CN113788783B - Self-reporting photosensitizer and preparation method and application thereof - Google Patents
Self-reporting photosensitizer and preparation method and application thereof Download PDFInfo
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- CN113788783B CN113788783B CN202111188502.8A CN202111188502A CN113788783B CN 113788783 B CN113788783 B CN 113788783B CN 202111188502 A CN202111188502 A CN 202111188502A CN 113788783 B CN113788783 B CN 113788783B
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- 239000003504 photosensitizing agent Substances 0.000 title claims abstract description 85
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 21
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
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- AJUHJMMNWVKCER-UHFFFAOYSA-N 2-(2-phenylphenyl)aniline Chemical compound NC1=CC=CC=C1C1=CC=CC=C1C1=CC=CC=C1 AJUHJMMNWVKCER-UHFFFAOYSA-N 0.000 claims description 6
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 claims description 6
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
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- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- -1 Small molecule compounds Chemical class 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles
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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
- A61K41/008—Two-Photon or Multi-Photon PDT, e.g. with upconverting dyes or photosensitisers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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Abstract
The invention discloses a self-reporting photosensitizer and a preparation method and application thereof, and belongs to the technical field of biomedical engineering. The photosensitizer structurally comprises a twisted Triphenylamine (TPA) unit, three benzene ring units and three cyanovinyl pyridine salt (PyA+) units; the preparation method is simple, has high singlet oxygen quantum yield (124%) in aqueous solution, and has remarkable anticancer performance. Meanwhile, the photosensitizer can realize living cell staining of double-color fluorescence, and the emission color, intensity and cell location change simultaneously along with the death degree of cells under continuous light irradiation, so that TPA-3PyA+ can monitor the photodynamic treatment process in situ in real time. In addition, after photodynamic therapy, TPA-3PyA+ can only illuminate the nuclei of dead cells with green fluorescence, and living cells and dead cells can be distinguished significantly by observing the change in luminescent color of TPA-3 PyA+.
Description
Technical Field
The invention particularly relates to a self-reporting photosensitizer and a preparation method and application thereof, and belongs to the technical field of biomedical engineering.
Background
Cancer is the second most fatal disease threatening human life, and only 1000 tens of thousands die worldwide in 2020. Today, precision diagnosis and treatment integrated technology has gradually become one of the most attractive research fields in cancer treatment. The integrated photodiagnosis and treatment technology is an advanced noninvasive cancer diagnosis and treatment integrated technology. The technique can simultaneously show good early diagnosis and treatment effects under the excitation of light. Among them, imaging guided photodynamic therapy has attracted general attention due to its non-invasive nature, traceability and low toxicity. Photodynamic therapy has the basic components of a light source, a photosensitizer and oxygen. When the photosensitizer is excited by a certain light source, the surrounding oxygen can be converted into active oxygen species (such as singlet oxygen) which are toxic to cancer cells, so that the effect of killing the cancer cells is achieved. However, the conventional phototherapy technology cannot feed back the therapeutic effect in real time, resulting in problems of delayed treatment, excessive treatment, and the like. Advanced imaging guided photodynamic therapy uses self-reported photosensitizer systems with both strong active oxygen production capability and good luminescence properties. By utilizing the mode, not only can cancer cells be destroyed, but also the photodynamic therapy process can be monitored in situ in real time, so that phototoxicity and other side effects caused by high irradiation intensity and excessive medicine can be remarkably reduced.
Small molecule compounds are ideal choices for constructing self-reporting photosensitizers due to their well-defined composition and good stability. Self-reporting photosensitizers can be used to kill cancer cells and monitor photodynamic therapy processes in real time by conjugated linking the photosensitizers and fluorescent dyes with chemical groups that are sensitive to singlet oxygen to form conjugates. However, due to complex structure and complicated preparation process, the photosensitizer is not easy to develop into clinically usable medicines. In addition, the preparation of the small molecule self-reporting photosensitizer can also avoid the introduction of fluorescent dye and realize the capability of in-situ tracking of the apoptosis process. However, the efficacy of such photosensitizers in tracking the cell death process by observing changes in the single emitted light is disturbed by the concentration of the photosensitizers and the intensity of the excitation light.
Disclosure of Invention
Technical problems: in order to solve the problems of the existing small-molecule self-reporting photosensitizer caused by tracking photodynamic therapy by adopting single-emission light, for example, the visual result of tracking therapy is easily influenced by the concentration of the photosensitizer and the intensity of excitation light, the invention provides the small-molecule self-reporting photosensitizer capable of emitting bicolor light. By observing dynamic changes (luminous color and luminous intensity) of the monochromatic light in the treatment process, interference factors affecting results in the monochromatic light mode can be avoided, and more effective diagnosis and treatment integrated effect is achieved than in the monochromatic light mode.
The technical scheme is as follows:
the invention provides a small molecule self-reporting photosensitizer (TPA-3 PyA+):
in one embodiment of the invention, TPA-3PyA+ structurally comprises one twisted Triphenylamine (TPA) unit (electron donor, D), three benzene ring units (pi-bridge) and three cyanovinylpyridine (PyA+) units (electron acceptor, A).
The invention also provides a method for preparing the photosensitizer, which comprises the following steps:
(1) Performing condensation reaction on tri (4-aldehyde biphenyl) amine (compound 1) and 4-pyridine acetonitrile to obtain a condensation product, namely, terphenyl amine trivinyl cyano pyridine (compound 2);
(2) The method comprises the steps of generating a methylation reaction of pyridine by using terphenylamine trivinyl cyano pyridine and methyl iodide, and finally obtaining a small molecule self-reporting photosensitizer shown in a formula (I);
in one embodiment of the present invention, in the condensation reaction of step (1), the molar ratio of tris (4-aldehydebiphenyl) amine to 4-pyridine acetonitrile is 1: (3-6); specifically, 1:4.5.
in one embodiment of the present invention, the condensation reaction of step (1) is carried out in an organic solvent; the organic solvent is optionally pyridine.
In one embodiment of the invention, in step (1), the concentration of tris (4-aldehydediphenyl) amine relative to the organic solvent is from 0.02 to 0.05mmol/mL; specifically, 0.036mmol/mL is optional.
In one embodiment of the invention, the condensation reaction of step (1) further comprises adding ammonium acetate and glacial acetic acid.
In one embodiment of the invention, the molar ratio of tris (4-aldehydebiphenyl) amine to ammonium acetate is 1: (1-2); specifically, the ratio of the two components is 1:1.
In one embodiment of the invention, the amount of ammonium acetate relative to glacial acetic acid is in the range of from 0.1 to 0.3mmol/mL; specifically, 0.18mmol/mL is optional.
In one embodiment of the present invention, the temperature of the condensation reaction in step (1) is room temperature (20-30 ℃); the time is 12-30h.
In one embodiment of the invention, in the reaction of step (2), the molar ratio of the trianilide trivinylcyanopyridine to the iodomethane is 1 (30-70); specifically, the ratio of the raw materials is 1:55.
In one embodiment of the invention, the reaction of step (2) is carried out with acetone as solvent.
In one embodiment of the invention, in the reaction of step (2), the concentration of the trianilines trivinylcyanopyridine relative to acetone is 2-5mmol/L; specifically, 2.9mmol/L is selected.
In one embodiment of the invention, the temperature of the reaction in step (2) is 55-70 ℃ for a period of 10-20 hours.
In one embodiment of the invention, the reaction of step (2) is carried out under an inert atmosphere. In particular, the method is carried out under the optional nitrogen atmosphere.
In one embodiment of the invention, compound 1 can be prepared by the following method:
the coupling reaction is carried out by taking tri (4-bromophenyl) amine and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde as substrate under catalysis of tetra (triphenylphosphine) palladium to obtain coupled product tri (4-aldehyde biphenyl) amine (compound 1).
In one embodiment of the present invention, the molar ratio of tris (4-bromophenyl) amine to 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde in the coupling reaction is 1: (3-6); specifically, the ratio of the components is 1:3.6.
In one embodiment of the invention, the coupling reaction is carried out at a temperature of 55-70℃for a period of 20-30 hours.
In one embodiment of the invention, the coupling reaction is carried out under an inert atmosphere. In particular, the method is carried out under the optional nitrogen atmosphere.
In one embodiment of the invention, the coupling reaction is carried out in a solvent environment; the solvent is a mixed system of tetrahydrofuran and water. Further, the volume ratio of tetrahydrofuran to water is (1-4): 1, a step of; and the specific selection ratio is 3:1.
In one embodiment of the invention, the coupling reaction is carried out with a solvent in an amount of 10-20mL/mmol relative to tris (4-bromophenyl) amine; specifically, 12mL/mmol is selected.
In one embodiment of the present invention, the coupling reaction further comprises adding an alkaline reagent selected from any one or more of the following: potassium carbonate, sodium carbonate, cesium carbonate.
In one embodiment of the invention, the coupling reaction is carried out with a molar ratio of tris (4-bromophenyl) amine to base reagent of 1 (20-40). And the specific selection ratio is 1:30.
In one embodiment of the present invention, the preparation steps of the photosensitizer specifically include the following:
firstly, uniformly mixing tris (4-bromophenyl) amine with 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde and a metal catalyst tetra (triphenylphosphine) palladium, and then heating and reacting for 24 hours at the temperature of 60 ℃ under the protection of nitrogen to obtain a coupling product tris (4-aldehyde biphenyl) amine; uniformly mixing the tri (4-aldehyde biphenyl) amine and 4-pyridine acetonitrile, and reacting for 24 hours at room temperature to generate a condensation product, namely, terphenyl amine trivinyl cyano pyridine; finally, the terphenyl amine trivinyl cyano pyridine and methyl iodide are uniformly mixed and reacted for 12 hours under the protection of nitrogen at the temperature of 60 ℃ to generate methylation reaction of pyridine, and finally the small-molecule self-reporting photosensitizer capable of emitting double-colored light is obtained.
The invention also provides application of the small molecule self-reporting photosensitizer in preparation of fluorescent probes for distinguishing proteins from DNA.
The invention also provides application of the small molecule self-reporting photosensitizer in preparation of antitumor drugs.
The invention also provides application of the small molecule self-reporting photosensitizer in preparing a medicament for monitoring cell death in real time.
The invention also provides application of the small molecule self-reporting photosensitizer in preparation of medicines for distinguishing cell activity states.
In one embodiment of the invention, the cellular active state comprises living cells, dead cells.
The beneficial effects are that:
1. the self-reporting photosensitizer TPA-3PyA+ can simultaneously realize photodynamic therapy and real-time monitoring of the photodiagnosis and treatment process in a dynamic double-color mode. The self-reported photosensitizer has high singlet quantum yield, and the singlet oxygen quantum yield of the photosensitizer in water is 124% by taking the photosensitizer of Bengal as a reference (the singlet oxygen quantum yield in water is 75%), so that cancer cells can be killed efficiently. The photosensitizer has the advantages of simple preparation method and remarkable anticancer performance, and has a certain application prospect in the field of accurate cancer treatment.
2. The self-reporting photosensitizer can emit fluorescence with different colors when the self-reporting photosensitizer acts with protein and DNA, so that the self-reporting photosensitizer can be used as a probe for detecting and distinguishing the protein and the DNA.
3. The photosensitizer TPA-3PyA+ can not only kill cancer cells with high efficiency, but also enter cytoplasm of living cells and realize living cell staining of double-color fluorescence. In addition, the emission color, intensity and intracellular localization of TPA-3PyA+ can be simultaneously changed along with the degree of cell death under continuous light irradiation, so that the TPA-3PyA+ can monitor the photodynamic therapy process in situ in real time. More importantly, after photodynamic therapy, TPA-3PyA+ was able to illuminate only the nuclei of dead cells with green fluorescence, indicating that living and dead cells could be clearly distinguished by observing the change in luminescent color of TPA-3 PyA+. This unique optical property of TPA-3PyA+ can effectively avoid the interference of tracking cell death by observing changes in fluorescence intensity in the traditional monochromatic mode. The photosensitizer can realize the function of tracking the cell death process in real time in a visual mode under a dynamic double-color mode, and the visual effect of the method is not influenced by the concentration of the photosensitizer and the intensity of excitation light.
4. The photosensitizer prepared by the invention can emit fluorescence with different colors after being combined with living/dead cells, so that the living/dead cells can be identified by simply observing the luminous color of the photosensitizer.
Drawings
FIG. 1 is a schematic diagram of the structure and performance of a small molecule self-reporting photosensitizer TPA-3 PyA+.
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the photosensitizer TPA-3 PyA+.
FIG. 3 is a nuclear magnetic resonance carbon spectrum of the photosensitizer TPA-3 PyA+.
FIG. 4 is a high resolution mass spectrum of the photosensitizer TPA-3 PyA+.
FIG. 5 is a photoluminescence spectrum of an aqueous solution of the photosensitizer TPA-3PyA+, containing 1% DMSO, added to various concentrations of BSA (0, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275. Mu.g/mL). Excitation wavelength: 488nm; concentration of TPA-3 pya+: 20. Mu. Mol/L.
FIG. 6 is a photoluminescence spectrum of an aqueous solution of the photosensitizer TPA-3PyA+, containing 1% DMSO, after addition of different concentrations of DNA (0, 1, 5,10, 15, 20, 25, 30, 35, 40. Mu.g/mL). Excitation wavelength: 488nm; concentration of TPA-3 pya+: 20. Mu. Mol/L.
FIG. 7 (a) shows cell viability under dark conditions of HeLa cells incubated with different concentrations of the photosensitizer TPA-3 PyA+; FIG. 7 (b) shows cell viability of HeLa cells incubated with different concentrations of the photosensitizer TPA-3PyA+ under different light conditions; wavelength range of white light source used: 400-800nm.
FIG. 8 is a two-channel confocal imaging of the photosensitizer TPA-3PyA+ after co-culturing with living HeLa cells: FIG. 8 (a) is a near infrared channel imaging (acquisition wavelength range: > 600 nm); FIG. 8 (b) is a green channel imaging plot (acquisition wavelength range: 500-600 nm); fig. 8 (c) shows a bright field diagram; fig. 8 (d) is an imaging overlay of fig. 8 (a), fig. 8 (b), and fig. 8 (c); excitation wavelength: 488nm; concentration of TPA-3 pya+: 40. Mu. Mol/L; scale bar: 15 μm.
FIG. 9 is a real-time confocal imaging of HeLa cells incubated with the photosensitizer TPA-3PyA+ under continuous light irradiation: fig. 9 (a) -9 (e) are images of cells imaged at near infrared light channels at different illumination time points; fig. 9 (f) -fig. 9 (j) are cell imaging plots at the green channel at different illumination time points; fig. 9 (k) -fig. 9 (o) are images of cells imaged at the bright field channel at different illumination time points; excitation wavelength: 488nm; concentration of TPA-3 pya+: 40. Mu. Mol/L; scale bar: 15 μm.
FIG. 10 is a confocal imaging of dead HeLa cells stained with the photosensitizer TPA-3 PyA+: FIG. 10 (a) is a green channel image (acquisition wavelength range: 500-558 nm); FIG. 10 (b) shows a near infrared channel image (acquisition wavelength range: 600 nm) and FIG. 10 (c) shows a bright field channel image; fig. 10 (d) is an imaging overlay of fig. 10 (a), fig. 10 (b), and fig. 10 (c); excitation wavelength: 488nm; concentration of TPA-3 pya+: 40. Mu. Mol/L; scale bar: 15 μm.
Detailed Description
Example 1:
the preparation route of the photosensitizer TPA-3 PyA+:
(1) Synthesis of Compound 1:
tris (4-bromophenyl) amine (500 mg,1.04 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (868 mg,3.74 mmol), potassium carbonate (4.30 g,31.20 mmol), tetrahydrofuran/water (9 mL/3 mL) and tetrakis (triphenylphosphine) palladium (109 mg,0.094 mmol) were added to a 35mL pressure-resistant reaction flask, and after freezing and deoxygenation, the mixture was reacted at 60℃under nitrogen protection for 24 hours. After the reaction, cooling to room temperature, removing tetrahydrofuran by rotary evaporation, washing with dichloromethane and water in sequence, drying with anhydrous sodium sulfate, and rotary drying the solvent to obtain a crude product. Column chromatography (eluent: petroleum ether/dichloromethane=1/10, v/v) afforded yellow-green compound 1 (530 mg), 92% yield.
1 H NMR(400MHz,CDCl 3 ,ppm)of Compound 1:δ10.05(s,3H,CHO),7.96(d,J＝8.4Hz,6H,ArH),7.76(d,J＝8Hz,6H,ArH),7.61(d,J＝8.8Hz,6H,ArH),7.28(d,J＝8.4Hz,6H,ArH).
(2) Synthesis of Compound 2:
compound 1 (0.20 g,0.36 mmol), 4-pyridineacetonitrile (0.19 g,1.62 mmol), ammonium acetate (0.028 g,0.36 mmol), 2mL glacial acetic acid and 10mL pyridine were added to a 50mL round bottom flask and the reaction stirred at room temperature for 24 hours. After the reaction is finished, water is added into the system to separate out orange solid. The crude product was collected after suction filtration and washing with water. Column chromatography (eluent: dichloromethane/methanol=45/1, v/v) afforded compound 2 (0.27 g) as an orange color in 87% yield.
1 H NMR(400MHz,CDCl 3 ,ppm):δ8.72(dd,J＝1.6Hz,J＝4.8Hz,6H,ArH),8.05(d,J＝8.4Hz,6H,ArH),7.76(s,3H,CH),7.75(d,J＝8.0Hz,6H,ArH),7.63(d,J＝8.4Hz,6H,ArH),7.60(dd,J＝1.6Hz,J＝4.4Hz,6H,ArH),7.30(d,J＝8.8Hz,6H,ArH). 13 C NMR(100MHz,CDCl 3 ,ppm):δ150.6,147.4,144.6,143.6,142.0,134.4,131.5,130.6,128.2,127.2,124.7,119.9,117.2,108.5.HRMS(ESI):m/z for C 60 H 40 N 7 + ([M+H] + ):calc.858.3340；found 858.3401.
(3) Synthesis of the Compound TPA-3 PyA+:
compound 2 (0.050 g,0.058 mmol), methyl iodide (0.2 mL,3.2 mmol) and acetone (20 mL) were added to a 50mL round bottom flask and reacted at 60℃under nitrogen for 12 hours. After the reaction, cooling to room temperature, removing acetone by rotary evaporation, washing the crude product with ethyl acetate and methanol in sequence, and carrying out suction filtration to obtain a purple black product TPA-3PyA+ (0.070 g) with the yield of 94%.
1 H NMR(400MHz,DMSO-d 6 Ppm) (shown in fig. 2), δ9.06 (d, j=6.8 hz,6h, arh), 8.77 (s, 3h, ch), 8.44 (d, j=6.8 hz,6h, arh), 8.23 (d, j=8.4 hz,6h, arh), 8.03 (d, j=8.4 hz,6h, arh), 7.89 (d, j=8.8 hz,6h, arh), 7.28 (d, j=8.4 hz,6h, arh), 4.35 (s, 9h, ch) 3 ). 13 C NMR(100MHz,DMSO-d 6 Ppm) (shown in FIG. 3) delta 151.0,149.0,147.0,145.8,143.7,133.3,131.5,131.1,128.4,126.9,124.5,123.1,116.5,104.5,47.4.HRMS (ESI) (shown in FIG. 4) m/z for C 63 H 48 N 7 3+ ([M] 3+ ):calc.300.7985；found 300.7984.
Example 2: TPA-3PyA+ as fluorescent probe for distinguishing protein from DNA
The photosensitizer TPA-3PyA+ is structurally composed of a twisted triphenylamine unit (electron donor, D), three benzene ring units (pi-bridge) and three cyanovinyl pyridine salt units (electron acceptor, A), and has a twisted D-pi-A structure. The inclusion of a distorted D-pi-A system in the molecule imparts a distorted intramolecular charge transfer effect to the molecule. This effect enables the molecules to have flexible emission behaviour in different media, for example to produce different emission colours and intensities. In addition, the cationic pyridine group allows TPA-3PyA+ to interact with negatively charged biological macromolecules (e.g., proteins or DNA). The photosensitizer is almost non-fluorescent in aqueous solution, and near infrared light at 734nm is continuously enhanced when protein (for example, bovine serum albumin BSA) is continuously added into the system (as shown in FIG. 5). While green fluorescence at 547nm was continuously enhanced when DNA (exemplified by calf thymus DNA) was continuously added to the system (as shown in FIG. 6). Therefore, the photosensitizer can be used as a fluorescent probe for distinguishing protein and DNA.
Example 3: photosensitizer (TPA-3 PyA+) as anticancer agent
The photosensitizer TPA-3PyA+ is structurally composed of a twisted triphenylamine unit (electron donor, D), three benzene ring units (pi-bridge) and three cyanovinyl pyridine salt units (electron acceptor, A), and has a twisted D-pi-A structure. The D-pi-A structure can enable molecules to have small singlet-triplet energy gaps, and is beneficial to the generation of singlet oxygen. The photosensitizer was measured to have a high singlet oxygen quantum yield (124%) in water with reference to the photosensitizer, manglared (75% singlet oxygen quantum yield in water).
Based on this, the biocompatibility of the present photosensitizer was first examined (as shown in fig. 7 (a)) before the killing effect of the present photosensitizer on cancer cells was examined. The classical MTT test shows that when cancer cells are co-cultured with different concentrations of the photosensitizer (0 mu mol/L,10 mu mol/L,20 mu mol/L,30 mu mol/L,40 mu mol/L) for 24 hours in the dark, the cells keep high survival rate (more than 90%), which indicates that the photosensitizer has good biocompatibility. When the photosensitizer is co-cultured with cancer cells for 8 hours, and is irradiated with white light of different intensities for 30 minutes (white light wavelength range: 400-800nm; intensity: 50 mW/cm) 2 ，70mW/cm 2 ，90mW/cm 2 ) The cell viability is continuously reduced along with the increase of the concentration of the photosensitizer and the illumination intensity (as shown in (b) of fig. 7), which shows that the photosensitizer has good anticancer effect and is expected to be an effective photodynamic anticancer drug.
Example 4: photosensitizer (TPA-3 PyA+) as a drug for real-time monitoring of cell death
In confocal cell imaging, the photosensitizer enters mainly the cytoplasm of the cell and can generate two-color fluorescence (green light and near infrared light) (as shown in fig. 8). Under continuous blue laser irradiation (wavelength: 488 nm), cell morphology changes, gradually losing integrity, while near infrared light generated by the photosensitizer gradually decreases, while green fluorescence continues to increase, and localization of the photosensitizer in the cell gradually shifts from the original cytoplasm to the nucleus, and finally lights up the nucleus (as shown in fig. 9). The above shows that the photosensitizer not only can effectively kill cancer cells under illumination conditions, but also can realize real-time tracking of cell death by observing color change, intensity change and intracellular localization change of double-color fluorescence.
Example 5: photosensitizer (TPA-3 PyA+) as a drug for distinguishing living/dead cells
The photosensitizer can effectively stain living cells and generate double-color fluorescence (green light and near infrared light), and only generates green fluorescence when stained with dead cells (as shown in fig. 10), so that the photosensitizer can be used as a probe for distinguishing living/dead cells.
Comparative example 1 comparison of different D-pi-A photosensitizers as reported previously
The results are shown in the following table, comparing the previously reported photosensitizers of different structures.
TABLE 1 comparison of the Properties of the different D-pi-A-type photosensitizers
Claims (10)
1. A small molecule self-reporting photosensitizer having the structure of formula (I):
2. a method of preparing the photosensitizer of claim 1, comprising the steps of:
(1) The condensation product, terphenylamine trivinyl cyano pyridine, is prepared by the condensation reaction of tri (4-aldehyde biphenyl) amine and 4-pyridine acetonitrile;
(2) And (3) carrying out pyridine methylation reaction on the terphenylamine trivinyl cyano pyridine and methyl iodide to finally obtain the small molecule self-reporting photosensitizer shown in the formula (I).
3. The method of claim 2, wherein in the condensation reaction of step (1), the molar ratio of tris (4-aldehydebiphenyl) amine to 4-pyridine acetonitrile is 1: (3-6).
4. The process according to claim 2, wherein the condensation reaction of step (1) is carried out in an organic solvent; the concentration of the tri (4-aldehyde biphenyl) amine relative to the organic solvent is 0.02-0.05mmol/mL.
5. The method of claim 2, wherein the condensation reaction of step (1) further comprises adding ammonium acetate and glacial acetic acid.
6. The process according to any one of claims 2 to 5, wherein in the reaction of step (2), the molar ratio of the trianilines trivinylcyanopyridine to methyl iodide is 1 (30 to 70).
7. Use of a small molecule self-reporting photosensitizer according to claim 1 for the preparation of a fluorescent probe for distinguishing proteins from DNA.
8. The use of the small molecule self-reporting photosensitizer of claim 1 in the preparation of an antitumor drug.
9. Use of a small molecule self-reporting photosensitizer of claim 1 in the manufacture of a medicament for monitoring cell death in real time.
10. Use of a small molecule self-reporting photosensitizer of claim 1 in the manufacture of a medicament for differentiating between cellular active states.
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| CN110105585A (en) * | 2019-06-04 | 2019-08-09 | 南开大学 | A kind of polyrotaxane shape two dimension supermolecule nano assembly system and preparation method and application of light reaction driving |
| CN111909203A (en) * | 2020-07-08 | 2020-11-10 | 广东工业大学 | Triphenylamine-triphenylphosphine compound and preparation method and application thereof |
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| CN110105585A (en) * | 2019-06-04 | 2019-08-09 | 南开大学 | A kind of polyrotaxane shape two dimension supermolecule nano assembly system and preparation method and application of light reaction driving |
| CN111909203A (en) * | 2020-07-08 | 2020-11-10 | 广东工业大学 | Triphenylamine-triphenylphosphine compound and preparation method and application thereof |
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