CN108727256B - Photosensitizer based on triphenylamine polypyridine salt and preparation method and application thereof - Google Patents
Photosensitizer based on triphenylamine polypyridine salt and preparation method and application thereof Download PDFInfo
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- CN108727256B CN108727256B CN201810699203.2A CN201810699203A CN108727256B CN 108727256 B CN108727256 B CN 108727256B CN 201810699203 A CN201810699203 A CN 201810699203A CN 108727256 B CN108727256 B CN 108727256B
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- China
- Prior art keywords
- triphenylamine
- photosensitizer
- diiodo
- pyridine
- monoaldehyde
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000003504 photosensitizing agent Substances 0.000 title claims abstract description 84
- ODHXBMXNKOYIBV-UHFFFAOYSA-N triphenylamine Chemical compound C1=CC=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 ODHXBMXNKOYIBV-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 150000003839 salts Chemical class 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 238000005286 illumination Methods 0.000 claims abstract description 12
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims abstract description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 8
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000004327 boric acid Substances 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 8
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 7
- 125000006575 electron-withdrawing group Chemical group 0.000 claims abstract description 6
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- 238000005859 coupling reaction Methods 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims description 19
- BHXFKXOIODIUJO-UHFFFAOYSA-N benzene-1,4-dicarbonitrile Chemical compound N#CC1=CC=C(C#N)C=C1 BHXFKXOIODIUJO-UHFFFAOYSA-N 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- -1 diiodo, dibromobenzothiadiazole Chemical compound 0.000 claims description 10
- NBIKPJUOLNNQLF-UHFFFAOYSA-N n,n-diphenylaniline;pyridine Chemical compound C1=CC=NC=C1.C1=CC=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 NBIKPJUOLNNQLF-UHFFFAOYSA-N 0.000 claims description 10
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
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- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 claims description 3
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- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 claims description 3
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
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- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
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- 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
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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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
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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
- A61K49/0032—Methine dyes, e.g. cyanine dyes
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
- C09K2211/1051—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms with sulfur
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a photosensitizer based on triphenylamine polypyridine salt and a preparation method and application thereof, belonging to the technical field of biomedical engineering. The preparation method comprises the steps of firstly carrying out coupling reaction on triphenylamine mono-aldehyde diiodo and 4-pyridine boric acid to generate triphenylamine mono-aldehyde dipyridyl, then carrying out condensation reaction on the triphenylamine mono-aldehyde dipyridyl and an electron-withdrawing group, and carrying out salt forming reaction on an obtained product and iodomethane to obtain the photosensitizer. The photosensitizer has electron-withdrawing groups, can generate singlet oxygen with high efficiency under the illumination condition, and achieves the aim of killing tumor cells quickly and efficiently; the photosensitizer can not only effectively kill tumor cells and inhibit tumor growth, but also monitor the death of the tumor cells and tumor tissues in real time, so that the photosensitizer medicine can judge the effect of the tumor cells under the action of the photosensitizer in time. The photosensitizer is simple in preparation method and low in cost.
Description
Technical Field
The invention belongs to the field of biomedical engineering, and relates to a photosensitizer based on triphenylamine polypyridine salt, and a preparation method and application thereof.
Background
With the continuous improvement of the living standard of human beings, people pay more attention to the health problem. However, the problems of cancer to the health of the whole human body have not been solved yet, and the influence of the cancer due to deterioration of the environment is even more serious. While many researchers have been working on exploring new methods for treating cancer, the most common methods currently used are surgery, radiation therapy, and chemotherapy. However, these conventional methods have their own drawbacks, such as: the operation can not completely eliminate malignant tumor, and radiotherapy and chemotherapy can bring huge toxic and side effects to the organism. In view of these current situations, we need to develop a novel drug with high efficiency and low toxic and side effects to solve the problem of cancer.
Photodynamic therapy (PDT) is becoming a promising approach for tumor therapy because of its advantages of small trauma, low toxic and side effects, good selectivity, good repeatability, and protection of important organ functions. The photosensitive medicine enters into body, is enriched in cancerated tissue, and promotes the photosensitive medicine to generate cell harmful substances such as singlet oxygen, free radicals or superoxide in cancer cells through the excitation of light, thereby leading to the process of tumor cell necrosis and death. However, the efficiency of the existing photodynamic therapy means is general, and meanwhile, the real-time monitoring of the drug effect of the photodynamic therapy means is a difficult problem. Some nano preparations coated with various functional materials often face the problems of low drug-loading rate, poor repeatability, difficult drug release and the like. Therefore, it is very important to develop a water-soluble small molecule drug which has high efficiency and also has the function of monitoring the drug effect in real time and integrates photodynamic therapy and diagnosis.
Disclosure of Invention
The invention solves the technical problems that the photosensitizer singlet oxygen quantum has low yield and the cell state can not be monitored in real time in the prior art.
According to a first aspect of the present invention, there is provided a triphenylamine polypyridinium-based photosensitizer having the structural formula shown in formula i:
wherein R is an electron withdrawing group.
Preferably, the electron withdrawing group R is
According to another aspect of the present invention, there is provided a method for preparing a triphenylamine polypyridinium-based photosensitizer, comprising the steps of:
(1) under the protection of inert gas, triphenylamine mono-aldehyde diiodo and a catalyst A are fully and uniformly mixed, heated to 50-70 ℃, then 4-pyridine boric acid is added, and the mixture is refluxed for 8-16 h at the temperature of 80-100 ℃ to enable the triphenylamine mono-aldehyde diiodo and the 4-pyridine boric acid to generate a coupling reaction, so as to generate triphenylamine mono-aldehyde dipyridyl; after the triphenylamine monoaldehyde dipyridine, the terephthalonitrile and the catalyst B are fully and uniformly mixed, refluxing is carried out for 10h-12h at the temperature of 80-100 ℃, so that the triphenylamine monoaldehyde dipyridine and the terephthalonitrile are subjected to condensation reaction to obtain the terephthalonitrile triphenylamine pyridine;
or the step (1) is the following technical scheme: under the protection of inert gas, mixing triphenylamine mono-aldehyde diiodo, methyl triphenyl phosphine bromide and catalyst C uniformly, carrying out ice bath for 20min-40min, then reacting for 3h-5h at 20 ℃ -30 ℃, and carrying out condensation reaction on the triphenylamine mono-aldehyde diiodo and the methyl triphenyl phosphine bromide to obtain triphenylamine mono-olefin diiodo; the triphenylamine monoene diiodo, dibromobenzothiadiazole and a catalyst D are fully and uniformly mixed and react for 20 to 25 hours at the temperature of between 90 and 110 ℃ to enable the triphenylamine monoene diiodo and the dibromobenzothiadiazole to carry out coupling reaction to obtain benzothiadiazole triphenylamine diiodo; reacting the diazosulfide triphenylamine diiodo with 4-pyridine boric acid under the action of a catalyst E to obtain diazosulfide triphenylamine pyridine;
(2) and (2) carrying out reflux reaction on the terephthalonitrile triphenylamine pyridine or benzothiadiazole triphenylamine pyridine obtained in the step (1) and iodomethane under the protection of inert gas, so that the terephthalonitrile triphenylamine pyridine or the benzothiadiazole triphenylamine pyridine and the iodomethane are subjected to salt forming reaction, and thus the triphenylamine polypyridine salt-based photosensitizer is obtained.
Preferably, in the process of generating triphenylamine monoaldehyde dipyridine in the step (1), the ratio of the amount of the triphenylamine monoaldehyde diiodo to the amount of the 4-pyridineboronic acid is 1.0: (2.0-3.0); the catalyst A in the step (1) is tetratriphenylphosphine palladium or bis (triphenylphosphine) palladium dichloride; the catalyst B and the catalyst C in the step (1) are potassium tert-butoxide or sodium tert-butoxide.
Preferably, the amount ratio of the triphenylamine monoaldehyde bipyridine to the terephthalonitrile in the step (1) is (2.0-3.0): 1.0; the catalyst D in the step (1) is palladium acetate; the catalyst E in the step (1) is palladium tetratriphenylphosphine.
Preferably, the ratio of the quantities of the terephthalonitrile triphenylamine pyridine or benzothiadiazole triphenylamine pyridine and methyl iodide in the step (2) is 1.0: (10.0-20.0); the refluxing time in the step (2) is 6-8 h.
According to another aspect of the present invention, there is provided the use of the triphenylamine polypyridinium-based photosensitizer for the preparation of an antitumor drug.
Preferably, the anti-tumor drug acts on tumor cells under the condition of illumination, and the wavelength of the illumination is 400nm-600 nm; the power of the light source for illumination is 1mW/cm2-50mW/cm2。
According to another aspect of the present invention, there is provided the use of said triphenylamine polypyridinium-based photosensitizer for the manufacture of a medicament for monitoring tumor cell death.
According to another aspect of the present invention, there is provided the use of the triphenylamine polypyridinium-based photosensitizer in a fluorescent probe for detecting DNA.
Generally, compared with the prior art, the above technical solution conceived by the present invention mainly has the following technical advantages:
(1) the photosensitizer can efficiently generate singlet oxygen, the relative singlet oxygen quantum yield phi of the photosensitizer under illumination can reach 0.79 (reference is Bengal, phi is 0.75), the purpose of efficiently killing tumor cells can be achieved, and cancer cells can be promoted to die within 15 s.
(2) After the photosensitizer promotes the death of the tumor cells, the nuclear membrane permeability of the tumor cells is enhanced, the photosensitizer in cytoplasm enters the cell nucleus and is combined with nucleic acid in the cell nucleus to cause aggregation-induced luminescence of the photosensitizer, and the aggregation-induced luminescence effect of the photosensitizer is enhanced along with the deepening of the death process of the tumor cells, so that the tumor cells in the death process and the death state of the cells can be monitored in real time. The photosensitizer fluorescence intensity is gradually increased along with the increase of the DNA concentration in the photosensitizer solution, so that the photosensitizer can be used as an enhanced fluorescent probe for detecting DNA.
(3) The photosensitizer can not only effectively kill tumor cells and inhibit tumor growth, but also monitor the death of the tumor cells and tumor tissues in real time, so that the photosensitizer medicine can judge the effect of the tumor cells under the action of the photosensitizer in time. The photosensitizer is simple in preparation method and low in cost.
Drawings
FIG. 1 is a schematic diagram of the action principle of the photosensitizer provided by the invention.
FIG. 2 shows 10. mu. mol. multidot.L in example 2-1The photosensitizer JP2 has fluorescence emission spectrum after adding ctDNA with different concentrations, and the ctDNA ion concentrations are 0, 2.5, 5.0, 7.5, 10, 12.5, 15.0, 17.5, 20.0 and 22.5 mu g.L in sequence-1The solution system is aqueous solution, and the excitation wavelength is 445 nm; wherein the abscissa is the wavelength and the ordinate is the fluorescence intensity value.
FIG. 3 is a photograph of cell death of live HeLa cancer cells incubated with a photosensitizer in example 3 under different times of light; the light source is a confocal built-in light source (488nm,10mW), the excitation wavelength of JP2 is 488nm, and the collection waveband is 500-550 nm; the mitochondrion dye MitoTracker is Mito Tracker Deep Red, the excitation wavelength is 640nm, and the collection wave band is 660-750 nm; the scale bar is 6 μm; wherein FIG. 3(a), FIG. 3(e) and FIG. 3(i) are bright field diagrams of the cells at 0 seconds, 8 seconds and 15 seconds, respectively, after addition of the photosensitizer JP 2; FIG. 3(b), FIG. 3(f) and FIG. 3(j) are fluorescence plots of the cells at 0 seconds, 8 seconds and 15 seconds, respectively, after addition of the photosensitizer JP 2; FIG. 3(c) is a graph showing the staining of mitochondria in cells at 0 second, 8 seconds and 15 seconds after addition of photosensitizer JP2, FIG. 3(g) and FIG. 3(k), respectively; FIGS. 3(d), 3(h) and 3(l) are superimposed graphs of fluorescence and mitochondrial staining of cells at 0, 8 and 15 seconds, respectively, after addition of photosensitizer JP 2.
FIG. 4(a) is the cell viability (465nm,30mW cm) of HeLa cancer cells at different concentrations under illumination conditions in example 4, which was determined by the MTT assay-2) (ii) a FIG. 4(b) is the cell viability (465nm,30mW cm) of the HeLa cancer cells at different concentrations in the absence of light in example 4 according to the MTT assay-2)。
FIG. 5 is the change of fluorescence intensity at the tumor site of the mouse before and after administration and irradiation of light in example 5; wherein the PBS group is a blank group, i.e. injecting equal volume of PBS solution and giving the same dose of illumination; the JP2-light group was a control group, i.e., an equal volume of JP2 solution was injected without light; the JP2+ light group was a test group, i.e. light was given in the case of injection of the JP2 solution. Wherein, FIG. 5(a), FIG. 5(b) and FIG. 5(c) are fluorescence images of mice irradiated with light before injection of photosensitizer JP2, after injection of photosensitizer JP2 and after injection of photosensitizer JP2 in the experimental groups, respectively; FIGS. 5(d), 5(e) and 5(f) are fluorescence images of mice not irradiated with light before injection of the photosensitizer JP2, after injection of the photosensitizer JP2 and after injection of the photosensitizer JP2, respectively, in the control group; FIGS. 5(g), 5(h) and 5(i) are fluorescence images of mice illuminated before the blank group is injected with the photosensitizer JP2, after the injection of the photosensitizer JP2 and after the injection of the photosensitizer JP2, respectively.
FIG. 6 tumor growth in groups of mice.
FIG. 7 is the NMR spectrum of the photosensitizer synthesized in example 1.
FIG. 8 is the NMR carbon spectrum of the photosensitizer synthesized in example 1.
FIG. 9 is a MALDI-TOF mass spectrum of the photosensitizer synthesized in example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1: synthesis of photosensitizer JP2
(1) Synthesis of Compound III
Trianiline monoaldehyde diiodoIV (4.2g, 8mmol), cesium carbonate (5.21g, 16mmol), palladium tetratriphenylphosphine (0.92g, 0.8mmol) as a catalyst and 50ml toluene were added to a 100ml two-neck flask, stirred for 10min under nitrogen, heated to 60 ℃, and ethanol dissolved with 4-pyridineboronic acid (2.96g, 24mmol) was poured into the two-neck flask, heated to 90 ℃, and refluxed for 10 h. After the reaction was completed, it was cooled to room temperature and filtered through celite to remove the catalyst. The filtrate was dried by evaporation, extracted with ethyl acetate and saturated brine solution, and the crude product was dried by evaporation and subjected to column chromatography (eluent DCM: Ethanol ═ 50: 1). Yield iii, yield: 3.15g (92%).1H NMR(400MHz,cdcl3)δ9.87(s,1H),8.66(dd,J＝4.5,1.6Hz,4H),7.89–7.71(m,2H),7.68–7.59(m,4H),7.50(dd,J＝4.5,1.6Hz,4H),7.37–7.25(m,4H),7.18(d,J＝8.7Hz,2H).
(2) Synthesis of Compound II
In a 100mL two-neck flask, compound III (427.5mg,1mmol), p-phenylenediacetonitrile (156.2mg,0.33mmol) and potassium tert-butoxide (561.1mg,5mmol) are dissolved in 30mL of methanol solution, and the reaction is heated under reflux for 12h under the protection of nitrogen, thus finishing the reaction. The reaction was quenched by addition of 10ml of deionized water, pH was adjusted to neutral with dilute hydrochloric acid, extraction was performed with dichloromethane and saturated sodium chloride solution, and the organic phase was dried by spin-drying to give a crude product, which was subjected to column chromatography (eluent dichloromethane: ethanol 15:1) to give product II (210mg, yield: 65%).1H NMR(400MHz,CDCl3)δ8.67(d,J＝6.1Hz,8H),7.89(d,J＝8.8Hz,4H),7.74(s,4H),7.64(d,J＝8.6Hz,8H),7.56–7.47(m,10H),7.30(d,J＝8.6Hz,8H),7.22(d,J＝8.8Hz,4H).13C NMR(101MHz,CDCl3)δ150.28,149.13,147.28,147.22,141.55,135.07,133.74,130.98,128.23,127.78,126.25,125.52,122.65,121.14,118.24,107.94.MALDI-TOF:[M]calcd for C68H46N8,975.1720；found,975.2053.
(3) Synthesis of Compound JP2
After compound II (100.0mg,0.10mmol) and iodomethane (0.24g,0.1mL,1.7mmol) were dissolved in 20mL acetonitrile in a 50mL round bottom flask and stirred under nitrogen at reflux for 10h, the mixture was cooled to room temperature and then poured into anhydrous ether to precipitate a precipitate, which was filtered and washed three times with anhydrous ether to obtain the product JP2 after drying. Yield: (122mg, yield: 79%).1H NMR(400MHz,DMSO-d6) δ 8.94(d, J ═ 6.9Hz,8H),8.45(d, J ═ 7.0Hz,8H),8.16(s,2H),8.12(d, J ═ 8.8Hz,8H),8.03(d, J ═ 8.8Hz,4H),7.90(s,4H),7.32(d, J ═ 8.7Hz,12H),4.29(s, 12H); as shown in fig. 7.13C NMR(101MHz,DMSO-d6) δ 156.88,153.45,153.31,149.53,145.86,132.47,131.69,130.29,128.90,126.81,125.03,123.60,118.39,111.11,108.39,100.62, 47.35; as shown in fig. 8. MALDI-TOF [ M ]4+]calcd for C72H58N8 4+1035.3098; 1035.2889 for found; as shown in fig. 9.
Example 2: fluorescence change of photosensitizer JP2 in different concentrations of ctDNA
At a concentration of 10. mu. mol. L-1Adding ctDNA with different concentrations into PBS solution of photosensitizer JP2, wherein the ion concentration of ctDNA is 0, 2.5, 5.0, 7.5, 10, 12.5, 15.0, 17.5, 20.0 and 22.5 μ g.L-1The excitation wavelength is 445nm, and the fluorescence intensity is increased with the increase of the ctDNA concentration, as shown in FIG. 2. It is shown that JP2 and ctDNA have certain binding capacity and can excite the aggregation-induced emission performance of JP2, so that the fluorescence is enhanced. This is also the main reason why JP2 lights the nucleus.
Example 3: cell death of live HeLa cancer cells under different time periods of light
After incubation of HeLa cells for 2h with 10. mu.M photosensitizer JP2, residual dye was washed out with PBS solution and incubated for 30min with the mitochondrial dye Mito Tracker Deep Red. Observing the fluorescence distribution of the photosensitizer in the cell under a microscope under the irradiation of a confocal built-in light source (488nm,10mW), the results of FIG. 3 are obtained, wherein FIG. 3(a), FIG. 3(e) and FIG. 3(i) are bright field diagrams of the cell at 0 second, 8 seconds and 15 seconds after adding the photosensitizer JP2, respectively; FIG. 3(b), FIG. 3(f) and FIG. 3(j) are fluorescence plots of the cells at 0 seconds, 8 seconds and 15 seconds, respectively, after addition of the photosensitizer JP 2; FIG. 3(c) is a graph showing the staining of mitochondria in cells at 0 second, 8 seconds and 15 seconds after addition of photosensitizer JP2, FIG. 3(g) and FIG. 3(k), respectively; FIGS. 3(d), 3(h) and 3(l) are superimposed graphs of fluorescence and mitochondrial staining of cells at 0, 8 and 15 seconds, respectively, after addition of photosensitizer JP 2. From fig. 3, it can be observed that JP2 fluorescence intensity in the cell nucleus is gradually increased, meanwhile mitochondrial dye fluorescence is gradually weakened and weakened, bright field cells show death symptoms such as spitting bubbles and cell morphology change, and the rapid cell death under the action of photodynamic is illustrated. Wherein, the excitation wavelength of JP2 is 488nm, and the collection waveband is 500-550 nm. The mitochondrial dye MitoTracker is Mito Tracker Deep Red, the excitation wavelength is 640nm, and the collection band is 660-750 nm. The scale bar is 6 μm.
Example 4: cell survival rate of HeLa cancer cells with different concentrations under illumination and without illumination by MTT test
After the HeLa cells are respectively incubated for 24h by 0, 10, 20, 30 and 40 mu M photosensitizer JP2, the MTT test shows that even if the concentration of JP2 is as high as 40 mu M, the cell survival rate is still very good under the stimulation of no light, as shown in figure 4 (a).
And the cells incubated with 0, 2,4, 6, 8, 10 μ M photosensitizer for 4h, and 2min illuminated (465nm,30mW cm)-2) After stimulation, after further incubation for 24h, cell viability was examined by the MTT assay, as can be seen by figure 4(b), the phototoxicity of the cells gradually increased with increasing concentration of JP 2. The toxicity of JP2 photodynamic therapy on Hela cell is obtained by fitting the experimental data respectively through SPSS softwareIC50It was 1.67. mu.M.
Example 5: fluorescence intensity of mouse tumor site before and after drug administration and illumination
FIG. 1 is a schematic diagram of the action principle of the photosensitizer provided by the invention. As can be seen from FIG. 1, the photosensitizer efficiently generates singlet oxygen under the illumination condition, and the singlet oxygen can efficiently kill tumor cells. After the tumor cells die, the nuclear membrane permeability of the tumor cells is enhanced, the photosensitizer in cytoplasm enters the cell nucleus and is combined with nucleic acid in the cell nucleus to cause aggregation-induced luminescence of the photosensitizer, and the aggregation-induced luminescence effect of the photosensitizer is enhanced along with the deepening of the death process of the tumor cells, so that the death state of the cells can be monitored in real time.
A total of 24 Bal/c males inoculated with subcutaneous H22 cell tumors were divided into three groups of 8 mice each. Wherein the PBS group was blank, and an equal volume of PBS solution was injected and given the same dose of light. The JP2-light group was a control group, i.e., an equal volume of JP2 solution was injected without light. The JP2+ light group was a test group, i.e. light was given in the case of injection of the JP2 solution. The injection dose was 50. mu.l of JP2PBS solution at a concentration of 0.8 mg/ml. The results are shown in FIG. 5, in which FIG. 5(a), FIG. 5(b) and FIG. 5(c) are fluorescence images of mice irradiated with light before injection of photosensitizer JP2, after injection of photosensitizer JP2 and after injection of photosensitizer JP2, respectively, in the test groups; FIGS. 5(d), 5(e) and 5(f) are fluorescence images of mice without light before injection of photosensitizer JP2, after injection of photosensitizer JP2 and after injection of photosensitizer JP2, respectively, in the control group; FIGS. 5(g), 5(h) and 5(i) are fluorescence images of mice irradiated with light before the injection of photosensitizer JP2, after the injection of photosensitizer JP2 and after the injection of photosensitizer JP2 in the blank group, respectively. The JP2+ light group showed a significant increase in tumor tissue fluorescence after 20 minutes of light exposure, indicating that photodynamic therapy had some effect. Whereas the PBS group and the JP2-light group did not change significantly.
Tumor volume was measured daily with a vernier caliper in each group of mice, and the tumor volume growth curve is shown in fig. 6. Tumors from mice in the JP2+ light group had a significant inhibitory effect compared to the PBS group and JP 2-light.
Example 6: synthesis of photosensitizer BZ
(1) Synthesis of Compound IVB
Trianiline monoaldehyde diiodoIV (213.75mg, 0.5mmol), methyl triphenyl phosphonium bromide (607.85mg, 1.5mmol), potassium tert-butoxide (280.53mg, 0.0027mmol) were added to a 100ml two-neck flask under nitrogen protection, 15ml tetrahydrofuran was injected under ice bath, and after half an hour of ice bath reaction under nitrogen protection, the mixture was heated to room temperature and stirred for reaction for 4 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and a saturated aqueous solution of sodium chloride, and the crude product was spin-dried and subjected to column chromatography (eluent: n-hexane: dichloromethane ═ 1: 1). Triphenylamine monoene diiodo IVB was obtained, yield: 190mg (73%).1H NMR(400MHz,CHCl3)δ7.51(dt,J＝3.6,1.7Hz,4H),7.29(d,J＝8.1Hz,2H),7.05–6.95(m,2H),6.81(dt,J＝4.3,2.1Hz,4H),6.65(dd,J＝17.6,10.8Hz,1H),5.66(d,J＝17.6Hz,1H),5.19(d,J＝10.8Hz,1H).
(2) Synthesis of Compound IIIB
In a 100mL two-neck round-bottom flask, the compounds triphenylamine monoene diiodo IVB (130mg,0.248mmol), dibromobenzothiadiazole (29.22mg,0.099mmol), palladium acetate (31.08mg,0.0099mmol), sodium acetate (1.60g,0.0198 mmol) and tetrabutylammonium bromide (95.63mg,0.33mmol) were added, 30mL of dry DMF solution was injected under the protection of argon, and after stirring and dissolving, the reaction system was heated to 100 ℃ for 24 hours. After the reaction was stopped and cooled to room temperature, the reaction solution was poured into 100ml of deionized water, and a large amount of black precipitate was observed. The solid was collected by filtration to give the crude product as a black solid. Performing column chromatography on the eluent by using a silica gel column, wherein the eluent is petroleum ether: 1-dichloromethane: 2, the final product diazosulfide triphenylamine diiodo IIIB was obtained as a purple black solid powder, weight 55mg, yield 47%.1H NMR(400MHz,cdcl3)δ7.95(d,J＝12.0Hz,2H),7.66(s,2H),7.57-7.53(m,14H),7.07(d,J＝8.6Hz,4H),6.90–6.85(m,8H).
(3) Synthesis of Compound IIB
A100 ml two-neck flask is added with benzothiadiazole triphenylamine diiodoIIIB (32mg, 0.027mmol), cesium carbonate (17.69mg, 0.054mmol), catalyst tetratriphenylphosphine palladium (3.13mg, 0..0027mmol) and 10ml toluene, heated to 60 ℃ under nitrogen protection, stirred for 10min, ethanol dissolved with 4-pyridine boric acid (10.01mg, 0.081mmol) is injected into the two-neck flask, heated to 90 ℃ and refluxed for 10 h. After the reaction was completed, it was cooled to room temperature and filtered through celite to remove the catalyst. The filtrate was dried by evaporation, extracted with ethyl acetate and saturated brine solution, and the crude product was dried by evaporation and subjected to column chromatography (eluent DCM: Ethanol ═ 50: 1). Diazosulfide triphenylamine dipyridyl IIB is obtained, and the yield is as follows: 15mg (57%).1H NMR(400MHz,CDCl3)δ8.65(dd,J＝4.7,1.4Hz,8H),8.00(d,J＝16.2Hz,2H),7.69(s,2H),7.69–7.51(m,14H),7.52(dd,J＝4.6,1.6Hz,8H),7.27(d,J＝8.6Hz,4H),7.21(d,J＝8.6Hz,4H).
(4) Synthesis of photosensitizer BZ
In a 50mL round bottom flask, the compounds benzothiadiazole triphenylamine dipyridyl IIB (15mg,0.015mmol) and iodomethane (0.24g,0.1mL,1.7mmol) were dissolved in 20mL acetonitrile, and after stirring under reflux for 10 hours under a nitrogen atmosphere, the mixture was cooled to room temperature, then poured into anhydrous ether to precipitate a precipitate, which was filtered and washed three times with anhydrous ether to obtain the product BZ after drying. Yield: (17mg, yield: 73%).1H NMR(400MHz,DMSO-d6)δ8.92(d,J＝6.8Hz,8H),8.43(d,J＝7.0Hz,8H),8.15–8.13(m,4H),8.10(d,J＝9.0Hz,8H),7.96(s,2H),7.78(d,J＝8.6Hz,6H),7.74–7.71(m,2H),7.28(d,J＝8.7Hz,8H),7.24(s,4H),4.28(s,12H).
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (8)
1. A triphenylamine polypyridine salt-based photosensitizer is characterized in that the structural formula of the photosensitizer is shown as a formula I:
wherein R is an electron withdrawing group; the electron withdrawing group is
2. The method of claim 1 for preparing triphenylamine polypyridinium-based photosensitizers comprising the steps of:
(1) under the protection of inert gas, triphenylamine monoaldehyde diiodo and a catalyst of tetratriphenylphosphine palladium are fully and uniformly mixed, heated to 50-70 ℃, then 4-pyridine boric acid is added, and the mixture is refluxed for 8-16 h at 80-100 ℃ to enable the triphenylamine monoaldehyde diiodo and the 4-pyridine boric acid to generate a coupling reaction, so as to generate triphenylamine monoaldehyde bipyridine; after the triphenylamine monoaldehyde dipyridine, the terephthalonitrile and a catalyst potassium tert-butoxide are fully and uniformly mixed, refluxing is carried out for 10h-12h at the temperature of 80-100 ℃, so that the triphenylamine monoaldehyde dipyridine and the terephthalonitrile are subjected to condensation reaction to obtain the terephthalonitrile triphenylamine pyridine;
or the step (1) is the following technical scheme: under the protection of inert gas, mixing triphenylamine mono-aldehyde diiodo, methyl triphenyl phosphine bromide and catalyst potassium tert-butoxide uniformly, carrying out ice bath for 20min-40min, reacting for 3h-5h at 20 ℃ -30 ℃, and carrying out condensation reaction on the triphenylamine mono-aldehyde diiodo and methyl triphenyl phosphine bromide to obtain triphenylamine mono-aldehyde diiodo; the triphenylamine monoene diiodo, dibromobenzothiadiazole and catalyst palladium acetate are fully and uniformly mixed and then react for 20h to 25h at the temperature of 90 ℃ to 110 ℃, so that the triphenylamine monoene diiodo and dibromobenzothiadiazole are subjected to coupling reaction to obtain benzothiadiazole triphenylamine diiodo; reacting the diazosulfide triphenylamine diiodo with 4-pyridine boric acid under the action of a catalyst of palladium tetratriphenylphosphine to obtain diazosulfide triphenylamine pyridine;
(2) and (2) carrying out reflux reaction on the terephthalonitrile triphenylamine pyridine or benzothiadiazole triphenylamine pyridine obtained in the step (1) and iodomethane under the protection of inert gas, so that the terephthalonitrile triphenylamine pyridine or the benzothiadiazole triphenylamine pyridine and the iodomethane are subjected to salt forming reaction, and thus the triphenylamine polypyridine salt-based photosensitizer is obtained.
3. The method of claim 2, wherein in the step of forming triphenylamine monoaldehyde bipyridine in the step (1), the ratio of the amounts of triphenylamine monoaldehyde diiodo to 4-pyridineboronic acid in the substance is 1.0: (2.0-3.0).
4. The method for preparing the triphenylamine polypyridine salt-based photosensitizer according to claim 2, wherein the amount ratio of the triphenylamine monoaldehyde bipyridine to the terephthalonitrile in the step (1) is (2.0 to 3.0): 1.0.
5. the method for preparing a triphenylamine polypyridine salt-based photosensitizer according to claim 2, wherein the amount ratio of the terephthalonitrile triphenylamine pyridine or benzothiadiazole triphenylamine pyridine to the methyl iodide in the step (2) is 1.0: (10.0-20.0); the refluxing time in the step (2) is 6-8 h.
6. Use of a triphenylamine polypyridinium-based photosensitizer as claimed in claim 1 for the preparation of an antitumor drug.
7. The use according to claim 6, wherein the antineoplastic drug acts on tumor cells under light having a wavelength of 400nm to 600 nm; the power of the light source for illumination is 1mW/cm2-50 mW/cm2。
8. Use of a triphenylamine polypyridinium-based photosensitizer of claim 1 for the manufacture of a medicament for monitoring tumor cell death.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201810699203.2A CN108727256B (en) | 2018-06-29 | 2018-06-29 | Photosensitizer based on triphenylamine polypyridine salt and preparation method and application thereof |
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| CN110699424B (en) * | 2019-10-09 | 2021-06-11 | 华中科技大学 | Application of small-molecule fluorescent probe with double fluorescence emission |
| CN112521381B (en) * | 2020-01-24 | 2023-11-28 | 香港科技大学 | AIE photosensitizers with different positive charges, preparation method and antibacterial application thereof |
| CN113735864B (en) * | 2021-07-30 | 2022-04-15 | 江苏师范大学 | D-benzothiadiazole-TB (-D) derivative and synthetic method and application thereof |
| CN113788783B (en) * | 2021-10-12 | 2023-08-22 | 江南大学 | Self-reporting photosensitizer and preparation method and application thereof |
| CN114436948A (en) * | 2022-01-19 | 2022-05-06 | 上海工程技术大学 | Dipyridyl triphenylamine aldehyde fluorescent material with aggregation-induced emission effect and preparation method and application thereof |
| CN114656398B (en) * | 2022-04-25 | 2023-05-19 | 郑州大学 | Application of aggregation-induced emission photosensitizer in preparation of iron death inducer |
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