CN116836565A - Water-soluble squaraine dye, and synthetic method and application thereof - Google Patents
Water-soluble squaraine dye, and synthetic method and application thereof Download PDFInfo
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- CN116836565A CN116836565A CN202310846412.6A CN202310846412A CN116836565A CN 116836565 A CN116836565 A CN 116836565A CN 202310846412 A CN202310846412 A CN 202310846412A CN 116836565 A CN116836565 A CN 116836565A
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- IHXWECHPYNPJRR-UHFFFAOYSA-N 3-hydroxycyclobut-2-en-1-one Chemical compound OC1=CC(=O)C1 IHXWECHPYNPJRR-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000010189 synthetic method Methods 0.000 title abstract description 4
- 239000000975 dye Substances 0.000 claims description 41
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- PWEBUXCTKOWPCW-UHFFFAOYSA-N squaric acid Chemical compound OC1=C(O)C(=O)C1=O PWEBUXCTKOWPCW-UHFFFAOYSA-N 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 239000007850 fluorescent dye Substances 0.000 claims description 5
- -1 pyridine quaternary ammonium salt Chemical class 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 5
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- MVXVYAKCVDQRLW-UHFFFAOYSA-N azain Natural products C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 150000008052 alkyl sulfonates Chemical class 0.000 claims description 3
- 230000005284 excitation Effects 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
- 238000001917 fluorescence detection Methods 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 4
- 210000000170 cell membrane Anatomy 0.000 abstract description 15
- 238000012984 biological imaging Methods 0.000 abstract description 5
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 abstract description 3
- GIAFURWZWWWBQT-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanol Chemical compound NCCOCCO GIAFURWZWWWBQT-UHFFFAOYSA-N 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 230000002776 aggregation Effects 0.000 abstract description 2
- 238000004220 aggregation Methods 0.000 abstract description 2
- 230000008859 change Effects 0.000 abstract description 2
- 230000002209 hydrophobic effect Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 29
- 229940125904 compound 1 Drugs 0.000 description 20
- 229940125782 compound 2 Drugs 0.000 description 18
- 229940126214 compound 3 Drugs 0.000 description 17
- 238000004519 manufacturing process Methods 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 231100000002 MTT assay Toxicity 0.000 description 5
- 238000000134 MTT assay Methods 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 3
- 238000000295 emission spectrum Methods 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- 238000007626 photothermal therapy Methods 0.000 description 3
- 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 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010034972 Photosensitivity reaction Diseases 0.000 description 2
- 238000004061 bleaching Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
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- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 208000007578 phototoxic dermatitis Diseases 0.000 description 2
- 231100000018 phototoxicity Toxicity 0.000 description 2
- 230000008569 process Effects 0.000 description 2
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- 230000008685 targeting Effects 0.000 description 2
- 238000007669 thermal treatment Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- SNKZJIOFVMKAOJ-UHFFFAOYSA-N 3-Aminopropanesulfonate Chemical compound NCCCS(O)(=O)=O SNKZJIOFVMKAOJ-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000006004 Quartz sand Substances 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
- 235000013487 Viola odorata Nutrition 0.000 description 1
- 235000002254 Viola papilionacea Nutrition 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- UYMKPFRHYYNDTL-UHFFFAOYSA-N ethenamine Chemical group NC=C UYMKPFRHYYNDTL-UHFFFAOYSA-N 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000012615 high-resolution technique Methods 0.000 description 1
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- 150000002500 ions Chemical class 0.000 description 1
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- 230000031700 light absorption Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000012221 photothermal agent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
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Classifications
-
- 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
- C09B57/007—Squaraine dyes
-
- 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
-
- 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
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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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
- 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
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention discloses a water-soluble squaraine dye, a synthesis method and application thereof. One type of water-soluble squaraine dye has the following structural general formula:the invention provides a water-soluble squaraine dye, a synthetic method and application thereof, wherein an amphiphilic squaraine dye is synthesized through design, and the squaraine dye is dyed in rigid azaindole squaraineHydrophilic diglycolamine is introduced into the material to regulate the hydrophilic and hydrophobic properties, so that the diglycolamine can be accurately positioned on cell membranes. Meanwhile, the change of aggregation form further improves the photo-thermal performance in organisms, and realizes real-time biological imaging and treatment.
Description
Technical Field
The invention relates to the technical field of organic dyes, in particular to a water-soluble squaraine dye, a synthesis method and application thereof.
Background
Cell membranes are elastic semipermeable membranes consisting of phospholipid bilayers at the periphery of cells, and are particularly important in regulating substance exchange and maintaining the stability of the intracellular environment due to their selectivity and permeability, and abnormalities in cell membranes are also commonly used as a reference indicator for some related diseases. Fluorescence imaging, which is a high-sensitivity and high-resolution technique, has been widely used in cell membrane imaging, and plays an important role in cell membrane real-time imaging and detection.
Photothermal therapy is to convert an external light source into local heat energy by using a photothermal material, so that proteins, nucleic acids or other intracellular biomacromolecules are denatured, the permeability of cell membranes is affected, and finally irreversible damage is caused, and the photothermal therapy can be applied to ablation of microorganisms or cancers. As a minimally invasive local cancer treatment method, there is a great deal of attention in recent years from researchers, with the advantages of non-invasive and remote controllability.
However, currently studied cell membrane fluorescent dyes still have some drawbacks, such as low signal-to-noise ratio, high cytotoxicity, easy photo bleaching, etc., which prevent their application. In addition, there are few reports of dyes capable of targeting cell membranes for photothermal therapy. Therefore, a cell membrane targeting photothermal agent with high signal-to-noise ratio and good biocompatibility is synthesized, and is necessary for real-time imaging and treatment of cancers.
Disclosure of Invention
Aiming at the problems of low signal-to-noise ratio, higher cytotoxicity, easiness in photo-bleaching and the like of the conventional cell membrane fluorescent dye, the invention aims to provide a water-soluble squaraine dye, a synthetic method and application thereof. Meanwhile, the change of aggregation form further improves the photo-thermal performance in organisms, and realizes real-time biological imaging and treatment.
In order to achieve the above object, the technical scheme of the present invention is as follows: a water-soluble squaraine dye, which has a structure shown in a general formula I:
in the general formula I, the components are shown in the specification,
R 1 and R is 4 Each independently selected from at least one of carboxyalkyl, hydroxy, alkyl sulfonate having 1 to 18 carbons;
R 2 and R is 3 Each independently selected from at least one of hydrogen, aryl, alkyl having 1 to 4 carbons.
Further, the R 1 And R is 4 Each independently selected from any one of the following structural groups:
further, the method comprises the steps of,
the R is 2 And R is 3 Each independently selected from any one of the following structural groups:
the synthesis method of the water-soluble squaraine dye comprises the following steps:
(1) Adding 7-azaindole J-1 substituted by carboxyl into methanol solution, slowly dropwise adding SOCl at 0 DEG C 2 After 3-5h of reaction, refluxing at 60-80 ℃ for 3-6h, then adding the compound with R 1 Substituted amine reacts for 3-5 hours at the temperature of 40-70 ℃ to obtain an intermediate J-2;
(2) Dissolving intermediate J-2 obtained in step (1) in a first organic solvent at 50-120deg.C, adding a solvent containing R 2 Reacting the substituted halogenated alkane to obtain an intermediate J-3;
(3) Dissolving the intermediate J-3 prepared in the step (2) in a second organic solvent at 70-120 ℃, adding squaric acid, condensing under the catalysis of a first organic base, and purifying to obtain an intermediate J-4;
(4) Dissolving intermediate J-4 obtained in step (3) in a third organic solvent at 100-120deg.C, adding a solvent containing R 3 、R 4 Substituted 5-amide-2, 3-trimethyl-3H-pyrrolo [2,3-b]And (3) carrying out condensation reaction on the pyridine quaternary ammonium salt S-1 under the catalysis of a second organic base to obtain the fluorescent dye.
Further, in the step (2), the first organic solvent is at least one selected from benzene, toluene, o-dichlorobenzene, acetonitrile and acetone.
Further, in the step (3), the second organic solvent is at least one selected from ethanol, acetic acid, acetic anhydride, DMF, n-butanol, trimethyl orthoformate, triethyl orthoformate;
the first organic base is selected from at least one of triethylamine, pyridine and DIPEA.
Further, in the step (4), the third organic solvent is at least one selected from ethanol, acetic acid, acetic anhydride, DMF, trimethyl orthoformate, triethyl orthoformate;
the second organic base is selected from at least one of triethylamine, pyridine and DIPEA.
Further, in step (2), a catalyst having R is added 1 The substituted amine reacts for 3-5 hours at the temperature of 40-70 ℃ and then is subjected to recrystallization and purification to obtain an intermediate J-3, wherein the solvent used for recrystallization is at least one selected from methanol, ethanol, ethyl acetate and diethyl ether.
The application of a water-soluble squaraine dye in the biological and medical fields.
Further, the method is applied to cell imaging and tumor photothermal treatment.
Further, the excitation wavelength is 600-950nm and the fluorescence detection wavelength is 650-1000nm when the fluorescent dye is applied.
In summary, the invention has the following beneficial effects:
1. according to the dye, due to the introduction of hydrophilic groups, the hydrophilic and hydrophobic properties of molecules are changed, the lipophilic structure in the dye matrix can enter cells, and hydrophilic flexible chains connected with two ends repel lipid layers, so that the dye is accurately positioned on cell membranes, and real-time cell imaging is realized.
2. The invention obviously enhances the water solubility of the dye by modifying the azaindole squaraine dye, solves the problem that the azaindole squaraine dye is easy to aggregate in aqueous solution, simultaneously leads dye molecules to generate molecular vibration more easily, improves the photo-thermal performance in organisms, shows good photo-thermal effects in vitro and cell experiments, has good biocompatibility, and can be applied to the aspects of tumor photo-thermal treatment and the like.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions of the prior art, the drawings that are needed in the embodiments or the description of the prior art will be briefly described below, it will be obvious that the drawings in the following description are some embodiments of the present invention, and that other drawings can be obtained according to these drawings without inventive effort to a person skilled in the art.
FIG. 1 is a high resolution mass spectrum of compound 1 prepared in example 1 of the present invention;
FIG. 2 is a graph showing normalized emission spectra of Compound 1, compound 2, compound 3 prepared in example 1 of the present invention in dichloromethane;
FIG. 3 is a graph showing MTT assay of Compound 1 prepared in example 1 of the present invention;
FIG. 4 is a graph showing MTT assay of Compound 2 prepared in example 2 of the present invention;
FIG. 5 is a graph showing MTT assay of Compound 3 prepared in example 3 of the present invention;
FIG. 6 is a confocal image of compound 1, compound 2, compound 3 and comparative examples in cells, prepared in examples of the present invention.
Detailed Description
The present invention will be described in further detail below.
Unless otherwise indicated, the terms used herein have the following meanings.
The term "MTT" as used herein refers to a method of detecting cell survival and growth.
Instruments and devices employed in the examples:
in the column chromatography process, 200-300 mesh column chromatography silica gel purchased from Qingdao Megao group Co., ltd., 100-200 mesh column chromatography silica gel and 20-40 mesh analytically pure quartz sand purchased from Tianda chemical reagent factory are adopted.
In the process of detecting the compound, a mass spectrometer adopts a Synta G2-Si HDMS high-resolution mass spectrometer of Waters company in the United states, and adopts a double-needle electrospray ion source to detect the positive and negative modes of the compound.
Dye absorption and emission spectra were measured using a Cary 60 UV visible spectrophotometer and a Cary Eclipse fluorescence spectrophotometer from Agilent corporation.
Cytotoxicity assays were measured using a Varioskan LUX Multimode Microplate Reader instrument from thermofsher, usa.
Cell uptake experiments were measured using a single photon confocal microscopy instrument from Olympus corporation, japan.
Cell membrane-targeted squaraine dyes of formula I are described in detail below in connection with the examples.
In the general formula I, the components are shown in the specification,
R 1 and R is 4 Each independently selected from any one of the following structural groups:
R 2 and R is 3 Each independently selected from any one of the following structural groups:
specific examples of the compounds represented by the general formula I are given below, but the present invention is not limited to these specific examples.
The synthesis mechanism of the compound shown in the general formula I is as follows:
the compounds of the present invention represented by the general formula I can be synthesized by the methods described below.
Examples
Example 1
Manufacture of R 1 And R is 4 Are all hydroxy, R 2 And R is 3 Compound 1 which is the same as methyl group
(1) Production of intermediate 1.1
Carboxyl-substituted 7-azaindole (1 g,4.90 mmol) was added to a solution of 20mL of methanol and 4mL of LSOCl was slowly added dropwise at 0deg.C 2 After 3h reaction, transfer to oil bath, raise the temperature to 60 ℃, reflux for 6h, then add 2.6mL diglycolamine, react for 3-5h at 50 ℃, concentrate to give intermediate 1.1 (0.42 g,1.44mmol, 29% yield).
HRMS-ESI:m/z calcd.M + for C 15 H 22 N 3 O 3 + ,292.1661;found,292.1658.
1 HNMR(400MHz,Chloroform-d)δ8.79(d,J=1.6Hz,1H),8.53(t,J=6.8Hz,1H),8.30(d,J=1.6Hz,1H),4.24(t,J=7.4Hz,1H),3.70–3.51(m,8H),2.66(s,3H),1.36(s,6H).
(2) Production of intermediate 1.2
Intermediate 1.1 obtained in step (1) was dissolved in 20mL of acetonitrile at 65℃and reacted with methyl iodide (0.82 g,5.77 mmol) to give intermediate 1.2 (0.34 g,1.11mmol, yield 77%) by recrystallization purification.
HRMS-ESI:m/z calcd.M + for C 16 H 24 N 3 O 3 + ,306.1812;found,306.1813.
(3) Production of Compound 1
The intermediate 1.2 obtained in the step (2) was dissolved in 10mL of n-butanol at 115℃and added with squaric acid (0.07 g,0.57 mmol) for condensation reaction, and the resultant was purified by column chromatography to obtain compound 1 (0.025 g,0.04mmol, yield 6%).
HRMS-ESI:m/z calcd.M + for C 36 H 45 N 6 O 8 + ,689.3283;found,689.3299.
1 HNMR (400 mhz, chloro-d) delta 8.86 (d, j=1.4 hz, 1H), 8.74 (d, j=1.4 hz, 1H), 8.37-8.26 (m, 2H), 8.12-8.02 (m, 2H), 7.98 (d, j=1.4 hz, 1H), 7.24 (s, 1H), 4.08-3.98 (m, 5H), 3.68-3.50 (m, 16H), 3.39 (s, 3H), 1.52 (s, 6H), 1.41 (s, 6H) (see fig. 1).
Example 2
Manufacture of R 1 And R is 4 The same groups are carboxyl groups, R 2 And R is 3 Compound 2 which is the same as methyl group
(1) Production of intermediate 2.1
Carboxyl-substituted 7-azaindole (1 g,4.90 mmol) was added to a solution of 20mL of methanol and slowly dropped at 0deg.C with 4mL of SOCl 2 Reverse, oppositeAfter 5h, the reaction mixture was transferred to an oil bath, heated to 60℃and refluxed for 6h, followed by the addition of 2.8mL of amino-monoethylene glycol-carboxylic acid, reacted at 40℃for 5h, and concentrated to give intermediate 2.1 (0.51 g,1.60mmol, 33% yield).
HRMS-ESI:m/z calcd.M + for C 16 H 22 N 3 O 4 + ,320.1610;found,320.1601.
1 HNMR(400MHz,Chloroform-d)δ8.79(d,J=1.6Hz,1H),8.64(td,J=6.6,0.9Hz,1H),8.30(d,J=1.4Hz,1H),3.76(t,J=7.1Hz,2H),3.66–3.50(m,4H),2.63(s,3H),2.49(t,J=7.0Hz,2H),1.36(s,6H).
(2) Production of intermediate 2.2
Intermediate 2.1 was dissolved in 20mL of acetonitrile at 65℃and reacted with methyl iodide (0.85 g,6.00 mmol) to give intermediate 2.2 (0.36 g,1.08mmol, 67% yield) by recrystallization purification.
HRMS-ESI:m/z calcd.M + for C 17 H 24 N 3 O 4 + ,334.1761;found,334.1750.
(3) Production of Compound 2
Intermediate 2 obtained in step (2) was dissolved in 10mL of n-butanol at 115℃and added with squaric acid (0.07 g,0.57 mmol) for condensation reaction, followed by purification by column chromatography to give compound 2 (0.028 g,0.04mmol, yield 7%).
1 HNMR(400MHz,Chloroform-d)δ8.86(d,J=1.4Hz,1H),8.40(d,J=1.6Hz,1H),8.37–8.30(m,1H),8.27(s,1H),8.10–8.02(m,2H),7.98(d,J=1.4Hz,1H),7.24(s,1H),4.06(s,3H),3.76(t,J=7.1Hz,4H),3.66–3.51(m,8H),3.39(s,3H),2.50(t,J=7.1Hz,4H),1.60(s,6H),1.42(s,6H).
Example 3
Manufacture of R 1 And R is 4 Are all the same as alkyl sulfonate, R 2 And R is 3 Compound 1 which is the same as methyl group
(1) Production of intermediate 3.1
Carboxyl-substituted 7-azaindole (1 g,4.90 mmol) was added to a solution of 20mL of methanol and slowly dropped at 0deg.C with 4mL of SOCl 2 After 5h reaction, transfer to oil bath, raise the temperature to 60 ℃, reflux for 6h, then add 2.4ml of 3-aminopropanesulfonic acid, react for 3-5h at 40 ℃, concentrate to give intermediate 3.1 (0.58 g,1.64mmol, 33% yield).
HRMS-ESI:m/z calcd.M - for C 15 H 20 N 3 O 5 S - ,354.1129;found,354.1140.
1 HNMR(400MHz,Chloroform-d)δ8.79(d,J=1.4Hz,1H),8.62(t,J=6.8Hz,1H),8.30(d,J=1.4Hz,1H),3.69(t,J=7.1Hz,2H),3.65–3.59(m,2H),3.59–3.50(m,2H),3.35(t,J=7.1Hz,2H),2.52(s,3H),1.37(s,6H) .
(2) Production of intermediate 3.2
Intermediate 3.1 obtained in step (1) was dissolved in 20mL of acetonitrile at 65℃and methyl iodide (0.92 g,6.56 mmol) was added for reaction, followed by purification by recrystallization to give intermediate 3.2 (0.43 g,1.16mmol, yield 71%).
HRMS-ESI:m/z calcd.M + for C 16 H 24 N 3 O 5 S + ,370.1437;found,370.1402.
(3) Production of Compound 3
The intermediate 3.2 obtained in the step (2) was dissolved in 10mL of n-butanol at 115℃and added with squaric acid (0.07 g,0.57 mmol) for condensation reaction, followed by purification by column chromatography to give compound 3 (0.027 g,0.03mmol, yield 6%).
1 HNMR(400MHz,Chloroform-d)δ8.86(d,J=1.4Hz,1H),8.73(d,J=1.6Hz,1H),8.34–8.26(m,1H),8.23(s,1H),8.10–8.02(m,2H),7.98(d,J=1.4Hz,1H),7.24(s,1H),4.06(s,3H),3.70(t,J=7.1Hz,4H),3.65–3.51(m,8H),3.41–3.31(m,7H),1.60(s,6H),1.42(s,6H).
Comparative example 1
Production of Compound 4
(1) Production of intermediate 4.1
7-azaindole (1.00 g,4 mmol) and iodomethane (1.77 g,8 mmol) were added to a 100mL two-necked round bottom flask containing 20mL of acetone and placed under nitrogen. The mixture was then heated to reflux overnight, the reaction was terminated, after cooling to room temperature, 50mL of diethyl ether was added to precipitate, and the resulting solid precipitate was filtered, washed with diethyl ether and dried to give intermediate 4.1 (1.64 g,5.4mmol, 87% yield) as a brown solid.
(2) Production of Compound 4
Under the protection of nitrogen, squaric acid (300 mg,2.6 mmol) and a compound 1.2 (1.59 g,5.3 mmol) are reacted in a mixed solvent of triethyl orthoformate and n-butanol under heating at 120 ℃, the reaction is stopped after stirring for 2 hours, the reaction liquid is dropped into 150mL of diethyl ether dropwise after cooling to room temperature, and the obtained crude product is recrystallized by a silica gel column, and then the crude product is purified by silica gel chromatography with 80:1 methylene chloride/methanol (v/v) as an eluting solvent to obtain a blue solid compound 4 (0.067 g,0.16mmol with the yield of 6%)
HRMS-ESI:m/z calcd.M + for C 26 H 26 N 4 O 2 + ,427.2129;found,427.2130.
1 HNMR(400MHz,Chloroform-d)δ8.25(d,J=4.7Hz,2H),7.60(d,J=7.2Hz,2H),7.05(dd,J=7.3,5.1Hz,2H),6.07(s,2H),3.68(s,6H),1.80(d,J=6.1Hz,12H).
Performance detection
The compounds prepared in examples 1-3 and comparative example 1 above were subjected to the following performance tests as follows:
test example 1
Fluorescence spectrometry of Compound 1, compound 2 and Compound 3 obtained in the above examples
Precisely weighing the dye subjected to vacuum drying by using a ten-thousandth balance, preparing 2mmol/L DMSO dye mother solution into a brown sample bottle, and storing in a refrigerator at 4 ℃ for later use.
When the ultraviolet-visible absorption spectrum and the fluorescence spectrum are tested, 3 mu L of dye mother solution is measured by a micropipette and is dissolved in a quartz cuvette containing 3mL of solvent to be tested, and the dye is uniformly mixed to obtain the dye with the concentration of 2.0 mu mol/L for testing the absorption spectrum and the fluorescence emission spectrum. All tests were completed at 25 ℃.
FIG. 2 is a graph of normalized emission spectra of Compound 1, compound 2, compound 3 in dichloromethane;
as shown in fig. 2, in the dichloromethane solution, the emission of the compound 1, the compound 2 and the compound 3 is between 640nm and 750nm, and in the near infrared region, the emission of the near infrared region is favorable for avoiding the influence of biological autofluorescence, and better resolution and presentation effect can be achieved, so that the dye is more favorable for the application of the dye in biological imaging and treatment.
Test example 2
Cytotoxicity test on Compound 1, compound 2 and Compound 3 prepared in examples
Toxicity of dye molecules to cells was assessed by MTT assay. The principle is as follows: succinate dehydrogenase in the mitochondria of living cells reduces exogenous MTT to water insoluble blue-violet crystalline Formazan (Formazan) and deposits in cells, whereas dead cells do not. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and the light absorption value can be measured at 490nm and 570nm by using an enzyme-labeled instrument, so that the number of living cells can be indirectly reflected.
MCF-7 cells were seeded in 96-well plates and incubated for 24h (number of cells per well 1X 10 4 And (c) a). DMEM medium containing different concentrations of compound 1, compound 2, compound 3 was added to the wells, respectively, light/dark treatment was given, and cell activity was detected by MTT assay after 24h incubation. The experimental data are shown in fig. 3, 4 and 5.
As can be seen from fig. 3, 4, 5, compound 1, compound 2, compound 3 showed good biocompatibility in MCF-7 cells, which is advantageous for specific imaging of the dye in the cells. Meanwhile, compound 1, compound 2 and compound 3 with different concentrations are selected for phototoxicity experiments, and the results show that the dye has good phototoxicity effect, can effectively kill cells at 300mW, and prove that the dye can efficiently generate heat under illumination, so that the dye has excellent photo-thermal treatment effect, and can be applied to the fields of biological imaging and biological imaging.
Test example 3
Cell uptake experiments were performed on the compound 1, compound 2, compound 3 and compound 4 prepared in comparative example 1
MCF-7 cells were inoculated into confocal dishes one day in advance, after the cells were attached, washed three times with PBS solution, then 2mL of medium and 1. Mu.M of Compound 1, compound 2, compound 3, comparative example were added, and fluorescence images of the cells were taken with a Confocal Laser Scanning Microscope (CLSM) to observe the uptake of dye and cells. The excitation wavelength is 640nm, the transmitting and receiving wave bands are 650-700nm, and experimental data are shown in figure 6.
As can be seen from fig. 6, compound 1, compound 2, and compound 3 can specifically localize to the cell membrane within 2 hours, whereas comparative example compound 4 entered the cell and had strong fluorescence in the cell, but not localized to the cell membrane. Therefore, it was found that the water solubility of the compound 1, the compound 2 and the compound 3 was enhanced after the introduction of the water-soluble group, and the compound had an amphiphilic structure, so that the compound was more easily localized to the cell membrane. The lipophilic structure in the dye matrix enables the dye matrix to enter cells, and hydrophilic flexible chains connected at two ends are repelled from a lipid layer, so that the compound 1, the compound 2 and the compound 3 can be specifically positioned on cell membranes, and have the potential of ideal fluorescent biological probes.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. A water-soluble squaraine dye is characterized by having a structure of a general formula I:
in the general formula I, the components are shown in the specification,
R 1 and R is 4 May be the same or different, R 1 And R is 4 Each independently selected from at least one of carboxyalkyl, hydroxy, alkyl sulfonate having 1 to 18 carbons;
R 2 and R is 3 May be the same or different, R 2 And R is 3 Each independently selected from at least one of hydrogen, aryl, alkyl having 1 to 4 carbons.
2. A class of water-soluble squaraine dyes according to claim 1, wherein R 1 And R is 4 Identical, R 1 And R is 4 Each independently selected from any one of the following structural groups:
-COOH -OH
3. a water-soluble squaraine dye according to claim 1, characterized in that,
the R is 2 And R is 3 Identical, R 2 And R is 3 Each independently selected from any one of the following structural groups:
4. a method for synthesizing a water-soluble squaraine dye according to any one of claims 1 to 3, comprising the steps of:
(1) Adding 7-azaindole J-1 substituted by carboxyl into methanol solution, slowly dropwise adding SOCl at 0 DEG C 2 After 3-5h of reaction, refluxing at 60-80 ℃ for 3-6h, then adding the compound with R 1 Substituted amine reacts for 3-5 hours at the temperature of 40-70 ℃ to obtain an intermediate J-2;
(2) Dissolving intermediate J-2 obtained in step (1) in a first organic solvent at 50-120deg.C, adding a solvent containing R 2 Reacting the substituted halogenated alkane to obtain an intermediate J-3;
(3) Dissolving the intermediate J-3 prepared in the step (2) in a second organic solvent at 70-120 ℃, adding squaric acid, condensing under the catalysis of a first organic base, and purifying to obtain an intermediate J-4;
dissolving the intermediate J-4 in a third organic solvent at 100-120deg.C, adding a solvent containing R 3 、R 4 Substituted 5-amide-2, 3-trimethyl-3H-pyrrolo [2,3-b]And (3) carrying out condensation reaction on the pyridine quaternary ammonium salt S-1 under the catalysis of a second organic base to obtain the fluorescent dye.
5. The method for synthesizing a water-soluble squaraine dye according to claim 4, wherein in step (2), the first organic solvent is at least one selected from benzene, toluene, o-dichlorobenzene, acetonitrile and acetone.
6. The method for synthesizing a water-soluble squaraine dye according to claim 4, wherein in step (3), the second organic solvent is at least one selected from ethanol, acetic acid, acetic anhydride, DMF, n-butanol, trimethyl orthoformate, triethyl orthoformate;
the first organic base is selected from at least one of triethylamine, pyridine and DIPEA.
7. The method for synthesizing a water-soluble squaraine dye according to claim 4, wherein in step (3), the third organic solvent is at least one selected from ethanol, acetic acid, acetic anhydride, DMF, trimethyl orthoformate, and triethyl orthoformate;
the second organic base is selected from at least one of triethylamine, pyridine and DIPEA.
8. The method of claim 4, wherein R is added in the step (2) 1 The substituted amine reacts for 3-5 hours at the temperature of 40-70 ℃ and then is subjected to recrystallization and purification to obtain an intermediate J-3, wherein the solvent used for recrystallization is at least one selected from methanol, ethanol, ethyl acetate and diethyl ether.
9. Use of a class of water-soluble squaraine dyes according to any one of claims 1 to 3 in the biological and pharmaceutical fields.
10. The use of a class of water-soluble squaraine dyes according to claim 9, characterized in that the excitation wavelength is 600-950nm and the fluorescence detection wavelength is 650-1000nm.
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