BODIPY compound, preparation method and application of BODIPY compound as photosensitizer

Abstract

The invention belongs to the technical field of photodynamic therapy, and particularly relates to a BODIPY compound, a preparation method and application of the BODIPY compound as a photosensitizer. The invention provides a series of novel-structure small molecule compound photosensitizers which take BODIPY dimers as basic frameworks and are pure I-type photodynamic. Under the combined action of a heavy atom introduced at a specific position, 2, 4, 6-trimethylphenyl and a defined structure R group, the yield of active oxygen is improved, and the regulation and control of the pure I-type photosensitizer are performed by regulating and controlling the energy level. Compared with a common photosensitizer molecule indocyanine green (ICG), the active oxygen yield is about 50 times that of ICG, higher photo-thermal stability is achieved, the applicability of a photodynamic reagent can be remarkably improved, the preparation method is simple, the reaction efficiency is high, the yield is high, and good industrial application prospects are achieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of photodynamic therapy, and particularly relates to a BODIPY compound, a preparation method thereof, and its use as a photosensitizer. Background Art

[0002] Photodynamic therapy (PDT) has the advantages of less invasiveness, high controllability, low toxicity, and high spatiotemporal precision. It is a safe, efficient, and low-cost cancer treatment technology and has been widely studied in the treatment of solid tumors, such as melanoma, skin cancer, esophageal cancer, and lung cancer. The mechanism of action of PDT is that under the excitation of light, photosensitizers (PSs) react with oxygen and other substances to generate reactive oxygen species (ROS). Reactive oxygen species have high reactivity and can induce apoptosis or necrosis of cells, closure of microvessels, and immune responses, thereby curing diseases such as cancer. PDT is a method that uses light of an appropriate wavelength to activate photosensitizers, enabling them to generate cytotoxic reactive oxygen species through type I photosensitization mechanism or type II photosensitization mechanism, thereby achieving the purpose of anti-tumor. Compared with traditional methods such as surgical resection, chemotherapy, and radiotherapy, PDT has unique advantages such as less trauma, low toxic and side effects, and a wide range of indications.

[0003] BODIPY molecules have excellent photophysical and chemical properties and are potential candidate substances for photosensitizers. However, the ability of existing photosensitizer molecules with a BODIPY dimer as the basic skeleton to generate reactive oxygen species is still not ideal. How to modify its structure to make it have a strong ability to generate reactive oxygen species is still a technical problem to be solved urgently. Summary of the Invention

[0004] In view of the deficiencies of the prior art, the present invention provides a BODIPY compound, a preparation method thereof, and its use as a photosensitizer. Through reasonable molecular design, the present invention realizes precise regulation of the excited state energy level, constructs a near-infrared pure type I photosensitive molecule with a high reactive oxygen yield, can increase the ISC rate of the photosensitizer, extend the triplet state lifetime, and increase the tumor treatment effect of photodynamic therapy.

[0005] In the first aspect, the present invention provides a BODIPY compound, and its structural formula is shown as formula (Ⅰ):

[0006]

[0007] Wherein: R is a C6-C10 aryl group or a C6-C10 aryl group substituted by a C1-C6 alkoxy group; X is a halogen atom.

[0008] In some embodiments, R is a phenyl group or a C1-C6 alkoxyphenyl group.

[0009] In some embodiments, R is phenyl, methoxyphenyl, ethoxyphenyl or propoxyphenyl.

[0010] In some embodiments, X is an iodine atom or a bromine atom.

[0011] In some embodiments, the structural formula of the compound is selected from any one of the following:

[0012]

[0013] In a second aspect, the present invention provides a method for preparing the aforementioned BODIPY compound, specifically as follows:

[0014]

[0015] Wherein: the definitions of R and X are the same as above and will not be elaborated here.

[0016] Step 1: In the presence of a solvent, the compound shown in formula (a) reacts with a halogenating reagent at 70 - 90 °C for 1 - 3 h to obtain the compound shown in formula (b);

[0017] Step 2: The compound shown in formula (b) reacts at 100 - 120 °C for 1 - 2 h in the presence of an inert gas, a catalyst and a solvent to obtain the compound shown in formula (c);

[0018] Step 3: In the presence of a solvent, the compound shown in formula (c) reacts with a halogenating reagent at room temperature for 1 - 3 h to obtain the compound shown in formula (d);

[0019] Step 4: In the presence of a catalyst, a solvent and a base, the compound shown in formula (d) reacts with the compound shown in formula (e) at 100 - 120 °C for 1 - 3 h to obtain the compound shown in formula (f);

[0020] Step 5: The compound shown in formula (f) reacts at 0 °C for 2 - 5 h in the presence of a halogenating reagent and a solvent to obtain the compound shown in formula (I).

[0021] In some embodiments, in Step 1, the molar ratio of the compound shown in formula (a) to the halogenating reagent is 1:8 - 12. The halogenating reagent is preferably copper halide, more preferably copper chloride, and most preferably copper chloride dihydrate. The solvent is preferably acetonitrile. An oxidizing agent is also included, preferably potassium persulfate.

[0022] In some embodiments, in step two, the inert gas includes but is not limited to nitrogen, argon, preferably argon. The catalyst includes palladium catalysts, organic phosphines, and organotin catalysts. Palladium catalysts include but are not limited to tetrakis(triphenylphosphine)palladium, palladium acetate, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, or dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium, preferably tris(dibenzylideneacetone)dipalladium; organic phosphines include but are not limited to tris(o-tolyl)phosphine, tributylphosphine, or triphenylphosphine, preferably tris(o-tolyl)phosphine; organotin catalysts include but are not limited to hexabutyltin, methyltin trichloride, triethyltin bromide, dibutyltin dichloride, dimethyltin dichloride, phenyltin trichloride, tin tetrachloride, trimethyltin chloride, stannous octoate, diphenyltin dichloride, tributyltin azide, preferably hexabutyltin. The solvent is preferably a mixed solvent of toluene and water.

[0023] In some embodiments, in step three, the molar ratio of the compound represented by formula (c) to the halogenating reagent is 1:8 - 12. The halogenating reagent is preferably copper halide, more preferably copper chloride, and most preferably copper chloride dihydrate. The solvent is preferably a CH3CN / DCM mixed solvent.

[0024] In some embodiments, in step four, the molar ratio of the compound represented by formula (d) to the compound represented by formula (e) is 1:2 - 4. The catalyst includes palladium catalysts, which include but are not limited to tetrakis(triphenylphosphine)palladium, palladium acetate, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, or dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium, preferably tetrakis(triphenylphosphine)palladium. The solvent is preferably a mixed solvent of toluene and water. The base includes but is not limited to sodium carbonate, potassium carbonate, cesium carbonate, piperidine, trimethylamine, triethylamine, pyridine, preferably sodium carbonate.

[0025] In some embodiments, in step five, the molar ratio of the compound represented by formula (f) to the halogenating reagent is 1:0.5 - 2. The halogenating reagent is N-halosuccinimide, preferably N-bromosuccinimide or N-iodosuccinimide. The solvent is preferably a DCM / DMF mixed solvent.

[0026] In a third aspect, the present invention provides the use of the aforementioned BODIPY compounds as photosensitizers for photodynamic therapy.

[0027] The beneficial effects of the present invention are as follows:

[0028] The present invention provides a series of novel small molecule compound photosensitizers with a BODIPY dimer as the basic skeleton and pure type-I photodynamic properties. In particular, through the combined action of heavy atoms introduced at specific positions, 2,4,6-trimethylphenyl, and a defined structural R group, the yield of reactive oxygen species is increased, and the regulation of pure type-I photosensitizers is achieved by adjusting the energy levels. Compared with the common photosensitizer molecule indocyanine green (ICG), the yield of reactive oxygen species is about 50 times that of ICG, with higher photothermal stability, which can significantly increase the applicability of photodynamic reagents. Moreover, the preparation method is simple, with high reaction efficiency and high yield, showing good prospects for industrial application. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the technical solutions of the present invention, the following will briefly introduce the drawings required for use in the embodiments. Obviously, the drawings in the following description are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0030] Figure 1 1H NMR spectrum of compound B-2;

[0031] Figure 2 1H NMR spectrum of compound B-3;

[0032] Figure 3A Normalized UV absorption spectra of compound B-2 in different solutions;

[0033] Figure 3B Normalized fluorescence emission spectra of compound B-2 in different solutions excited at 750 nm;

[0034] Figure 4A Degradation curve of DPBF blank indicator in methanol (10 mW cm -2 );

[0035] Figure 4B Degradation curve of DPBF blank indicator in dimethyl sulfoxide (10 mW cm -2 );

[0036] Figure 4C Degradation curve of DPBF blank indicator in toluene (10 mW cm -2 );

[0037] Figure 5A Degradation curve of DPBF in methanol with ICG (10 mW cm -2 );

[0038] Figure 5B Degradation curve of DPBF in dimethyl sulfoxide with ICG (10 mW cm -2) Degradation curve;

[0039] Figure 5C is the degradation curve of ICG in toluene with DPBF (10 mW cm -2 ) Degradation curve;

[0040] Figure 6A is the degradation curve of compound B-2 in dichloromethane with DPBF (5 mW cm -2 ) Degradation curve;

[0041] Figure 6B is the degradation curve of compound B-2 in dichloromethane with DPBF (5 mW cm -2 ) Linear relationship of the degradation curve;

[0042] Figure 6C is the degradation curve of compound ICG in dichloromethane with DPBF (5 mW cm -2 ) Degradation curve;

[0043] Figure 6D is the degradation curve of compound ICG in dichloromethane with DPBF (5 mW cm -2 ) Linear relationship of the degradation curve;

[0044] Figure 6E is the degradation curve of compound B-2 in chloroform with DPBF (5 mW cm -2 ) Degradation curve;

[0045] Figure 6F is the degradation curve of compound B-2 in chloroform with DPBF (5 mW cm -2 ) Linear relationship of the degradation curve;

[0046] Figure 6G is the degradation curve of compound ICG in chloroform with DPBF (5 mW cm -2 ) Degradation curve;

[0047] Figure 6H is the degradation curve of compound ICG in chloroform with DPBF (5 mW cm -2 ) Linear relationship of the degradation curve;

[0048] Figure 6I is the slope comparison of compound B-2 and ICG in different solvents;

[0049] Figure 7A is the degradation curve of ABDA blank indicator in tetrahydrofuran (70 mW cm -2 ) Degradation curve;

[0050] Figure 7B is the degradation curve of ICG in tetrahydrofuran with ABDA (70 mW cm -2 ) Degradation curve;

[0051] Figure 7C The degradation curve of compound B-2 in tetrahydrofuran for ABDA (70 mW cm -2 );

[0052] Figure 8 The curve change of DHE (300 mW cm -2 ) of compound B-2 in chloroform;

[0053] Figure 9A The temperature change curve of compound B-2 with a concentration of 50 μg mL -1 under laser irradiation at different power densities;

[0054] Figure 9B The temperature change curve of compound B-2 with different concentrations under laser irradiation at 1 W cm -2 ;

[0055] Figure 9C The heating and cooling curve of compound B-2 with a concentration of 20 μg / mL irradiated with 1 W cm -2 power;

[0056] Figure 9D The heating and cooling broken line of compound B-2 with a concentration of 20 μg / mL irradiated with 1 W cm -2 power. Detailed implementation manners

[0057] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Apparently, the described embodiments are some but not all of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0058] Term Definition

[0059] Unless otherwise specified, the technical terms used in the present invention have the meanings commonly understood by those skilled in the art. The laboratory operation steps involved are conventional steps widely used by those skilled in the art. To better understand the present invention, the definitions and explanations of related terms are provided below.

[0060] The term "C6-C10 aryl group" used herein refers to a hydrocarbon group containing a benzene ring with 6-10 carbon atoms, such as phenyl, benzyl, phenethyl, etc.

[0061] As used herein, the term "C1-C6 alkoxy-substituted C6-C10 aryl group" means that 1 to 3 H atoms on the benzene ring of the C6-C10 aryl group are substituted by C1-C6 alkoxy groups.

[0062] As used herein, the term "C1-C6 alkoxy" means an O-alkyl group having 1 to 6 carbon atoms, such as -OCH3, -OC2H5, -OC3H7, -OC4H9, -OC5H 11 、-OC6H 13 。

[0063] As used herein, the term "halogen atom" means a fluorine, chlorine, bromine, or iodine atom.

[0064] Synthesis of Compound B-2 in Example 1

[0065] (1) Synthesis of Compound A-1

[0066]

[0067] In a round-bottom flask, add Compound A (310 mg, 1 mmol, 1.0 eq), potassium persulfate (1080 mg, 4 mmol, 4.0 eq), copper(II) chloride dihydrate (1700 mg, 10 mmol, 10.0 eq), and acetonitrile (20.0 mL), and react at 80 °C for 2 h. After the reaction solution is cooled to room temperature, pour the reaction solution into dichloromethane (30 mL) and wash with water (3 × 50 mL). After drying with anhydrous sodium sulfate, remove the organic solvent by distillation under reduced pressure, and obtain 150 mg of a red solid by silica gel column chromatography, which is Compound A-1.

[0068] (2) Synthesis of Compound B

[0069]

[0070] In a Schlenk tube, add Compound A-1 (577.9 mg, 1.68 mmol, 2.1 eq), tris(dibenzylideneacetone)dipalladium(0) (40.48 mg), tris(ortho-tolyl)phosphine (52.80 mg), hexabutyltin (404 μL, 0.8 mmol, 1 eq), and toluene 20 mL. React at 110 °C for 1.5 h. After the reaction solution is cooled to room temperature, obtain 60 mg of a blue solid by silica gel column chromatography, which is Compound B.

[0071] (3) Synthesis of Compound B-Cl

[0072]

[0073] In a round-bottom flask, compound B (618 mg, 1 mmol, 1.0 eq), copper(II) chloride dihydrate (1700 mg, 10 mmol, 10.0 eq), and a mixed solvent of CH3CN / DCM (V / V = 1:1, 200.0 mL) were added, and the reaction was carried out at room temperature for 2 h. The reaction solution was poured into water (250 mL), and the flask was rinsed with water (3 × 100 mL). After drying with anhydrous sodium sulfate, the organic solvent was removed by distillation under reduced pressure, and 300 mg of a blue solid was obtained by silica gel column chromatography, which was compound B-Cl.

[0074] (4) Synthesis of compound B-1

[0075]

[0076] In a Schlenk tube, compound B-Cl (131 mg, 0.2 mmol, 1.0 eq), 4-methoxystyrylphenylboronic acid (106.8 mg, 0.6 mmol, 3.0 eq), tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol, 1.0 eq) were added. After evacuating air, toluene (5.0 mL), water (1 mL), and sodium carbonate (32 mg, 0.3 mmol, 3.0 eq) were added. The reaction was carried out at 110 °C for 2 h. The reaction solution was poured into dichloromethane (50 mL), and the tube was rinsed with water (3 × 50 mL). After drying with anhydrous sodium sulfate, the organic solvent was removed by distillation under reduced pressure, and 25 mg of a blue-black solid was obtained by silica gel column chromatography, which was compound B-1.

[0077] (5) Synthesis of compound B-2

[0078]

[0079] In a round-bottom flask, compound B-1 (15 mg, 0.02 mmol, 1.0 eq) and NBS (3.56 mg, 0.02 mmol, 3.0 eq) were added. 5 mL of DCM and 5 mL of DMF were added, and the reaction was started at 0 °C. After completion, the reaction mixture was poured into dichloromethane (20 mL), washed three times with water (20 mL), dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography to obtain 2.1 mg of a black-green solid product, which was compound B-2. The 1H NMR spectrum is as Figure 1 shown.

[0080] Example 2 Synthesis of compound B-3

[0081] Steps (1), (2), and (3) for the preparation of compound B-3 were carried out according to Example 1.

[0082] (4) Synthesis of compound B-3-1

[0083]

[0084] In a Schlenk tube, compound B-Cl (131 mg, 0.2 mmol, 1.0 eq), styreneboronic acid (264.6.8 mg, 0.6 mmol, 3.0 eq), tetrakis(triphenylphosphine)palladium (12 mg, 0.01 mmol, 1.0 eq) were added respectively. After evacuating air, toluene (5.0 mL), water (1 mL), and sodium carbonate (32 mg, 0.3 mmol, 3.0 eq) were added. The reaction was carried out at 110 °C for 2 h. The reaction mixture was poured into dichloromethane (50 mL) and washed with water (3 × 50 mL). After drying over anhydrous sodium sulfate, the organic solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 25 mg of a blue-black solid, which was compound B-3-1.

[0085] (5) Synthesis of compound B-3

[0086]

[0087] In a round-bottom flask, compound B-3-1 (14.4 mg, 0.02 mmol, 1.0 eq) and NIS (13.5 mg, 0.02 mmol, 3.0 eq) were added respectively. 5 mL of DCM and 5 mL of DMF were added, and the reaction was started at 0 °C. After completion, the reaction mixture was poured into dichloromethane (20 mL) and washed three times with water (20 mL). After drying over anhydrous sodium sulfate, filtration was carried out, and the filtrate was evaporated to dryness. The crude product was purified by column chromatography to obtain 3.8 mg of a black-green solid product, which was compound B-3. The hydrogen NMR spectrum is as Figure 2 shown.

[0088] Example 3 Synthesis of compound B-4

[0089] The preparation steps (1), (2), (3), and (4) of compound B-4 were carried out according to Example 1.

[0090] (5) Synthesis of compound B-4

[0091]

[0092] In a round-bottom flask, compound B-1 (15 mg, 0.02 mmol, 1.0 eq) and NIS (13.5 mg, 0.02 mmol, 3.0 eq) were added respectively. 5 mL of DCM and 5 mL of DMF were added, and the reaction was started at 0 °C. After completion, the reaction mixture was poured into dichloromethane (20 mL) and washed three times with water (20 mL). After drying over anhydrous sodium sulfate, filtration was carried out, and the filtrate was evaporated to dryness. The crude product was purified by column chromatography to obtain 2.3 mg of a carbon-green solid product, which was compound B-4.

[0093] Example 4 Synthesis of compound B-5

[0094] Steps for the preparation of Compound B-5: Steps (1), (2), (3), and (4) are prepared according to Example 2.

[0095] (5) Synthesis of Compound B-5

[0096]

[0097] In a round-bottom flask, add Compound B-3-1 (14.4 mg, 0.02 mmol, 1.0 eq), NBS (3.56 mg, 0.02 mmol, 3.0 eq) respectively, add 5 mL of DCM and 5 mL of DMF, start the reaction at 0 °C. After completion, pour the reaction mixture into dichloromethane (20 mL), wash three times with water (20 mL), dry over anhydrous sodium sulfate, filter, and evaporate to dryness. The crude product is purified by column chromatography to obtain 4.3 mg of a dark green solid product, which is Compound B-5.

[0098] Test Example 1: Basic spectra of the compounds of the present invention

[0099] In this test example, the absorption spectra and fluorescence spectra of Compound B-2 of the present invention in various solvents were measured. Figure 3A It is the normalized UV absorption spectrum of Compound B-2 in different solutions. Figure 3B It is the normalized fluorescence emission spectrum of Compound B-2 in different solutions under excitation at 750 nm.

[0100] Test Example 2: Test for the ability of the compounds of the present invention to generate reactive oxygen species

[0101] 1. Test principle: DPBF (1,3-Diphenylisobenzofuran) is mainly used for the detection of reactive oxygen species (ROS). Reactive oxygen species (ROS) generally refer to oxygen-derived free radicals and non-free radicals, including superoxide anion (O2 ·— ), hydrogen peroxide (H2O2), hydroxyl radical (·OH) and singlet oxygen ( 1 O2). Since they contain unpaired electrons, they have high chemical reactivity. When DPBF combines with reactive oxygen species, DPBF is irreversibly oxidized, and the absorption intensity at ultraviolet-visible light (414 nm) decreases rapidly, so it can be used to detect the generation of reactive oxygen species.

[0102] ABDA (9,10-anthracenediyl-bis(methylene)dicarboxylic acid) is a singlet oxygen indicator fluorescent probe. This water-soluble anthracene derivative reacts with singlet oxygen to photobleach to form the corresponding endoperoxide. This reaction is monitored by recording the decrease in the optical density at 400 nm by spectrophotometry and can be used to detect the generation of singlet oxygen.

[0103] DHE (Dihydroethidium) is a commonly used fluorescent probe for superoxide anions and is often used to detect the level of reactive oxygen species (ROS) in cells. After entering the cells, DHE can be dehydrogenated under the action of superoxide anions in the cells to form ethidium, which further embeds into the RNA or DNA of the cells, producing red fluorescence. The intensity of the fluorescence signal is positively correlated with the concentration of superoxide anions in the cells and can be used to detect the generation of superoxide anions.

[0104] 2. Test method: Dissolve compound B-2 or indocyanine green in different solvents, then add DPBF respectively, and irradiate each solution with laser (10 mW cm -2 ) for different times, and then measure the relative attenuation diagram of the absorbance intensity at 414 nm. Dissolve compound B-2 or indocyanine green in different solvents, then add ABDA respectively, and irradiate each solution with laser (10 mW cm -2 ) for different times, and then measure the relative attenuation diagram of the absorbance intensity of the characteristic peak.

[0105] 3. Test results:

[0106] Figure 4A is the degradation curve of the DPBF blank indicator in methanol (10 mW cm -2 ); Figure 4B is the degradation curve of the DPBF blank indicator in dimethyl sulfoxide (10 mW cm -2 ); Figure 4C is the degradation curve of the DPBF blank indicator in toluene (10 mW cm -2 ). It can be seen that as the irradiation time increases, the absorption at 414 nm basically does not change, indicating that the DPBF blank indicator does not degrade in different solvents and has stability.

[0107] Figure 5A is the degradation curve of DPBF of ICG in methanol (10 mW cm -2 ), Figure 5B is the degradation curve of DPBF of ICG in dimethyl sulfoxide (10 mW cm -2 ), Figure 5C is the degradation curve of DPBF of ICG in toluene (10 mW cm -2 ). It can be seen that as the irradiation time increases, the absorption at 414 nm degrades less, indicating that the ROS production rate of ICG is low.

[0108] Figure 6A is the degradation curve of DPBF of compound B-2 in dichloromethane (5 mW cm -2 ), Figure 6BThe linear relationship of the degradation curve of compound B-2 with DPBF (5 mW cm -2 ) in dichloromethane. It can be seen that as the irradiation time increases, the absorption at 414 nm degrades significantly, indicating a relatively high reactive oxygen species yield of the compound.

[0109] Figure 6C The degradation curve of compound ICG with DPBF (5 mW cm -2 ) in dichloromethane, Figure 6D The linear relationship of the degradation curve of compound ICG with DPBF (5 mW cm -2 ) in dichloromethane. It can be seen that as the irradiation time increases, the absorption at 414 nm degrades less, indicating a relatively low reactive oxygen species yield of the compound.

[0110] Figure 6E The degradation curve of compound B-2 with DPBF (5 mW cm -2 ) in chloroform, Figure 6F The linear relationship of the degradation curve of compound B-2 with DPBF (5 mW cm -2 ) in chloroform. It can be seen that as the irradiation time increases, the absorption at 414 nm degrades significantly, indicating a relatively high reactive oxygen species yield of the compound.

[0111] Figure 6G The degradation curve of compound ICG with DPBF (5 mW cm -2 ) in chloroform, Figure 6H The linear relationship of the degradation curve of compound ICG with DPBF (5 mW cm -2 ) in chloroform. It can be seen that as the irradiation time increases, the absorption at 414 nm degrades less, indicating a relatively low reactive oxygen species yield of the compound.

[0112] Figure 6I The slope comparison of compound B-2 and ICG in different solvents. The calculation by slope comparison is shown in Table 1:

[0113] Table 1

[0114]

[0115] Reactive oxygen species yield calculation formula: Φ Δx =Φ Δs (S x / S s )(F s / F x); where the subscript X represents the sample participating in the test, S represents the reference compound ICG; Φ represents the reactive oxygen production, S is the slope of the straight line obtained by linearly fitting with the irradiation time as the x-axis and the absorbance of DPBF at 414 nm after the corresponding irradiation time as the y-axis, F represents the absorption correction factor, and the calculation formula is F = 1 - 10 -OD , OD represents the ultraviolet absorption value of the compound at the wavelength corresponding to the irradiation laser (uniformly 755 nm in this test).

[0116] It can be seen that the reactive oxygen production rate of compound B-2 in DCM is 51.95 times that of ICG, and the reactive oxygen production rate of compound B-2 in TCM is 52.29 times that of ICG.

[0117] Figure 7A is the degradation curve of ABDA blank indicator in tetrahydrofuran (70 mW cm -2 ), Figure 7B is the degradation curve of ICG in ABDA in tetrahydrofuran (70 mW cm -2 ), Figure 7C is the degradation curve of compound B-2 in ABDA in tetrahydrofuran (70 mW cm -2 ). The above test data show that under the same power, ABDA itself does not undergo any degradation, compound ICG undergoes degradation, indicating that ICG generates singlet oxygen and is not a pure type I photosensitizer. B-2 basically does not undergo degradation, indicating that B-2 basically does not generate singlet oxygen, indicating that the types of reactive oxygen generated are superoxide radicals and hydroxyl radicals, and it is a pure type I photosensitizer.

[0118] Figure 8 is the curve change of DHE (300 mW cm -2 ) of compound B-2 in chloroform. It can be seen that the fluorescence of DHE at 610 nm is significantly enhanced, indicating that compound B-2 can effectively generate superoxide radicals.

[0119] Test Example 3 Photothermal performance test of the compounds of the present invention

[0120] In this test example, the photothermal performance of compound B-2 in Example 1 was tested. Compounds with different concentrations were irradiated with lasers of different optical powers, and their temperatures were measured and recorded. Using a laser power device of 20 μg / mL and 1 W cm -2 , the temperature was recorded every 10 s, and the photothermal heating curve and the negative natural logarithm graph of the cooling time and the temperature in the cooling stage were plotted. The test results are shown in Figure 9A 、 9B 、9C、9D.

[0121] Figure 9AIt is the temperature change curve of Compound B-2 with a concentration of 50 μg / mL under laser irradiation at different power densities. The results show that at the same concentration, as the laser power increases, the temperature of the compound rises higher.

[0122] Figure 9B It is the temperature change curve of Compound B-2 with different concentrations under laser irradiation of 1 W / cm². -2 The results show that under the condition of the same power, as the concentration of the compound increases, the temperature rises higher.

[0123] Figure 9C It is the heating and cooling curve of Compound B-2 with a concentration of 20 μg / mL after irradiation with a power of 1 W / cm². -2

[0124] Figure 9D It is the heating and cooling broken line of Compound B-2 with a concentration of 20 μg / mL after irradiation with a power of 1 W / cm². The results show that after repeating four times, the maximum temperature value of Compound B-2 under repeated irradiation remains basically unchanged, indicating good photothermal stability. -2

[0125] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. A BODIPY compound, characterized in that: The structural formula of the compound is shown in formula (I): in: R is a C6-C10 aromatic hydrocarbon group, or a C6-C10 aromatic hydrocarbon group substituted by a C1-C6 alkoxy group; X is a halogen atom.

2. The BODIPY compound according to claim 1, characterized in that: The R is a phenyl group or a C1-C6 alkoxyphenyl group.

3. The BODIPY compound according to claim 2, characterized in that: The R is phenyl, methoxyphenyl, ethoxyphenyl or propoxyphenyl.

4. The BODIPY compound according to claim 1, characterized in that: The X is an iodine atom or a bromine atom.

5. The BODIPY compound according to claim 3, characterized in that: The structural formula of the compound is selected from any one of the following:

6. A method for preparing the BODIPY compound according to any one of claims 1 to 5, characterized in that: The preparation method comprises: performing a first reaction on a compound represented by formula (d) and a compound represented by formula (e), and performing a second reaction on the first reaction product and a halogenating agent; in: R is a C6-C10 aromatic hydrocarbon group, or a C6-C10 aromatic hydrocarbon group substituted by a C1-C6 alkoxy group; X is a halogen atom.

7. The preparation method according to claim 6, characterized in that: The conditions of the first reaction include: reacting at 100-120° C. for 1-3 hours in the presence of an inert gas, a palladium catalyst, a solvent and a base.

8. The preparation method according to claim 6, characterized in that: The conditions of the second reaction include: reacting at 0° C. for 2 to 5 hours in the presence of a solvent.

9. The preparation method according to claim 6, characterized in that: The halogenating agent is N-halosuccinimide.

10. Use of the BODIPY compound according to any one of claims 1 to 5 as a photosensitizer for photodynamic therapy.

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