 selenium Inorganic materials 0.000 claims description 9
- 239000011669 selenium Chemical group 0.000 claims description 9
- 229910052714 tellurium Chemical group 0.000 claims description 9
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical group [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical group [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 229910052740 iodine Chemical group 0.000 claims description 5
- 239000011630 iodine Chemical group 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 4
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical group C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- 125000003748 selenium group Chemical group *[Se]* 0.000 claims description 4
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 4
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 4
- 125000004266 aziridin-1-yl group Chemical group [H]C1([H])N(*)C1([H])[H] 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 150000004893 oxazines Chemical class 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 208000035143 Bacterial infection Diseases 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 claims description 2
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 2
- 238000003384 imaging method Methods 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000005864 Sulphur Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000004973 liquid crystal related substance Substances 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 abstract description 11
- 238000005286 illumination Methods 0.000 abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 6
- 210000004881 tumor cell Anatomy 0.000 abstract description 3
- 244000052616 bacterial pathogen Species 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 241000894006 Bacteria Species 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000007853 buffer solution Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 5
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 239000010413 mother solution Substances 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000012221 photothermal agent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 2
- 229960004657 indocyanine green Drugs 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- OLNMJIHADFYHAK-UHFFFAOYSA-N n,n-diethyl-4-nitrosoaniline Chemical compound CCN(CC)C1=CC=C(N=O)C=C1 OLNMJIHADFYHAK-UHFFFAOYSA-N 0.000 description 2
- 239000002086 nanomaterial Substances 0.000 description 2
- 238000007626 photothermal therapy Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- 125000001989 1,3-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([H])C([*:2])=C1[H] 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical group NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000002041 carbon nanotube Substances 0.000 description 1
- 229910021393 carbon nanotube Inorganic materials 0.000 description 1
- 239000003575 carbonaceous material Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/36—[b, e]-condensed, at least one with a further condensed benzene ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D293/00—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms
- C07D293/10—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms condensed with carbocyclic rings or ring systems
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- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to the field of photo-thermal reagents, in particular to an oxazine compound and a preparation method and application thereof. The oxazine compound provided by the invention has a structure shown as a formula (1). The oxazine compound provided by the invention has high molar absorption coefficient in a near infrared region, high photo-thermal conversion efficiency and excellent photo-thermal stability, and under near infrared illumination, the oxazine compound has high photo-thermal conversion efficiency, and generated heat can efficiently kill pathogenic bacteria or tumor cells.
Description
Technical Field
The invention relates to the field of photo-thermal reagents, in particular to an oxazine compound and a preparation method and application thereof.
Background
Photothermal therapy, which is a method of killing disease-treating bacteria or tumor cells by converting light energy into heat energy by a photothermal agent, is attracting much attention because it is non-invasive and well-controllable. Compared with photodynamic therapy, photothermal therapy plays a role in treatment through generated heat, is not limited by hypoxia conditions of microenvironment tissues of diseases, and therefore has better development prospect. On the other hand, near infrared light (650-900 nm) has less tissue absorption and thus has good penetration depth. In addition, the near infrared light has low phototoxicity to normal tissues, so the development of photothermal agents with near infrared light excitation is a hot research spot in recent years.
Inorganic nanomaterials typified by gold nanomaterials and carbon materials typified by carbon nanotubes are photothermal conversion materials widely studied at present, but the materials are high in preparation cost, difficult to degrade in vivo and unclear in toxicity to the human body, so that clinical conversion is difficult to perform and large-scale application is difficult. The organic small molecule photothermal reagent has the characteristics of definite structure and easy degradation and removal in vivo, and is clinically approved for application. For example, porphyrin compounds and indocyanine green photothermal agents, but porphyrin compounds have weak near infrared absorption and low photothermal conversion efficiency, and indocyanine green has the defect of poor light stability.
Disclosure of Invention
Therefore, the invention aims to solve the technical problems of low photo-thermal conversion efficiency and poor photo-stability of the existing organic photo-thermal reagent, and provides an oxazine compound and a preparation method and application thereof.
In order to solve the technical problems, the invention adopts the following technical scheme:
an oxazine compound has a structure shown as a formula (1):
wherein n has a value of 0 or 1;
r1 is selected from C1-C5 alkyl substituted amino and C3-C6 nitrogen-containing heterocycle;
r2 is selected from halogen, m represents R 2 A number selected from an integer of 1 to 6, such as 1,2,3,4, 5 or 6;
r3 is selected from optionally substituted alkyl or optionally substituted aryl;
x is selected from sulfur, selenium and tellurium.
Preferably, R 3 Selected from substituted or unsubstituted alkyl groups selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl;
the number of the substituent groups in the substituted alkyl group is 1-3, and the substituent groups are independently selected from phenyl, 4-hydroxymethyl phenyl, 4-carboxyl phenyl, 3-sulfonic propyl and 3-amino propyl.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the substituted compound is stable. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on an achievable basis.
In the present invention, the alkyl group may be a straight chain alkyl group or a branched chain alkyl group. Meanwhile, the alkyl group may be an unsubstituted alkyl group or a substituted alkyl group.
In the present invention, "unsubstituted alkyl" refers to alkyl groups that do not contain heteroatoms, including but not limited to the following examples: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. "unsubstituted alkyl" also includes branched isomers of straight chain alkyl groups, including but not limited to the following examples: -CH (CH) 3 ) 2 、-CH(CH 3 )(CH 2 CH 3 )、-CH(CH 2 CH 3 ) 2 、-C(CH3) 3 、-C(CH 2 CH 3 ) 3 、-CH 2 CH(CH 3 ) 2 or-CH 2 CH(CH 3 )(CH 2 CH 3 ) And the like.
"substituted alkyl" may be alkyl substituted with substituent groups including, but not limited to:
in the present invention, the aryl group may be an unsubstituted aryl group or a substituted aryl group.
"unsubstituted aryl" refers to aryl groups that do not contain heteroatoms, including, but not limited to: such as phenyl, biphenyl, or anthracenyl, and the like.
Preferably, the compound has a structure shown in formula (2):
wherein R1 is selected from C1-C5 alkyl substituted amino and C3-C6 nitrogen-containing heterocyclic ring;
r2 is selected from halogen;
r3 is selected from optionally substituted alkyl or optionally substituted aryl;
x is selected from sulfur, selenium and tellurium.
Preferably, R1 is selected from the group consisting of azodimethylamino, azodiethylamino, aziridin-1-yl, azetidin-1-yl, pyrrol-1-yl, piperidin-1-yl;
r2 is selected from chlorine, bromine and iodine.
Preferably, R1 is selected from the group consisting of nitrogen dimethylamino group, nitrogen diethylamino group;
r2 is selected from chlorine, bromine and iodine;
R 3 is selected from
X is selected from sulfur.
Preferably, the oxazine compound has the following structure:
the oxazine compound provided by the invention has high molar absorption coefficient in a near infrared region, high photo-thermal conversion efficiency and excellent photo-thermal stability.
The invention also provides a preparation method of the oxazine compound, and when X is selected from sulfur, the preparation method comprises the following steps:
dissolving a compound shown as a formula (3) and a compound shown as a formula (4) in a solvent, heating the obtained solution to reflux, adding a catalyst, and continuing reflux reaction to obtain the oxazine compound;
when X is selected from selenium or tellurium, the method comprises the following steps:
dissolving a compound shown in a formula (3) and a compound shown in a formula (5) in a solvent, adding a catalyst, and heating and refluxing to react to obtain the oxazine compound;
wherein the compound represented by the formula (3) has the following structure:
the compound represented by the formula (4) has the following structure:
the compound represented by the formula (5) has the following structure:
wherein n, m, R1, R2, R3 are as defined above.
The oxazine compound with sulfur X can be prepared by the method, and an exemplary reaction flow is as follows:
the oxazine compound with X being selenium or tellurium can be prepared by the method, and an exemplary reaction flow is as follows:
preferably, when X is selected from sulfur, the solvent is methanol;
the molar ratio of the compound represented by the formula (3) to the compound represented by the formula (4) is (2-2.01): 1, preferably 2;
the catalyst is silver carbonate, and the molar amount of the catalyst is 9-35% of the total molar amount of the compound shown in the formula (3) and the compound shown in the formula (4);
continuously refluxing and reacting for 1-1.5 hours;
preferably, the method further comprises the steps of filtering and purifying after the reflux reaction is finished. Preferably, the purification method is column chromatography, the solvent used in the column chromatography is dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 10.
Preferably, when X is selected from selenium or tellurium, the solvent is ethanol;
the molar ratio of the compound represented by the formula (3) to the compound represented by the formula (5) is 1 (3-3.05), preferably 1;
the catalyst is hydrochloric acid or acetic acid, and the molar consumption of the catalyst is 0.2-12% of the total molar amount of the compound shown in the formula (3) and the compound shown in the formula (5);
heating reflux reaction time is 1-3 hours;
preferably, the method further comprises the steps of filtering and purifying after the reflux reaction is finished. Preferably, the purification method is column chromatography, the solvent used in the column chromatography is dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 5.
The invention also provides application of the oxazine compound in preparation of an antibacterial or anti-tumor photothermal treatment reagent.
The invention also provides application of the oxazine compound in imaging of bacterial infection sites or tumors.
Has the advantages that:
the oxazine compound provided by the invention has a general formula structure shown in a formula (1), and has a high molar absorption coefficient in a near infrared region as a photo-thermal reagent by matching a main ring structure with substituents R1-R3, and has high photo-thermal conversion efficiency and excellent photo-thermal stability.
Meanwhile, under near-infrared illumination, the oxazine compound provided by the invention has high photo-thermal conversion efficiency, and the generated heat can efficiently kill pathogenic bacteria or tumor cells. In addition, under the near-infrared illumination, the fluorescence can also image the pathogen infected part or the tumor tissue to construct a diagnosis and treatment integrated system.
Further, the invention provides an oxazine compound, when R1 is selected from nitrogen dimethylamino group, nitrogen diethylamino group; r2 is selected from chlorine, bromine and iodine; r 3 Is selected from
When X is selected from sulfur, the oxazine compound has more excellent photo-thermal conversion efficiency and photo-thermal stability.
Furthermore, the preparation method of the oxazine compound provided by the invention selects appropriate raw materials, synthesizes the oxazine compound through one-step reaction, and has simple and feasible process.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 shows absorption spectra of MtNBS in methanol and water in example 1 of the present invention;
FIG. 2 is the fluorescence emission spectrum of MtNBS in methanol in example 1 of the present invention;
FIG. 3 is a graph showing the temperature of the MtNBS solution as a function of the illumination time in example 1 of the present invention;
FIG. 4 is the temperature rise and natural cooling curve of the MtNBS aqueous solution under laser irradiation in example 1 of the present invention;
FIG. 5 shows the photothermal efficiency of an aqueous solution of MtNBS in example 1 of the present invention;
FIG. 6 is a temperature change curve of MtNBS under repeated irradiation of external laser in example 1 of the present invention;
FIG. 7 shows the photothermal bacteriostasis results of MtNBS against Pseudomonas aeruginosa in example 1 of the present invention;
FIG. 8 shows the photothermal bacteriostasis results of MtNBS against E.coli in example 1 of the present invention;
FIG. 9 shows the photothermal bacteriostasis results of MtNBS against Staphylococcus aureus in example 1 of the present invention;
FIG. 10 shows the photothermal bacteriostasis results of MtNBS against methicillin-resistant Staphylococcus aureus in example 1 of the present invention.
Detailed Description
The invention provides an oxazine compound with high-efficiency photothermal conversion efficiency in a near infrared region, a preparation method and application thereof in the aspects of antibiosis and tumor resistance, and the invention is further described in detail below in order to make the purpose, technical scheme and effect of the invention clearer and more clear and definite. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
This example provides a method for preparing 4- (((1, 2,3, 4-tetrachloro-9- (dimethylamino) -5H-phenylphenothiazin-5-ylidene) amino) methyl) benzyl alcohol (MtNBS, a compound of formula C below) from oxazines, comprising the steps of:
adding 20 mmol of 4- (((5, 6,7, 8-tetrachloronaphthalene-1-yl) amino) methyl) benzyl alcohol (formula (5)) [ formula A ] and 10 mmol of dimethylamino-substituted bunte salt (formula (B)) into a reactor, adding 30 ml of methanol for dissolving, heating and refluxing, then adding 3 mmol of silver carbonate, continuing to reflux for 1 hour, filtering to remove insoluble substances, collecting filtrate, and carrying out column chromatography (the solvent used for column chromatography is dichloromethane and methanol, the volume ratio of the two is 10) to obtain a pure product of 4- (((1, 2,3, 4-tetrachloro-9- (dimethylamino) -5H-benzophenothiazin-5-ylidene) amino) methyl) benzyl alcohol, wherein the structural formula of the pure product is shown in a formula (C).
Example 2
This example provides a method for preparing 4- (((1, 2,3, 4-tetrabromo-9- (diethylamino) -5H-benzophenoselenazine-5-ylidene) amino) methyl) benzoic acid (EtNBSe) as an oxazine compound, comprising the following steps:
adding 10 mmol of 3,3' -diselenediylbis (N, N-diethyl-4-nitrosoaniline) (formula (6)) and 30 mmol of 4- (((5, 6,7, 8-tetrabromo naphthalene-1-yl) amino) methyl) benzoic acid (formula (7)) into a reactor, adding 30 ml of ethanol for dissolution, then adding 0.1 mmol of hydrochloric acid, heating and refluxing for 2 hours, carrying out suction filtration on the reaction system to collect filtrate, and carrying out column chromatography (the solvent used for column chromatography is dichloromethane and methanol, the volume ratio of the two is 5) to obtain a pure product 4- (((1, 2,3, 4-tetrabromo-9- (diethylamino) -5H-benzophenoselenazine-5-subunit) amino) methyl) benzoic acid, the structural formula of which is shown as (formula 8):
example 3
This example provides a method for preparing 7- (benzylimino) -9, 10, 11, 12-tetrabromo-N, N-diethyl-7H-naphtho [2,3] phenoselenazine-3-amine (BTNSe) from oxazines, which includes the following steps:
adding 10 mmol of 3,3' -diselenediylbis (N, N-diethyl-4-nitrosoaniline) and 30 mmol of N-benzyl-5, 6,7, 8-tetrabromoanthracene-1-amine (formula (9)) into a reactor, adding 30 ml of ethanol for dissolving, then adding 0.1 mmol of acetic acid, heating and refluxing for 2 hours, carrying out suction filtration on the reaction system to collect filtrate, and carrying out column chromatography (the solvent used for column chromatography is dichloromethane and methanol, the volume ratio of the two is 5 1) to purify to obtain a pure product 7- (benzylimino) -9, 10, 11, 12-tetrabromo-N, N-diethyl-7H-naphtho [2,3] selenophenazine-3-amine, the structural formula of which is shown as formula (10):
example 4
This example provides a process for the preparation of an oxazine compound 1,1' - ((((((((((5- (((3- (aziridin-1-yl) -8, 13-dibromo-9, 10, 11, 12-tetraiodo-7H-naphtho [2,3] phenoselenazine-7-ylidene) amino) methyl) -2- (2- (2- (2-guanidinoethoxy) ethoxy) -1, 3-phenylene) bis (oxy)) bis (ethane-2, 1-diyl)) diguanidino (ABIG)) comprising the steps of:
20 mmol of 1,1' - (((((((((((5- (((9, 10-dibromo-5, 6,7, 8-tetraiodoanthracen-1-yl) amino) methyl) -2- (2- (2- (2-guanidinoethoxy) ethoxy) -1, 3-phenylene) bis (oxy)) bis (ethane-2, 1-diyl)) diguanidino (formula (11)) and 10 mmol of aziridin-1-yl substituted bunte salt (formula (12)) were charged into a reactor and dissolved by adding 30 ml of methanol, heating and refluxing, then adding 3 millimole of silver carbonate, continuously refluxing for 1 hour, filtering to remove insoluble substances, collecting filtrate, carrying out column chromatography (the solvent used in column chromatography is dichloromethane and methanol, the volume ratio of the dichloromethane to the methanol is 10 1, 3-phenylene) bis (oxy)) bis (ethane-2, 1-diyl)) biguanide groups having the formula (13):
example 5
The absorption spectrum of the oxazine compound MtNBS prepared in example 1 is tested, and the test result is shown in figure 1, wherein a dimethylsulfoxide mother solution of MtNBS with a concentration of 10 millimoles per liter is prepared, then the dimethylsulfoxide mother solution is diluted by methanol to obtain a 30 micromole MtNBS methanol solution with a concentration per liter, and an absorption curve is obtained by scanning within a range of 400-800 nanometers, wherein the maximum absorption peak of the absorption curve is located at 660 nanometers. Meanwhile, a 30-mol/L MtNBS aqueous solution is prepared, and the absorption spectrum is tested under the same condition, so that the absorption intensity is reduced and the absorption peak is widened compared with the absorption peak in methanol.
The fluorescence emission spectrum of the oxazine compound MtNBS prepared in example 1 was tested, and the test result is shown in fig. 2, wherein a dimethylsulfoxide mother solution of 10 mmol/l MtNBS was prepared, then the solution was diluted with methanol to obtain a MtNBS methanol solution with a concentration of 10 micromol/l, and the emission spectrum of MtNBS was obtained by excitation with light of 660 nm, and the maximum emission peak was 690 nm.
Example 6
The photothermal performance of the oxazine compound MtNBS prepared in example 1 was tested, and the test results are shown in fig. 3, in which 10 mmol/l of MtNBS dimethylsulfoxide mother liquor was first prepared, and diluted with water to obtain a 30 μmol/l MtNBS aqueous solution, and 660 nm laser was used as a control to irradiate the solution with laser of 1 watt/cm, and the temperature rise of the solution was recorded, so that the temperature rise of the pure water in the control group was not significant, and the temperature of the sample solution rapidly increased to 60 ℃ or higher within 180 seconds of irradiation time.
As shown in fig. 4, the laser irradiation was turned off after 180 seconds, and the temperature change with time during natural cooling was recorded. As shown in fig. 5, the photothermal conversion efficiency of MtNBS was calculated to be as high as 89% by temperature drop curve data processing.
As shown in fig. 6, mtNBS has good photothermal stability and still maintains high photothermal conversion efficiency over at least five repeated temperature ramp-down cycles.
Example 7
Photothermal sterilization test of oxazine compound MtNBS prepared in example 1
As shown in fig. 7, pseudomonas aeruginosa was cultured in the broth for 24 hours, then the bacterial dispersion was centrifuged at 3000 rpm for 3 minutes and washed 3 times with the buffer solution, the bacteria were diluted into the buffer solution to a concentration of about 107 colonies per ml, mtNBS was added to a concentration of 30 micromoles per liter for 1 hour, and then irradiated with a 660 nm laser for 180 seconds with a set laser power of 1 watt per square centimeter. A control (blank) was also prepared according to the above method, which was different from the above method in that MtNBS was not added. After the irradiation was completed, the control group to which MtNBS was not added and the experimental group to which MtNBS was added (sample illumination) were diluted and plated, and the growth of bacteria was observed after 24 hours, wherein the survival rate of bacteria was almost 0 in the experimental group to which MtNBS was added, and the control group showed many bacteria.
As shown in fig. 8, escherichia coli was cultured in a broth for 24 hours, then the bacterial dispersion was centrifuged at 3000 rpm for 3 minutes and washed 3 times with a buffer solution, the bacteria were diluted into the buffer solution so that the concentration of the bacteria was about 107 colonies per ml, mtNBS was added so that the concentration thereof was 30 micromoles per liter, cultured for 1 hour, and then irradiated with a 660 nm laser for 180 seconds, with the laser power being set at 1 watt per square centimeter. A control (blank) was also prepared according to the above method, which was different from the above method in that MtNBS was not added. After the irradiation was completed, the control group to which MtNBS was not added and the experimental group to which MtNBS was added (sample illumination) were diluted and plated, and the growth of bacteria was observed after 24 hours, wherein the survival rate of bacteria was almost 0 in the experimental group to which MtNBS was added, and the control group showed many bacteria.
As shown in fig. 9, staphylococcus aureus was cultured in broth for 24 hours, then the bacterial dispersion was centrifuged at 3000 rpm for 3 minutes and washed 3 times with buffer solution, the bacteria were diluted into buffer solution to a concentration of about 107 colonies per ml, mtNBS was added to a concentration of 30 micromoles per liter for 1 hour, and then irradiated with 660 nm laser for 180 seconds with a laser power set at 1 watt per square centimeter. A control (blank) was also set up as described above, which differed from the above method in that no MtNBS was added. After the irradiation was completed, the control group to which MtNBS was not added and the experimental group to which MtNBS was added (sample illumination) were diluted and plated, and the growth of bacteria was observed after 24 hours, wherein the survival rate of bacteria was almost 0 in the experimental group to which MtNBS was added, and the control group showed many bacteria.
As shown in fig. 10, methicillin-resistant staphylococcus aureus was cultured in broth for 24 hours, then the bacterial dispersion was centrifuged at 3000 rpm for 3 minutes and washed 3 times with buffer solution, the bacteria were diluted into the buffer solution to a concentration of about 107 colonies per ml, mtNBS was added to a concentration of 30 micromoles per liter for 1 hour, and then irradiated with 660 nm laser for 180 seconds with a laser power set at 1 watt per square centimeter. A control (blank) was also set up as described above, which differed from the above method in that no MtNBS was added. After the irradiation was completed, the control group to which MtNBS was not added and the experimental group to which MtNBS was added (sample light) were diluted and plated, and the growth of bacteria was observed after 24 hours, and the bacterial survival rate of the experimental group to which MtNBS was added was almost 0, whereas the control group showed many bacteria.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications derived therefrom are intended to be within the scope of the invention.
Claims (10)
1. An oxazine compound, which is characterized by having a structure shown in a formula (1):
wherein n has a value of 0 or 1;
r1 is selected from C1-C5 alkyl substituted amino and C3-C6 nitrogen-containing heterocycle;
r2 is selected from halogen, m represents R 2 A number selected from integers from 1 to 6;
r3 is selected from optionally substituted alkyl or optionally substituted aryl;
x is selected from sulfur, selenium and tellurium.
2. The oxazine compound of claim 1, wherein R 3 Selected from substituted or unsubstituted alkyl groups selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl;
the number of the substituent groups in the substituted alkyl group is 1-3, and the substituent groups are independently selected from phenyl, 4-hydroxymethyl phenyl, 4-carboxyl phenyl, 3-sulfonic propyl and 3-aminopropyl.
3. The oxazine compound of claim 1 or 2, having a structure according to formula (2):
wherein R1 is selected from C1-C5 alkyl substituted amino and C3-C6 nitrogen-containing heterocycle;
r2 is selected from halogen;
r3 is selected from optionally substituted alkyl or optionally substituted aryl;
x is selected from sulfur, selenium and tellurium.
4. The oxazine compound of any of claims 1-3, wherein R1 is selected from the group consisting of azodimethylamino, azodiethylamino, aziridin-1-yl, azetidin-1-yl, pyrrol-1-yl, piperidin-1-yl;
r2 is selected from chlorine, bromine and iodine;
preferably, the first and second liquid crystal materials are,
r1 is selected from nitrogen dimethyl amino and nitrogen diethyl amino;
r2 is selected from chlorine, bromine and iodine;
R 3 is selected from
X is selected from sulfur.
5. The oxazine compound of any of claims 1-4, wherein said oxazine compound has the following structure:
6. a method for preparing oxazine compounds according to any of claims 1-5, wherein when X is selected from sulphur, the method comprises the following steps:
dissolving a compound shown as a formula (3) and a compound shown as a formula (4) in a solvent, heating the obtained solution to reflux, adding a catalyst, and continuing reflux reaction to obtain the oxazine compound;
when X is selected from selenium or tellurium, the method comprises the following steps:
dissolving a compound shown as a formula (3) and a compound shown as a formula (5) in a solvent, adding a catalyst, and carrying out heating reflux reaction to obtain the oxazine compound;
wherein the compound represented by the formula (3) has the following structure:
the compound represented by the formula (4) has the following structure:
the compound represented by the formula (5) has the following structure:
wherein n, m, R1, R2 and R3 are as defined in claim 1.
7. The method according to claim 6, wherein when X is selected from sulfur, the solvent is methanol;
the molar ratio of the compound shown in the formula (3) to the compound shown in the formula (4) is (2-2.01): 1;
the catalyst is silver carbonate, and the molar amount of the catalyst is 9-35% of the total molar amount of the compound shown in the formula (3) and the compound shown in the formula (4);
continuously refluxing and reacting for 1-1.5 hours;
preferably, the method further comprises the steps of filtering and purifying after the reflux reaction is finished.
8. The method according to claim 6, wherein when X is selected from selenium or tellurium, the solvent is ethanol;
the mol ratio of the compound shown in the formula (3) to the compound shown in the formula (5) is 1 (3-3.05);
the catalyst is hydrochloric acid or acetic acid, and the molar consumption of the catalyst is 0.2-12% of the total molar amount of the compound shown in the formula (3) and the compound shown in the formula (5);
heating reflux reaction time is 1-3 hours;
preferably, the method further comprises the steps of filtering and purifying after the reflux reaction is finished.
9. Use of an oxazine compound of any of claims 1-5 for the preparation of an antibacterial or anti-tumor photothermal therapeutic agent.
10. Use of an oxazine compound of any of claims 1-5 for imaging of a bacterial infection site or a tumor.
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