Fluorine boron complexed [a]-benzodipyrrole photosensitizer as well as preparation method and application thereof

Abstract

The invention discloses a fluorine-boron complexed [a]-benzodipyrrole photosensitizer with a structural formula shown in the specification. A preparation method of the photosensitizer comprises the step of catalyzing o-alkenyl benzonitrile and phenylboronic acid by using palladium to synthesize the photosensitizer in one step, the method is very simple and convenient, has good functional group compatibility, and can realize structural diversity and synthesis of the boron-fluoride complexed [a]-benzodipyrrole photosensitizer which is difficult to prepare in the past.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and more specifically to a fluoroboron complex [a]-benzodipyrrole photosensitizer and its preparation method and application. Background Art

[0002] Photodynamic therapy (PDT) is one of the clinical methods for treating cancer and has attracted much attention due to its safety, precision, non-invasiveness and low drug risk. This therapy induces cancer cell death by generating reactive oxygen free radicals through light-activated photosensitizers. Compared with traditional therapies (such as surgery, chemotherapy and radiotherapy), photodynamic therapy has the advantages of strong local effects and few side effects, making it a powerful option for treating various malignant tumors. However, the key to the success of PDT treatment depends on the properties of the photosensitizer, which has promoted important research on the development of innovative photosensitizers with enhanced efficacy.

[0003] Boron-dipyrrole (BODIPY) is an ideal candidate for photosensitizer due to its excellent photostability, biocompatibility and modifiability. Despite the progress, many BODIPYs have not yet fully realized their potential due to their low singlet quantum yield. To address this problem, a common approach is to introduce heavy atoms (such as platinum, iridium, iodine and bromine) into the BODIPYs structure to enhance the singlet oxygen ( 1 O2). Although this strategy is effective, it usually raises concerns about increased dark toxicity, short triplet lifetime, poor photostability, and the potential high cost of heavy metals, which is not conducive to its clinical application. Therefore, the development of BODIPY photosensitizers without heavy atoms is of great scientific research significance. Common strategies to achieve this goal include introducing electron spins or electron-donating groups, constructing orthogonal BODIPY dimers or trimers, and fusing aromatic rings to expand the π conjugated system. Among them, fusing aromatic rings to expand the π conjugated system is particularly effective and research has mainly focused on the fusion of [b]-aromatic rings. However, research on BODIPY photosensitizers without heavy atoms and [a]-fused aromatic rings for in vivo photodynamic anticancer therapy has not been reported, indicating that innovation is urgently needed in this field. Summary of the Invention

[0004] In view of the shortcomings of the prior art, the present invention aims to provide a fluoroboron complex [a]-benzodipyrrole photosensitizer.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] A fluoroboron complex [a]-benzodipyrrole photosensitizer, the structural formula of which is:

[0007]

[0008] As a further improvement of the present application,

[0009] wherein the R1 group is a hydrogen bond or a methoxy group or a trifluoromethyl group or a nitro group or a fluorine group.

[0010] As a further improvement of the present application,

[0011] wherein the R2 group is a hydrogen bond or a methoxy group or an ethoxy group or a benzyloxy group.

[0012] As a further improvement of the present application,

[0013] wherein the R3 group is a hydrogen bond or a fluorine group.

[0014] As another object of the present application, a preparation method of a fluoroboron complex [a]-benzo dipyrromethene photosensitizer is provided, comprising:

[0015] Step one: under an oxygen atmosphere, 2-styrylbenzonitrile compound, 2,6-dimethylphenylboronic acid compound, palladium trifluoroacetate, 4,4'-di-tert-butyl-2,2'-bipyridine, trifluoroacetic acid, potassium fluoride are reacted to obtain a first product;

[0016] Step two: the first product is dissolved with a solvent, and triethylamine is added under stirring at low temperature for alkalization and dehydrogenation, then ether boron trifluoride is added dropwise, and after stirring at low temperature, reaction is carried out at room temperature, and after quenching the reaction with water, spinning drying, extraction, drying, concentration, separation, the photosensitizer is obtained;

[0017] The structural formula of the 2-styrylbenzonitrile compound is:

[0018]

[0019] The structural formula of the 2,6-dimethylphenylboronic acid compound is:

[0020]

[0021] The structural formula of the first product is:

[0022]

[0023] As a further improvement of the present application,

[0024] The step one is specifically:

[0025] Under an oxygen atmosphere, the raw materials 2-styrylbenzonitrile compound, 2,6-dimethylphenylboronic acid compound, palladium trifluoroacetate, 4,4'-di-tert-butyl-2,2'-bipyridine, trifluoroacetic acid, potassium fluoride are added in a Schlenk tube, and reaction is carried out at 110°C for 24h, and separation is carried out by using a silica gel chromatographic column, and the eluent is petroleum ether and ethyl acetate with a volume ratio of 50-100:1, to obtain the first product.

[0026] As a further improvement of the present application,

[0027] The step one is specifically:

[0028] The molar ratio of 2-styrylbenzonitrile, 2,6-dimethylphenylboronic acid, palladium trifluoroacetate, 4,4'-di-tert-butyl-2,2'-bipyridine, trifluoroacetic acid, potassium fluoride is 1.5-2.5:5-8:0.05-0.15:0.1-0.3:5-8:3-5.

[0029] Preferably, the molar ratio of 2-styrylbenzonitrile, 2,6-dimethylphenylboronic acid, palladium trifluoroacetate, 4,4'-di-tert-butyl-2,2'-bipyridine, trifluoroacetic acid, potassium fluoride is 2:6:0.1:0.2:6:4.

[0030] The 2-styrylbenzonitrile is synthesized from 2-iodobenzonitrile and a styrene compound, wherein the styrene compound is one of styrene, p-trifluoromethylstyrene, p-methoxystyrene, 4-nitrostyrene, 3,4-difluorostyrene.

[0031] The specific steps are mixing 2-iodobenzonitrile, sodium carbonate, palladium acetate (Pd(OAc)2), tetrabutylammonium bromide (TBAB), dimethylacetamide (DMA), styrene, and reacting at 100-150°C for 30-60h to obtain the 2-styrylbenzonitrile compound.

[0032] For the synthesis of 2-styrylbenzonitrile, it has been a relatively mature prior art, such as Pyridinyl functionalized MCM-48 supported highly active heterogeneous palladium catalyst for cross-coupling reactions RSC. Adv. 2015, 519630. discloses the synthesis method, and the present application does not make too much description.

[0033] As a further improvement of the present application,

[0034] The step two is specifically:

[0035] The first product is dissolved in dichloromethane, triethylamine is added dropwise under stirring at 0 DEG C, after stirring for 10 min, the dehydrogenation is alkalized, ether boron trifluoride is added dropwise, after stirring for 10-15 min at low temperature, the reaction is carried out at normal temperature, the reaction process is monitored by TLC, 1-2 drops of water are added to quench the reaction, the reaction liquid is dried by vacuum rotation, extracted with ethyl acetate and saturated brine, the EA layer is dried by adding anhydrous magnesium sulfate, concentrated under vacuum, the reaction system is separated and purified by eluent system through fast column chromatography, the eluent is petroleum ether and ethyl acetate with a volume ratio of 50-100:1, and the photosensitizer is obtained.

[0036] As a further improvement of the present application,

[0037] In the step two:

[0038] The molar ratio of the first product, triethylamine and ether boron trifluoride is 0.3-0.8:3-8:3-8.

[0039] Preferably, the molar ratio of the first product, triethylamine and ether boron trifluoride is 0.5:5:5.

[0040] The overall reaction general formula is:

[0041]

[0042] As another application purpose of the present application, the application of fluorine boron complex [a]-benzo dipyrrole photosensitizer in preparing photodynamic antitumor drugs is provided.

[0043] The present application designs a new fluorine boron complex [a]-benzo dipyrrole photosensitizer based on the BODIPY structure skeleton through a drug design method. The in vitro antitumor activity test results show that most of the fluorine boron complex [a]-benzo dipyrrole photosensitizer of the present application has high antitumor activity.

[0044] The present application also provides a synthesis method of the new fluorine boron complex [a]-benzo dipyrrole photosensitizer.

[0045] The present application prepares a new fluorine boron complex [a]-benzo dipyrrole photosensitizer, which is used in a drug composition for photodynamic treatment of tumors, and further comprises a pharmaceutically acceptable adjuvant. The term "pharmaceutically acceptable adjuvant" is well known to those skilled in the art, including pharmaceutically acceptable carriers, excipients, diluents, etc., which are compatible with the active ingredients. The preparation of the drug composition using the pharmaceutically acceptable adjuvant can be carried out by using the technology known to those skilled in the art.

[0046] The new type of boron-fluorine complex [a]-benzo-dipyrromethene photosensitizer prepared by the present application is combined with pharmaceutically acceptable adjuvants to prepare various formulations, preferably solid formulations and liquid formulations. The formulations of the present application can be in unit dosage forms, such as tablets, pills, capsules (including sustained release or delayed release forms), powders, suspensions, granules, tinctures, syrups, emulsions, suspensions, injections, and various sustained release dosage forms, so as to be suitable for various administration modes, such as oral, parenteral injection, mucosal, intramuscular, intravenous, subcutaneous, intraocular, intradermal or transdermal administration, etc.

[0047] The new type of boron-fluorine complex [a]-benzo-dipyrromethene photosensitizer prepared by the present application is used for photodynamic anti-tumor treatment, which produces active oxygen free radicals by light activation to treat tumors and diseases related to tumors. The diseases related to tumors include, but are not limited to: cancers, such as liver cancer (including small cell liver cancer), bladder cancer, breast cancer, colon cancer, kidney cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer and skin cancer (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, hairy cell lymphoma and Burkett's lymphoma; myeloid lineage hematopoietic tumors, including acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; multiple myeloma; tumors of mesenchymal origin, including fibroma and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xanthogranuloma, thyroid follicular carcinoma and Kaposi's sarcoma.

[0048] In this text, the term "reagent" refers to a reagent that does not meet the pharmaceutical standard, such as a reagent used in laboratory research, unless otherwise indicated.

[0049] The present application has the beneficial effect of providing a new type of boron-fluorine complex [a]-benzo-dipyrromethene photosensitizer, a new preparation method and a new use in photodynamic anti-tumor treatment. The preparation method of the photosensitizer of the present application is to synthesize the obtained product by one step of palladium-catalyzed ortho-alkenyl benzonitrile and phenylboronic acid, which is very simple, has good functional group compatibility, can realize structural diversity and synthesis of boron-fluorine complex [a]-benzo-dipyrromethene photosensitizer which is difficult to prepare in the past. In addition, the photosensitizer of the present application has high fluorescence quantum yield and singlet oxygen generation yield, excellent light / dark toxicity ratio, high selectivity in endoplasmic reticulum localization and induction of apoptosis, and the in vivo photodynamic anti-tumor effect is obviously better than that of the commercially available clinical photosensitizer Ce6. BRIEF DESCRIPTION OF DRAWINGS

[0050] Figure 1 The reaction equation of Example 1 of the present application;

[0051] Figure 2 Reaction equation for Example 2 of the present application;

[0052] Figure 3 Reaction equation for Example 3 of the present application;

[0053] Figure 4 Reaction equation for Example 4 of the present application;

[0054] Figure 5 Reaction equation for Example 5 of the present application;

[0055] Figure 6 Reaction equation for Example 6 of the present application;

[0056] Figure 7 Reaction equation for Example 7 of the present application;

[0057] Figure 8 Reaction equation for Example 8 of the present application;

[0058] Figure 9 Reaction equation for Example 9 of the present application;

[0059] Figure 10 Reaction equation for Example 10 of the present application;

[0060] Figure 11 Figure for the results of Example Test 1 of the present application testing the photophysical properties and singlet quantum yield of the photosensitizers of the present application;

[0061] Figure 12 Figure for the results of Example Test 2 of the present application testing the IC50values of the photosensitizers of the present application against different tumor cell lines;

[0062] Figure 13 Figure for the results of Example Test 3 of the present application testing the organelle localization ability of the photosensitizers of the present application;

[0063] Figure 14 Figure for the results of Example Test 4 of the present application testing the anti-tumor activity of the photosensitizers of the present application at the animal level. DETAILED DESCRIPTION

[0064] The present application will be further described with reference to the following examples given by way of illustration.

[0065] Example 1: Reference Figure 1

[0066] 1. Compound 1a, wherein, was synthesized by the laboratory itself, the specific steps are as follows:

[0067] A 100 mL Schlenk flask was charged with the corresponding 2-iodobenzonitrile (2.18 mmol), sodium carbonate (3.27 mmol, 0.347 g), palladium acetate (Pd(OAc)2) (0.11 mmol, 0.024 g) and tetrabutylammonium bromide (TBAB) (2.62 mmol, 0.844 g), dimethylacetamide (DMA) (15 mL), styrene (2.62 mmol). The mixture was stirred at 130 °C in an oil bath for 48 h. After cooling to room temperature, the reaction was quenched with water and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgS04, filtered and concentrated. Compound 1a was obtained by column chromatography (silica gel, using a mixture of n-hexane / ethyl acetate (30:1 by volume) as eluent). The yield was 87%.

[0068] The NMR results of compound 1a are as follows:

[0069] 1H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.4 Hz, 3H), 7.43 (dd, J = 24.6, 15.5 Hz, 3H), 7.32 (dd, J = 13.5, 6.6 Hz, 3H).13C NMR (100 MHz, Chloroform-d) δ 139.82, 139.65, 133.28, 132.94, 131.82, 128.27, 127.28, 126.60, 125.90, 125.86, 125.83, 125.79, 125.60, 117.84, 111.66.

[0070] 5,9-Bis(2,6-dimethylphenyl)-7,7-difluoro-14-phenyl-7H-6λ 4 ,7λ 4 -[1,3,2]diazaborinine[4,3_a:6,1-a']diisoindole (photosensitizer 4a);

[0071] Step one: A Schlenk tube was charged with the starting material 2-styrylbenzonitrile (compound 1a) (0.2 mmol), 2,6-dimethylphenylboronic acid (compound 2a) (0.6 mmol) and the additives palladium trifluoroacetate (0.01 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.02 mmol), trifluoroacetic acid (0.6 mmol), potassium fluoride (0.4 mmol) under an oxygen atmosphere, and the reaction was carried out at 110 °C for 24 h. The product 3a was isolated by silica gel chromatography using a mixture of petroleum ether / ethyl acetate (50:1 by volume) as eluent. The yield was 82% (40 mg) of a purple powder.

[0072] wherein the structural formula of 2-styrylbenzonitrile (compound la) is:

[0073]

[0074] wherein the structural formula of 2,6-dimethylphenylboronic acid (compound 2a) is:

[0075]

[0076] Step two: Compound 3a was weighed 26.43 mg (0.05 mmol) and dissolved in 3 L of ultra-dry grade dichloromethane, 70 ul (0.5 mmol) of triethylamine was added dropwise while stirring at 0°C, after stirring for 10 min, the base was dehydrated, and then 75 ul (0.5 mmol) of ether boron trifluoride was added dropwise, after stirring at low temperature for 10-15 min, the reaction was carried out at room temperature, and the reaction progress was monitored by TLC. 2 drops of water were added to quench the reaction, and the reaction solution (fluorescent powder) was dried under vacuum, extracted with 20 ml of ethyl acetate and saturated brine, the EA layer was dried with an appropriate amount of anhydrous magnesium sulfate, concentrated under vacuum, and the reaction system was separated and purified by flash column chromatography with petroleum ether / ethyl acetate (v 50:1) eluent system, to obtain photosensitizer 4a blue-purple powder 22 mg, with a yield of about 87%.

[0077] The nuclear magnetic resonance result of photosensitizer 4a is:

[0078] 1 H NMR (400 MHz, Chloroform-d) δ 7.77 (s, 5H), 7.29 (d, J = 5.3 Hz, 1H), 7.24 (s, 1H), 7.16-7.04 (m, 10H), 6.32 (d, J = 7.4 Hz, 2H), 2.10 (s, 12H). 13 C NMR (100 MHz, CDCl3) δ 153.0, 138.3, 133.8, 131.0, 130.3, 130.1, 129.3, 129.2, 127.0, 126.6, 124.7, 123.0, 120.9, 77.4, 77.1, 76.8, 20.3. HRMS (ESI) Calcd for C 39 H 31 BF2N2[M+Na] + m / z: 599.2441; found: 599.2447.

[0079] Example 2: Refer to Figure 2

[0080] 1. Compound la, synthesized by the laboratory itself, the specific steps are as follows:

[0081] A 100 mL Schlenk flask was charged with the corresponding 2-iodobenzonitrile (2.18 mmol), sodium carbonate (3.27 mmol, 0.347 g), palladium acetate (Pd(OAc)2) (0.11 mmol, 0.024 g) and tetrabutylammonium bromide (TBAB) (2.62 mmol, 0.844 g), tetrabutylammonium bromide (DMA) (15 mL), p-trifluoromethylstyrene (2.62 mmol). The mixture was stirred at 130 °C in an oil bath for 48 h. After cooling to room temperature, the reaction was quenched with water and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated. Compound 1b was obtained by column chromatography (silica gel, using a mixture of n-hexane / ethyl acetate (v 30: 1) as eluent). The yield was 70%.

[0082] The NMR results of compound 1b are as follows:

[0083] 1H NMR (400 MHz, Chloroform-d) δ 7.81 (d, J = 8.1 Hz, 1H), 7.71-7.58 (m, 6H), 7.53 (d, J = 16.2 Hz, 1H), 7.29 (d, J = 16.3 Hz, 2H).13C NMR (100 MHz, Chloroform-d) δ 139.82, 139.63, 133.29, 132.96, 131.81, 128.28, 127.28, 126.57, 125.87, 125.83, 125.59, 117.87, 111.64.

[0084] 2, 5, 9-tris(2, 6-dimethylphenyl)-7, 7-difluoro-14-(4- (trifluoromethyl) phenyl)-7H-6λ 4 , 7λ 4 [1, 3, 2] diaza borabicyclo [4, 3_a: 6, 1-a'] diisoindole (photosensitizer 4b);

[0085] The preparation method was the same as that of Example 1, except that 2- (4-(trifluoromethyl)styryl)benzonitrile (compound 1b) was used instead of 2- styrylbenzonitrile (compound 1a) in step one. The product obtained in step one was compound 3b (yield 77%), and the product obtained in step two was photosensitizer 4b (yield 80%).

[0086] The NMR results of photosensitizer 4b are as follows:

[0087] 1H NMR (400 MHz, Chloroform-d) δ 8.07 (d, J = 7.9 Hz, 2H), 7.97 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 10.0 Hz, 2H), 7.14 (m, 10H), 6.23 (d, J = 7.4 Hz, 2H), 2.11 (s, 12H). 13 C NMR (100 MHz, Chloroform-d) δ 138.4, 135.3, 130.8, 130.5, 129.5, 129.3, 129.1, 128.9, 127.0, 124.5, 122.7, 121.4, 20.3. HRMS (ESI) Calcd for C 40 H 30 BF5N2[M+Na] + m / z: 645.2495; found: 645.2502.

[0088] Example 3: Reference Figure 3

[0089] 1, wherein compound 1c, was synthesized in the laboratory by the following procedure:

[0090] A 100 mL Schlenk flask was charged with the corresponding 2-iodobenzonitrile (2.18 mmol), sodium carbonate (3.27 mmol, 0.347 g), palladium acetate (Pd(OAc)2) (0.11 mmol, 0.024 g) and tetrabutylammonium bromide (TBAB) (2.62 mmol, 0.844 g), tetrabutylammonium bromide (DMA) (15 mL), p-methoxystyrene (2.62 mmol). The mixture was stirred at 130 °C in an oil bath for 48 h. After cooling to room temperature, the reaction was quenched with water and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgS04, filtered and concentrated. Compound 1c was obtained by column chromatography (silica gel, using a mixture of n-hexane / ethyl acetate (v 30: 1) as eluent). The yield was 80%.

[0091] The NMR results of compound 1c are as follows:

[0092] 1H NMR (400 MHz, Chloroform-d) δ 7.75 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 6.3 Hz, 1H), 7.53 (dd, J = 16.6, 8.3 Hz, 3H), 7.33 - 7.19 (m, 3H), 6.91 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H).13C NMR (100 MHz, Chloroform-d) δ 160.03, 140.76, 132.87, 132.73, 132.49, 128.77, 128.30, 126.86, 124.75, 121.65, 117.93, 114.09, 110.68, 77.16, 76.84, 76.52.55.15..

[0093] 2. Preparation of 5, 9-bis (2, 6-dimethylphenyl) -7, 7-difluoro-14- (4- methoxyphenyl) -7H-6λ 4 ,7λ 4 - [1, 3, 2] diaza borabicyclo [4, 3_a: 6, 1-a'] diisoindole (photosensitizer 4c) ;

[0094] The preparation method is the same as that in Example 1, except that 2- (4-methoxy) styryl) benzonitrile (compound 1c) is used instead of 2-styrylbenzonitrile (compound 1a) in step one; the product obtained in step one is compound 3c (yield 55%), and the product obtained in step two is photosensitizer 4c (yield 75%).

[0095] The nuclear magnetic resonance result of photosensitizer 4c is as follows:

[0096] 1 1H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J = 8.6 Hz, 2H), 7.25 - 7.20 (m, 3H), 7.07 (m, 10H), 6.42 (d, J = 8.0 Hz, 2H), 4.04 (s, 3H), 2.06 (s, 12H). 13 C NMR (100 MHz, Chloroform-d) δ 160.5, 138.4, 130.5, 129.1, 128.9, 127.0, 124.4, 122.7, 121.5, 114.9, 55.6, 20.3. HRMS (ESI) Calcd for C 40 H 33 BF2N2O [M + H] + m / z: 607.2727; found: 606.2734.

[0097] Example 4: ReferenceFigure 4

[0098] Preparation 7, 7-difluoro-5, 9-bis (4-ethoxy-2, 6-dimethylphenyl) -14-phenyl-7H-6 4 , 7 4 - [1, 3, 2] diazaborol [4, 3_a: 6, 1-a'] diisoindole (photosensitizer 4d) ;

[0099] The preparation method is the same as example 1, except that 2, 6 dimethylphenyl boronic acid (compound 2a) in step one is replaced by 4-methoxy-2, 6-dimethylphenyl boronic acid (compound 2b) ; The product obtained in step one is compound 3d (yield 42%), and the product obtained in step two is photosensitizer 4d (yield 75%).

[0100] The nuclear magnetic result of photosensitizer 4d is:

[0101] 1 H NMR (400 MHz, Chloroform-d) δ 7.73 (s, 5H), 7.15-7.10 (m, 2H), 7.03 (t, J = 4.6 Hz, 4H), 6.64 (s, 4H), 6.30-6.26 (m, 2H), 3.80 (s, 6H), 2.05 (s, 12H). 13 C NMR (100 MHz, CDCl3) δ 159.9, 139.9, 136.4, 135.4, 134.0, 131.2, 129.5, 129.8, 129.3, 128.8, 125.9, 124.4, 122.9, 122.7, 121.3, 112.5, 77.4, 77.1, 76.77, 55.1, 20.6. HRMS (ESI) Calcd for C 41 H 35 BF2N2O2[M+H] + m / z: 637.2832; found: 637.2839.

[0102] Example 5: Reference Figure 5

[0103] Preparation 7, 7-difluoro-5, 9-bis (4-ethoxy-2, 6-dimethylphenyl) -14-phenyl-7H-6 4 , 7 4 - [1, 3, 2] diazaborol [4, 3_a: 6, 1-a'] diisoindole (photosensitizer 4d) ;

[0104] The preparation method is the same as that in Example 1, except that 2,6-dimethylphenylboronic acid (compound 2a) in step one is replaced by 4-ethoxy-2,6-dimethylphenylboronic acid (compound 2c); the product obtained in step one is compound 3e (yield 54%), and the product obtained in step two is photosensitizer 4e (yield 70%).

[0105] The NMR result of photosensitizer 4e is:

[0106] 1 H NMR (400 MHz, Chloroform-d) δ 7.77-7.72 (m, 1H), 7.68-7.48 (m, 3H), 7.39-7.32 (m, 1H), 7.19-7.01 (m, 6H), 6.62 (s, 4H), 6.33 (d, J = 8.2 Hz, 2H), 4.01 (q, J = 6.9 Hz, 4H), 2.02 (s, 12H), 1.41 (t, J = 7.0 Hz, 6H). 13 C NMR (100 MHz, CDC13) δ 159.3, 152.4, 139.9, 137.4, 135.3, 134.0, 131.2, 129.5, 129.5, 129.3, 128.9, 128.6, 127.9, 127.7, 125.9, 124.4, 123.1, 122.8, 121.3, 113.3, 77.4, 77.1, 76.8, 69.8, 20.6. HRMS (ESI) Calcd for C 43 H 39 BF2N2O2[M+H] + m / z: 665.3145; found: 665.3153.

[0107] Example 6: Reference Figure 6

[0108] The preparation method is the same as that in Example 1, except that 2,6-dimethylphenylboronic acid (compound 2a) in step one is replaced by 4-ethoxy-2,6-dimethylphenylboronic acid (compound 2c); the product obtained in step one is compound 3e (yield 54%), and the product obtained in step two is photosensitizer 4e (yield 70%). 4 ,7λ 4 _[1,3,2]diazaborinine[4,3_a:6,1-a']diisoindole (photosensitizer 4f);

[0109] The preparation method is the same as that in Example 1, except that 2,6-dimethylphenylboronic acid (compound 2a) in step one is replaced by 4-ethoxy-2,6-dimethylphenylboronic acid (compound 2c); the product obtained in step one is compound 3e (yield 54%), and the product obtained in step two is photosensitizer 4e (yield 70%).

[0110] The NMR result of photosensitizer 4f is:

[0111] 1 H NMR (400 MHz, Chloroform-d) δ 7.73 (s, 5H), 7.40 (ddd, J = 25.9, 18.4, 7.1 Hz, 11H), 7.15 (d, J = 12.4 Hz, 2H), 7.05 - 7.00 (m, 4H), 6.71 (s, 4H), 6.28 (d, J = 8.8 Hz, 2H), 5.08 (d, J = 8.6 Hz, 1H), 4.98 (s, 2H), 2.05 (s, 12H). 13 C NMR (100 MHz, CDC13) δ 159.3, 152.4, 139.9, 137.4, 135.3, 134.0, 131.2, 129.5, 129.3, 128.9, 128.6, 127.9, 127.7, 125.9, 124.4, 123.1, 122.8, 121.3, 113.3, 77.4, 77.1, 76.8, 69.8, 20.6. HRMS (ESI) Calcd for C 53 H 43 BF2N2O2[M+H] + m / z: 789.3458; found: 789.3467.

[0112] Example 7: Reference Figure 7

[0113] 1. Compound 1d, wherein, was synthesized by the laboratory itself, the specific steps are as follows:

[0114] A 100 mL Schlenk flask was charged with the corresponding 2-iodobenzonitrile (2.18 mmol), sodium carbonate (3.27 mmol, 0.347 g), palladium acetate (Pd(OAc)2) (0.11 mmol, 0.024 g) and tetrabutylammonium bromide (TBAB) (2.62 mmol, 0.844 g), tetrabutylammonium bromide (DMA) (15 mL), 4-nitrostyrene (2.62 mmol). The mixture was stirred at 130°C in an oil bath for 48 hours. After cooling to room temperature, the reaction was quenched with water, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgS04, filtered and concentrated. Compound 1d was obtained by column chromatography (silica gel, using n-hexane / ethyl acetate mixture (v 30:1) as eluent). The yield was 70%.

[0115] The nuclear magnetic resonance result of compound 1d is as follows:

[0116] 1H NMR (400 MHz, Chloroform-d) δ 8.25 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.1 Hz, 1H), 7.73 - 7.55 (m, 5H), 7.42 (td, J = 7.6, 1.2 Hz, 1H), 7.32 (d, J = 16.3 Hz, 1H).13C NMR (100 MHz, Chloroform-d) δ 147.97, 142.91, 139.69, 133.76, 133.43, 131.30, 129.15, 128.87, 128.03, 126.19, 124.64, 118.09, 112.27, 77.80, 77.48..

[0117] 2. Preparation of 5, 9-bis (4-ethoxy-2, 6-dimethylphenyl) -7, 7-difluoro-14- (4-nitrophenyl) -7H-6λ 4 , 7λ 4 -[1, 3, 2] diaza borol [4, 3_a: 6, 1-a'] diisoindole (compound 4g)

[0118] The preparation method is the same as example 5, except that 2-styrylbenzonitrile (compound 1a) in step one is replaced by 2- (4-nitrophenyl) styrylbenzonitrile (compound 1d) ; the product obtained in step one is compound 3g (yield 56%), and the product obtained in step two is photosensitizer 4g (yield 75%).

[0119] The nuclear magnetic result of photosensitizer 4g is as follows:

[0120] 1 H NMR (400 MHz, Chloroform-d) δ 8.65 - 8.58 (m, 2H), 8.02 - 7.95 (m, 2H), 7.18 - 7.15 (m, 2H), 7.08 - 7.05 (m, 3H), 6.63 (s, 4H), 6.18 (dt, J = 6.8, 2.8 Hz, 2H), 4.00 (q, J = 7.0 Hz, 4H), 2.02 (s, 12H), 1.41 (t, J = 7.0 Hz, 6H). 13 C NMR (100 MHz, Chloroform-d) δ 159.5, 153.7, 148.7, 142.4, 139.7, 133.5, 133.3, 131.4, 131.0, 129.4, 124.8, 123.3, 122.3, 120.6, 113.0, 63.2, 20.6, 15.0. HRMS (ESI) Calcd for C 43 H 38 BF2N3O4[M + H]+ m / z: 710.2996; found: 710.3000.

[0121] Example 8: Reference Figure 8

[0122] Example 8: Reference 4 ,7H-6λ 4 -[1,3,2]diazaborinine[4,3_a:6,1-a']diisoindole (compound 4h);

[0123] The preparation method is the same as example 5, except that 2-styrylbenzonitrile (compound 1a) in step one is replaced by 2-(4-(trifluoromethyl)styryl)benzonitrile (compound 1b); the product obtained in step one is compound 3h (yield 62%), and the product obtained in step two is photosensitizer 4h (yield 64%).

[0124] The nuclear magnetic result of photosensitizer 4h is as follows:

[0125] 1 H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 7.9 Hz, 2H), 7.92 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 9.5, 6.1 Hz, 6H), 7.53 (d, J = 16.2 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.30 (s, 1H), 7.06 (s, 3H), 4.00 (q, J = 6.8 Hz, 4H), 2.03 (s, 12H), 1.40 (t, J = 7.0 Hz, 6H). 13 CNMR (100 MHz, Chloroform-d) δ 159.4, 139.9, 139.7, 133.3, 133.0, 131.8, 128.3, 127.3, 126.6, 125.9, 125.9, 125.8, 125.6, 123.1, 117.9, 113.0, 111.6, 63.2, 20.6, 15.0. HRMS (ESI) Calcd for C 44 H 38 BF5N2O2[M+H] + m / z: 733.3019; found: 733.3027.

[0126] Example 9: Reference Figure 9

[0127] Preparation of 5, 9-bis (4-ethoxy-2, 6-dimethylphenyl) -7, 7-difluoro-14- (4- methoxyphenyl) -7H-6λ 4 ,7λ 4 - [1, 3, 2] diaza borabicyclo [4, 3_a: 6, 1-a'] diisoindole (compound 4i) ;

[0128] The preparation method is the same as example 5, except that 2-styrylbenzonitrile (compound 1a) in step one is replaced by 2- (4-methoxy) styryl) benzonitrile (compound 1c) ; the product obtained in step one is compound 3i (yield 45%), and the product obtained in step two is photosensitizer 4i (yield 75%).

[0129] The nuclear magnetic result of photosensitizer 4i is as follows:

[0130] 1 H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 3H), 7.15-6.99 (m, 6H), 6.62 (s, 4H), 6.40 (d, J = 7.9 Hz, 1H), 4.02 (d, J = 14.0 Hz, 7H), 2.02 (s, 12H), 1.41 (t, J = 7.1 Hz, 6H). 13 C NMR (100 MHz, Chloroform-d) δ 160.4, 159.3, 152.3, 139.8, 136.4, 134.0, 131.2, 130.6, 128.8, 127.4, 126.3, 124.3, 122.7, 121.4, 114.8, 112.9, 63.2, 55.6, 20.6, 15.0. HRMS (ESI) Calcd for C 44 H 41 BF2N2O3[M + Na] + m / z: 717.3071; found: 717.3078.

[0131] Example 10: Reference Figure 10

[0132] 1, wherein compound 1e, is synthesized by the laboratory itself, and the specific steps are as follows:

[0133] A 100 mL Schlenk flask was charged with the corresponding 2-iodobenzonitrile (2.18 mmol), sodium carbonate (3.27 mmol, 0.347 g), palladium acetate (Pd(OAc)2) (0.1 1 mmol, 0.024 g) and tetrabutylammonium bromide (TBAB) (2.62 mmol, 0.844 g), tetrabutylammonium bromide (DMA) (15 mL), 3,4-difluorostyrene (2.62 mmol). The mixture was stirred at 130 °C in an oil bath for 48 h. After cooling to room temperature, the reaction was quenched with water and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgS04, filtered and concentrated. Compound 1e was obtained by column chromatography (silica gel, using a mixture of n-hexane / ethyl acetate (v 30: 1) as eluent). The yield was 82%.

[0134] The NMR results of compound 1e are as follows:

[0135] 1H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.41 - 7.32 (m, 3H), 7.30 - 7.25 (m, 1H), 7.24 - 7.12 (m, 2H).13C NMR (100 MHz, Chloroform-d) δ 139.94, 133.27, 132.91, 131.26, 128.03, 125.46, 125.26, 125.23, 123.46, 117.89, 117.83, 117.65, 115.61, 115.44, 111.46.

[0136] 2, Preparation of 14-(3,4-difluorophenyl)-5,9-bis(4-ethoxy-2,6-dimethylphenyl)-7,7-difluoro-7H-6λ4,7λ4_[1,3,2]diazaborol[4,3_a:6,1-a']diisoindole (photosensitizer 4j);

[0137] The preparation method was the same as that in Example 5, except that 2- (3,4-difluorophenyl)styrylbenzonitrile (compound 1e) was used to replace 2- styrylbenzonitrile (compound 1a) in step one. Compound 3j was obtained in step one (yield 58%) and photosensitizer 4j was obtained in step two (yield 80%).

[0138] The NMR results of photosensitizer 4j are as follows:

[0139] 1H NMR (400 MHz, Chloroform-d) δ 7.73 (s, 5H), 7.13 (d, J = 3.9 Hz, 2H), 7.05-7.00 (m, 3H), 6.62 (s, 4H), 6.28 (s, 1H), 3.99 (q, J = 6.9 Hz, 4H), 2.03 (s, 12H), 1.40 (t, J = 7.0 Hz, 6H). 13 C NMR (100 MHz, Chloroform-d) δ 159.4, 152.5, 139.8, 135.4, 133.9, 131.2, 129.5, 129.5, 129.3, 128.8, 124.4, 122.8, 122.7, 121.3, 112.9, 63.2, 20.6, 15.0. HRMS (ESI) Calcd for C 43 H 37 BF4N2O2[M+Na] + m / z: 701.2957; found: 701.2964.

[0140] From the synthesis results of Examples 1-10, compounds 1a, compound 1b, compound 1c, compound 1d, compound 1e, photosensitizer 4a, photosensitizer 4b, photosensitizer 4c, photosensitizer 4d, photosensitizer 4e, photosensitizer 4f, photosensitizer 4g, photosensitizer 4h, photosensitizer 4i, and photosensitizer 4j were successfully synthesized.

[0141] Test 1: Test the photophysical properties and singlet quantum yield of the photosensitizer of the present application (refer to Figure 11 )

[0142] The photosensitizers 4a, photosensitizer 4b, photosensitizer 4c, photosensitizer 4d, photosensitizer 4e, photosensitizer 4f, photosensitizer 4g, photosensitizer 4h, photosensitizer 4i, and photosensitizer 4j prepared in Examples 1-10 were tested.

[0143] The spectra and photophysical properties of the photosensitizers in dichloromethane (DCM), a non-polar solvent, were preliminarily evaluated. These photosensitizers were respectively configured into 10 μΜ dichloromethane solutions, and tested with a UV-Vis spectrometer. The maximum absorption and fluorescence emission data of the photosensitizers are summarized in Table 1. Figure 11These compounds exhibit strong absorption with maximum absorption wavelengths between 610 and 615 nanometers. Notably, their emission maxima are located between 615 and 625 nanometers and have high quantum yields (Φf = 0.33-0.39). Compound 4g is a notable exception, with a significantly reduced quantum yield (Φf = 0.0031). This reduction is attributed to the presence of a nitro group, which is a well-known fluorescence quenching group. Given the importance of aqueous environments in PDT applications, we further studied the spectral and photophysical behaviors of the photosensitizers of the present invention in polar media. Since these compounds are hydrophobic, they may aggregate in aqueous solutions, thereby changing their photosensitization properties. In order to simulate biological conditions, we also prepared these photosensitizers into 10 μM solutions in phosphate buffered saline (PBS) containing 1% dimethyl sulfoxide (DMSO), and then examined their UV-visible absorption properties. The data are shown in Figure 11 In this polar medium, all derivatives maintained strong fluorescence, with the emission peak shifted to 635-640 nm, a red shift of approximately 20 nm compared to the spectrum in dichloromethane (DCM). Surprisingly, the fluorescence quantum yields of these photosensitizers in PBS were close to those measured in DCM. These results indicate that despite solvent-induced modulation of their electronic properties, these compounds retain their photophysical stability in an aqueous environment.

[0144] 1 O2, as an important cytotoxic agent in photodynamic therapy (PDT) applications, plays a key role in the PDT process by oxidizing essential small molecules and biomacromolecules. This oxidation further induces oxidative stress, ultimately leading to tumor cell death and tumor ablation. In order to evaluate the singlet oxygen generation efficiency of the photosensitizer of the present invention, the singlet oxygen generation ability of PS was studied using DPBF as a singlet oxygen capture molecule in dichloromethane (DCM). Methylene blue (MB) was used as a reference compound with a singlet oxygen quantum yield of 0.57 (in DCM). After DPBF interacts with singlet oxygen, the absorption at 415 nm will gradually decrease. In the early stage of the experiment, the absorbance value of DPBF at 415 nm was controlled between 1.0 and 1.5, the photosensitizer concentration was controlled between 2 and 5 micromolar, and the power density of the 638 nm laser was 20 mW / cm2. Through the equation Calculate Φ Δ value, where K s and K MB are the slopes of the absorbance of DPBF at 415 nm in the presence of photosensitizer and MB, A MB and As are the absorbances of MB and PS at the irradiation wavelength (638 nm), Φ Δ(MB) is the singlet oxygen quantum yield of MB. The calculated Φ of our photosensitizer isΔ Values ​​are listed in Figure 11 In. From Figure 11 It can be seen that our photosensitizer has a considerably higher Φ among most reported BODIPY photosensitizers. Δ value, which provides great potential for efficient PDT.

[0145] Test 2: Test the IC50 values ​​of the photosensitizer of the present invention on different tumor cell lines (refer to Figure 12 )

[0146] Photosensitizer 4a, photosensitizer 4b, photosensitizer 4c, photosensitizer 4d, photosensitizer 4e, photosensitizer 4f, photosensitizer 4g, photosensitizer 4h, photosensitizer 4i, and photosensitizer 4j prepared in Examples 1 to 10 were tested.

[0147] High phototoxicity and low dark toxicity are key parameters for selecting photosensitizers, because these two directly determine the efficacy and safety of photodynamic therapy. In order to evaluate these characteristics, this study evaluated the IC50 values ​​of the photosensitizer of the present invention on different tumor cell lines under light and dark conditions through MTT experiments. Human cervical cancer cells (HeLa) and human breast cancer cells (MCF-7) were selected for proliferation inhibition activity tests. During the determination, PBS was used as the blank control, dimethyl sulfoxide (DMSO) as the negative control, and Ce6 (Ce6 is a commercially available photosensitizer Ce6 for clinical use) as the positive control. Six concentration gradients were set for each sample of the test compound, and three replicate wells were set. The IC50 values ​​were calculated under light and non-light conditions. The experimental results are shown in Figure 12 .

[0148] The results showed that most photosensitizers exhibited low dark toxicity against both tumor cell lines. For example, the IC50 values ​​of 4a, 4b, 4c, 4d, 4f, and 4h were all greater than 50 μM, significantly superior to the positive drug Ce6. Particularly noteworthy was the fact that 4j exhibited higher phototoxicity and lower dark toxicity against MCF-7 cells than the positive drug.

[0149] Test 3: Test the organelle localization ability of the photosensitizer of the present invention (refer to Figure 13 )

[0150] The photosensitizer 4j prepared in Example 10 was tested.

[0151] The subcellular localization of photosensitizer 4j is crucial for its photodynamic efficacy, and organelles such as mitochondria, lysosomes, and endoplasmic reticulum (ER) are the main targets that can enhance the therapeutic effect. To elucidate the mechanism of action of photosensitizer 4j, we used commercially available specific organelle fluorescent probes (Mito-Tracker Green FM, ER-Tracker Green, and Lyso-Tracker Green DND-26) for systematic co-localization studies. The results of quantitative co-localization analysis are shown in Figure 13 .

[0152] The results show that 4j accumulates significantly in the endoplasmic reticulum, showing a very high Pearson correlation coefficient (0.97 for MCF-7 cells and 0.93 for HeLa cells; Figure 13 C). Moderate co-localization with mitochondrial (0.69 for HeLa cells and 0.67 for MCF-7 cells; Figure 13 A) and lysosomal markers (0.67 for HeLa cells and 0.68 for MCF-7 cells; Figure 13 B) was also observed. These findings establish 4j as an endoplasmic reticulum preferentially localized photosensitizer, whose subcellular localization characteristics directly contribute to its outstanding photodynamic activity.

[0153] Test 4: Test the anti-tumor activity of the photosensitizer of the present application at the animal level (refer to Figure 14 )

[0154] The photosensitizer 4j prepared in Example 10 was used for the test.

[0155] The in vivo anti-tumor effect of 4j was further evaluated using a MCF-7 tumor-bearing nude mouse model, and the commercially available high-efficiency photosensitizer Ce6 was used as a positive reference drug. After the MCF-7 ectopic tumor model was successfully constructed, it was divided into a treatment group and a control group (6 in each group), and the nude mice in the treatment group received the corresponding concentration of drug by intratumoral injection, while the control group was injected with an equal amount of normal saline. One hour after injection, the nude mice were given a single red light irradiation of wavelength greater than 590 nm, 50 mW / cm2, and 10 min at the tumor site, and the body weight and tumor volume changes were continuously monitored for 6 days. The experimental results are shown in Figure 14 .

[0156] The results show that the tumor growth rate of the control group of nude mice is slower, and the Ce6 group shows a certain inhibitory effect. In contrast, 4j shows a better anti-tumor effect, significantly inhibiting the growth of the tumor Figure 14 A). Notably, in the high-dose treatment group of 4bl at 40 mg / kg, the tumors of 3 (50%) nude mice have completely regressed. In addition, the tumor volume changes during the monitoring period and the final tumor weight statistics further support the excellent in vivo anti-tumor activity of 4j in vivoFigure 14 B, 14C). At the same time, the body weight monitoring results of the nude mice show that 4j has good tolerance in the nude mice, and the body weight of the nude mice steadily increases during the experiment, and no significant decrease occurs Figure 14 D).

[0157] Subsequently, we performed histological analysis on the tumors of the nude mice in each group by hematoxylin and eosin (H&E) staining Figure 14 E). The experimental results show that the nuclei of the tumors of the nude mice in the 4j treatment group present obvious morphological deformation, and the number of the nuclei decreases with the increase of the concentration of 4j, indicating that 4j has a significant destructive effect on the MCF-7 tumor cells, and further confirms that the PDT mediated by 4j has a strong anti-tumor effect in vivo.

[0158] Raw material table:

[0159]

[0160]

[0161] The present application is based on the BODIPY structure skeleton, and a new type of fluorine boron complex [a]-benzo dipyrrole photosensitizer is designed by a drug design method. The in vitro anti-tumor activity test results show that most of the fluorine boron complex [a]-benzo dipyrrole photosensitizers have high anti-tumor activity.

[0162] The present application also provides a synthesis method of the new type of fluorine boron complex [a]-benzo dipyrrole photosensitizer.

[0163] The present application prepares a new type of fluorine boron complex [a]-benzo dipyrrole photosensitizer, which is used for a drug composition for photodynamic therapy of tumors, and further comprises a pharmaceutically acceptable adjuvant. The term "pharmaceutically acceptable adjuvant" is well known to those skilled in the art, including pharmaceutically acceptable carriers, excipients, diluents, etc., which are compatible with the active ingredients. The preparation of the drug composition by using the pharmaceutically acceptable adjuvant can be carried out by using the technology known to those skilled in the art.

[0164] The new type of fluorine boron complex [a]-benzo dipyrrole photosensitizer prepared by the present application and the pharmaceutically acceptable adjuvant are combined together to prepare various preparations, preferably solid preparations and liquid preparations. The preparation of the present application can be in unit dose forms, such as tablets, pills, capsules (including sustained release or delayed release forms), powders, suspensions, granules, tinctures, syrups, emulsions, suspensions, injections, etc. and various sustained release dosage forms, so as to be suitable for various administration modes, such as oral administration, parenteral injection, mucosal, intramuscular, intravenous, subcutaneous, intraocular, intradermal or transdermal administration, etc.

[0165] The new type of fluoroborate complex [a]-benzo dipyrromethene photosensitizer prepared by the present application is used for photodynamic anti-tumor treatment, and active oxygen free radicals are generated by light activation to treat tumors and diseases related to tumors. The diseases related to tumors include but are not limited to: cancer, such as liver cancer (including small cell liver cancer), bladder cancer, breast cancer, colon cancer, kidney cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer and skin cancer (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, hairy cell lymphoma and Burkett's lymphoma; myeloid hematopoietic tumors, including acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia; multiple myeloma; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xanthogranuloma, thyroid cystic carcinoma and Kaposi's sarcoma.

[0166] In this text, the term "reagent" refers to a reagent that does not meet the standard of pharmaceutical use, such as a reagent used in laboratory research, unless otherwise indicated.

[0167] The present application has the beneficial effect of providing a new fluoroborate complex [a]-benzo dipyrromethene photosensitizer, a new preparation method and a new use in photodynamic anti-tumor. The preparation method of the photosensitizer of the present application is to synthesize the obtained by using palladium catalytic o-alkenyl benzonitrile and phenylboronic acid, which is very simple, good functional group compatibility, can realize the synthesis of fluoroborate complex [a]-benzo dipyrromethene photosensitizer with structural diversity and difficult to prepare in the past. In addition, the photosensitizer of the present application has high fluorescence quantum yield and singlet oxygen generation yield, excellent light / dark toxicity ratio, high selectivity of endoplasmic reticulum localization and induction of apoptosis, and the in vivo photodynamic anti-tumor effect is obviously better than that of the commercially available clinical photosensitizer Ce6.

[0168] The above is only the preferred embodiment of the present application, and the protection scope of the present application is not limited to the above-mentioned embodiments, and any technical solutions belonging to the idea of the present application shall belong to the protection scope of the present application. It should be pointed out that for ordinary skilled in the art, some improvements and decorations without departing from the principle of the present application shall also be considered as the protection scope of the present application.

Claims

1. A fluoroboron complex [a]-benzodipyrrole photosensitizer, characterized in that: Its structural formula is:

2. A fluoroboron complex [a]-benzodipyrrole photosensitizer according to claim 1, characterized in that: The R1 group is a hydrogen bond, a methoxy group, a trifluoromethyl group, a nitro group, or a fluoro group.

3. A fluoroboron complex [a]-benzodipyrrole photosensitizer according to claim 1, characterized in that: The R2 group is a hydrogen bond or a methoxy group or an ethoxy group or a benzyloxy group.

4. The fluoroboron complex [a]-benzodipyrrole photosensitizer according to claim 1, characterized in that: The R3 group is a hydrogen bond or a fluorine group.

5. The method for preparing a fluoroboron complexed [a]-benzodipyrrole photosensitizer according to any one of claims 1 to 4, characterized in that: include: Step 1: Under an oxygen atmosphere, reacting a 2-phenylvinylbenzonitrile compound, a 2,6-dimethylphenylboronic acid compound, palladium trifluoroacetate, 4,4'-di-tert-butyl-2,2'-bipyridine, trifluoroacetic acid, and potassium fluoride to obtain a first product; Step 2: Take the first product, dissolve it with a solvent, add triethylamine while stirring at low temperature, alkalize and dehydrogenate, then dropwise add boron trifluoride etherate, stir at low temperature, react at room temperature, add water to quench the reaction, spin dry, extract, dry, concentrate, and separate to obtain a photosensitizer; The structural formula of the 2-phenylvinylbenzonitrile compound is: The structural formula of the 2,6-dimethylphenylboronic acid compound is: The structural formula of the first product is:

6. The method for preparing a fluoroboron complex [a]-benzodipyrrole photosensitizer according to claim 5, characterized in that: The step 1 is specifically as follows: Under an oxygen atmosphere, raw materials 2-phenylbenzonitrile compounds, 2,6-dimethylphenylboronic acid compounds, palladium trifluoroacetate, 4,4'-di-tert-butyl-2,2'-bipyridine, trifluoroacetic acid, and potassium fluoride were added to a Schlenk tube, reacted at 110°C for 24 hours, and separated by silica gel chromatography column. The eluent was petroleum ether and ethyl acetate in a volume ratio of 50 to 100:1 to obtain the first product.

7. The method for preparing a fluoroboron complex [a]-benzodipyrrole photosensitizer according to claim 6, characterized in that: In step one The molar ratio of 2-phenylvinylbenzonitrile compounds, 2,6-dimethylphenylboronic acid compounds, palladium trifluoroacetate, 4,4'-di-tert-butyl-2,2'-bipyridine, trifluoroacetic acid and potassium fluoride is: 1.5-2.5: 5-8: 0.05-0.15: 0.1-0.3: 5-8: 3-5.

8. The method for preparing a fluoroboron complex [a]-benzodipyrrole photosensitizer according to claim 6, characterized in that: The step 2 is specifically as follows: The first product is dissolved in dichloromethane, and triethylamine is added dropwise with stirring at 0°C. After stirring for 10 minutes, the product is alkalized and dehydrogenated, and then boron trifluoride etherate is added dropwise. After stirring at low temperature for 10-15 minutes, the product is reacted at room temperature. After the reaction progress is monitored by TLC, 1-2 drops of water are added to quench the reaction. The reaction liquid is vacuum-dried and extracted with ethyl acetate and saturated brine. The EA layer is dried with anhydrous magnesium sulfate and concentrated in vacuo. The reaction system is separated and purified by flash column chromatography using an eluent system, wherein the eluent is petroleum ether and ethyl acetate in a volume ratio of 50-100:1 to obtain a photosensitizer.

9. The method for preparing a fluoroboron complex [a]-benzodipyrrole photosensitizer according to claim 6, characterized in that: In the step 2: The molar ratio of the first product, triethylamine and boron trifluoride etherate is 0.3-0.8: 3-8: 3-8.

10. Use of a fluoroboron complex [a]-benzodipyrrole photosensitizer according to any one of claims 1 to 4, characterized in that: The photosensitizer is used for preparing photodynamic anti-tumor drugs.

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