CN115304633B - Heavy atom-free photodynamic photosensitizer and preparation method and application thereof - Google Patents
Heavy atom-free photodynamic photosensitizer and preparation method and application thereof Download PDFInfo
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- 239000003504 photosensitizing agent Substances 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000001022 rhodamine dye Substances 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 23
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- -1 10- (4-bromo-2-methylphenyl) phenoxazine Chemical compound 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- QSQOGKONVJDRNH-UHFFFAOYSA-N 1-bromo-4-iodo-2-methylbenzene Chemical compound CC1=CC(I)=CC=C1Br QSQOGKONVJDRNH-UHFFFAOYSA-N 0.000 claims description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 4
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 claims description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- SBMKUYWJJATBFV-UHFFFAOYSA-N C1=CC=CC=2OC3=CC=CC=C3NC12.[Si] Chemical compound C1=CC=CC=2OC3=CC=CC=C3NC12.[Si] SBMKUYWJJATBFV-UHFFFAOYSA-N 0.000 claims description 2
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- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract description 9
- 238000010521 absorption reaction Methods 0.000 abstract description 8
- 230000007246 mechanism Effects 0.000 abstract description 7
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 abstract description 6
- 229910052710 silicon Inorganic materials 0.000 abstract description 6
- 239000010703 silicon Substances 0.000 abstract description 6
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
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- 208000007578 phototoxic dermatitis Diseases 0.000 description 3
- 231100000018 phototoxicity Toxicity 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- DNUYOWCKBJFOGS-UHFFFAOYSA-N 2-[[10-(2,2-dicarboxyethyl)anthracen-9-yl]methyl]propanedioic acid Chemical compound C1=CC=C2C(CC(C(=O)O)C(O)=O)=C(C=CC=C3)C3=C(CC(C(O)=O)C(O)=O)C2=C1 DNUYOWCKBJFOGS-UHFFFAOYSA-N 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
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- 238000002835 absorbance Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 229910052760 oxygen Inorganic materials 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom
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- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
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- Chemical Kinetics & Catalysis (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the technical field of photosensitizers, and particularly relates to a heavy-atom-free photodynamic photosensitizer, a preparation method and application thereof. In order to provide a photosensitizer with longer absorption wavelength, the invention selects the silicon rhodamine dye with strong absorption in the near infrared region as a parent chromophore and an electron acceptor, takes phenoxazine as an electron donor, designs and synthesizes a heavy atom-free triplet photosensitizer of silicon rhodamine-phenoxazine (SiPPhO) based on an SOCT-ISC mechanism, and the photosensitizer has the characteristics of being positioned in the near infrared region in absorption wavelength, good biocompatibility, low dark toxicity, high singlet oxygen generation efficiency and the like, and has potential biological application value.
Description
Technical Field
The invention belongs to the technical field of photosensitizers, and particularly relates to a heavy-atom-free photodynamic photosensitizer, a preparation method and application thereof.
Background
Photodynamic therapy (Photodynamic therapy, PDT) is a non-destructive tumor treatment method developed in recent years, has the advantages of high spatial-temporal resolution, small damage to normal tissues, no drug resistance, repeated treatment and the like, and has been clinically applied. Photodynamic therapy principle is that photosensitizers in a triplet excited state transfer excitation energy to oxygen or other biomolecules leading to the production of highly Reactive Oxides (ROS), the key to the therapeutic effect being the selection of the appropriate Photosensitizer (PS). Ideal photosensitizers generally require good water solubility, a large molar absorptivity, and an excitation wavelength as long as possible. Furthermore, studies have shown that mitochondria are important targets for photodynamic therapy and mitochondria-targeted photosensitizers can kill tumor cells more effectively. The traditional and most widely used PS is designed based on the heavy atomic effect of Br and I, however, the PS has larger biotoxicity and short triplet state life and is not an ideal triplet state photosensitizer. In contrast, heavy atom-free triplet photosensitizers are low in cost, low in toxicity and long in triplet lifetime, and are receiving great attention.
In recent years, based on 1 (n,π*)→ 3 The series of photodynamic photosensitizers are reported by (pi, pi) transitions, exciton coupling, singlet fission, twisted conformation promoted intersystem crossing, radical promoted intersystem crossing (EISC), radical pair-intersystem crossing (RP-ISC), spin-orbit coupled electron transfer-intersystem crossing (SOCT-ISC), etc., mechanisms based on the SOCT-ISC mechanismThe constructed triplet state photosensitizer has the advantages of simple molecular structure and easy design and synthesis, and only needs to connect an electron donor and an electron acceptor in a vertical conformation in structural design. However, absorption of PS designed based on this mechanism is mainly in the visible region, and PS with longer wavelength still needs to be designed and developed.
Disclosure of Invention
Aiming at the problems, the invention selects the silicon rhodamine dye with strong absorption in the near infrared region as a parent chromophore and an electron acceptor, takes the phenoxazine as an electron donor, designs and synthesizes a heavy atom-free triplet photosensitizer of silicon rhodamine-phenoxazine (SiPPhO) based on an SOCT-ISC mechanism, and uses the photosensitizer for photodynamic therapy of cancer cells.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a photodynamic photosensitizer without heavy atoms has the structural formula:
the preparation method of the heavy atom-free photodynamic photosensitizer comprises the following steps:
step 1, under the protection of nitrogen, sequentially adding phenoxazine (compound 1), 2-bromo-5-iodotoluene (compound 2), sodium tert-butoxide and cuprous iodide into 1, 4-dioxane, fully and uniformly stirring, then adding a complexing agent 1, 2-diaminocyclohexane into the solution, carrying out reflux reaction, cooling to room temperature after the reaction is finished, evaporating the solvent, and separating a crude product by column chromatography to obtain 10- (4-bromo-2-methylphenyl) phenoxazine (compound 3);
and 2, under the protection of nitrogen, adding anhydrous THF (tetrahydrofuran) into the 10- (4-bromo-2-methylphenyl) phenoxazine (compound 3) obtained in the step 1, cooling the obtained solution, dropwise adding n-butyllithium solution for reaction, dropwise adding a THF solution of the silica-pyridine Luo Gongtong, continuing the reaction after the reaction solution is restored to room temperature, quenching with water and acidizing with hydrochloric acid after the reaction is finished, continuing stirring, and obtaining the phenoxazine-silicon rhodamine dye through extraction, drying and column chromatography separation, namely the photosensitizer.
Further, the molar ratio of the phenoxazine, the 2-bromo-5-iodotoluene, the sodium tert-butoxide and the cuprous iodide in the step 1 is 1:1.1:2:0.02.
further, the reflux reaction in the step 1 is carried out at a temperature of 130 ℃ for 18 hours, and the developing agent CH is separated by column chromatography 2 Cl 2 : the volume ratio of the n-hexane is 1:4.
further, the molar ratio of 10- (4-bromo-2-methylphenyl) phenoxazine, n-butyllithium and silicoaluminophosphate Luo Gongtong in step 2 is 3:3:1.
further, the obtained solution is cooled to-78 ℃ in the step 2, the reaction temperature of adding the n-butyl lithium solution is-78 ℃ for 60min, the reaction is continued for 4h after the room temperature, the stirring is continued for 30min, and the developing agent CH is separated by column chromatography 2 Cl 2 ：CH 3 The volume ratio of OH is 20:1.
further, the molar concentration of hydrochloric acid in the step 2 is 3mol/L.
Use of a heavy atom-free photodynamic photosensitizer to produce reactive oxides under near infrared light irradiation for killing cancer cells.
Compared with the prior art, the invention has the following advantages:
compared with the currently reported photosensitizer designed based on the SOCT-ISC mechanism, the photosensitizer provided by the invention has the characteristics of being positioned in a near infrared region in absorption wavelength, good in biocompatibility, low in dark toxicity, high in singlet oxygen generation efficiency and the like. Therefore, the photosensitizer provided by the invention can generate active oxide under the irradiation of near infrared light, so that cancer cells are killed, and the photosensitizer has potential biological application value.
Drawings
FIG. 1 is a diagram of Compound 3 1 H NMR chart (CDCl) 3 ，600MHz)；
FIG. 2 shows the photosensitizer SiPPhOP 1 H NMR chart (d-DMSO, 600 MHz);
FIG. 3 shows the photosensitizer SiPPhOP 13 C NMR chart (d-DMSO, 150 MHz);
FIG. 4 is an HRMS plot of photosensitizer SiPPhOP;
FIG. 5 is a graph showing the change of the UV-visible absorption spectrum of the photosensitizer SiPPhOP under illumination;
FIG. 6 shows the laser irradiation of 9, 10-anthracenediyl-bis (methylene) bis (malonic acid) (ABDA) at 650nm,1.5mW/cm 2 ) Capturing an ultraviolet visible absorption spectrum change chart of singlet oxygen generated by photosensitive under illumination, and recording once every 30 seconds of illumination, wherein (A) is ABDA and a photosensitizer SiPPhOP; (B) ABDA and a comparison compound SiP; (C) ABDA and reference compound MB; (D) The absorbance values of ABDA at 380nm are plotted as a function of time in the graphs (A) - (C);
FIG. 7 is a graph showing the results of cytotoxicity experiments on the photosensitizers SiPPhO, wherein (black) A549 cells were incubated for further 24 hours after treatment with different concentrations (0. Mu.M, 0.5. Mu.M, 1.0. Mu.M, 1.5. Mu.M, 2.0. Mu.M, and 2.5. Mu.M) of SiPPhO for 1 hour; (Gray) A549 cells were treated with SiPPhO at various concentrations (0. Mu.M, 0.5. Mu.M, 1.0. Mu.M, 1.5. Mu.M, 2.0. Mu.M and 2.5. Mu.M) for 1 hour, followed by 650nm laser (20 mW/cm) 2 20 min) was continued to incubate for 24 hours after irradiation.
Detailed Description
Example 1
A photodynamic photosensitizer without heavy atoms has the structural formula:
the preparation method of the heavy atom-free photodynamic photosensitizer comprises the following steps:
(1) Phenoxazine (1.83 g,10.0 mmol), 2-bromo-5-iodotoluene (1.57 mL,11.0 mmol), sodium tert-butoxide (1.92 g,20.0 mmol) and cuprous iodide (0.38 g,0.2 mmol) were added sequentially to 1, 4-dioxane (30 mL) under nitrogen, the mixture was stirred well, 1, 2-diaminocyclohexane (complexant, 2 mL) was added to the above solution, the mixture was refluxed at 130℃for 18 hours, and after the reaction was completed, it was cooled to room temperature, and the solvent was evaporated. Crude product warpColumn Chromatography (CH) 2 Cl 2 : n-hexane, 1:4, v/v) to give 10- (4-bromo-2-methylphenyl) phenoxazine (1.6 g, 45.5% yield).
1 H NMR(600Hz,CDCl 3 )7.79(d,J＝6.0Hz,1H),7.24(s,2H),7.07(d,J＝8.4Hz,1H),6.72(s,2H),6.61(s,4H),5.92(s,2H),2.47(s,3H)。
(2) 10- (4-bromo-2-methylphenyl) phenoxazine (306 mg,0.869 mmol) was added to a dry round bottom flask, anhydrous THF (10.0 mL) was added under nitrogen protection, and the resulting solution was cooled to-78 ℃, followed by dropwise addition of n-butyllithium solution (2.5 m,0.34mL,0.869 mmol), reaction at-78 ℃ for 60 minutes, followed by dropwise addition of a THF solution of silica Luo Gongtong (94.1 mg,0.29 mmol), the reaction gradually returning to room temperature and continuing the reaction for 4 hours. After the reaction was completed, the reaction mixture was quenched with water and acidified with 3M hydrochloric acid, and stirring was continued for 30 minutes. The mixture was extracted, dried and column chromatographed (DCM/meoh=20/1) to give a blue-violet solid (157 mg, 29.3%).
1 H NMR(600Hz,d-DMSO)δ7.53(s,1H),7.47(d,J＝3.0Hz,2H),7.44(m,2H),7.09(d,J＝9.6Hz,2H),6.94(dd,J 1 ＝3.0Hz,J 2 ＝9.6,2H),6.75(m,6H),6.11(dd,J 1 ＝1.8Hz,J 2 ＝7.2,2H),3.63(q,J＝9.0Hz,8H),3.32(s,6H),2.50(s,6H),2.04(s,3H),0.64(s,3H),0.61(s,3H)；
13 C NMR(150MHz,d-DMSO)δ166.5,154.1,147.6,143.5,140.5,139.5,139.2,138.7,134.1,132.3,132.1,128.1,126.6,124.2,122.0,115.7,115.3,113.8；
ESI-MS:[M] + calcd for 580.278,Found 580.280.
Example 2
1. Preparation of test solutions
The photosensitizer sipph o was formulated with acetonitrile as a 2mM stock solution and then diluted to the test concentration with organic solvent or 20mM PBS (pH 7.4).
2. Stability study of photosensitizers
To ensure stability of sipph o under light irradiation, changes in the uv-vis absorption spectrum of sipph o (1 μm) under near infrared light (650 nm) irradiation were first tested. As shown in FIG. 5, the maximum absorption wavelength of SiPPhO in DCM was 654nm, and the absorption spectrum (scanned every 30 s) did not change significantly after 4 minutes of continuous illumination (1.5 mV,650 nm). The above results indicate that the photosensitizer sipph o has excellent stability under light conditions, a property critical for photodynamic therapy.
3. Photosensitizer in vitro performance study
In order to verify that the photosensitizer developed based on the SOCT-ISC mechanism has a stronger singlet oxygen generating capability under the illumination condition, a silicon rhodamine dye (SiP) was selected as a comparative compound. To simulate the cellular environment, the generation of singlet oxygen by sipph o and SiP in PBS was examined (fig. 6). ABDA is taken as a singlet oxygen capturing agent, MB is taken as a reference compound, 650nm (1.5 mV) is taken as excitation light, and the singlet oxygen generation efficiency of SiPPhO and a comparison compound SiP thereof in PBS is calculated to be 0.12 and 0.0009 respectively. The results demonstrate that the silicon rhodamine dye SiP does not have the capability of intersystem crossing under the light excitation, while SiPPhO has effective intersystem crossing under the light excitation, and the singlet oxygen generation efficiency is improved by 133 times compared with that of a comparison compound.
4. Photosensitizer photodynamic therapy effect research
To further verify the bio-application effect of the photosensitizer, the biotoxicity and photodynamic therapy effect of the photosensitizer were tested by CCK8 experiments. A549 cells were incubated with SiPPhO at various concentrations (0-2.5. Mu.M) for 1 hr, and the control group was placed in a cell incubator for further incubation for 24 hr, with laser light (650 nm,20mW/cm 2 ) After 20 minutes of irradiation, the cells were placed in a cell incubator and incubated for a further 24 hours. As shown in fig. 7, sipph o has negligible dark toxicity, its phototoxicity increases gradually with increasing concentration, and the concentration of photoperiod (EC 50 ) About 1.17 μm. Experimental results show that the photosensitizer SiPPhO has high phototoxicity and low darkness, and is an effective photodynamic therapeutic agent.
In conclusion, the invention constructs the heavy atom-free photodynamic photosensitizer SiPPhO based on the SOCT-ISC mechanism, and the photosensitizer has the advantages of absorption wavelength in a near infrared region, good biocompatibility, high singlet oxygen generation efficiency, low darkness and high phototoxicity, and has potential biological application value.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (8)
1. The photodynamic photosensitizer without heavy atoms is characterized by comprising the following structural formula:
2. a method of preparing the heavy atom-free photodynamic photosensitizer as set forth in claim 1, comprising the steps of:
step 1, under the protection of nitrogen, sequentially adding phenoxazine, 2-bromo-5-iodotoluene, sodium tert-butoxide and cuprous iodide into 1, 4-dioxane, fully and uniformly stirring, then adding a complexing agent 1, 2-diaminocyclohexane into the solution, carrying out reflux reaction, cooling to room temperature after the reaction is finished, evaporating the solvent, and separating a crude product by column chromatography to obtain 10- (4-bromo-2-methylphenyl) phenoxazine;
and 2, under the protection of nitrogen, adding anhydrous THF into the 10- (4-bromo-2-methylphenyl) phenoxazine obtained in the step 1, cooling the obtained solution, dropwise adding n-butyllithium solution for reaction, then dropwise adding THF solution of silica-pyridine Luo Gongtong, continuing the reaction after the reaction solution is restored to room temperature, quenching with water and acidizing with hydrochloric acid after the reaction is finished, continuing stirring, and obtaining the phenoxazine-silicon rhodamine dye through extraction, drying and column chromatography separation, namely the photosensitizer.
3. The method for preparing the photodynamic photosensitizer without heavy atoms according to claim 2, wherein the molar ratio of the phenoxazine, the 2-bromo-5-iodotoluene, the sodium tert-butoxide and the cuprous iodide in the step 1 is 1:1.1:2:0.02.
4. the method for preparing a heavy atom-free photodynamic photosensitizer according to claim 2, wherein the reflux reaction in step 1 is carried out at 130 ℃ for 18 hours, and the developing solvent CH is separated by column chromatography 2 Cl 2 : the volume ratio of the n-hexane is 1:4.
5. the method for preparing the photodynamic photosensitizer without heavy atoms according to claim 2, wherein the molar ratio of 10- (4-bromo-2-methylphenyl) phenoxazine, n-butyllithium and silico-pyridine Luo Gongtong in the step 2 is 3:3:1.
6. the method for preparing a heavy atom-free photodynamic photosensitizer according to claim 2, wherein the solution obtained in the step 2 is cooled to-78 ℃, the reaction temperature of adding n-butyllithium solution is-78 ℃ for 60min, the reaction is continued for 4h after room temperature, stirring is continued for 30min, and the developing agent CH is separated by column chromatography 2 Cl 2 ：CH 3 The volume ratio of OH is 20:1.
7. the method for preparing the photodynamic photosensitizer without heavy atoms according to claim 2, wherein the molar concentration of hydrochloric acid in the step 2 is 3mol/L.
8. Use of the heavy atom free photodynamic photosensitizer of claim 1 for the preparation of a reagent for killing cancer cells.
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| CN1886353A (en) * | 2003-09-29 | 2006-12-27 | 阿伯丁大学董事会 | Methods of [11C]-radiolabelling phenothiazine and phenothiazine-like compounds |
| CN105085556A (en) * | 2015-07-28 | 2015-11-25 | 沈阳化工大学 | Ring-fused structural near-infrared photosensitizer and preparation method thereof |
| CN113480551A (en) * | 2021-08-16 | 2021-10-08 | 合肥学院 | Targeted phenoxazine porphyrin, preparation method and application thereof as triplet photosensitizer |
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| CN1886353A (en) * | 2003-09-29 | 2006-12-27 | 阿伯丁大学董事会 | Methods of [11C]-radiolabelling phenothiazine and phenothiazine-like compounds |
| CN105085556A (en) * | 2015-07-28 | 2015-11-25 | 沈阳化工大学 | Ring-fused structural near-infrared photosensitizer and preparation method thereof |
| CN113480551A (en) * | 2021-08-16 | 2021-10-08 | 合肥学院 | Targeted phenoxazine porphyrin, preparation method and application thereof as triplet photosensitizer |
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