CN108503673A - A kind of near-infrared aza pyrrolidines dyestuff and its preparation method and application - Google Patents
A kind of near-infrared aza pyrrolidines dyestuff and its preparation method and application Download PDFInfo
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- CN108503673A CN108503673A CN201810398916.5A CN201810398916A CN108503673A CN 108503673 A CN108503673 A CN 108503673A CN 201810398916 A CN201810398916 A CN 201810398916A CN 108503673 A CN108503673 A CN 108503673A
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- dyestuff
- pyrrolidines
- azepine
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- 239000000975 dye Substances 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims description 8
- -1 aza pyrrolidines Chemical class 0.000 title description 2
- YCRRFGIOUUBPNG-UHFFFAOYSA-N N1CCCC1.N1C=CC=CC=C1 Chemical class N1CCCC1.N1C=CC=CC=C1 YCRRFGIOUUBPNG-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000003384 imaging method Methods 0.000 claims abstract description 16
- 230000003287 optical effect Effects 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 40
- 239000000243 solution Substances 0.000 claims description 40
- 206010028980 Neoplasm Diseases 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 230000015572 biosynthetic process Effects 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- 238000002560 therapeutic procedure Methods 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 235000019441 ethanol Nutrition 0.000 claims description 8
- 239000003446 ligand Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000007626 photothermal therapy Methods 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052697 platinum Inorganic materials 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005695 Ammonium acetate Substances 0.000 claims description 3
- 229940043376 ammonium acetate Drugs 0.000 claims description 3
- 235000019257 ammonium acetate Nutrition 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- UOZDOLIXBYLRAC-UHFFFAOYSA-L [2-hydroxy-3-(trimethylazaniumyl)propyl]-trimethylazanium;diiodide Chemical compound [I-].[I-].C[N+](C)(C)CC(O)C[N+](C)(C)C UOZDOLIXBYLRAC-UHFFFAOYSA-L 0.000 claims description 2
- 238000007259 addition reaction Methods 0.000 claims description 2
- 238000010719 annulation reaction Methods 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 238000010668 complexation reaction Methods 0.000 claims description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 2
- 150000002561 ketenes Chemical class 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 238000003760 magnetic stirring Methods 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 26
- 230000005284 excitation Effects 0.000 abstract description 7
- 238000010521 absorption reaction Methods 0.000 abstract description 6
- 229910052736 halogen Inorganic materials 0.000 abstract description 5
- 150000002367 halogens Chemical class 0.000 abstract description 5
- 239000011159 matrix material Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 208000027418 Wounds and injury Diseases 0.000 abstract description 3
- 239000012620 biological material Substances 0.000 abstract description 3
- 230000006378 damage Effects 0.000 abstract description 3
- 238000001514 detection method Methods 0.000 abstract description 3
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 3
- 208000014674 injury Diseases 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 25
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 21
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 21
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 7
- 238000000295 emission spectrum Methods 0.000 description 6
- 238000000074 matrix-assisted laser desorption--ionisation tandem time-of-flight detection Methods 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- 230000005311 nuclear magnetism Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 6
- 238000004140 cleaning Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 4
- ZKSVYBRJSMBDMV-UHFFFAOYSA-N 1,3-diphenyl-2-benzofuran Chemical compound C1=CC=CC=C1C1=C2C=CC=CC2=C(C=2C=CC=CC=2)O1 ZKSVYBRJSMBDMV-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 210000004209 hair Anatomy 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001931 thermography Methods 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 description 1
- AEILRGAWIMOYRB-UHFFFAOYSA-N 1h-azepine;1h-pyrrole Chemical group C=1C=CNC=1.N1C=CC=CC=C1 AEILRGAWIMOYRB-UHFFFAOYSA-N 0.000 description 1
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 241000254173 Coleoptera Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- DZJXKISLUDYJSV-UHFFFAOYSA-N [N].C1CCNC1 Chemical class [N].C1CCNC1 DZJXKISLUDYJSV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012779 reinforcing material Substances 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
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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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0086—Platinum compounds
-
- 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
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/04—Nickel compounds
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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
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic System without C-Metal linkages
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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
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/02—Magnesium compounds
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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
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/06—Zinc compounds
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B57/00—Other synthetic dyes of known constitution
Abstract
The invention discloses a kind of azepine pyrrolidines dyestuff, the dyestuff is made of halogen, heavy metal and azepine pyrrolidines skeleton, and the more remarkable light light and heat power effect of dyestuff is imparted by introducing halogen and multiple heavy metal on azepine pyrrolidines matrix.The dyestuff has stronger absorption and transmitting in near-infrared wavelength region, photo-thermal property and chemical stability are all improved, reduce interference of the autofluorescence to detection signal, reduce injury of the excitation light source to biological tissue, the light power photo-thermal oncotherapy that can be used under the guiding of the multi-modality imagings such as photothermal imaging, photoacoustic imaging, is good optical bio material, and it is simple to prepare industry, production efficiency is high, can be used for mass producing.
Description
Technical field
The invention belongs to organic photoelectric, technical field of biological materials.More particularly to it is a kind of it is based on azepine pyrrolidines, can be single
Wavelength excitation, photo-thermal light power dyestuff near infrared absorption and preparation method and its fluorescence imaging, photothermal imaging,
Application in the fields such as photoacoustic imaging, photo-thermal therapy and optical dynamic therapy.
Background technology
Tumour is always the fatal disease for being difficult to capture, and also rests on traditional operation to the therapy of tumour at present
Therapy, chemotherapy or radiotherapy；For these therapeutic modalities often along with the generation of toxic side effect, therapeutic effect is bad.It explores
Increase some supplementary means on the basis of the therapy new, toxic side effect is small or existing therapy, and then improves and treat
Effect mitigates toxic side effect, is current oncotherapy urgent problem to be solved.
With the continuous development of science and technology, researcher gradually has developed various new therapeutic scheme, wherein light
A kind of oncotherapy means of the hot optical dynamic therapy as Noninvasive can carry out tumor locus in real time and accurately treat, greatly
The big effect for improving oncotherapy.However the weary oxygen characteristic of tumor locus hinders the development of optical dynamic therapy.Low light
Thermal conversion efficiency hinders the photo-thermal therapy of tumour.But light power and photo-thermal synergistic treatment then greatly facilitate disappearing for tumour
It removes, on the one hand, photo-thermal therapy can increase tumor locus temperature, to enhance tumor locus blood circulation, improve the confession of oxygen
It gives, to improve optical dynamic therapy effect.On the other hand, photodynamic tumor-treatment can make up the defect of photo-thermal therapy.Therefore,
Ideal material how is selected to cause everybody deepest concern for oncotherapy.
Nir dye is a kind of Functional dye of good performance, has good absorption in near-infrared region, wireless
The fields such as electric radio frequency identification, oncotherapy, solar cell are widely used.It is close red in addition to having when for bio-imaging
Outer absorption, launch wavelength also have a good water-soluble and lower bio-toxicity, special tissue or it is cell targeted and
Good Cell permeable etc., to reach safer, efficient, sensitive fluorescence imaging purpose.
Organic photosensitizer and optothermal material are a kind of Functional dyes of good performance, include mainly pyrrolidines, side's acid, flower
The dyestuffs such as cyanines, porphyrin, rhodamine.Wherein, azepine pyrrolidines dyestuff has relatively good photostability, adjustable close red
Outer absorption, this enables it to be widely used in the fields such as optical technology, bio-imaging.It is worth noting that, the light power of material
Effect and the composition of photo-thermal effect and material are closely related, and the introducing of general heavy atom can enhance intersystem crossing to improve material
The light power effect of material, pertinent literature also indicate that heavy metal platinum can be with the photo-thermal effect of reinforcing material.
Therefore, the property in conjunction with heavy atom and azepine pyrrolidines designs the photo-thermal with good light light and heat power effect
Light dynamic material will be of great significance.
Invention content
It is an object of the invention to solve deficiency in the prior art, by the way that halogen and transition metal are bonded to azepine pyrrole
Cough up on alkane, design and synthesize a kind of miscellaneous nitrogen pyrrolidines dyestuff, this kind of dyestuff can monochromatic light source excitation and with good photoacoustic imaging,
The therapeutic effect that the light light and heat power of photothermal imaging and tumor is combined.
The technical scheme is that：A kind of azepine pyrrolidines dyestuff, general structure are as follows：
Wherein, R1、R2One kind in having structure：
M=Pt, Zn, Ni or Mg；A^B is C^N ligands or N^N ligands；X=Br or I；
Wherein, R3For straight chain, branch or cyclic alkyl chain with 0 to 16 carbon atom；
C^N ligands and N^N ligands are any of having structure：
Further, the specific synthetic route of the preparation method of the azepine pyrrolidines dyestuff is as follows：
Further, the specific synthesis step of the preparation method of the azepine pyrrolidines dyestuff is：
1) synthesis of ketenes：Compound 1 is reacted into 10- with compound 2 in dilute sodium hydroxide and alcohol mixed solution
After 15h, for the acid-base value of dilute hydrochloric acid adjusting reaction solution to pH value between 4~7, filtering, is dried to obtain product 3 at the washing of cold ethyl alcohol；
2) addition reaction：Under the conditions of nitrogen protection, the product 3, nitromethane and diethylamine are dissolved in absolute methanol
In, be heated to reflux 16-28h, with dilute hydrochloric acid adjust reaction solution acid-base value to pH value between 5~7, filtering, cold methanol washing
Three times, dry, obtain product 4；
3) annulation：The product 4 is heated to reflux 20-30h under magnetic stirring in butanol solution with ammonium acetate,
Postcooling is concentrated to room temperature, filtering, the washing of cold ethyl alcohol, obtains product 5；
4) substitution reaction：In anhydrous methylene chloride solution, the product 5 and propiodal or bromine source are carried out under room temperature
It is protected from light 20-30h, is dried under reduced pressure, product 6 is obtained by column chromatography；
5) complexation reaction：The product 6 is dissolved in dry methylene chloride solution, new steaming three is added under nitrogen protection
The halide complex of metal is added dropwise in ethamine later, and after 6-12h is stirred at room temperature, concentration passes through column chromatography after adding water to filter
Obtain product E.
Further, the azepine pyrrolidines dyestuff can be applicable in photothermal imaging.
Further, the azepine pyrrolidines dyestuff can be applicable in photoacoustic imaging.
Further, the azepine pyrrolidines dyestuff can be applicable in the optical dynamic therapy of tumour.
Further, the azepine pyrrolidines dyestuff can be applicable in the photo-thermal therapy of tumour.
The beneficial effects of the invention are as follows：
1. azepine pyrrolidines dyestuff of the present invention excites near infrared light region, reduces autofluorescence and detection is believed
Number interference, reduce injury of the excitation light source to biological tissue, and enhance penetration depth of the light source to tissue；
2. azepine pyrrolidines dyestuff of the present invention on azepine pyrrolidines skeleton by introducing halogen and transition metal
So that the photo-thermal light power effect of dyestuff is obviously improved, can be used for swollen under the guiding of the multi-modality imagings such as photothermal imaging, photoacoustic imaging
The light power and photo-thermal therapy of tumor are good optical bio materials；
3. azepine pyrrolidines dyestuff preparation method of the present invention is simple for process, abundant raw material.
Description of the drawings
Fig. 1 is the MALDI-TOF/TOF figures of the compound C measured in the embodiment of the present invention 4；
Fig. 2 is the MALDI-TOF/TOF figures of the compound D measured in the embodiment of the present invention 5；
Fig. 3 is the MALDI-TOF/TOF figures of the compound E measured in the embodiment of the present invention 6；
Fig. 4 is the compound C measured in the embodiment of the present invention 71H-NMR schemes；
Fig. 5 is the compound D measured in the embodiment of the present invention 81H-NMR schemes；
Fig. 6 is the compound E measured in the embodiment of the present invention 91H-NMR schemes；
Fig. 7 is the UV-visible spectrum of the compound C measured in the embodiment of the present invention 10；
Fig. 8 is the UV-visible spectrum of the compound D measured in the embodiment of the present invention 11；
Fig. 9 is the UV-visible spectrum of the compound E measured in the embodiment of the present invention 12；
Figure 10 is the launching light spectrogram of the compound C measured in the embodiment of the present invention 13；
Figure 11 is the launching light spectrogram of the compound D measured in the embodiment of the present invention 14；
Figure 12 is the launching light spectrogram of the compound E measured in the embodiment of the present invention 15；
Figure 13 is the photo-thermal effect figure of the compound C measured in the embodiment of the present invention 16；
Figure 14 is the photo-thermal effect figure of the compound D measured in the embodiment of the present invention 17；
Figure 15 is the photo-thermal effect figure of the compound E measured in the embodiment of the present invention 18；
Figure 16 is the photo-thermal effect figure of compound C, D, E for being measured in the embodiment of the present invention 19；
Figure 17 is the photo-thermal effect figure that the compound E measured in the embodiment of the present invention 20 acts on mouse tumor locus.
Specific implementation mode
The content that following embodiment further illustrates the present invention, but should not be construed as limiting the invention.Without departing substantially from
In the case of essence of the present invention, to changing and replacing made by the method for the present invention, step or condition, the model of the present invention is belonged to
It encloses.
The specific synthetic route of azepine pyrrolidines is：
Embodiment 1：The synthesis of azepine pyrrolidines dyestuff C
(1) synthesis of compound 1
A clean single port bottle is taken, the bromooctane of magneton, the parahydroxyben-zaldehyde (about 10mmol) of 1.22g, 9.66g is added
The anhydrous DMF of (about 50mmol), 6.91g potassium carbonate and 25mL, under magnetic agitation, 80 DEG C of reactions are for 24 hours.After reaction, water/bis-
Chloromethanes extraction is multiple, merges organic phase, and organic phase after drying, chromatographs post separation, obtains light yellow liquid 2.34g (yields
About 99%).
(2) synthesis of compound 2
Take a clean two-mouth bottle, be added magneton, the compound 1 (about 10mmol) of 2.34g, 1.06g 2- acetyl bromides
The ethanol solution of thiophene (about 10mmol) and 40mL.Stirring is slowly added to 5mL sodium hydroxide solutions after solid all dissolving
(sodium hydroxide containing 1.00g).The reaction is stirred for 24 hours at room temperature, there is yellow solid precipitation in reaction process.After reaction, 1M
Hydrochloric acid solution adjust reaction solution acid-base value to neutrality, filter to obtain solid, deionized water is washed three times.It is dried in vacuo to obtain 3.36g
Yellow solid (yield about 99%).
1H NMR(400MHz,CDCl3)：δ (ppm)=8.04 (d, J=8Hz 2H), 7.81 (d, J=16Hz, 2H),
7.65-7.63 (m, 2H), 7.56 (d, J=16Hz, 2H), 7.44-7.38 (m, 3H), 7.97 (d, J=8Hz, 1H), 4.04-
4.01 (t, J=8Hz, J=4Hz, 2H), 1.84-1.78 (m, 2H), 1.50-1.28 (m, 10H), 0.91-0.88 (m, 3H)
(3) synthesis of compound 3
A clean bottle with two necks is taken, magneton is added, the compound 2 of 3.36g is added (about under the protection of nitrogen
10mmol), the nitromethane (about 50mmol) of 2.60mL, the diethylamine (about 50mmol) of 5.20mL and 20.0ml without water beetle
Alcohol.After being heated to reflux for 24 hours, reaction solution acid-base value is adjusted to neutrality with the hydrochloric acid solution of 1M, filters to obtain solid, cold methanol washing three
It is secondary.The product (yield about 85%) of 3.38g is obtained after vacuum drying.
1H NMR(400MHz,CDCl3):δ (ppm)=7.89 (d, J=8Hz, 2H), 7.34-7.23 (m, 5H), 6.90 (d,
J=8Hz, 2H), 4.85-4.81 (dd, J=4Hz, 8Hz, 1H), 4.70-4.64 (dd, J=8Hz, 12Hz, 1H), 4.25-4.18
(m, 1H), 4.00 (t, J=8Hz, 1H), 3.44-3.31 (m, 2H), 1.84-1.76 (m, 2H), 1.50-1.29 (m, 10H),
0.92–0.88(m,3H).
(4) synthesis of compound 4
A cleaning 100mL single port bottles are taken, magneton, 3.38g (8.5mmol) compounds 3,22.83g is added (about
298mmol) ammonium acetate solid, 20mL n-butanols are heated to reflux about for 24 hours under magnetic agitation.Reaction solution is concentrated under reduced pressure to original body
Long-pending 1/4 waits for that solution is cooled to room temperature, and blue solid is obtained by filtration, and it is solid to obtain 1.80g blues for absolute ethyl alcohol washing after dry
Body product (yield about 60%).
(5) synthesis of compound 5
A cleaning 100mL single port bottles are taken, magneton, 0.706g (1.0mmol) compounds 4,5.63g is added
(2.5mmol) N-iodosuccinimide (NIS), 20mL anhydrous methylene chlorides, are protected from light, and normal-temperature reaction is for 24 hours.Reaction terminates, reaction
Liquid is dried under reduced pressure, through chromatographing post separation, obtains 0.479g blue solids product (yield about 50%).
(6) synthesis of compound C
A cleaning 50mL single port bottles are taken, the dichloro that magneton, 0.35g (0.5mmol) compounds 4,10mL are dried is added
Methane dissolves.0.44g is added at 0~5 DEG C, under nitrogen protection and newly steams triethylamine (4.4mmol), then is slowly added to dropwise
The halide complex (2.0mmol) of 1.29g platinum, is added dropwise, moves to and 6h is stirred at room temperature, and after reaction, concentrates, column chromatography is pure
Change, obtains 0.047g blue solids product (yield about 9%).
1H NMR(400MHz,CDCl3):δ=8.45 (d, J=8.8Hz, 4H), 8.10 (dd, J=6.8,2.0Hz, 5H),
7.49 (t, J=8.4Hz, 1H), 7.41-7.30 (m, 9H), 7.21 (d, J=7.6Hz, 1H), 6.90-6.84 (m, 5H), 6.78
(t, J=8.4Hz, 1H), 6.62 (t, J=6.4Hz, 1H), 6.41 (t, J=6.0Hz, 1H), 3.99-3.91 (m, 4H), 1.80-
1.71(m,4H),1.46–1.29(m,20H),0.91–0.88(m,6H).
13C NMR(100MHz,CDCl3):δ=161.30,160.45,147.84,144.97,132.45,132.00,
130.76,129.40,127.96,123.01,113.88,83.09,68.04,31.86,29.53,29.28,26.03,22.71,
14.17.
Embodiment 2：The synthesis of azepine pyrrolidines photo-thermal dyestuff D
The synthesis of compound D
A cleaning 50mL single port bottles are taken, the dichloro that magneton, 0.09g (0.1mmol) compounds 5,10mL are dried is added
Methane dissolves.0.01g is added at 0~5 DEG C, under nitrogen protection and newly steams triethylamine (0.1mmol), then is slowly added to dropwise
0.44g Eorontrifluoride etherates (0.3mmol), are added dropwise, and move to and 6h is stirred at room temperature, and after reaction, mixed solution is through water
Wash, saturated sodium-chloride is washed, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, column chromatography purifying, obtaining 0.10g blue solids product, (yield is about
99%).
1H NMR(400MHz,CDCl3):δ=7.79 (dd, J=3.6,7.2Hz, 4H), 7.69 (d, J=8.4Hz, 4H),
7.44-7.42 (m, 6H), 6.96 (d, J=8.8Hz, 4H), 4.02 (t, J=6.4Hz, 4H), 1.84-1.77 (m, 4H), 1.51-
1.28(m,20H),0.92-0.89(m,6H).
13C NMR(100MHz,CDCl3):δ=161.30,160.45,147.84,144.97,132.45,132.00,
130.76,129.40,127.96,123.01,113.88,83.09,68.04,31.86,29.53,29.28,26.03,22.71,
14.17.
Embodiment 3：The synthesis of azepine pyrrolidines photo-thermal dyestuff E
The synthesis of compound E
A cleaning 50mL single port bottles are taken, the dichloro that magneton, 0.479g (0.5mmol) compounds 5,10mL are dried is added
Methane dissolves.0.44g is added at 0~5 DEG C, under nitrogen protection and newly steams triethylamine (4.4mmol), then is slowly added to dropwise
The halide complex (2.0mmol) of 1.29g platinum, is added dropwise, moves to and 6h is stirred at room temperature, and after reaction, concentrates, column chromatography is pure
Change, obtains 0.105g blue solids product (yield about 20%).
1H NMR(400MHz,CDCl3):δ=8.47 (d, J=8.8Hz, 2H), 8.32 (d, J=8.8Hz, 2H), 7.99
(d, J=4.8Hz, 1H), 7.62-7.58 (m, 4H), 7.48 (t, J=8.0Hz, 1H), 7.38-7.34 (m, 2H), 7.29 (t, J
=7.6Hz, 5H), 7.09 (d, J=8.8Hz, 1H), 6.90 (d, J=8.8Hz, 2H), 6.86-6.69 (m, 5H), 6.46 (t, J
=7.2Hz, 1H), 3.97-3.91 (m, 4H), 1.80-1.70 (m, 4H), 1.47-1.27 (m, 20H), 0.92-0.89 (m, 6H)
13C NMR(100MHz,CDCl3):δ (ppm)=167.22,160.52,160.19,158.69,150.05,
149.28,148.91,146.14,144.35,143.09,137.28,135.32,134.46,133.53,132.60,130.76,
127.67,127.40,126.86,122.82,122.00,119.50,117.43,113.82,112.97,78.27,68.11,
31.85,29.51,28.98,26.02,22.69,14.14.
Embodiment 4：The test of the molecular weight of compound C
A small amount of compound C is taken, with matrix mixing, then point sample, is measured with MALDI-TOF/TOF, such as Fig. 1,
The preliminary proof correctness of C molecules.
[m/e] (M, MALDI-TOF) theoretical value:1054.26 experiment value:1054.66.
Embodiment 5：The test of the molecular weight of compound D
A small amount of compound D is taken, with matrix mixing, then point sample, is measured with MALDI-TOF/TOF, such as Fig. 2,
The preliminary proof correctness of D molecules.
[m/e] (M, MALDI-TOF) theoretical value:1005.58 experiment value:1005.08.
Embodiment 6：The test of the molecular weight of compound E
A small amount of compound E is taken, with matrix mixing, then point sample, is measured with MALDI-TOF/TOF, such as Fig. 3,
The preliminary proof correctness of E molecules.
[m/e] (M, MALDI-TOF) theoretical value:1306.05 experiment value:1305.87
Embodiment 7:The nuclear-magnetism of compound C is tested
It takes compound C described in 0.5mg to be dissolved in 0.5mL deuterochloroforms, is tested through nuclear-magnetism, such as Fig. 4, further demonstrate C
The correctness of molecule.
1H NMR(400MHz,CDCl3):δ=8.45 (d, J=8.8Hz, 4H), 8.10 (dd, J=6.8,2.0Hz, 5H),
7.49 (t, J=8.4Hz, 1H), 7.41-7.30 (m, 9H), 7.21 (d, J=7.6Hz, 1H), 6.90-6.84 (m, 5H), 6.78
(t, J=8.4Hz, 1H), 6.62 (t, J=6.4Hz, 1H), 6.41 (t, J=6.0Hz, 1H), 3.99-3.91 (m, 4H), 1.80-
1.71(m,4H),1.46–1.29(m,20H),0.91–0.88(m,6H).
Embodiment 8:The nuclear-magnetism of compound D is tested
It takes compound D described in 0.5mg to be dissolved in 0.5mL deuterochloroforms, is tested through nuclear-magnetism, such as Fig. 5, further demonstrate D
The correctness of molecule.
1H NMR(400MHz,CDCl3):δ=7.79 (dd, J=3.6,7.2Hz, 4H), 7.69 (d, J=8.4Hz, 4H),
7.44-7.42 (m, 6H), 6.96 (d, J=8.8Hz, 4H), 4.02 (t, J=6.4Hz, 4H), 1.84-1.77 (m, 4H), 1.51-
1.28(m,20H),0.92-0.89(m,6H).
Embodiment 9:The nuclear-magnetism of compound E is tested
It takes compound D described in 0.5mg to be dissolved in 0.5mL deuterochloroforms, is tested through nuclear-magnetism, such as Fig. 6, further demonstrate E
The correctness of molecule.
1H NMR(400MHz,CDCl3):δ=8.47 (d, J=8.8Hz, 2H), 8.32 (d, J=8.8Hz, 2H), 7.99
(d, J=4.8Hz, 1H), 7.62-7.58 (m, 4H), 7.48 (t, J=8.0Hz, 1H), 7.38-7.34 (m, 2H), 7.29 (t, J
=7.6Hz, 5H), 7.09 (d, J=8.8Hz, 1H), 6.90 (d, J=8.8Hz, 2H), 6.86-6.69 (m, 5H), 6.46 (t, J
=7.2Hz, 1H), 3.97-3.91 (m, 4H), 1.80-1.70 (m, 4H), 1.47-1.27 (m, 20H), 0.92-0.89 (m, 6H)
Embodiment 10：The ultraviolet-visible spectrum of compound C is tested：
Configure the weak solution (10 of compound C described in embodiment 1-5M, dichloromethane are solvent), pipette chemical combination described in 2mL
The solution of object C carries out ultraviolet-visible luminous spectrum test in cuvette, as a result such as Fig. 7, spectrum normalized.
Embodiment 11：The ultraviolet-visible spectrum of compound D is tested：
Configure the weak solution (10 of compound D described in embodiment 2-5M, dichloromethane are solvent), pipette chemical combination described in 2mL
The solution of object D carries out ultraviolet-visible luminous spectrum test in cuvette, as a result such as Fig. 8, spectrum normalized.
Embodiment 12：The ultraviolet-visible spectrum of compound E is tested：
Configure the weak solution (10 of compound E described in embodiment 3-5M, dichloromethane are solvent), pipette chemical combination described in 2mL
The solution of object E carries out ultraviolet-visible luminous spectrum test in cuvette, as a result such as Fig. 9, spectrum normalized.
It can be seen that there is maximum near-infrared in wavelength for 690nm or so described compound C, D and E from the result of Fig. 7-9
Absorption value, and photostability is good.
Embodiment 13：The emission spectrum of compound C is tested：
Configure the weak solution (10 of the compound C in embodiment 1-5M, dichloromethane are solvent), it pipettes and changes described in 2mL
The solution for closing object C carries out emission spectrum test in cuvette.As a result such as Figure 10, spectrum normalized.
Embodiment 14：The emission spectrum of compound D is tested：
Configure the weak solution (10 of the compound D in embodiment 2-5M, toluene are solvent), pipette compound described in 2mL
The solution of D carries out emission spectrum test in cuvette.As a result such as Figure 11, spectrum normalized.
Embodiment 15：The emission spectrum of compound E is tested：
Configure the weak solution (10 of the compound E in embodiment 3-5M, dichloromethane are solvent), it pipettes and changes described in 2mL
It closes object E solution and carries out emission spectrum test in cuvette.As a result such as Figure 12, spectrum normalized.
As can be seen that described compound C, D and E have emission maximum value, explanation in wavelength 740nm or so on from Figure 10-12
The compound that the present invention prepares can single laser excitation, and be near infrared light excitation, autofluorescence can be reduced to detection signal
Interference reduces injury of the excitation light source to tissue, and can enhance penetration depth of the light source to tissue.
Embodiment 16：The light power effect of compound C
The compound C in embodiment 1 is dissolved with dichloromethane, and singlet oxygen indicator (DPBF) is added, is used
690nm laser illuminations record the variation of the absorbance of different irradiation time solution with uv-visible absorption spectra instrument, thus
Reflection generates the amount and its rate of singlet oxygen.Show to extend with irradiation time by Figure 13, the amount of singlet oxygen indicator by
Decrescence few, i.e. the content of singlet oxygen increases successively.
Embodiment 17：The light power effect of compound D
The compound D in embodiment 2 is dissolved with dichloromethane, and singlet oxygen indicator (DPBF) is added, is used
690nm laser illuminations record the variation of the absorbance of solution under different irradiation times with uv-visible absorption spectra instrument, by
This reflection generates the amount and its rate of singlet oxygen.Show to extend with irradiation time by Figure 14, the amount of singlet oxygen indicator
It gradually decreases, i.e. the content of singlet oxygen increases successively.
Embodiment 18：The light power effect of compound E
The compound E in embodiment 3 is dissolved with dichloromethane, and singlet oxygen indicator (DPBF) is added, is used
690nm laser illuminations are recorded with uv-visible absorption spectra instrument under different irradiation times, the variation of solution absorbance, thus
Reflection generates the amount and its rate of singlet oxygen.Show to extend with irradiation time by Figure 15, the amount of singlet oxygen indicator by
Decrescence few, both the content of singlet oxygen increased successively.
Embodiment 19：The photo-thermal effect of compound C, D, E
Described compound C, D, E in embodiment 1-3 is dissolved with dichloromethane respectively, with 690nm 0.5W cm-2Laser
Device irradiates, and is recorded under different irradiation times with light thermal imaging system, the variation of solution temperature, thus reflects photothermal conversion effect.By
Figure 16 shows to extend with irradiation time, and solution temperature gradually increases, and after 5min, the temperature change of E solution is more than C, D
Temperature change.That is the introducing of multi-metal and halogen enhances the photo-thermal effect of material.
Embodiment 20：Photo-thermal effects of the compound E in mouse body
By the compound E dmso solutions in embodiment 3, respectively by 50 μ L, 20 μM of compound E's
In dimethyl sulphoxide solution and 50 μ L PBS (pH=7.4) solution intratumor injection mouse tumours.With 690nm 0.5W cm-2Laser
Device irradiate 7min, recorded under different irradiation times with light thermal imaging system, the variation of tumor locus temperature, by Figure 17 show with
Irradiation time extends, and the mouse tumor locus temperature for injecting the compound E gradually increases, and after 5min, temperature is up to 55 DEG C,
And the mouse tumor locus for injecting PBS does not have apparent temperature change, shows that the compound E has good photo-thermal effect,
It can be used for the oncotherapy of mouse.
The basic principles and main features and advantage of the present invention have been shown and described above.But the foregoing is merely this hairs
Bright specific embodiment, technical characteristic of the invention are not limited thereto, and any those skilled in the art is not departing from this hair
The other embodiment obtained under bright technical solution should all cover among the scope of the claims of the present invention.
Claims (7)
1. a kind of azepine pyrrolidines dyestuff, which is characterized in that the general structure of the dyestuff is as follows：
Wherein, R1、R2One kind in having structure：
M=Pt, Zn, Ni or Mg；A^B is C^N ligands or N^N ligands；X=Br or I；
Wherein, R3For straight chain, branch or cyclic alkyl chain with 0 to 16 carbon atom；
C^N ligands and N^N ligands are any of having structure：
2. a kind of preparation method of azepine pyrrolidines dyestuff as described in claim 1, which is characterized in that specific synthetic route is such as
Under：
3. a kind of preparation method of azepine pyrrolidines dyestuff as claimed in claim 2, which is characterized in that specific synthesis step
For：
1) synthesis of ketenes：Compound 1 is reacted into 10-15h with compound 2 in dilute sodium hydroxide and alcohol mixed solution
Afterwards, for the acid-base value of dilute hydrochloric acid adjusting reaction solution to pH value between 4~7, filtering, is dried to obtain product 3 at the washing of cold ethyl alcohol；
2) addition reaction：Under the conditions of nitrogen protection, the product 3, nitromethane and diethylamine are dissolved in absolute methanol, added
Heat reflux 16-28h, with dilute hydrochloric acid adjust reaction solution acid-base value to pH value between 5~7, filtering, cold methanol washing three times,
It is dry, obtain product 4；
3) annulation：The product 4 is heated to reflux 20-30h under magnetic stirring in butanol solution with ammonium acetate, concentration
Postcooling obtains product 5 to room temperature, filtering, the washing of cold ethyl alcohol；
4) substitution reaction：In anhydrous methylene chloride solution, the product 5 and propiodal or bromine source are subjected to being protected from light under room temperature
20-30h is reacted, is dried under reduced pressure, product 6 is obtained by column chromatography；
5) complexation reaction：The product 6 is dissolved in dry methylene chloride solution, three second of new steaming are added under nitrogen protection
The halide complex of metal is added dropwise in amine later, and after 6-12h is stirred at room temperature, concentration is obtained after adding water to filter by column chromatography
To product E.
4. application of the azepine pyrrolidines dyestuff as claimed in any one of claims 1-3 in photothermal imaging.
5. application of the azepine pyrrolidines dyestuff as claimed in any one of claims 1-3 in photoacoustic imaging.
6. application of the azepine pyrrolidines dyestuff as claimed in any one of claims 1-3 in the optical dynamic therapy of tumour.
7. application of the azepine pyrrolidines dyestuff as claimed in any one of claims 1-3 in the photo-thermal therapy of tumour.
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