CN114736200A - 一类基于硫代五甲川菁染料的无重原子三重态光敏剂、其制备方法和应用 - Google Patents
一类基于硫代五甲川菁染料的无重原子三重态光敏剂、其制备方法和应用 Download PDFInfo
- Publication number
- CN114736200A CN114736200A CN202210282908.0A CN202210282908A CN114736200A CN 114736200 A CN114736200 A CN 114736200A CN 202210282908 A CN202210282908 A CN 202210282908A CN 114736200 A CN114736200 A CN 114736200A
- Authority
- CN
- China
- Prior art keywords
- triplet
- solid
- dye
- tcy5
- heavy atom
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003504 photosensitizing agent Substances 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 claims abstract description 25
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 24
- 210000004027 cell Anatomy 0.000 claims abstract description 18
- 238000002428 photodynamic therapy Methods 0.000 claims abstract description 16
- 206010021143 Hypoxia Diseases 0.000 claims abstract description 10
- 230000001146 hypoxic effect Effects 0.000 claims abstract description 7
- 230000005284 excitation Effects 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 50
- 239000007787 solid Substances 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- DXYYSGDWQCSKKO-UHFFFAOYSA-N 2-methylbenzothiazole Chemical compound C1=CC=C2SC(C)=NC2=C1 DXYYSGDWQCSKKO-UHFFFAOYSA-N 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- -1 cyano, amino, carboxyl Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical class O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 229940118019 malondialdehyde Drugs 0.000 claims description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000003172 aldehyde group Chemical group 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 3
- 210000003463 organelle Anatomy 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
- 229930192474 thiophene Natural products 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000005577 anthracene group Chemical group 0.000 claims description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 238000002648 combination therapy Methods 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 238000004020 luminiscence type Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical class [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 230000004700 cellular uptake Effects 0.000 claims 1
- 238000003745 diagnosis Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 230000010354 integration Effects 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 13
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- 238000006862 quantum yield reaction Methods 0.000 abstract description 7
- 230000005281 excited state Effects 0.000 abstract description 5
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 5
- 210000003470 mitochondria Anatomy 0.000 abstract description 5
- 230000008033 biological extinction Effects 0.000 abstract description 2
- 230000008685 targeting Effects 0.000 abstract description 2
- 239000000975 dye Substances 0.000 description 26
- 239000000243 solution Substances 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 238000010521 absorption reaction Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000013461 design Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000012737 fresh medium Substances 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000007954 hypoxia Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000002932 luster Substances 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- RUVJFMSQTCEAAB-UHFFFAOYSA-M 2-[3-[5,6-dichloro-1,3-bis[[4-(chloromethyl)phenyl]methyl]benzimidazol-2-ylidene]prop-1-enyl]-3-methyl-1,3-benzoxazol-3-ium;chloride Chemical compound [Cl-].O1C2=CC=CC=C2[N+](C)=C1C=CC=C(N(C1=CC(Cl)=C(Cl)C=C11)CC=2C=CC(CCl)=CC=2)N1CC1=CC=C(CCl)C=C1 RUVJFMSQTCEAAB-UHFFFAOYSA-M 0.000 description 2
- 101100377855 Artemia franciscana ABDA gene Proteins 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- CEFVCNWQCJCMHZ-UHFFFAOYSA-N 2-(bromomethyl)furan Chemical compound BrCC1=CC=CO1 CEFVCNWQCJCMHZ-UHFFFAOYSA-N 0.000 description 1
- QZOBOLDDGXPTBP-UHFFFAOYSA-N 2-(bromomethyl)thiophene Chemical compound BrCC1=CC=CS1 QZOBOLDDGXPTBP-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- XJHABGPPCLHLLV-UHFFFAOYSA-N benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(=O)NC2=O)=C3C2=CC=CC3=C1 XJHABGPPCLHLLV-UHFFFAOYSA-N 0.000 description 1
- 238000012984 biological imaging Methods 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-N bromoacetic acid Chemical compound OC(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-N 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000031857 establishment of mitochondrion localization Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000025608 mitochondrion localization Effects 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000007959 normoxia Effects 0.000 description 1
- 230000030589 organelle localization Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- 238000007146 photocatalysis Methods 0.000 description 1
- 230000001443 photoexcitation Effects 0.000 description 1
- 238000010248 power generation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/0008—Methine or polymethine dyes, e.g. cyanine dyes substituted on the polymethine chain
-
- 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
- C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
- C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
- C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
- C09B23/083—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines five >CH- groups
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
- C09K2211/1037—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom with sulfur
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1092—Heterocyclic compounds characterised by ligands containing sulfur as the only heteroatom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E10/00—Energy generation through renewable energy sources
- Y02E10/50—Photovoltaic [PV] energy
- Y02E10/542—Dye sensitized solar cells
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类基于硫代五甲川菁染料的无重原子三重态光敏剂、其制备方法和应用。其属于高效三重态光敏剂技术领域。通过在硫代五甲川菁染料上连接相应的杂环或活性基团不仅充分发挥菁染料本身摩尔消光系数大、合成简洁、荧光发射强、生物相容性好等优点;更有效促进了单重态到三重态的系间窜越,所述无重原子三重态光敏剂可以同时拥有中等荧光发射、超长的三重激发态寿命和高的单线态氧量子产率。同时该类光敏剂具有良好的水溶性和线粒体靶向,可以实现近红外光激发下的常氧/乏氧细胞和活体肿瘤的光动力治疗,具有良好的生命科学领域应用前景。
Description
技术领域
本发明涉及一种高效三重态光敏剂,特别涉及一类基于硫代五甲川菁染料的无重原子三重态光敏剂、其制备方法和应用。
背景技术
三重态光敏剂是指被光激发后能够通过系间窜越产生三重态的一类化合物。具有长寿命三重态激发态的光敏剂更有利于电子转移或能量转移来充分利用三重态性质,可广泛应用于光动力治疗(PDT)、光催化、三重态-三重态湮灭(TTA)上转换、和光伏发电等,在能源和生命科学领域有良好的应用前景。为了实现高效的系间窜越,利用分子设计策略来构建能够有效产生三重态的化合物成为该领域的研究热点。目前,利用重原子效应仍然是最方便、最有效的方法,但生物毒性大和三重态寿命短等缺点极大限制了三重态能量的进一步应用于其他领域。相反,无重原子三重态光敏剂可以在不受重原子效应影响下获得长三重态寿命。然而,分子结构与系间窜越性质之间的关系还没有完全明确的规律,系统地设计高效的无重原子三重态光敏剂仍然是一个挑战。
目前,一些不依赖于重原子且可以有效促进系间窜越的策略已经被开发出来,并且已成功应用于萘酰亚胺、芘、氟硼吡咯等染料中,但是一般难以克服荧光量子产率低、合成路线复杂、吸收波长处于可见区、三重态寿命短、结构高度疏水等缺点。菁染料具有合成简洁、近红外吸收可调、荧光量子产率高、生物相容性好等优点,由于不具备三重态性质起初被广泛应用于荧光探针中。为了设计适用于光动力治疗的三重态光敏剂,选择本身性质优异的菁染料进行合理修饰是一条新的途径。目前对于菁染料的分子设计均选择在共轭链中位进行修饰,这大大限制了光敏剂的发展,迫切需要一系列新的分子来指导无重原子三重态光敏剂的设计。
光动力治疗作为一种新兴的癌症治疗手段被广泛研究,其主要原理是使无毒的光敏剂进入目标靶点,随后利用与之匹配的光照激发光敏剂产生具有细胞毒性的活性氧物质来破坏病变组织,从而达到治疗的目的。然而,目前使用的光敏剂仍然存在许多缺陷,理想的光敏剂至少需要具备以下性质:1.在近红外区拥有优异的光子捕获能力;2.高的活性氧量子产率和长的三重激发态寿命;3.良好的生物相容性、光稳定性和适宜的水溶性;4重要的亚细胞器(线粒体、内质网等)定位性和肿瘤靶向性。至今,具有以上所有优点的三重态光敏剂尚未开发问世。
发明内容
针对菁染料在三重态光敏剂方面技术的不足,本发明公开了一类基于硫代五甲川菁染料的无重原子三重态光敏剂,该类光敏剂在生命科学领域,尤其是光动力治疗方面具有良好的应用前景。首先根据菁染料确定的中位基团和苯环上的功能基团确定荧光发射和近红外吸收波长,进一步通过在硫代五甲川菁染料上连接不同杂环进行修饰有效限制了非辐射跃迁,在尽可能不改变荧光发射和近红外吸收波长的情况下,增强了系间窜越并延长了三重态寿命。此类分子具有良好的水溶性、线粒体定位性和光稳定性,能够在近红外光激发下产生活性氧,进行癌细胞或活体肿瘤的光动力治疗。
本发明第一方面提供了一类基于硫代五甲川菁染料的无重原子三重态光敏剂,其如结构通式I所示:
通式中:
X为:Cl、Br、I中的一种;
R1、R2各自独立的选自H、甲基、甲氧基、F、Cl、氰基、氨基、羧基、硝基、磺酸基中的一种;
R3、R4各自独立的选自-CmH2m-R6中的一种,其中m选自1-5的整数,包括1、2、3、4、5,更优选地,m=1-3;
R6选自呋喃基、噻吩基、异噁唑基、异噻唑基、吡唑基、噁唑基、噻唑基、咪唑基、哒嗪基、嘧啶基、吡嗪基、苯并呋喃基、苯并噻唑基、吲哚基、喹啉基、异喹啉基、嘌呤基、噻吩[3,2-b]并噻吩基、带有单个或多个二级取代基的上述基团衍生结构中的一种;
R5选自醛基、苯基、萘基、蒽基、带有单个或多个二级取代基的上述基团衍生结构中的一种;
本发明第二方面在于保护一类基于硫代五甲川菁染料的无重原子三重态光敏剂的制备方法,包括如下合成步骤:
步骤S2:0-5℃下,将三氯氧磷滴加到DMF中,搅拌1-4小时,随后加入溴乙酸,加热至80℃-100℃反应完全后,进行相应的后处理获得固体1即为R5取代基的丙二醛;其中,后处理分为两种情况:当S2加入时,向反应液中加入饱和NaClO4溶液直至产生沉淀获得固体,随后将固体溶解于NaOH并用盐酸将溶液调至酸性pH=1-3可得固体1;当S2加入溴乙酸时,向反应液中加入乙醇和高氯酸直至产生沉淀获得固体2,随后将固体2溶解于甲醇并用NaOH调pH=11-14得固体3,将固体3溶于二氯甲烷中并用盐酸调pH=1-3,最后利用二氯甲烷萃取并旋干获得固体1;
步骤S3:将相应的2-甲基苯并噻唑衍生物季铵盐和带有R5取代基的丙二醛混合于溶剂II,添加催化剂后升温至50-100℃反应完全后,通过柱层析纯化,除去溶剂后获得硫代五甲川菁染料。
进一步优选的情况下,所述步骤S1中的2-甲基苯并噻唑衍生物与卤代烷基衍生物摩尔比为1:1-10;更为优选的是1-4。
进一步优选的情况下,所述步骤S1中的溶剂I为乙腈、乙醇、甲苯、二甲苯中的至少一种。
进一步优选的情况下,所述步骤S2中的三氯氧磷和乙酸衍生物的摩尔比为2-8:1。
进一步优选的情况下,所述步骤S3中的2-甲基苯并噻唑衍生物季铵盐与带有R5取代基的丙二醛摩尔比为1-4:1。
进一步优选的情况下,所述步骤S3中的溶剂为乙醇、甲醇、乙酸酐、乙酸中的至少一种。
进一步优选的情况下,所述步骤S3中的催化剂为吡啶、哌啶、醋酸钠、碳酸钾中的至少一种;步骤S3中的催化剂与带有R5取代基的丙二醛摩尔比为3-20:1。
进一步优选的情况下,所述步骤S3中柱层析纯化的洗脱剂配比为甲醇与二氯甲烷按体积比1:5-100。
本发明第三方面在于保护一类基于硫代五甲川菁染料的无重原子三重态光敏剂的应用,主要涉及生命科学领域。
进一步优选的情况下,所述应用包括在生物成像、近红外发光、联合治疗或光动力治疗等方面中的应用。
这类基于硫代五甲川菁染料的无重原子三重态光敏剂具有优异的水溶性,能够被细胞快速摄取并定位于亚细胞器(普遍为线粒体)中,在近红外光激发下产生活性氧物质,并进一步诱导细胞凋亡。良好的生物相容性和优异的三重态性质展现了生命科学领域方面优异的应用前景。
与现有技术相比,本发明具有下列有益效果:
目前,基于菁染料的三重态光敏剂开发仍然普遍采用重原子效应,难以获得具有优异生物应用前景的三重态性质。少数基于菁染料的无重原子三重态光敏剂的分子设计通常在于共轭链中位进行修饰,这容易显著改变分子的光谱性质,尤其是由于荧光发射与三重态产生是竞争关系,因此通常难以同时保证。本发明首先选择优异的中位基团来确定良好的近红外吸收和荧光发射,并进一步通过在硫代五甲川菁染料侧链进行合理修饰有效改善了其三重态性质,从而在光动力治疗中充分发挥菁染料本身摩尔消光系数大、合成简洁、荧光发射强、生物相容性好等优点。更为重要的是,修饰前后,三重态性质有了质的改变,系间窜越从无到有,并且具有优异的系间窜越效率,单线态氧量子产率最高能够接近90%;三重激发态寿命对于普通三重态光敏剂提升2-3个数量级,即使对比其他无重原子三重态光敏剂也有4-5倍的提升。该类分子由于优异的水溶性,能够不依赖于纳米粒子直接进行细胞或活体的光动力治疗,并且获得了优异的细胞杀伤和肿瘤抑制效果,肿瘤抑制率达到85%。
附图说明
图1为本发明实施例TCy5-S、TCy5-O和对比例TCy5-Et在二氯甲烷中的紫外吸收光谱;
图2为本发明实施例TCy5-S、TCy5-O和对比例TCy5-Et在二氯甲烷中的荧光发射光谱;
图3为本发明实施例TCy5-S、TCy5-O和对比例TCy5-Et在水中的单线态氧捕获剂ABDA的紫外吸收衰减曲线;
图4为本发明实施例TCy5-S、TCy5-O和对比例TCy5-Et的三线态寿命测试图;
图5为本发明实施例TCy5-S在MCF-7细胞中的线粒体定位图;
图6为本发明实施例TCy5-S对MCF-7细胞在常氧或乏氧条件下的细胞毒性测试数据图;
图7为不同实验组在活体肿瘤光动力治疗实验中的肿瘤体积变化曲线;
图8为不同实验组在活体肿瘤光动力治疗实验中的小鼠体重变化曲线。
具体实施方式
结合附图,下面对本发明的具体实施方式进行详细地描述,但应当理解本发明的保护范围并不受具体实施方式的限制。
除非另有说明,本发明使用的原料均可通过市售获得,或者可通过本领域技术人员公知的方法简单制备得到。
实施例1
本实施例为光敏剂TCy5-S的制备方法,包括如下步骤:
步骤1:2-甲基苯并噻唑季铵盐的合成
将2-甲基苯并噻唑(10mmol)与2-溴甲基噻吩(10mmol)溶解于乙腈(15mL)中,随后升温至80℃搅拌过夜。反应完全后,冷却至0℃并用乙醚洗涤,可得纯度足够的固体产物(7.5mmol,产率75%)。
步骤2:合成中间体丁三醛
将溴乙酸(60mmol)加入到DMF(30mL)中,随后在冰浴下缓慢滴加POCl3(200mmol)并搅拌3h。将冰浴换成油浴后,继续在90℃下搅拌过夜。反应完成后,在冰浴下加入乙醇(25mL)、水(3mL)和高氯酸(16mL),溶液析出固体。将固体混合于甲醇(48mL)中,搅拌下缓慢加入NaOH颗粒,溶液先变为澄清再变为浑浊,收集固体溶解于二氯甲烷中,并用盐酸调pH至1。最后,利用二氯甲烷萃取并旋干溶剂所得固体即为丁三醛(40mmol,产率67%)。
步骤3:硫代五甲川菁染料的合成
将2-甲基苯并噻唑季铵盐(0.5mmol)和丁三醛(0.25mmol)溶解于乙醇(15mL)中,随后加入一滴吡啶并升温至65℃反应。利用薄层色谱法检测反应进程,直至产物不再增加时,减压除去溶剂,并用柱层析(MeOH:DCM=1:5-100)纯化可得带金属光泽的产物即为侧链为噻吩、中位为醛基的硫代五甲川菁染料TCy5-S。
实施例2
本实施例为光敏剂TCy5-O的制备方法,包括如下步骤:
步骤1:2-甲基苯并噻唑季铵盐的合成
将2-甲基苯并噻唑(10mmol)与2-溴甲基呋喃(10mmol)溶解于乙腈(15mL)中,随后升温至70℃搅拌过夜。反应完全后,冷却至0℃并用乙醚洗涤,可得纯度足够的固体产物(9mmol,产率90%)。
步骤2:合成中间体丁三醛
将溴乙酸(60mmol)加入到DMF(30mL)中,随后在冰浴下缓慢滴加POCl3(200mmol)并搅拌3h。将冰浴换成油浴后,继续在90℃下搅拌过夜。反应完成后,在冰浴下加入乙醇(25mL)、水(3mL)和高氯酸(16mL),溶液析出固体。将固体混合于甲醇(48mL)中,搅拌下缓慢加入NaOH颗粒,溶液先变为澄清再变为浑浊,收集固体溶解于二氯甲烷中,并用盐酸调pH至3。最后,利用二氯甲烷萃取并旋干溶剂所得固体即为丁三醛(40mmol,产率67%)。
步骤3:硫代五甲川菁染料的合成
将2-甲基苯并噻唑季铵盐(0.5mmol)和丁三醛(0.25mmol)溶解于乙醇(15mL)中,随后加入一滴吡啶并升温至65℃反应。利用薄层色谱法检测反应进程,直至产物不再增加时,减压除去溶剂,并用柱层析(MeOH:DCM=1:5-100)纯化可得带金属光泽的产物即为侧链为呋喃、中位为醛基的硫代五甲川菁染料TCy5-O。
对比例1
本实施例为光敏剂TCy5-Et的制备方法,包括如下步骤:
步骤1:2-甲基苯并噻唑季铵盐的合成
将2-甲基苯并噻唑(10mmol)与碘乙烷(30mmol)溶解于乙腈(15mL)中,随后升温至80℃搅拌过夜。反应完全后,冷却至0℃并用乙醚洗涤,可得纯度足够的固体产物(5mmol,产率50%)。
步骤2:合成中间体丁三醛
将溴乙酸(60mmol)加入到DMF(30mL)中,随后在冰浴下缓慢滴加POCl3(200mmol)并搅拌3h。将冰浴换成油浴后,继续在90℃下搅拌过夜。反应完成后,在冰浴下加入乙醇(25mL)、水(3mL)和高氯酸(16mL),溶液析出固体。将固体混合于甲醇(48mL)中,搅拌下缓慢加入NaOH颗粒,溶液先变为澄清再变为浑浊,收集固体溶解于二氯甲烷中,并用盐酸调pH至2。最后,利用二氯甲烷萃取并旋干溶剂所得固体即为丁三醛(40mmol,产率67%)。
步骤3:硫代五甲川菁染料的合成
将2-甲基苯并噻唑季铵盐(0.5mmol)和丁三醛(0.25mmol)溶解于乙醇(15mL)中,随后加入一滴吡啶并升温至65℃反应。利用薄层色谱法检测反应进程,直至产物不再增加时,减压除去溶剂,并用柱层析(MeOH:DCM=1:5-100)纯化可得带金属光泽的产物即为侧链为乙基、中位为醛基的硫代五甲川菁染料TCy5-Et。
效果例1
光敏剂TCy5-S、TCy5-O、TCy5-Et的光谱测试:
将TCy5-S、TCy5-O、TCy5-Et分别溶解于二氯甲烷中,分别测试相应的紫外吸收和荧光发射谱图。
如紫外吸收谱图(图1)所示,TCy5-S、TCy5-O、TCy5-Et具有相似覆盖500-700nm的紫外吸收带,最大吸收波长为620nm,与600-800nm的“治疗窗口”重叠,表明侧链连接杂环不会影响其最大吸收波长。
效果例2
光敏剂TCy5-S、TCy5-O、TCy5-Et的单线态氧产生能力测试:
将光敏剂TCy5-S加入到含有3mL水溶液的石英皿中,并加入一定量的ABDA使其380nm处的吸光度约等于1。随后,利用近红外光(630nm,10mW/cm2)照射测试石英皿,每隔1分钟测试一次紫外吸收。TCy5-O和TCy5-Et的单线态氧产生能力测试操作同TCy5-S,测试结果整理如图3所示。
根据图3,按照相关计算公式可得TCy5-S、TCy5-O、TCy5-Et在水溶液中的单线态氧量子产率分别为50%,28%,2%。相比于对比例1的TCy5-Et,TCy5-S和TCy5-O的单线态氧量子产率有一个明显的提升(分别提高25倍和14倍),说明在菁染料的侧链进行非共轭连接杂环可以有效促进化合物的系间窜越。
效果例3
光敏剂TCy5-S、TCy5-O、TCy5-Et的三线态寿命测试:
用574nm激光脉冲(1Hz,100mJ/脉冲,fwhm≈7ns)在室温下激发脱氧DCM中的TCy5-S、TCy5-O、TCy5-Et,在620nm处测量了瞬态物质的衰减轨迹。
如图4所示,TCy5-S具有超长的三线态寿命,高达472.4μs,这即使在无重原子三重态光敏剂中都是十分难得的,有利于克服肿瘤乏氧微环境,从而充分发挥TCy5-S的光动力治疗潜力。并且,TCy5-S和TCy5-O的三线态寿命相比于不进行侧链杂环修饰的TCy5-Et均有一个倍数级别的提升,说明了该系列分子的有效性。
效果例4
光敏剂TCy5-S的亚细胞器定位实验:
当MCF-7细胞密度在共聚焦培养皿中达到80%左右时,利用共聚焦激光扫描显微镜(CLSM)进行线粒体共定位实验。首先用PBS清洗培养皿3次,然后加入2mL新鲜培养基、2μLTCy5-S(1mM)和线粒体绿色荧光探针(Mito-Tracker Green)。培养皿置于培养箱中孵育30分钟,倒掉培养基,用PBS清洗3次后添加新鲜培养基。最后,使用CLSM进行细胞荧光成像。
如图5所示,TCy5-S的红色荧光与Mito-Tracker Green的绿色荧光很好的重叠,皮尔森相关系数达到0.965,表示TCy5-S进入细胞后可以很好的定位于线粒体。线粒体是细胞重要的能量工厂,定位于线粒体有利于后续的光动力治疗。
效果例5
光敏剂TCy5-S在常氧或乏氧条件下对MCF-7的细胞毒性实验:
将MCF-7细胞接种于96孔板中,置于培养箱中培养1-2天。当细胞密度达到90%左右时,在孔中加入100μL含不同浓度TCy5-S的新鲜培养基,浓度分别为2.5、1.25、0.63、0.31、0.16、0.08、0.04、0.02和0μM。在常氧或乏氧条件下,将细胞孵育2小时后光照(630nm,20mW/cm2)10分钟,再孵育12小时。上述治疗后,将原先培养基更换为含有MTT(0.5mg/mL)的新鲜培养基并放置在培养箱中进一步培养4小时。最后,向每孔中加入100μL DMSO溶解甲臜晶体。最后,用酶标仪测定各孔在570nm(OD)和630nm(ODK)下的吸光度,并按照相关公式计算细胞存活率。每次向孔中加入新溶液前,用棉花将之前的溶液从孔中除去。
如图6所示,TCy5-S在常氧和乏氧条件下均能对细胞造成杀伤,并且IC50低至0.25μM(常氧)和0.47μM(乏氧),这表明高的单线态氧量子产率和长的三重激发态寿命使TCy5-S具有克服缺氧限制的肿瘤光动力治疗能力。
效果例6
光敏剂TCy5-S的活体肿瘤光动力治疗实验:
预先扩增4T1细胞,选择雌性小鼠腋窝部位皮下注射含5×106个4T1细胞的100μLPBS建立4T1肿瘤模型。肿瘤体积增大到200mm3后,将4T1荷瘤小鼠随机分为4组,每组3只。按组给予相应处理:(1)PBS-暗组:小鼠原位注射100μL PBS;(2)PBS-光组:小鼠原位注射100μL PBS,1小时后用近红外光源(630nm,50mW/cm2)照射15分钟;(3)TCy5-S-暗组:小鼠原位注射100μL含TCy5-S(50μM)的PBS;(4)TCy5-S-光组:小鼠原位注射100μL含TCy5-S(50μM)的PBS,1小时后用近红外光源(630nm,50mW/cm2)照射15分钟。每隔2天测量肿瘤的长度、宽度和小鼠的体重,根据以下公式计算:肿瘤体积=(宽度×宽度×长度)/2。
如图7所示,仅注射了TCy5-S且光照的小鼠肿瘤体积维持在可控范围,而其他组别小鼠的肿瘤均生长至初始体积的12倍以上。这证明了TCy5-S能在近红外光激发下产生单线态氧,从而有效抑制乏氧肿瘤生长。
如图8所示,活体肿瘤光动力治疗实验过程中,各组别小鼠体重均无异常变化,说明TCy5-S良好的生物相容性。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,本领域的技术人员在本发明披露的技术范围内,可轻易想到的变化或替换,都应涵盖在本发明的保护范围之内。因此,本发明的保护范围应该以权利要求书的保护范围为准。
Claims (10)
1.一类基于硫代五甲川菁染料的无重原子三重态光敏剂,其特征在于,所述染料结构如通式Ⅰ所示:
通式中:
X选自Cl、Br、I中的一种;
R1、R2各自独立的选自H、甲基、甲氧基、F、Cl、氰基、氨基、羧基、硝基、磺酸基中的一种;
R3、R4各自独立的选自-CmH2m-R6中的一种,其中m选自1-5的整数;
R6选自呋喃基、噻吩基、异噁唑基、异噻唑基、吡唑基、噁唑基、噻唑基、咪唑基、哒嗪基、嘧啶基、吡嗪基、苯并呋喃基、苯并噻唑基、吲哚基、喹啉基、异喹啉基、嘌呤基、噻吩[3,2-b]并噻吩基、带有单个或多个二级取代基的上述基团衍生结构中的一种;
R5选自醛基、苯基、萘基、蒽基、带有单个或多个二级取代基的上述基团衍生结构中的一种。
2.根据权利要求1所述的一类基于硫代五甲川菁染料的无重原子三重态光敏剂的制备方法,其特征在于,该方法包括如下合成步骤:
步骤S2:0-5℃下,将三氯氧磷滴加到DMF中,搅拌1-4小时,随后加入或溴乙酸,加热至80℃-100℃反应完全后,进行相应的后处理获得固体1即为R5取代基的丙二醛;其中,后处理分为两种情况:当S2加入时,向反应液中加入饱和NaClO4溶液直至产生沉淀获得固体,随后将固体溶解于NaOH并用盐酸将溶液调至酸性pH=1-3可得固体1;当S2加入溴乙酸时,向反应液中加入乙醇和高氯酸直至产生沉淀获得固体2,随后将固体2溶解于甲醇并用NaOH调pH=11-14得固体3,将固体3溶于二氯甲烷中并用盐酸调pH=1-3,最后利用二氯甲烷萃取并旋干获得固体1;
步骤S3:将相应的2-甲基苯并噻唑衍生物季铵盐和带有R5取代基的丙二醛混合于溶剂II,添加催化剂后升温至50-100℃反应完全后,通过柱层析纯化,除去溶剂后获得硫代五甲川菁染料。
3.根据权利要求2所述的制备方法,其特征在于,所述步骤S1中的2-甲基苯并噻唑衍生物与卤代烷基衍生物摩尔比为1:1-10;所述步骤S3中的溶剂II为乙醇、甲醇、乙酸酐、乙酸中的至少一种。
4.根据权利要求2所述的制备方法,其特征在于,所述步骤S1中的溶剂I为乙腈、乙醇、甲苯、二甲苯中的至少一种。
5.根据权利要求2所述的制备方法,其特征在于,所述步骤S2中的三氯氧磷和乙酸衍生物的摩尔比为2-8:1。
6.根据权利要求2所述的制备方法,其特征在于,所述步骤S3中的2-甲基苯并噻唑衍生物季铵盐与带有R5取代基的丙二醛摩尔比为1-4:1。
7.根据权利要求2所述的制备方法,其特征在于,所述步骤S3中的催化剂为吡啶、哌啶、醋酸钠、碳酸钾中的至少一种;步骤S3中的催化剂与带有R5取代基的丙二醛摩尔比为3-20:1。
8.如权利要求1所述的一类基于硫代五甲川菁染料的无重原子三重态光敏剂在生命科学方面的应用。
9.根据权利要求8所述的应用,其特征在于,所述应用包括在生物成像、近红外发光、联合治疗或光动力治疗中的应用。
10.根据权利要求8所述的应用,其特征在于,所述基于硫代五甲川菁染料的无重原子三重态光敏剂用于细胞快速摄取并富集于亚细胞器;或在诊疗一体化中的应用、或在近红外光激发下的常氧/乏氧癌细胞或活体肿瘤的光动力治疗及配合其他药物进行联合治疗中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210282908.0A CN114736200A (zh) | 2022-03-22 | 2022-03-22 | 一类基于硫代五甲川菁染料的无重原子三重态光敏剂、其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210282908.0A CN114736200A (zh) | 2022-03-22 | 2022-03-22 | 一类基于硫代五甲川菁染料的无重原子三重态光敏剂、其制备方法和应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN114736200A true CN114736200A (zh) | 2022-07-12 |
Family
ID=82277309
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210282908.0A Pending CN114736200A (zh) | 2022-03-22 | 2022-03-22 | 一类基于硫代五甲川菁染料的无重原子三重态光敏剂、其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114736200A (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103382189A (zh) * | 2012-12-28 | 2013-11-06 | 大连理工大学 | 一类菁类化合物、其制备方法及应用 |
WO2018206126A1 (en) * | 2017-05-08 | 2018-11-15 | Vysoká škola chemicko-technologická v Praze | Imaging agents and methods |
CN113384695A (zh) * | 2021-05-03 | 2021-09-14 | 大连理工大学 | 具有长激发态寿命的五甲川菁染料类光敏染料、其制备方法和应用 |
CN113773666A (zh) * | 2021-08-11 | 2021-12-10 | 大连理工大学 | 一类三线态系间窜越菁染料、其制备方法及应用 |
-
2022
- 2022-03-22 CN CN202210282908.0A patent/CN114736200A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103382189A (zh) * | 2012-12-28 | 2013-11-06 | 大连理工大学 | 一类菁类化合物、其制备方法及应用 |
WO2018206126A1 (en) * | 2017-05-08 | 2018-11-15 | Vysoká škola chemicko-technologická v Praze | Imaging agents and methods |
CN113384695A (zh) * | 2021-05-03 | 2021-09-14 | 大连理工大学 | 具有长激发态寿命的五甲川菁染料类光敏染料、其制备方法和应用 |
CN113773666A (zh) * | 2021-08-11 | 2021-12-10 | 大连理工大学 | 一类三线态系间窜越菁染料、其制备方法及应用 |
Non-Patent Citations (1)
Title |
---|
MA,HE 等: "New Cy5 photosensitizers for cancer phototherapy: a low singlet-triplet gap provides high quantum yield of singlet oxygen", CHEMICAL SCIENCE, vol. 12, no. 41 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Li et al. | A lysosome-targeted BODIPY as potential NIR photosensitizer for photodynamic therapy | |
Zhao et al. | The triplet excited state of Bodipy: formation, modulation and application | |
Ciubini et al. | Design and synthesis of symmetrical pentamethine cyanine dyes as NIR photosensitizers for PDT | |
Çakır et al. | Synthesis and photophysicochemical properties of novel water soluble phthalocyanines | |
Wang et al. | Enhancing near-infrared AIE of photosensitizer with twisted intramolecular charge transfer characteristics via rotor effect for AIE imaging-guided photodynamic ablation of cancer cells | |
Wu et al. | A new near-infrared phosphorescent iridium (III) complex conjugated to a xanthene dye for mitochondria-targeted photodynamic therapy | |
CN111689955A (zh) | 一类萘并噻二唑自由基型光敏剂及其制备方法与应用 | |
Bai et al. | A near-infrared and lysosomal targeting thiophene-BODIPY photosensitizer: Synthesis and its imaging guided photodynamic therapy of cancer cells | |
Şenkuytu et al. | Cyclotriphosphazene-BODIPY Dyads: Synthesis, halogen atom effect on the photophysical and singlet oxygen generation properties | |
Luo et al. | The synthesis and 1 O 2 photosensitization of halogenated asymmetric aniline-based squaraines | |
Eçik et al. | Novel Bodipy-triazine conjugates: Synthesis and the generation of singlet oxygen | |
CN114539232B (zh) | 一种pH可逆激活近红外二区聚集诱导发光I型光敏剂及其应用 | |
Liu et al. | Novel indole-BODIPY photosensitizers based on iodine promoted intersystem crossing enhancement for lysosome-targeted imaging and photodynamic therapy | |
Liao et al. | Tetraphenylporphyrin derivatives possessing piperidine group as potential agents for photodynamic therapy | |
CN114045045B (zh) | 一类单光子上转换五甲川菁类光敏染料、其制备方法和应用 | |
Karanlık et al. | Water-soluble meso-thienyl BODIPY therapeutics: Synthesis, characterization, exploring photophysicochemical and DNA/BSA binding properties | |
Chen et al. | Photostability investigation of a near-infrared-II heptamethine cyanine dye | |
RU2621710C1 (ru) | Порфиразин, порфиразиновый комплекс гадолиния и их применение | |
CN113384695A (zh) | 具有长激发态寿命的五甲川菁染料类光敏染料、其制备方法和应用 | |
Paul et al. | Amino Acid–Porphyrin Conjugates: Synthesis and Study of their Photophysical and Metal Ion Recognition Properties | |
CN110128844B (zh) | 一种吲哚方酸菁染料及其制备方法和应用 | |
RU2476218C1 (ru) | Фотосенсибилизаторы для фотодинамической терапии | |
CN108358972B (zh) | 邻菲罗啉钌配合物类光敏染料及其制备方法和用途 | |
CN114736200A (zh) | 一类基于硫代五甲川菁染料的无重原子三重态光敏剂、其制备方法和应用 | |
CN116332923A (zh) | 一类咔唑及吩嗪类化合物中位取代花菁染料及其制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |