Near-infrared N2O2 type BODIPY photosensitizer as well as preparation method and application thereof

Abstract

The chemical structural formula of the near-infrared N2O2 type BODIPY photosensitizer is shown in figure 1, the invention also discloses a preparation method of the near-infrared N2O2 type BODIPY photosensitizer, phenyl is substituted by a 3, 5-bit strong electron-donating group julolidine, so that the maximum absorption wavelength of the N2O2 type BODIPY photosensitizer is subjected to red shift to a near-infrared region, and the near-infrared N2O2 type BODIPY photosensitizer is obtained. And meanwhile, the yield of singlet oxygen is improved by replacing central boron atoms with five-coordinated silicon atoms. The invention also discloses an application of the near-infrared N2O2 type BODIPY photosensitizer in PDT treatment of tumors. The problems that the maximum absorption wavelength of an existing N2O2 type BODIPY photosensitizer is in a visible light region and the yield of a photosensitizer preparation method is low are solved.

Description

Technical Field

[0001] This invention belongs to the field of photodynamic therapy technology, specifically relating to a near-infrared N2O2 type BODIPY photosensitizer, and also to the preparation method and application of the above-mentioned photosensitizer. Background Technology

[0002] In recent years, photodynamic therapy (PDT) has shown great potential in the treatment of head and neck cancer, skin cancer, and esophageal cancer due to its advantages such as precision, controllability, high specificity, and minimal invasiveness. PDT is a therapeutic technology based on the photochemical reaction induced by photosensitizers and specific wavelength light sources within target tissues, selectively killing diseased cells by generating cytotoxic reactive oxygen species (ROS). Photosensitizers are the core element of PDT, being molecules that absorb specific wavelengths of light and convert their energy into ROS. Currently, most photosensitizers can only be activated by ultraviolet / visible light. However, ultraviolet / visible light only penetrates a few millimeters into biological tissues, and the high photon energy of this wavelength band may damage tissues, which is unfavorable for PDT of deep tumors. Compared to ultraviolet / visible light, near-infrared light (700-1700nm) has advantages such as high biocompatibility, strong deep tissue penetration, and low autofluorescence background, showing significant clinical translational potential in the field of PDT.

[0003] Based on their molecular structure, near-infrared organic photosensitizers are mainly classified into cyanine derivatives, rhodamine derivatives, BODIPY derivatives, BBTD derivatives, and others. J Among the five types of aggregates, BODIPY has been widely studied in the field of photodynamic therapy (PDT) due to its unique photophysical and chemical properties, including strong light absorption, high fluorescence quantum yield, long triplet excited-state lifetime, ease of functionalization, and excellent photostability. Constructing a benzo[1,2,3]oxadiazole boron heterocyclic structure through intramolecular BO coordination can further induce a redshift of the maximum absorption wavelength of BODIPY, forming a BODIPY derivative with an N2O2 coordination mode (referred to as N2O2-type BODIPY). Although N2O2-type BODIPY has shown potential in tumor PDT applications, it still faces challenges such as the maximum absorption wavelength being in the visible light region and low singlet oxygen quantum yield. Summary of the Invention

[0004] The first objective of this invention is to provide a near-infrared N2O2 type BODIPY photosensitizer, which solves the problem that the maximum absorption wavelength of existing N2O2 type BODIPY photosensitizers is in the visible light region.

[0005] The second objective of this invention is to provide a method for preparing the aforementioned near-infrared N2O2 type BODIPY photosensitizer, which solves the problem of low yield in existing photosensitizer preparation methods.

[0006] A third objective of this invention is to provide the application of the aforementioned near-infrared N2O2 type BODIPY photosensitizer.

[0007] The first technical solution adopted in this invention is as follows: The chemical structural formula of the near-infrared N2O2 type BODIPY photosensitizer is as follows:

[0008] Wherein, the R group is B or SiCH3.

[0009] The second technical solution adopted in this invention is: a method for preparing near-infrared N2O2 type BODIPY photosensitizer, which red-shifts the maximum absorption wavelength of N2O2 type BODIPY photosensitizer to the near-infrared region by replacing the phenyl group with the 3,5-position strong electron-donating group julonidine, and at the same time, replaces the central boron atom with a five-coordinate silicon atom to improve the singlet oxygen yield.

[0010] The second technical solution adopted in this invention is further characterized by: Furthermore, the preparation method of the near-infrared N2O2 type BODIPY photosensitizer is specifically implemented according to the following steps: Step 1: Dissolve 9-bromo-8-methoxyjulonidine, 1-Boc-pyrrole-2-boronic acid, potassium carbonate, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and palladium acetate sequentially in n-butanol under nitrogen protection and stir at room temperature for 3-5 hours. After the reaction is complete, filter and collect the filtrate. The filtrate is then extracted, washed, dried, concentrated, and purified to obtain compound 1. Step 2: Dissolve compound 1 in dry tetrahydrofuran, add methanol solution containing 30% sodium methoxide, react at room temperature for 1-2 hours. After the reaction is completed, add saturated ammonium chloride to quench the reaction, and then extract, wash, dry, concentrate and purify to obtain compound 2. Step 3: Dissolve compound 2 and 2,4,6-trimethylbenzaldehyde in dry dichloromethane. Under nitrogen protection and stirring in an ice-water bath, slowly add trifluoroacetic acid and react at room temperature for 4-6 hours. Then add 2,3-dichloro-5,6-dicyanobenzoquinone and react at room temperature for 2-4 hours. After the reaction is complete, concentrate and purify to obtain compound 3. Step 4: First, dissolve sodium hydride in dry N,N-dimethylformamide under nitrogen protection, add dodecathiol, stir at room temperature for 1-2 hours, then quickly add compound 3, react at 110-120℃ for 3-5 hours. After the reaction is complete, cool to room temperature, quench with saturated ammonium chloride, and then obtain compound 4 after extraction, washing, drying, concentration and purification. Step 5: Dissolve compound 4 in a mixed solvent of chloroform and methanol, add trimethyl borate, and react at 75-80℃ for 3-5 h under nitrogen protection. After the reaction is complete, concentrate under reduced pressure to remove the solvent, and purify by silica gel column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v) as eluent to obtain product 1, a blackish-purple powder MB-DBJ. Step 6: Dissolve compound 4 in dry tetrahydrofuran, add N,N-diisopropylethylamine, under nitrogen protection, stir in an ice-water bath, add methyltrichlorosilane dropwise, and react overnight at room temperature. After the reaction is complete, quench with an appropriate amount of methanol, concentrate under reduced pressure to remove the solvent, use petroleum ether / ethyl acetate (20 / 1, v / v) as eluent, and purify by silica gel column chromatography to obtain product 2, a dark blue powder MSi-DBJ.

[0011] Furthermore, step 1 is detailed as follows: The ratio of 9-bromo-8-methoxyjulonidine, 1-Boc-pyrrole-2-boronic acid, potassium carbonate, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and palladium acetate is 1:1.2:2:0.05:0.03. After the reaction was completed, the mixture was filtered and the filtrate was collected. It was extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography with petroleum ether / ethyl acetate (80 / 1, v / v) as the eluent to obtain a white solid compound 1.

[0012] Furthermore, step 2 is detailed as follows: The ratio of compound 1 to sodium methoxide is 1:10; After quenching, the solution was extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography using petroleum ether / ethyl acetate (80 / 1, v / v) as the eluent to obtain a white solid compound 2.

[0013] Furthermore, step 3 is detailed as follows: The ratio of compound 2, 2,4,6-trimethylbenzaldehyde, trifluoroacetic acid, and 2,3-dichloro-5,6-dicyanobenzoquinone is 1:0.4:0.01:0.4; After the reaction was completed, the solvent was removed by concentration under reduced pressure. Petroleum ether / ethyl acetate (2 / 1, v / v) was used as the eluent, and the compound 3 was obtained by silica gel column chromatography as a purple-red powder.

[0014] Furthermore, step 4 is detailed as follows: The ratio of sodium hydride, dodecyl mercaptan, and compound 3 is 1:0.8:0.1; After quenching, the solution was extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography using petroleum ether / ethyl acetate (2 / 1, v / v) as the eluent to obtain blue powder compound 4.

[0015] Furthermore, in step 5, the ratio of compound 4 to trimethyl borate is 1:12.

[0016] Furthermore, in step 6, the ratio of compound 4, N,N-diisopropylethylamine, and methyltrichlorosilane is 1:24:3.

[0017] The third technical solution adopted in this invention is: the application of near-infrared N2O2 type BODIPY photosensitizer in tumor PDT treatment.

[0018] The beneficial effects of this invention are: (1) Innovative molecular design. This invention uses the 3,5-position strong electron-donating group julonidine to replace the phenyl group, thereby redshifting the maximum absorption wavelength of the N2O2 type BODIPY photosensitizer to the near-infrared region. At the same time, it introduces a silicon center to improve the singlet oxygen yield, thus solving the problem of the incompatibility between "absorption depth" and "ROS efficiency" faced by near-infrared photosensitizers.

[0019] (2) Optimization of preparation process. This invention increases the yield of complex N2O2 type BODIPY photosensitizer to 45-59%, which is much higher than the level of less than 30% reported in the literature. At the same time, the reaction conditions are mild and the use of precious metal catalysts is avoided, which provides mass production feasibility for clinical translation.

[0020] (3) Breakthrough in PDT performance. The MSi-DBJ photosensitizer proposed in this invention has a high efficiency in near-infrared induced singlet oxygen generation capability and a high phototoxicity index (PI>50), which effectively solves the problem of difficulty in balancing deep tissue penetration and treatment safety. Attached Figure Description

[0021] Figure 1 These are structural diagrams of the MB-DBJ and MSi-DBJ of this invention; Figure 2 This is a synthesis route diagram of MB-DBJ and MSi-DBJ of the present invention; Figure 3 The nuclear magnetic resonance hydrogen spectrum of compound 1 of the present invention ( 1 H NMR spectrum; Figure 4 The nuclear magnetic resonance hydrogen spectrum of compound 2 of the present invention ( 1 H NMR spectrum; Figure 5 The nuclear magnetic resonance hydrogen spectrum of compound 3 of the present invention ( 1 H NMR spectrum; Figure 6 The nuclear magnetic resonance hydrogen spectrum of compound 4 of the present invention ( 1 H NMR spectrum; Figure 7 The 1H NMR spectrum of MB-DBJ of this invention ( 1 H NMR spectrum; Figure 8 The carbon NMR spectrum of MB-DBJ of this invention ( 13 C NMR spectrum; Figure 9 This is the high-resolution mass spectrometry (HRMS) image of the MB-DBJ of this invention; Figure 10 The 1H NMR spectrum of the MSi-DBJ of this invention ( 1 H NMR spectrum; Figure 11 The carbon NMR spectrum of the MSi-DBJ of this invention ( 13 C NMR spectrum; Figure 12 This is the high-resolution mass spectrometry (HRMS) spectrum of the MSi-DBJ of this invention; Figure 13 This is a single-crystal structure diagram of MB-DBJ of the present invention; Figure 14 These are the UV-Vis absorption and fluorescence spectra of MB-DBJ and MSi-DBJ of the present invention; Figure 15 This is a graph showing the ROS generation results of MB-DBJ and MSi-DBJ in DMSO solution using DBPF as a capture agent in Example 9 of the present invention; Figure 16 This is a graph showing the results of detecting singlet oxygen generation by MB-DBJ and MSi-DBJ in DMSO solution using TEMP as a capture agent in Example 10 of the present invention; Figure 17 This is an MTT result diagram of MSi-DBJ in Embodiment 11 of the present invention; Figure 18 This is a diagram showing the results of detecting ROS generation in cells by MSi-DBJ using DCF-DA as a probe in Example 12 of the present invention. Detailed Implementation

[0022] The present invention will be further described below with reference to the accompanying drawings and embodiments.

[0023] This invention discloses a near-infrared N2O2 type BODIPY photosensitizer, with the specific chemical structural formula as follows: Figure 1 As shown, its synthetic route is as follows Figure 2 As shown.

[0024] This invention also provides a method for preparing a near-infrared N2O2 type BODIPY photosensitizer. By substituting the phenyl group with a strong electron-donating group julonidine at the 3,5-position, the maximum absorption wavelength of the N2O2 type BODIPY photosensitizer is red-shifted to the near-infrared region. At the same time, a five-coordinated silicon atom is used to replace the central boron atom to improve the singlet oxygen yield.

[0025] The specific steps are as follows: Step 1: Dissolve 9-bromo-8-methoxyjulonidine, 1-Boc-pyrrole-2-boronic acid, potassium carbonate, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and palladium acetate sequentially in n-butanol under nitrogen protection and stir at room temperature for 3-5 hours. After the reaction is complete, filter and collect the filtrate. The filtrate is then extracted, washed, dried, concentrated, and purified to obtain compound 1. In step 1, the ratio of 9-bromo-8-methoxyjulonidine, 1-Boc-pyrrole-2-boronic acid, potassium carbonate, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and palladium acetate is 1:1.2:2:0.05:0.03. After the reaction was completed, the mixture was filtered and the filtrate was collected. It was extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography using petroleum ether / ethyl acetate (80 / 1, v / v) as the eluent to obtain a white solid compound 1.

[0026] Step 2: Dissolve compound 1 in dry tetrahydrofuran, add methanol solution containing 30% sodium methoxide, react at room temperature for 1-2 hours. After the reaction is completed, add saturated ammonium chloride to quench the reaction, and then extract, wash, dry, concentrate and purify to obtain compound 2. In step 2, the ratio of compound 1 to sodium methoxide is 1:10; After quenching, the solution was extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography using petroleum ether / ethyl acetate (80 / 1, v / v) as the eluent to obtain a white solid compound 2.

[0027] Step 3: Dissolve compound 2 and 2,4,6-trimethylbenzaldehyde in dry dichloromethane. Under nitrogen protection and stirring in an ice-water bath, slowly add trifluoroacetic acid and react at room temperature for 4-6 hours. Then add 2,3-dichloro-5,6-dicyanobenzoquinone and react at room temperature for 2-4 hours. After the reaction is complete, concentrate and chromatographically obtain compound 3. In step 3, the ratio of compound 2, 2,4,6-trimethylbenzaldehyde, trifluoroacetic acid, and 2,3-dichloro-5,6-dicyanobenzoquinone is 1:0.4:0.01:0.4; After the reaction was completed, the solvent was removed by concentration under reduced pressure. Petroleum ether / ethyl acetate (2 / 1, v / v) was used as the eluent, and the compound 3 was obtained by silica gel column chromatography as a purple-red powder.

[0028] Step 4: First, dissolve sodium hydride in dry N,N-dimethylformamide under nitrogen protection, add dodecathiol, stir at room temperature for 1-2 hours, then quickly add compound 3, react at 110-120℃ for 3-5 hours. After the reaction is complete, cool to room temperature, quench with saturated ammonium chloride, and then obtain compound 4 after extraction, washing, drying, concentration and purification. In step 4, the ratio of sodium hydride, dodecyl mercaptan, and compound 3 is 1:0.8:0.1; After quenching, the solution was extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography using petroleum ether / ethyl acetate (2 / 1, v / v) as the eluent to obtain blue powder compound 4.

[0029] Step 5: Dissolve compound 4 in a mixed solvent of chloroform and methanol, add trimethyl borate, and react at 75-80℃ for 3-5 h under nitrogen protection. After the reaction is complete, concentrate under reduced pressure to remove the solvent, and purify by silica gel column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v) as eluent to obtain blackish-purple powder MB-DBJ. In step 5, the ratio of compound 4 to trimethyl borate is 1:12; Step 6: Stir in an ice-water bath, add methyltrichlorosilane dropwise, react overnight at room temperature. After the reaction is complete, add an appropriate amount of methanol to quench the reaction, concentrate under reduced pressure to remove the solvent, use petroleum ether / ethyl acetate (20 / 1, v / v) as eluent, and purify by silica gel column chromatography to obtain dark blue powder MSi-DBJ. In step 6, the ratio of compound 4, N,N-diisopropylethylamine, and methyltrichlorosilane is 1:24:3.

[0030] The present invention also provides the application of the above-mentioned near-infrared N2O2 type BODIPY photosensitizer in tumor PDT treatment.

[0031] The present invention will be further explained and described below with reference to the accompanying drawings and specific embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the protection scope of the present invention.

[0032] Example 1: Synthesis of Compound 1.

[0033] 9-Bromo-8-methoxyjulonidine (5.00 g, 17.8 mmol), 1-Boc-pyrrole-2-boronic acid (4.40 g, 21.0 mmol), potassium carbonate (7.50 g, 35.3 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (421 mg, 0.9 mmol), and palladium acetate (99 mg, 0.5 mmol) were dissolved sequentially in n-butanol (80 mL) under nitrogen protection and stirred at room temperature for 3 h. After the reaction was complete, the mixture was filtered and the filtrate was collected. The filtrate was extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography using petroleum ether / ethyl acetate (80 / 1, v / v) as the eluent to obtain a white solid compound 1. Its 1H NMR spectrum (…) 1 H NMR) such as Figure 3 As shown, (4.90g, yield: 68.7%). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.31 (s, 1H), 6.73 (s, 1H), 6.20-6.08 (m, 2H), 3.29 (d, J = 4.7Hz, 3H), 3.11 (s, 4H), 2.73 (d, J = 5.7 Hz, 4H), 1.99-1.92 (m, 4H), 1.32 (d, J =4.6 Hz, 9H).

[0034] Example 2: Synthesis of compound 2.

[0035] Compound 1 (3.40 g, 9.2 mmol) was dissolved in dry tetrahydrofuran, and 17 mL of a methanol solution containing 30% sodium methoxide was added. The reaction was carried out at room temperature for 1 h. After the reaction was completed, saturated ammonium chloride was added to quench the reaction. The mixture was extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and further purified by silica gel column chromatography using petroleum ether / ethyl acetate (80 / 1, v / v) as the eluent to give a white solid compound 2 (1.20 g, yield: 48.6%). Its 1H NMR spectrum (…) 1 HNMR) such as Figure 4 As shown, 1 H NMR (400MHz, CDCl3) δ (ppm) 9.45 (s, 1H), 7.07 (d, J = 6.2Hz,1H), 6.82 (s, 1H), 6.39 (s, 1H), 6.32-6.22 (m, 1H), 3.61 (d,J = 6.8Hz, 3H), 3.21-3.10 (m, 4H), 2.87-2.72 (m, 4H), 2.01 (s, 4H).

[0036] Example 3: Synthesis of compound 3.

[0037] Compound 2 (500 mg, 1.9 mmol) and 2,4,6-trimethylbenzaldehyde (125 mg, 0.8 mmol) were dissolved in dry dichloromethane. Under nitrogen protection and stirring in an ice-water bath, trifluoroacetic acid (100 mg, 1.9 mmol) was slowly added. μ L), reacted at room temperature for 4 h. Then 2,3-dichloro-5,6-dicyanobenzoquinone (203 mg, 0.8 mmol) was added, and the reaction was continued at room temperature for 4 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure, using petroleum ether / ethyl acetate (2 / 1, v / v) as the eluent. Silica gel column chromatography was used to obtain a purple-red powder compound 3 (210 mg, yield: 37.6%), whose 1H NMR spectrum (… 1 H NMR) such as Figure 5 As shown, 1 H NMR (400MHz, CDCl3) δ (ppm) 7.68 (s,2H), 6.91 (s, 2H), 6.79 (d, J = 4.2Hz, 2H), 6.32 (d, J = 4.2Hz, 2H), 3.73 (s,6H), 3.21 (q, J = 5.0Hz, 8H), 2.85 (q, J = 5.8Hz, 8H), 2.35 (s, 3H), 2.17 (s, 6H), 2.02-1.96 (m, 8H).

[0038] Example 4: Synthesis of compound 4.

[0039] First, dissolve sodium hydride (120 mg, 3.0 mmol) in dry... N , N - Dimethylformamide, under nitrogen protection, with the addition of dodecyl mercaptan (600) μThe mixture was stirred at room temperature for 1 h. Then, compound 3 (200 mg, 0.3 mmol) was rapidly added, and the reaction was carried out at 110 °C for 3 h. After the reaction was complete, the mixture was cooled to room temperature, quenched with saturated ammonium chloride, extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography using petroleum ether / ethyl acetate (2 / 1, v / v) as the eluent to give compound 4 (90 mg, yield: 47.1%) as a blue powder. Its 1H NMR spectrum (…) 1 H NMR) such as Figure 6 As shown, 1 HNMR (400MHz, CDCl3) δ (ppm) 7.16 (s, 2H), 6.92 (s, 2H), 6.71 (s, 2H), 6.37 (s,2H), 3.21 (s, 8H), 2.81 (s, 8H), 2.36 (s, 3H), 2.12 (s, 6H), 2.02 (d, J =26.5Hz, 8H).

[0040] Example 5: Synthesis of MB-DBJ.

[0041] Compound 4 (80 mg, 0.1 mmol) was dissolved in a mixed solvent (chloroform / methanol, 1 / 1, v / v), and trimethyl borate (144 mg) was added. μ L, 1.2 mmol), under nitrogen protection, reacted at 75 °C for 3 h. After the reaction, the solvent was removed by concentration under reduced pressure, and purified by silica gel column chromatography using petroleum ether / ethyl acetate (5 / 1, v / v) as eluent to give a blackish-purple powder MB-DBJ (46 mg, yield: 59.7%). Its 1H NMR spectrum ( 1 H NMR) such as Figure 7 As shown, carbon NMR spectrum ( 13 (C NMR) such as Figure 8 As shown, high-resolution mass spectrometry (HRMS) is as follows Figure 9 As shown, 1 H NMR (400MHz, CDCl3) δ (ppm) 7.11 (s, 2H), 6.93 (s, 2H), 6.55(s, 4H), 3.19 (s, 8H), 2.78 (s, 3H), 2.40 (d, J = 42.6Hz, 8H), 2.12 (s, 6H), 2.05-1.81 (m, 8H). 13 C NMR (100MHz, CDCl3) δ(ppm) 151.43, 149.99, 145.81,137.67, 137.53, 127.97, 126.21, 123.03, 114.36, 110.47, 50.22, 50.02, 29.73,27.50, 22.25, 21.79, 21.39, 21.16, 20.24. HRMS (ESI): m / z [M+H] + calcd. forC 42 H 42 BN4O2 + 645.3401; found 645.3352.

[0042] Example 6: Synthesis of MSi-DBJ.

[0043] Compound 4 (80 mg, 0.1 mmol) was dissolved in dry tetrahydrofuran and added... N , N -Diisopropylethylamine (405) μ Under nitrogen protection and with stirring in an ice-water bath, methyltrichlorosilane (51 mg, 0.3 mmol) was added dropwise, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, an appropriate amount of methanol was added to quench the reaction, and the solvent was removed by concentration under reduced pressure. Petroleum ether / ethyl acetate (20 / 1, v / v) was used as the eluent, and the product was purified by silica gel column chromatography to obtain MSi-DBJ deep blue powder (37 mg, yield: 45.7%). Its 1H NMR spectrum (… 1 H NMR) such as Figure 10 As shown, carbon NMR spectrum ( 13 (C NMR) such as Figure 11 As shown, high-resolution mass spectrometry (HRMS) is as follows Figure 12 As shown, 1 H NMR (400MHz, CDCl3) δ (ppm) 7.18 (s, 2H), 6.97 (d, J = 4.2Hz, 2H), 6.75 (s, 2H), 6.61(d, J = 4.3Hz, 2H), 3.25 (s, 8H), 2.94-2.60 (m, 8H), 2.39 (s, 3H), 2.25 (s,3H), 2.04 (s, 3H), 2.02 (d, J = 2.5Hz, 8H), 0.04 (s, 3H). 13 C NMR (100MHz, CDCl3) δ(ppm) 156.92, 154.81, 137.34, 137.24, 136.02, 130.60, 129.13, 127.12,127.07, 125.25, 119.61, 118.99, 117.06, 114.02, 37.82, 32.18, 30.90, 29.14,28.69, 28.34, 25.71, 24.86, 21.67, 20.15, 18.61, 13.10, 9.85, 3.09. HRMS(ESI): m / z [M+H] + calcd. for C 43 H 45 N4O2Si + 677.3312; found 677.3253.

[0044] Example 7: Single crystal structure diagram of MB-DBJ.

[0045] A dichloromethane solution of MB-DBJ was placed in a refrigerator, and single crystals were grown using a general solvent slow evaporation method. After approximately seven days, needle-shaped MB-DBJ single crystals were obtained. Crystals of suitable size (~0.05 × 0.05 × 0.04 mm³) and without cracks were selected for X-ray single-crystal diffraction analysis. Figure 13 The results show that the bond angles of O2-B1-O1, N2-B1-N1 and O1-B1-N1 are 106.58(9)°, 104.72(9)° and 106.36(10)°, respectively, which are significantly different from the standard tetrahedral angle of 109.5°, indicating that the core plane where the boron atom is located in MB-DBJ is significantly distorted.

[0046] Example 8: UV-Vis absorption spectrum and fluorescence spectrum.

[0047] Both the UV-Vis absorption spectrum and the fluorescence spectrum were obtained from tests in dichloromethane solution. Figure 14 The results show that the maximum absorption wavelengths of MB-DBJ and MSi-DBJ are 756 nm and 732 nm, respectively, and their emission peaks are located at 822 nm and 790 nm, respectively. This indicates that the introduction of the strong electron-donating group julonidin at the 3,5-position causes the maximum absorption wavelength of N2O2 type BODIPY to redshift to the near-infrared region.

[0048] Example 9: The ability to generate ROS in solution.

[0049] Lipid-soluble DPBF was selected as the ROS scavenger, and the ability of MB-DBJ and MSi-DBJ to generate ROS under light conditions was determined. The ability to generate reactive oxygen species was evaluated by the change in absorbance at 415 nm. Experiments were conducted at 785 nm (0.2 W / cm²). 2 The laser was used as the light source, with each illumination lasting 1 minute, and this was repeated 5 times. The test samples were dissolved in DMSO at a concentration of 5%. μ M. For example Figure 15 As shown, when the DMSO solution of MB-DBJ / MSi-DBJ was placed in the dark, the absorption peak of DPBF did not change. However, under 785nm light irradiation, the intensity of the characteristic peak of DPBF gradually decreased with the extension of light irradiation time, confirming that both have the ability to induce ROS generation by near-infrared light.

[0050] Example 10: Types of ROS generated in solution.

[0051] EPR spectroscopy analysis was used to determine the types of ROS generated by MB-DBJ and MSi-DBJ under illumination. TEMP, as a singlet oxygen scavenger, is readily oxidized by singlet oxygen to paramagnetic TEMPO, which exhibits a characteristic 1:1:1 triplet signal in the EPR spectrum. The photosensitizer was prepared in PBS solutions (5% v / v DMSO, 0.3% F127, pH=7.4), both at a concentration of 50 mM, using 785 nm (0.2 W / cm²). 2 After 10 minutes of light irradiation, the sample was immediately drawn into a capillary tube and sealed before testing. The main spectrometer parameters were set as follows: microwave frequency, 9.8 GHz; power, 15 mW; modulation amplitude, 0.5 G; modulation frequency, 100 kHz; time constant, 0.01 ms; scan time, 10 s; receiver gain, 60 dB; central magnetic field, 3495 G. Figure 16 As shown, after the PBS solution of MB-DBJ / MSi-DBJ was irradiated with 785nm light, a typical triplet signal appeared on the EPR spectrum, indicating that the ROS generated by the two under light conditions is singlet oxygen.

[0052] Example 11: MTT of cells treated with MSi-DBJ.

[0053] MCF-7 cells were cultured and incubated at 37°C in 96-well plates until adherence. Cells were incubated with different concentrations of photosensitizer for 4 hours, and cultured at 785 nm (0.5 W / cm²). 2 After irradiation with light for 10 minutes, incubation continued for 12 hours. Then, freshly prepared MTT (20 mg / L) was added to each well. μ Incubate with 5 mg / mL of DMSO for 4 hours. Finally, add DMSO (150 μL). μL) The crystals were completely dissolved, and the absorbance at 490 nm was monitored using a microplate reader. Dark treatment showed that MSi-DBJ absorbs light at 200 nm. μ M showed no cytotoxicity, but after irradiation with 785nm light, cell viability gradually decreased with increasing concentration, demonstrating significant phototoxicity. The results are as follows: Figure 17 As shown.

[0054] Example 12: ROS generated in cells.

[0055] The DCF-DA probe was used to assess ROS generation by MSi-DBJ in cells. After DCF-DA enters the cells, its hydrolysis product DCFH is rapidly oxidized by ROS to generate green fluorescent DCF. MCF-7 cells were incubated with a photosensitizer for 4 h, then incubated for another 30 min with freshly prepared DMEM medium containing DCF-DA. A 785 nm (0.5 W / cm²) light source was used. 2 Immediately after 10 minutes of light irradiation, the cells were imaged using an inverted fluorescence microscope. The results are as follows: Figure 18 As shown, MCF-7 cells treated with MSi-DBJ exhibited obvious green fluorescence after irradiation with 785nm light, confirming the generation of ROS during PDT.

[0056] The above description is only a preferred embodiment of the present invention. It should be noted that for researchers using this technical field, various modifications made to these embodiments without departing from the technical principles of the present invention should be considered within the scope of protection of the present invention.

Claims

1. A near-infrared N2O2 type BODIPY photosensitizer, characterized in that, The chemical structural formula of the near-infrared N2O2 type BODIPY photosensitizer is as follows: Wherein, the R group is B or SiCH3.

2. The preparation method of the near-infrared N2O2 type BODIPY photosensitizer according to claim 1, characterized in that, By substituting the phenyl group with the strong electron-donating group julonidine at the 3,5-position, the maximum absorption wavelength of the N2O2 type BODIPY photosensitizer is red-shifted to the near-infrared region. At the same time, the singlet oxygen yield is improved by replacing the central boron atom with a five-coordinate silicon atom.

3. The preparation method of the near-infrared N2O2 type BODIPY photosensitizer according to claim 2, characterized in that, The specific steps are as follows: Step 1: Dissolve 9-bromo-8-methoxyjulonidine, 1-Boc-pyrrole-2-boronic acid, potassium carbonate, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and palladium acetate sequentially in n-butanol under nitrogen protection and stir at room temperature for 3-5 hours. After the reaction is complete, filter and collect the filtrate. The filtrate is then extracted, washed, dried, concentrated, and purified to obtain compound 1. Step 2: Dissolve compound 1 in dry tetrahydrofuran, add methanol solution containing 30% sodium methoxide, react at room temperature for 1-2 hours. After the reaction is completed, add saturated ammonium chloride to quench the reaction, and then extract, wash, dry, concentrate and purify to obtain compound 2. Step 3: Dissolve compound 2 and 2,4,6-trimethylbenzaldehyde in dry dichloromethane. Under nitrogen protection and stirring in an ice-water bath, slowly add trifluoroacetic acid and react at room temperature for 4-6 hours. Then add 2,3-dichloro-5,6-dicyanobenzoquinone and react at room temperature for 2-4 hours. After the reaction is complete, concentrate and chromatographically obtain compound 3. Step 4: First, dissolve sodium hydride in dry N,N-dimethylformamide under nitrogen protection, add dodecathiol, stir at room temperature for 1-2 hours, then quickly add compound 3, react at 110-120℃ for 3-5 hours. After the reaction is complete, cool to room temperature, quench with saturated ammonium chloride, and then obtain compound 4 after extraction, washing, drying, concentration and purification. Step 5: Dissolve compound 4 in a mixed solvent of chloroform and methanol, add trimethyl borate, and react at 75-80℃ for 3-5 hours under nitrogen protection. After the reaction is completed, concentrate under reduced pressure to remove the solvent. Use petroleum ether / ethyl acetate at a volume ratio of 5 / 1 as the eluent and purify by silica gel column chromatography to obtain product 1, a blackish-purple powder MB-DBJ. Step 6: Dissolve compound 4 in dry tetrahydrofuran, add N,N-diisopropylethylamine, under nitrogen protection, stir in an ice-water bath, add methyltrichlorosilane dropwise, and react overnight at room temperature. After the reaction is complete, add an appropriate amount of methanol to quench the reaction, concentrate under reduced pressure to remove the solvent, use petroleum ether / ethyl acetate at a volume ratio of 20 / 1 as the eluent, and purify by silica gel column chromatography to obtain product 2, a dark blue powder MSi-DBJ.

4. The method for preparing the near-infrared N2O2 type BODIPY photosensitizer according to claim 3, characterized in that, Step 1 is specifically as follows: The ratio of 9-bromo-8-methoxyjulonidine, 1-Boc-pyrrole-2-boronic acid, potassium carbonate, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, and palladium acetate is 1:1.2:2:0.05:0.

03. After the reaction was completed, the mixture was filtered and the filtrate was collected. It was extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography using petroleum ether / ethyl acetate at a volume ratio of 80 / 1 as the eluent to obtain a white solid compound 1.

5. The method for preparing the near-infrared N2O2 type BODIPY photosensitizer according to claim 3, characterized in that, Step 2 is specifically as follows: The ratio of compound 1 to sodium methoxide is 1:10; After quenching, the solution was extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and further purified by silica gel column chromatography with petroleum ether / ethyl acetate at a volume ratio of 80 / 1 as the eluent to obtain a white solid compound 2.

6. The method for preparing the near-infrared N2O2 type BODIPY photosensitizer according to claim 3, characterized in that, Step 3 is specifically as follows: The ratio of compound 2, 2,4,6-trimethylbenzaldehyde, trifluoroacetic acid, and 2,3-dichloro-5,6-dicyanobenzoquinone is 1:0.4:0.01:0.4; After the reaction was completed, the solvent was removed by concentration under reduced pressure. Petroleum ether / ethyl acetate (volume ratio 2 / 1) was used as the eluent, and the mixture was purified by silica gel column chromatography to obtain a purple-red powder compound 3.

7. The method for preparing the near-infrared N2O2 type BODIPY photosensitizer according to claim 3, characterized in that, Step 4 is specifically as follows: The ratio of sodium hydride, dodecyl mercaptan, and compound 3 is 1:0.8:0.1; After quenching, the solution was extracted three times with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography using petroleum ether / ethyl acetate at a volume ratio of 2 / 1 as the eluent to obtain blue powder compound 4.

8. The method for preparing the near-infrared N2O2 type BODIPY photosensitizer according to claim 3, characterized in that, In step 5, the ratio of compound 4 to trimethyl borate is 1:

12.

9. The method for preparing the near-infrared N2O2 type BODIPY photosensitizer according to claim 3, characterized in that, In step 6, the ratio of compound 4, N,N-diisopropylethylamine, and methyltrichlorosilane is 1:24:

3.

10. The application of the near-infrared N2O2 type BODIPY photosensitizer according to any one of claims 1-9 in tumor PDT treatment.

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