CN115043860A - Meso-chloromethyl halogenated boron dipyrromethene photosensitizer and application thereof - Google Patents
Meso-chloromethyl halogenated boron dipyrromethene photosensitizer and application thereof Download PDFInfo
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- CN115043860A CN115043860A CN202210244170.9A CN202210244170A CN115043860A CN 115043860 A CN115043860 A CN 115043860A CN 202210244170 A CN202210244170 A CN 202210244170A CN 115043860 A CN115043860 A CN 115043860A
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- photosensitizer
- chloromethyl
- meso
- photodynamic
- acid
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- OVTCUIZCVUGJHS-UHFFFAOYSA-N dipyrrin Chemical compound C=1C=CNC=1C=C1C=CC=N1 OVTCUIZCVUGJHS-UHFFFAOYSA-N 0.000 title abstract description 6
- 150000001638 boron Chemical class 0.000 title abstract description 5
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- 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
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- 206010034972 Photosensitivity reaction Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
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- TXZFBHYDQGYOIT-UHFFFAOYSA-N 2-(chloromethyl)benzoyl chloride Chemical compound ClCC1=CC=CC=C1C(Cl)=O TXZFBHYDQGYOIT-UHFFFAOYSA-N 0.000 description 1
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- RCOVTJVRTZGSBP-UHFFFAOYSA-N 4-(chloromethyl)benzoyl chloride Chemical compound ClCC1=CC=C(C(Cl)=O)C=C1 RCOVTJVRTZGSBP-UHFFFAOYSA-N 0.000 description 1
- IXAUCVOJRVFRBJ-UHFFFAOYSA-N 4-(trichloromethyl)triazine Chemical class ClC(Cl)(Cl)C1=CC=NN=N1 IXAUCVOJRVFRBJ-UHFFFAOYSA-N 0.000 description 1
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- 125000005520 diaryliodonium group Chemical group 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
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- 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
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- 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
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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
- 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
- C09K2211/1055—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms with other heteroatoms
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- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a photosensitizer based on meso-chloromethyl halogenated boron dipyrromethene and application thereof. The photosensitizer with the structure has simple synthesis method and mild condition, and has commercial application prospect of mass production. Under the irradiation of a light source matched with the absorption wavelength, the photosensitizer breaks allyl chloride, and abstracts H of solvents such as acetonitrile, methanol, water and the like to generate hydrogen ions. Not only has high singlet oxygen yield, but also has higher photoacid quantum yield. The photosensitizer can be applied to relieving the problem of hypoxia limitation of the photodynamic therapy photosensitizer, and has the capability of cell fluorescence imaging.
Description
Technical Field
The invention belongs to the technical field of photodynamic therapy and photoacid generators, and particularly relates to a meso-chloromethyl halogenated boron dipyrromethene photosensitizer and application of the photosensitizer with photodynamic characteristics in the photodynamic therapy and the photoacid generator.
Background
The current photodynamic therapy for cancer treatment has oxygen deficiency limitation and low efficiency of generating active oxygen in the cellular hypoxia environment.To address the issue of hypoxia limitation, oxygen carriers have been developed to transport oxygen directly to the tumor area, generating O in situ 2 Two strategies for free radicals. However, these strategies are limited to oxygenation to produce reactive oxygen species, directly addressing the issue of hypoxia limitation, ignoring the essential characteristics of extra-basic acids within cancer cells. Pathological changes of organisms can cause acid-base imbalance, for example, pH imbalance of cancer cells becomes a remarkable sign, and the regulation of acid-base equilibrium can also bring forward the treatment of diseases. Cancer cells present internal alkali and external acid, the propagation speed is high under the alkaline pH condition, and the cancer cell selectivity can be damaged by reducing the pH. The existing method for adjusting the pH of the microenvironment mainly comprises the steps of indirectly using an ionic protein inhibitor and directly using a micromolecular alkaline medicament, and the problems of medicament resistance and the like easily occur when medicament treatment is adopted. Therefore, it is a necessary trend to realize precise and precise medical treatment by coordinating a photodynamic therapy with various cancer treatment methods for regulating the microenvironment of cells.
The use of photoacid generators to modulate the acid-base equilibrium of the microenvironment is a strategy to directly generate hydrogen protons to reduce pH. A photoacid generator (PAG) is a compound that provides the required protons to the environment. It reacts or dissociates under light, photolyzes via free radicals and the like, and usually requires the extraction of protons from surrounding compounds or solvents and the release of protons
Or a Lewis acid. The photoacid generator is used as a photoinitiator and is widely applied to photoresist, electronic packaging materials, adhesives, printing ink, coatings and 3D printing. Various commercially available photoacid generators are available, such as diaryliodonium salts, triarylsulfonium salts, ferrocenium salts, trichloromethyltriazines. Many commercially used photoacid generators are concentrated in the industrial field, and few studies are currently made on photoacid generators for in vivo applications. The photoacid generator used in industry concentrates ultraviolet band, which is harmful to human skin, eyes and immune system, so it is significant to develop photoacid generators in visible and near infrared regions.
meso-methyl-BODIPY-structured photocages (BODIPY-LG) have been reported in J.Am.chem.Soc.2017, 139, 15168-Astro 15175 as a class of photoresponsive molecules with photocleavage function. The photocage forms a carbocation and a corresponding anion pair after bond breaking by light irradiation with specific wavelength, and a corresponding photoproduct (photocage-Nu, H-LG) is generated after attack of a nucleophilic reagent (NuH). The property that the photocage breaks bonds when being irradiated by light with specific wavelength and releases protected groups (LG) after being attacked by a nucleophilic reagent has been applied to the light-controlled release of transport substances such as enzymes, prodrugs and the like in organisms. The research on the light-operated release related to the photo cage is mostly limited to the transport of drugs, enzymes and the like, the research on the photo product H-LG is few, the current photo-acid generator is mostly applied to the field of photo-curing of ultraviolet light regions, and the research on the combination of the photo cage and the photo-acid generator is lack of experimental exploration.
Disclosure of Invention
Aiming at the problem of oxygen deficiency limitation existing in the existing photodynamic therapy, the inventor provides a structure of a halogenated chloromethyl BODIPY photosensitizer (photoacid generator). Under the irradiation of a light source matched with the absorption wavelength, the photoacid generator with the structure breaks allyl chloride, and abstracts H of solvents such as acetonitrile, methanol, water and the like to generate hydrogen ions. Not only has high singlet oxygen yield, but also has higher photoacid quantum yield. The photosensitizer can be applied to relieving the problem of hypoxia limitation of the photodynamic therapy photosensitizer, and has the capability of cell fluorescence imaging.
The technical scheme of the invention is as follows:
a meso-chloromethyl halofluoroboron dipyrrole-based photosensitizer having the molecular structure of the following general formula I:
wherein:
r1 and R2 are respectively and independently selected from one of hydrogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylcyano, aryl, aralkyl, thienyl and cycloalkyl;
x is one of halogens, more preferably, X is selected from Br, Cl or I;
r is selected from one of chloromethyl, trichloromethyl and benzyl chloride.
More preferably, for the above technical solution, R is 1 、R 2 Each independently selected from one of alkyl, aralkyl, thienyl and cycloalkyl.
More preferably, for the above-described embodiments, the chloromethyl group is in the para, meta or para position of the phenyl ring.
In another aspect of the invention, a method for preparing a photosensitizer based on meso-chloromethyl halogenated boron fluoride dipyrromethene is disclosed, which comprises the following steps:
step (1): under the protection of nitrogen, reacting pyrrole derivatives with acyl chloride in anhydrous dichloro, cooling to room temperature when the reaction color becomes dark red, adding triethylamine, stirring, and adding boron trifluoride diethyl etherate when the color fades to obtain an intermediate A; the specific reaction formula is as follows:
step (2): dissolving the obtained intermediate A in a mixed solution of anhydrous dichloro and methanol, adding a halogenating reagent in the atmosphere of nitrogen, and reacting at room temperature in a dark place to obtain meso-chloromethyl halogenated boron dipyrromethene B.
More preferably, for the above-mentioned technical solution, the acid chloride is selected from one of chloroacetyl chloride, trichloroacetyl chloride, 4- (chloromethyl) benzoyl chloride, 3- (chloromethyl) benzoyl chloride, 2- (chloromethyl) benzoyl chloride.
More preferably, for the above technical solution, the halogenating agent is selected from one of NIS, NCS, NBS;
for the technical scheme, more preferably, the molar ratio of the pyrrole derivative to the acyl chloride is 2:1.05, the molar ratio of the pyrrole derivative to the triethylamine is 1: 2-4, and the molar ratio of the pyrrole derivative to the boron trifluoride diethyl etherate is 1:2 to 4.
More preferably, for the above-described technical scheme, the molar ratio of meso-chloromethylfluorodipyrrole A (intermediate A) and halogenating agent obtained is 1: 2.05.
in the technical scheme, more preferably, the dimethyl pyrrole reacts with acyl chloride for 2-5 h, the triethylamine is stirred for 15-30 min, and the reaction is carried out for 3-12 h after the boron trifluoride diethyl etherate is added.
For the technical scheme, more preferably, after the reaction in step (2) is finished, the method further comprises the steps of washing, extracting, drying, filtering, spin-drying and purifying; wherein, dichloromethane is adopted for extraction, anhydrous sodium sulfate is used for drying, and silica gel column is adopted for purification.
For the technical scheme, more preferably, the eluent adopted by the silica gel column is dichloromethane and petroleum ether according to the volume ratio of 4-20: 1.
For the above-described technical solutions, more preferably, the reaction solvent is anhydrous dichloro and methanol in a ratio of 1:1, and the reaction time is 10 min-2 h.
Another aspect of the present invention is to disclose the application of the photosensitizer (meso-chloromethyl halofluoroboron dipyrrole) described above, specifically including the application of utilizing the photo-induced acid-producing property of the photosensitizer to regulate the acid-base equilibrium of the micro-environment of the cell to relieve the limitation of the photodynamic hypoxia; and as photosensitizers for cellular imaging and photodynamic therapy of cancer tissue. More preferably, the photoacid generator (meso-chloromethyl halogenated boron dipyrrole) is used for releasing hydrogen ions by means of light source irradiation.
For the technical scheme, the illumination intensity and the illumination time of the acid production are more preferably within the acceptable illumination intensity of the living organisms, and the illumination intensity is more preferably 4-20 mW/cm 2 The illumination time is 3-30 min.
More preferably, the compound with the meso-chloromethyl halogenated BODIPY structure has photodynamic characteristics, can stably generate singlet oxygen under neutral or acidic conditions, has low dark toxicity and strong phototoxicity, and can be used as a potential drug for photodynamic therapy.
Advantageous effects
(1) The meso-chloromethyl halogenated boron difluoride-based photosensitizer prepared by the invention has the advantages of simple synthesis method, mild conditions and commercial application prospect of mass production.
(2) The photosensitizer has the characteristics of photo-induced acid production and photodynamic effect, and has application prospects in regulating and controlling cell microenvironment and enhancing photodynamic treatment effect.
(3) The invention is based on meso-chloromethyl halogenated boron difluoride photosensitizer, has high yield of photoacid quantum, and is a photoacid generator in visible light wave band.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of photosensitizers B-I-Cl, B-I-OH, in which: FIG. A is a nuclear magnetic hydrogen spectrum of the photosensitizer B-I-Cl of example 1, and FIG. B is a nuclear magnetic hydrogen spectrum of the photosensitizer B-I-OH of comparative example 1.
FIG. 2 is a mass spectrum of photosensitizers B-I-Cl and B-I-OH. Wherein: FIG. A is a mass spectrum of the photoacid generator B-I-Cl of example 1, and FIG. B is a mass spectrum of the comparative example 1B-I-OH.
FIG. 3 shows the performance of photosensitizer B-I-Cl at (550nm, 10 mW/cm) 2 ) Ultraviolet spectrum is photodegraded under the irradiation of green light.
FIG. 4 shows photosensitizers B-I-Cl (10. mu.M, acetonitrile) and tetrabromophenol blue (550nm, 10 mW/cm) at different times 2 ) Ultraviolet spectrum of light irradiation.
FIG. 5 shows the ultraviolet absorption spectrum of the photosensitizer B-I-Cl and the singlet oxygen probe DPBF irradiated by 550nm monochromatic light.
FIG. 6 is a graph comparing the phototoxicity and dark toxicity data for example 1B-I-Cl and comparative example B-I-OH.
FIG. 7 is a single-confocal cellular uptake of example 1B-I-Cl in MCF-7 cells, and a co-localization analysis of commercial mitochondrial, lysosomal localization dyes (upper row for mitochondrial localization and lower row for lysosomal localization).
FIG. 8 is a single-photon confocal photograph of intracellular pH change of MCF-7 by intracellular pH fluorescent probe (BCECF AM) monitoring uptake of B-I-Cl before and after illumination (upper row is before illumination, and lower row is after illumination).
Detailed Description
The present invention is further illustrated by the following examples, but it should be understood that the scope of the present invention is not limited by the examples.
In the present invention, percentages and percentages are by mass unless otherwise specifically indicated. Unless otherwise specified, the experimental methods used are conventional methods, and the materials, reagents and the like used are commercially available.
The synthesis of the photoacid generator of the present invention is illustrated below by way of example (but not limited thereto).
According to the invention, the terms "photoacid generator" and "photosensitizer" are interchangeable and refer to a compound of the halogenated chloromethyl fluoroboron dipyrrole structure.
EXAMPLE 1 Synthesis of photoacid generators B-I-Cl
2, 4-dimethylpyrrole (200mg) was accurately weighed and dissolved in 20mL of anhydrous dichloro-chloride, 0.15mL of chloroacetyl chloride was slowly added dropwise under a nitrogen atmosphere, the reaction liquid was changed from colorless to reddish blood, and the reaction was stirred at room temperature for 3 hours. Under the condition of ice water bath, 8mL of triethylamine is slowly added, stirring is continued for 15min after the addition is finished, 8mL of boron trifluoride ethyl ether is slowly dropped, and reaction is carried out for 3h at room temperature. After the reaction is finished, the reaction mixture is treated with H 2 O (3 × 100mL) was washed and the solution was extracted with dichloromethane, and the combined dichloromethane was dried over anhydrous sodium sulfate and filtered and spun dry on a rotary evaporator to give the crude product. The crude product was purified by silica gel column (dichloromethane: petroleum ether ═ 1:1) to give the intermediate compound 8-chloromethyl-4, 4' -difluoro-1, 3, 5, 7-tetramethyl-4-boron-3 a, 4 a-diazaindole as a bright red solid (35%). Intermediate product with a mixture of water-free dichloro: methanol 1:1, adding N-iodosuccinimide under the atmosphere of nitrogen, and reacting for 20min at room temperature in a dark place. After the reaction was complete, the reaction mixture was washed with sodium thiosulfate (3X 100mL) and the solution was extracted with dichloromethane, the combined dichloromethane was dried over anhydrous sodium sulfate and filtered, and spin dried on a rotary evaporator to give the crude product, crudeThe resulting product was purified by silica gel column (dichloromethane: petroleum ether ═ 4:1) to give the final product 4, 4' -difluoro-2, 6-diiodo-8-chloromethyl-1, 3, 5, 7-tetramethyl-4-boron-3 a, 4 a-diazaindole (B-I-Cl, as purple crystals, 80%).
Test example 1B-I-Cl Nuclear magnetic, Mass Spectrometry test
The test method comprises the following steps: 3mg of B-I-Cl solid powder is dissolved in 0.5mL of deuterated chloroform and placed in a nuclear magnetic tube, and the nuclear magnetic tube is placed in a Bruker Avance II 400 for testing, and the characterization results are shown in a figure 1A and a figure 2A, and the attribution of each peak is marked. Dissolving a little solid powder in dichloromethane, and measuring high resolution mass spectrum (HRMS-MALDI)
1 H NMR(400MHz，CDCl3):δ(ppm)4.63(s，2H，CH 2 )，2.60(s，6H，2CH 3 )，2.49(s，6H，2CH 3 ).
HRMS-MALDI-m/z:[M]-calcd for C 14 H 14 BClF 2 I 2 N 2 547.8996，found 547.9009.
Test example 2 variation spectra of photoacid generators for different irradiation times
The test method comprises the following steps: dissolve B-I-Cl in DMSO to prepare 5mM DMSO stock solution, and dilute 6. mu.L of stock solution in 3mL acetonitrile (10% concentration) -5 mol·L -1 Then adding the mixture into a clean quartz vessel, and setting a scanning wavelength range: 200-800 nm, 10mW/cm at 550nm xenon lamp 2 And irradiating the quartz dish, and sequentially testing samples with the illumination time of 0s, 10s, 20s, 30s and 5min to obtain a series of different absorbance curves.
As shown in FIG. 3, the spectrum of B-I-Cl is changed with the illumination time, the spectrum is changed rapidly at 30s, the maximum absorption wavelength is blue-shifted by 10nm, the waveform is changed from double peaks to single peak, the molar absorption coefficient is slightly reduced, and the ultraviolet absorption spectrum is maintained after 30s, which indicates that B-I-Cl is sensitive to light.
Test example 3 photoacid Quantum yield test
The test method comprises the following steps: tetrabromophenol blue is used as a hydrogen ion probe, dissolved in acetonitrile solvent according to a certain concentration, and then added with trifluoroacetic acid solution with a calibrated concentration, and passed through violetThe external-visible spectrophotometer measures the change of absorbance of the tetrabromophenol blue characteristic peak, and a univariate function graph of the acid concentration with the acid concentration as the abscissa and the change of absorbance as the ordinate is drawn, namely a standard working curve. B-I-Cl was dissolved in DMSO to prepare a 5mM DMSO stock solution, and 6. mu.L of the stock solution was diluted in 3mL of acetonitrile (10 concentration) -5 mol·L -1 ) Dissolving tetrabromophenol blue in an organic solvent, adding the solution into a clean quartz vessel, and setting a scanning wavelength range: 200-800 nm, and 10mW/cm at 550nm 2 Irradiating a quartz dish, and tracking the absorbance change delta of the mixed solution by using an ultraviolet-visible spectrophotometer under different illumination conditions ABS (FIG. 4B). The standard working curve (figure 4A) of tetrabromophenol blue at different hydrogen proton concentrations and absorbances is taken as a reference according to delta ABS The concentration of the corresponding acid can be obtained, and the photo-acid quantum yield phi in the solution can be obtained by calculating according to the formula (1) H + 0.64, the acid-generating capacity is much stronger than that of meso-modified triaryl sulfide salt (doi. org/10.1021/acs. orglett.0c00118).
Formula for calculation
Test example 4 photoacid generator active oxygen generating Properties
The photodynamic activity of the photoacid generator was examined by the quantum yield of singlet oxygen. Methylene blue as standard (. PHI. in methylene chloride) Δ 0.57), the absorbance of the singlet oxygen capturing reagent 1, 3-Diphenylisobenzofuran (DPBF) was adjusted to about 1.0 in a dichloromethane solvent, and then the photoacid generator was added to the cuvette and the absorbance was adjusted to 0.2 to 0.3. The cuvette was irradiated with 550nm monochromatic light for 10 seconds, and the absorbance was measured several times after each irradiation. As shown in FIG. 5A, the singlet oxygen capture reagent 1, 3-Diphenylisobenzofuran (DPBF) is sensitive to the detection of singlet oxygen. FIG. 5B shows that the absorbance change at 415nm of DPBF is linearly related to time, and a graph of the absorbance of DPBF at 415n as a function of time was calculated to calculate phi Δ ＝0.79。
Formula for calculation
Wherein ABS is the absorbance
K is the slope of DPBF absorbance change at 415nm and time
Test example 5 mitochondrial and lysosomal Co-localization imaging of photoacid generators B-I-Cl
Culturing 100 μ L MCF-7 cells in 2ml culture medium in a confocal dish at 37 deg.C under 5% CO2 for 24 hr, adding photoacid generator B-I-Cl, incubating for 1 hr, washing with PBS for 2 times, adding 1 μ L mitochondrial and lysosome commercial localization dye (Mito-Tracker Green, λ) ex ＝488nm，λ em ＝500～550nm；Lyso Tracker Green，λ ex ＝488nm，λ em 500-550 nm) for 30min, washed 2 times with PBS, and fresh medium was added. Confocal imaging observation is carried out, fluorescence channel images are recorded, and superposition positioning of photoacid generator detection is carried out, as can be seen from fig. 7, a Mito-Tracker Green dye signal (or Lyso Tracker Green) acquired by a Green channel is well superposed with a fluorescence signal of a red channel B-I-Cl, the lysosome co-localization coefficient is 0.71, the mitochondria co-localization coefficient is 0.71, and most of the B-I-Cl can enter lysosomes and mitochondria.
Comparative example 1 Synthesis of B-I-OH
2, 4-dimethylpyrrole (200mg) was accurately weighed, dissolved in 20mL of anhydrous dichloro, 0.14mL of acetoxyacetyl chloride was slowly added dropwise under a nitrogen atmosphere, the reaction mixture was changed from colorless to reddish blood, and the reaction was stirred at room temperature for 2 hours. Under the condition of ice water bath, 0.8mL of N, N-diisopropylethylamine is slowly added, stirring is continued for 15min after the addition is finished, 0.8mL of boron trifluoride ethyl ether is slowly dropped, and the reaction is carried out for 3h at room temperature. After the reaction is finished, the reaction mixture is treated with H 2 O (3 × 100mL) was washed and the solution was extracted with dichloromethane, and the combined dichloromethane was dried over anhydrous sodium sulfate and filtered and spun dry on a rotary evaporator to give the crude product. Crude product byPurification on silica gel (dichloromethane: petroleum ether ═ 1:1) afforded the intermediate compound 8-acetoxy-4, 4' -difluoro-1, 3, 5, 7-tetramethyl-4-boron-3 a, 4 a-diazaindole as an orange solid (35%). The intermediate product was reacted with a mixture of: methanol 1:1, adding N-iodosuccinimide in the atmosphere of nitrogen, and reacting for 1h at room temperature in a dark place. After the reaction was completed, the reaction mixture was washed with sodium thiosulfate (3 × 100mL), and the solution was extracted with dichloromethane, and the combined dichloromethane was dried over anhydrous sodium sulfate and filtered, and dried by rotary evaporator to give a crude product, which was purified by silica gel column (dichloromethane: petroleum ether ═ 4:1) to give 4, 4' -difluoro-2, 6-diiodo-8-acetoxy-1, 3, 5, 7-tetramethyl-4-boron-3 a, 4 a-diazaindole (B-I-OAc, as purple crystals, 87%). 4, 4' -difluoro-2, 6-diiodo-8-acetoxy-1, 3, 5, 7-tetramethyl-4-boron-3 a, 4 a-diazaindole was dissolved in 10mL of a mixed solution (tetrahydrofuran: methanol ═ 1:1), 2mL of 0.1M sodium hydroxide solution was added, and after completion of the reaction, the reaction mixture was treated with NH 4 Cl (3 × 100mL) and the solution was extracted with dichloromethane, the combined dichloromethane was dried over anhydrous sodium sulfate and filtered and spun dry on a rotary evaporator to give the crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate ═ 30:1) as a dark brown solid (10%). Test example 6 killing Effect of B-I-Cl and B-I-OH on human Breast cancer cells
B-I-Cl and B-I-OH were separately mixed into the cell culture medium and used for incubation of cells in a carbon dioxide incubator. After 2 hours of incubation, the supernatant was removed, washed twice with phosphate buffered saline solution, replaced with fresh medium and then illuminated (550nm, 10 mW/cm) 2 10min), then placed in an incubator for another 12 hours, added with a medium containing thiazole blue (0.5mg/ml), incubated for another 4 hours, taken out the solution in a 96-well plate, dissolved the crystals with DMSO, and measured for absorbance at 630nm and 570nm with a microplate reader. As shown in FIG. 6, the survival rate of B-I-Cl cells in the 32 μ M concentration without light is above 80%, and the survival rate of B-I-OH group is 28%; the cell survival rate of B-I-Cl under illumination is below 10 percent at 0.25 mu M, and the cell survival rate of B-I-OH group is 34 percent, so thatThe above shows that the photoacid generator B-I-Cl has better biocompatibility and cell killing effect. Test example 7 Effect of B-I-Cl on the microenvironment pH of human Breast cancer cells
An intracellular pH fluorescent probe (BCECF AM) was able to monitor changes in the intracellular environmental pH, a decrease in pH affecting the fluorescence intensity of BCECF AM. mu.L of MCF-7 cells were diluted to 2mL medium in a confocal dish at 37 ℃ with 5% CO 2 After 24h incubation at ambient, photosensitizer B-I-Cl was added and incubated for 1h, washed 2 times with PBS, and 1. mu.L (. lamda.BCECF AM stock solution of 10mM was added ex ＝488nm，λ em 500-530 nm), washed 2 times with PBS, added with fresh medium, and then irradiated with light (550nm, 10 mW/cm) 2 10 min). Confocal imaging observation is carried out, and fluorescence channel images before and after illumination are recorded. As shown in FIG. 8, the fluorescence intensity of BCECF AM in MCF-7 cells after light irradiation was significantly weaker than that before light irradiation, indicating that B-I-Cl was able to lower the pH inside the cells.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and those skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (8)
1. A meso-chloromethyl halofluoroboron dipyrrole-based photosensitizer, characterized in that said photosensitizer has the following molecular structure of the general formula I:
wherein:
r1 and R2 are respectively and independently selected from one of hydrogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylcyano, aryl, aralkyl, thienyl and cycloalkyl;
x is one of halogens.
R is selected from one of chloromethyl, trichloromethyl and benzyl chloride.
2. The meso-chloromethyl halofluoroboron-based dipyrrole photosensitizer according to claim 1, characterized in that said R is 1 、R 2 Each independently selected from one of alkyl, aralkyl, thienyl and cycloalkyl.
3. The meso-chloromethyl halofluorodiboron-based photosensitizer according to claim 1, characterized in that the chloromethyl group is in the para, meta or para position of the benzene ring.
4. The use of a meso-chloromethyl halofluorodipyrromethene-based photosensitizer according to claim 1, comprising the use of the photoacid generating properties of said photosensitizer to modulate the acid-base equilibrium in the cellular microenvironment to alleviate photodynamic hypoxia limitation; and as photosensitizers for cellular imaging and photodynamic therapy of cancer tissue.
5. The use of meso-chloromethyl halofluorodiboron-based photosensitizer according to claim 4, characterized in that said photosensitizer (photoacid generator) is used for the release of hydrogen ions by means of light source irradiation.
6. The use of meso-chloromethyl halofluorodipyrromethene-based photosensitizer according to claim 4, characterized in that said compound has photodynamic properties, stably producing singlet oxygen under neutral or acidic conditions.
7. The use of meso-chloromethyl halofluorodiboron-based photosensitizer according to claim 5, characterized in that the light intensity and the light time of the light source for producing acid are within the acceptable intensity for living organisms.
8. Use of a photosensitizer based on meso-chloromethyl halofluorodipyrromethene according to claim 6, characterized in that it is prepared byThe illumination intensity is 4-20 mW/cm 2 The illumination time is 3-30 min.
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| US20200219664A1 (en) * | 2017-08-31 | 2020-07-09 | Gwangju Institute Of Science And Technology | Bodipy-based copolymer and solar cell comprising same |
| CN113527350A (en) * | 2021-07-27 | 2021-10-22 | 大连理工大学 | Near-infrared lysosome fluorescence indicator and application |
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| US20090204057A1 (en) * | 2006-07-24 | 2009-08-13 | Quest Pharmatech Inc. | Method and device for photodynamic therapy |
| US20200219664A1 (en) * | 2017-08-31 | 2020-07-09 | Gwangju Institute Of Science And Technology | Bodipy-based copolymer and solar cell comprising same |
| CN113527350A (en) * | 2021-07-27 | 2021-10-22 | 大连理工大学 | Near-infrared lysosome fluorescence indicator and application |
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