CN111171060A

CN111171060A - Pyridine-containing boron dipyrrole and quaternary ammonium salt photosensitizer thereof, and preparation method and application thereof

Info

Publication number: CN111171060A
Application number: CN201811238213.2A
Authority: CN
Inventors: 赵伟利; 董肖椿; 林光宇; 喻支梁
Original assignee: Fudan University
Current assignee: Fudan University
Priority date: 2018-10-23
Filing date: 2018-10-23
Publication date: 2020-05-19
Anticipated expiration: 2038-10-23
Also published as: CN111171060B

Abstract

The invention belongs to the field of drug synthesis, relates to a pyridine-containing BODIPY compound with a general formula (I) and a quaternary ammonium salt thereof, and particularly relates to a pyridine quaternary ammonium salt photosensitizer, a preparation method thereof and medical application thereof. The compound has good anti-tumor activity through in vitro photosensitization efficiency and tumor cell inhibition activity tests, and the result shows that the compound has good anti-tumor activity, can be further used for preparing a new anti-tumor medicament and is used for treating wide tumors without specificity, such as gastric cancer, breast cancer, prostatic cancer, lung cancer, colon cancer, bladder cancer, ovarian cancer, skin cancer and cervical cancer.

Description

Pyridine-containing boron dipyrrole and quaternary ammonium salt photosensitizer thereof, and preparation method and application thereof

Technical Field

The invention belongs to the field of drug synthesis, and relates to a novel pyridine-containing BODIPY and quaternary ammonium salt photosensitizer thereof, and a preparation method and application thereof. In particular to a pyridine-containing boron dipyrrole and quaternary ammonium salt photosensitizer thereof, a preparation method and application thereof in pharmacy.

Background

Malignant tumors have been reported to be common diseases seriously harming the life health of people. According to incomplete statistics, there are about 2000 million new cases worldwide each year; the number of new cases is 160-200 ten thousand per year and 130 ten thousand deaths in China. The existing methods commonly used for treating malignant tumors comprise radiotherapy, chemotherapy, surgical operation treatment and the like, and research shows that about 50% of patients in clinical diagnosis of primary tumors have distant metastasis due to the early metastatic capacity of tumor cells, and the tumor cells are rapidly increased and easily mutated, so that multiple drug resistance is frequently generated in chemotherapy, and chemotherapy failure is caused; according to relevant statistics, more than 90% of the total tumor cell markers are related to multidrug resistance of tumor cells, and the antitumor drugs applied in current clinical practice far from meeting the treatment requirements.

The literature describes Photodynamic therapy (PDT) as a new technique for diagnosing and treating tumors and other pathological target tissues using Photodynamic effects; photosensitizers targeted to tumor sites and oxygen molecules in tissues under irradiation with light of a specific wavelength: (³O2) to generate Reactive Oxygen Species (ROS) to further oxidize tumor cells and realize the effect of killing the tumor cells. It is considered that photodynamic therapy is a potential tumor therapy technology, and the systemic toxicity of the whole body is greatly reduced by tumor targeting positioning of the photosensitizer and selective irradiation of tumor sites.

BODIPY photosensitizer has become a research hotspot in the field of light treatment in recent years due to the advantages of high molar extinction coefficient, high singlet oxygen yield, photobleaching resistance, high light-dark toxicity ratio and the like. Researches show that the maximum absorption peak of the BODIPY photosensitizer can be adjusted to a near infrared region through proper modification, so that the tissue penetrability in PDT is effectively increased; heavy atoms can enhance spin-orbit coupling, thereby facilitating inter-hopping and increasing the yield of singlet oxygen, which is called as "heavy atom effect"; however, it has been shown that too many halogen atom-substituted boron dipyrromethene BODIPY photosensitizers are not conducive to increasing their singlet oxygen yield, and that increasing halogen atoms increases the depth of penetration of the photosensitizer into dark toxic tissue is a major challenge for practical photodynamic therapy; biocompatible and highly efficient Near Infrared (NIR) -absorbing carbazole substituted BODIPY (Car-BDP) molecules are reported as a class of imageable deep tissue active PDT photosensitizers; Car-BDP has a strong, broad absorption band in the near infrared spectrum (600-800nm) and a very high singlet oxygen yield.

Based on the industry consensus: the photosensitizer should have good water solubility and lipid solubility, especially amphiphilicity; on one hand, the water-soluble liposome has water solubility and is convenient to administer, and on the other hand, the liposome has certain lipid solubility and is beneficial to the permeation of the drug through cell membranes. Mitochondria are the main site of cellular respiration, and both tricarboxylic acid cycle and oxidative phosphorylation are carried out in mitochondria, which when dysfunctional will lead to a range of diseases such as sepsis, ischemia-reperfusion injury, diabetes, and the like. The difference of the structure and the function of the tumor cell mitochondria and the normal cell mitochondria, the transmembrane potential of the tumor cell mitochondria is obviously higher than that of the normal cell, and the medicament is selectively accumulated in the tumor cell mitochondria on the basis of the difference, thereby inhibiting the growth of the tumor cell and triggering the apoptosis.

Based on the current state and foundation of the prior art, based on research on fluorescent probes, quaternary pyridinium salt can improve water solubility, impart mitochondrial targeting ability, and have lower toxicity (chem.Commun.,2013,49, 10620-10622; org.biomol.chem.,2013,11, 555-558); the inventor intends to provide a pyridine-containing BODIPY and its quaternary ammonium salt photosensitizer, and its preparation method and pharmaceutical use; the BODIPY structure containing pyridine and pyridine quaternary ammonium salt can meet the structural requirement of photosensitizer preparation, possibly improve the water solubility of the photosensitizer, and can target mitochondria to have better anti-tumor effect.

Disclosure of Invention

The invention aims to provide novel pyridine-containing BODIPY and quaternary ammonium salt compounds thereof with good anti-tumor activity based on the current situation and the foundation of the prior art, and the main advantages of the novel pyridine-containing BODIPY and the quaternary ammonium salt compounds thereof are long-wavelength absorption, good water solubility, mitochondrial targeting and the like.

The pyridine-containing BODIPY and quaternary ammonium salt photosensitizer compound thereof are BODIPY framework compounds containing pyridine, carbazole and polyethylene glycol chains, have a structure shown in a general formula (I),

wherein:

more specifically, the pyridine-containing BODIPY and quaternary ammonium salt compound thereof of the present invention have the following structures:

the invention also aims to provide a preparation method of the novel pyridine-containing BODIPY and quaternary ammonium salt compounds thereof.

Taking compound 4 as an example, the preparation process of the compound of the present invention is as follows:

the compound disclosed by the invention is tested by in vitro photosensitization efficiency and cell level, and the result shows that the compound has good tumor inhibition activity, is obviously improved compared with a Car-BDP compound, and can be further developed into a novel pyridine-containing BODIPY and pyridine quaternary ammonium salt photosensitizer thereof and an antitumor drug.

The invention carries out in vitro tests, carries out anti-tumor activity tests on Hela cervical carcinoma cells, SW480 colon cancer cells and A549 non-small cell lung cancer cells respectively, and the results show that the compound of the invention shows better active oxygen yield and anti-tumor activity, wherein the compounds 1,3, 4 and 5 have D activityThe MF photosensitization efficiency value versus the zinc phthalocyanine dye (0.56) singlet oxygen yield value was 0.45, 0.44, 0.42 and 0.30, respectively; and IC of Compounds 2,4,6 on three tumor cells under the conditions tested₅₀Less than 2. mu.M.

The compound of the invention can further prepare a novel pyridine-containing BODIPY photosensitizer.

Furthermore, the pyridine-containing BODIPY compound can be used for preparing a medicine for treating malignant tumors; the malignant tumor is wide nonspecific tumor, and is selected from gastric cancer, breast cancer, prostatic cancer, lung cancer, colon cancer, bladder cancer, ovarian cancer, skin cancer, and cervical cancer.

Detailed Description

EXAMPLE 1 Synthesis of Compound 1

1) Synthesis of 2- (2- (2-methoxyethoxy) ethoxy) ethyl 4-methylbenzenesulfonate

Dissolving 2g of 2- (2- (2-methoxyethoxy) ethoxy) ethanol and 2.2g of p-toluenesulfonic acid in a mixed solution of 80mL of dichloromethane and 80mL of tetrahydrofuran, adding 1.4mL of triethylamine dropwise, stirring at room temperature for 24H, monitoring the reaction by TLC, distilling off THF and DCM under reduced pressure, adding ethyl acetate and water each 150mL of which, shaking and separating, extracting an aqueous layer with ethyl acetate, combining organic layers, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, distilling off the solvent under reduced pressure, and purifying by column chromatography, wherein EA is 1:4 to obtain a purified product 3.16g, the yield is 81.6%, and the content of MS (ESI) M/z ([ M + H ] M/z ([ M + ESI) M/z]⁺):319.1；

2) Synthesis of 9- (2- (2- (2-methoxyethoxy) ethoxy) ethyl) -9H-carbazole

2.4g of carbazole is dissolved in dry 15ml DMF, 577mg of 60% NaH (diethyl ether) is added, stirring is carried out for 30 minutes in ice bath under the protection of argon, and then stirring is carried out for 50 minutes at room temperature, thus obtaining the nitrogen anion nucleophile. The mixed solution was slowly dropped into a dry DMF solution of 5.4g of 2- (2- (2-methoxyethoxy) ethoxy) ethyl 4-methylbenzenesulfonate, stirred for 10 minutes in an ice bath under argon protection, and stirred for 30 minutes at room temperature. TLC monitored the reaction was complete and the reaction was quenched by addition of ice water. The aqueous layer was extracted with ethyl acetate (150 ml. times.3), the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressureAnd purifying by column chromatography to obtain 3.2g of a product, wherein the yield is as follows: 75%, MS (ESI) M/z ([ M + H)]⁺):314.3；

3) Synthesis of 9- (2- (2- (2-methoxyethoxy) ethoxy) ethyl) -9H-carbazole-3-carbaldehyde

In a 25mL two-necked flask, 10mL dry DMF was added, ice-cooled, and protected with argon. Slowly dropwise adding 2.4ml of OCOCl₃Stirring for 30 minutes under the ice bath condition to prepare a Vilsmeier reagent;

1.2g of 9- (2- (2- (2-methoxyethoxy) ethoxy) ethyl) -9H-carbazole are dissolved in 12mL of dry DMF solution. The prepared Vilsmeier reagent is added under ice bath condition, and stirred for 20 minutes under argon protection. After the temperature is returned to the room temperature, the temperature is raised to 80 ℃ and the mixture is stirred for 7 hours; the reaction was poured into ice water and saturated NaHCO was used₃The Ph of the solution was adjusted to neutral, stirring was carried out for hours, the aqueous layer was extracted with ethyl acetate (150ml × 3), the organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and column chromatography PE: EA ═ 1:4 was carried out to obtain 800mg of the product, yield: 62%, MS (ESI) M/z ([ M + H)]⁺):342.3；

4) Synthesis of 1,3,5, 7-tetramethyl-8- (2-pyridinyl) -4,4' -difluoroboradipyrrole

470mg of 2-pyridinecarboxaldehyde and 920mg of 2, 4-dimethylpyrrole are dissolved in 250mL of dry DCM, a catalytic amount of TFA is added, argon is used for protection, the mixture is stirred at room temperature for 24 hours, a part of DCM is evaporated under reduced pressure until the volume of the solution is 70mL, 1.5g of 2, 3-dichloro-5, 6-dicyan-p-benzoquinone is added, argon is used for protection, and the mixture is stirred at room temperature for 2 hours. Adding 7mL of triethylamine and 7mL of boron trifluoride diethyl etherate, stirring at room temperature overnight, removing the solvent under reduced pressure, dissolving the residual solid in 150mL of DCM, washing with water for three times, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and purifying DCM/PE by column chromatography to obtain 390mg of an orange solid. Yield: 27%, MS (ESI) M/z ([ M + H)]⁺):326.2；

5) Synthesis of 2, 6-diiodo-1, 3,5, 7-tetramethyl-8- (2-pyridyl) -4,4' -difluoroboron dipyrrole

Compound 1,3,5, 7-tetramethyl-8- (2-pyridyl) -4,4' -difluoroboradipyrrole (100mg) was placed in a 25mL eggplant-shaped bottle, and HOAc/DCM ═ 1/3(6mL) was added thereto and dissolved. 340mg of N-iodosuccinimide was added, stirred at room temperature for 1 hour, and the reaction was monitored by TLC for completion20mL of saturated sodium thiosulfate solution, 20mL of water, 20mL of saturated NaHCO₃Washing with an aqueous solution, drying over anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and performing column chromatography on the solvent PE: EA ═ 1:1 to obtain 142mg of a brown solid, yield: 80%, MS (ESI) M/z ([ M + H)]⁺):578.0，¹H NMR(400MHz,CDCl₃)δ8.80(d,J＝4.1Hz,1H),7.87(t,J＝7.8Hz,1H),7.53–7.44(m,1H),7.40(d,J＝7.8Hz,1H),2.64(s,6H),1.30(s,6H)；

6) Synthesis of Compound 1

Dissolving the compound 2, 6-diiodo-1, 3,5, 7-tetramethyl-8- (2-pyridyl) -4,4 '-difluoroboron dipyrrole (100mg) and 9- (2- (2- (2-methoxyethoxy) ethoxy) ethyl) -9H-carbazole-3-formaldehyde (300mg) in toluene (10mL), adding glacial acetic acid (0.1mL) and piperidine (0.1mL), refluxing in a two-necked flask for 10H, removing the oil bath after the reaction is finished, extracting dichloromethane and water (25 mL. times.3), drying with anhydrous sodium sulfate, filtering, and evaporating the solvent to obtain the product CH-I-1, 3,5, 7-tetramethyl-8- (2-pyridyl) -4,4' -difluoroboron dipyrrole₂Cl₂Purification by column chromatography with MeOH (30:1, v/v, triethylamine 1%) afforded BODIPY 942 mg as a green solid. Yield: 19.8 percent of the total weight of the steel,¹H NMR(400MHz,CDCl₃)δ8.84(d,J＝3.6Hz,1H),8.45(d,J＝16.6Hz,2H),8.34-8.33(m,2H),8.15(d,J＝7.7Hz,2H),7.90-7.83(m,4H),7.79-7.78(m,1H),7.51-7.48(m,8H),7.25-7.22(m,2H),4.51(t,J＝5.5Hz,4H),3.89(t,J＝5.4Hz,4H),3.52-3.51(m,4H),3.50-3.49(m,4H),3.45-3.44(m,4H),3.41-3.40(m,4H),3.32(s,6H),1.40(s,6H)。

example 2 Synthesis of Compound 2

Putting 140 mg of the compound in a sealed tube, adding 0.5mL of methyl iodide, reacting for 12 hours at 60 ℃, adding a small amount of DCM to dissolve the methyl iodide completely after the methyl iodide is volatilized completely, adding methyl tert-butyl ether to separate out a purple black solid, filtering, drying to obtain 29mg of a product with the yield of 65 percent,¹H NMR(400MHz,CDCl₃)δ8.68(s,1H),8.59(d,J＝16.1Hz,2H),8.42(s,1H),8.35-8.34(m,2H),8.16-8.14(m,2H),8.05(s,1H),7.89-7.87(m,2H),7.80-7.75(m,2H),7.58-7.56(m,2H),7.50-7.49(m,5H),7.26-7.25(m,2H),4.54(s,7H),3.92-3.91(m,4H),3.54-3.53(m,4H),3.51-3.50(m,4H),3.46-3.65(m,4H),3.42-3.40(m,4H),3.32(s,6H),1.36(s,6H)。

example 3: synthesis of Compound 3

1) Synthesis of 1,3,5, 7-tetramethyl-8- (3-pyridinyl) -4,4' -difluoroboradipyrrole

470mg of 3-pyridinecarboxaldehyde and 920mg of 2, 4-dimethylpyrrole are dissolved in 250mL of dry DCM, and a catalytic amount of TFA under argon is added and the mixture is stirred at room temperature for 24 hours. Part of DCM was evaporated under reduced pressure to a solution volume of 70mL, 1.5g of 2, 3-dichloro-5, 6-dicyan p-benzoquinone was added under argon protection, and the mixture was stirred at room temperature for 2 hours. Adding 7mL of triethylamine and 7mL of boron trifluoride diethyl etherate, stirring at room temperature overnight, removing the solvent under reduced pressure, dissolving the residual solid in 150mL of DCM, washing with water for three times, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and purifying DCM/PE (DCM/PE) by column chromatography to obtain 195mg of an orange solid, wherein the yield is as follows: 13.5%, MS (ESI) M/z ([ M + H)]⁺):326.2；

2) Synthesis of 2, 6-diiodo-1, 3,5, 7-tetramethyl-8- (3-pyridyl) -4,4' -difluoroboron dipyrrole

Compound 1,3,5, 7-tetramethyl-8- (3-pyridyl) -4,4' -difluoroboradipyrrole (100mg) was placed in a 25mL eggplant-shaped bottle, and HOAc/DCM ═ 1/3(6mL) was added thereto and dissolved. 340mg of N-iodosuccinimide were added, stirred at room temperature for 1h and the reaction was monitored by TLC for completion. 20mL of saturated sodium thiosulfate solution, 20mL of water, 20mL of saturated NaHCO₃Washing with an aqueous solution, drying over anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and performing column chromatography on the solvent PE: EA ═ 1:1 to obtain 142mg of a brown solid, yield: 80%, MS (ESI) M/z ([ M + H)]+):578.0。¹H NMR(400MHz,CDCl₃)δ8.83(d,J＝3.3Hz,1H),8.56(s,1H),7.65(d,J＝8.0Hz,1H),7.57-7.49(m,1H),2.66(s,6H),1.40(s,6H)；

3) Synthesis of Compound 3

The compound 2, 6-diiodo-1, 3,5, 7-tetramethyl-8- (3-pyridinyl) -4,4' -difluoroboradipyrrole (200mg), 9- (2- (2- (2-methoxyethoxy) ethoxy) ethyl) -9H-carbazole-3-carbaldehyde (591mg) was dissolved in toluene (15mL), glacial acetic acid (0.1mL) and piperidine (0.1mL) were added, and the mixture was refluxed in a two-necked flask for 10 hours. After the reaction, the oil bath was removed, dichloromethane and water (50 mL. times.3) were extracted, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated to CH₂Cl₂Purification by column chromatography with MeOH (30:1, v/v, triethylamine 1%) afforded BODIPY 9200 mg as a green solid. Yield: the content of the active ingredients in the active ingredients is 47%,¹H NMR(400MHz,CDCl₃)δ8.83(d,J＝4.7Hz,1H),8.63(s,1H),8.47(d,J＝16.6Hz,2H),8.35-8.34(s,2H),8.15(d,J＝7.7Hz,2H),7.87-7.83(m,3H),7.79-7.78(m,1H),7.69(d,J＝8.3Hz,1H),7.53-7.47(m,7H),7.25-7.23(m,2H),4.53(t,J＝5.2Hz,4H),3.90(t,J＝5.4Hz,4H),3.53-3.52(m,8H),3.51-3.50(m,4H),3.41-3.10(m,4H),3.32(s,6H),1.49(s,6H)。

example 4: synthesis of Compound 4

Putting 340mg of the compound in a sealed tube, adding 0.5mL of methyl iodide, reacting for 12 hours at 60 ℃, adding a small amount of DCM to dissolve the methyl iodide completely after the methyl iodide is volatilized completely, adding methyl tert-butyl ether to separate out a purple black solid, filtering, drying to obtain 36mg of a product with the yield of 81 percent,¹H NMR(400MHz,CDCl₃)δ9.64(s,1H),9.03(s,1H),8.40(d,J＝16.3Hz,2H),8.22-8.17(m,4H),8.07(d,J＝7.4Hz,2H),7.75-7.68(m,4H),7.41-7.40(m,6H),7.20-7.17(s,2H),4.71(s,3H),4.37-4.36(m,4H),3.79-3.78(m,4H),3.46-3.44(m,8H),3.40-3.39(m,4H),3.36-3.35(m,4H),3.27(s,6H),1.36(s,6H)。

example 5: synthesis of Compound 5

1) Synthesis of 1,3,5, 7-tetramethyl-8- (4-pyridinyl) -4,4' -difluoroboradipyrrole

470mg of 4-pyridinecarboxaldehyde and 920mg of 2, 4-dimethylpyrrole are dissolved in 250mL of dry DCM, and a catalytic amount of TFA under argon is added and the mixture is stirred at room temperature for 24 hours. Part of DCM was evaporated under reduced pressure to a solution volume of 70mL, 1.5g of 2, 3-dichloro-5, 6-dicyan p-benzoquinone was added under argon protection, and the mixture was stirred at room temperature for 2 hours. 7mL of triethylamine and 7mL of boron trifluoride etherate solution were added, under argon protection, and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residual solid was dissolved in 150mL DCM, washed with water three times, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and DCM/PE 1/3 was purified by column chromatography to give 130mg of an orange solid, yield: 9 percent.

2) Synthesizing 2, 6-diiodo-1, 3,5, 7-tetramethyl-8- (4-pyridyl) -4,4' -difluoborodipyrrole;

compound 1,3,5, 7-tetramethyl-8- (4-pyridinyl) -4,4' -difluoroboradipyrrole (100mg) was placed in a 25mL eggplant-shaped bottle, and HOAc/DCM ═ 1/3(6mL) was added thereto and dissolved. 340mg of N-iodosuccinimide were added, stirred at room temperature for 1h, monitored by TLCIt should be complete. 20mL of saturated sodium thiosulfate solution, 20mL of water, 20mL of saturated NaHCO₃Washing with water solution, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure, and performing column chromatography with PE: EA being 1:1 to obtain brown solid 142 mg. Yield: 80 percent. MS (ESI) M/z ([ M + H)]+):578.0。¹H NMR(400MHz,CDCl₃)δ8.83(d,J＝4.1Hz,2H),7.30(d,J＝3.7Hz,2H),2.66(s,6H),1.43(s,6H).，

3) Synthesis of Compound 5

The compound 2, 6-diiodo-1, 3,5, 7-tetramethyl-8- (4-pyridinyl) -4,4' -difluoroboradipyrrole (100mg), 9- (2- (2- (2-methoxyethoxy) ethoxy) ethyl) -9H-carbazole-3-carbaldehyde (300mg) was dissolved in toluene (10mL), glacial acetic acid (0.1mL) and piperidine (0.1mL) were added thereto, and the mixture was refluxed in a two-necked flask for 10 hours. After the reaction, the oil bath was removed, dichloromethane and water (25 mL. times.3) were extracted, dried over anhydrous sodium sulfate, filtered and the solvent was evaporated to CH₂Cl₂Purification by column chromatography with MeOH (30:1, v/v, triethylamine 1%) afforded BODIPY 9120 mg as a green solid. Yield: in the content of 56%,¹H NMR(400MHz,CDCl₃)δ8.84-8.83(m,2H),8.47(d,J＝16.0Hz,2H),8.36-8.35(m,2H),8.25–8.13(m,2H),7.88-7.73(m,4H),7.52-7.48(m,6H),7.39-7.38(m,2H),7.26-7.22(m,2H),4.43-4.41(m,4H),3.91-3.90(m,4H),3.53-3.50(m,8H),3.46-3.45(m,4H),3.41-3.30(m,4H),3.32-3.31(m,6H),1.51(s,6H)。

example 6: synthesis of Compound 6

540 mg of the compound was put in a sealed tube, and 0.5mL of methyl iodide was added thereto to react at 60 ℃ for 12 hours. And (3) adding a small amount of DCM to dissolve the iodomethane when the iodomethane is completely volatilized, adding methyl tert-butyl ether to separate out a purple black solid, performing suction filtration and drying to obtain a product 32mg, wherein the yield is 72%.¹H NMR(400MHz,CDCl₃)δ9.33-9.32(m,2H),8.39(d,J＝16.6Hz,2H),8.24-8.23(m,2H),8.07(d,J＝7.0Hz,2H),7.92-7.90(m,2H),7.80(d,J＝8.3Hz,2H),7.72(d,J＝16.5Hz,2H),7.43-7.42(m,6H),7.15-7.14(m,2H),4.54(s,3H),4.42-4.41(m,4H),3.82-3.81(m,4H),3.48-3.47(m,4H),3.47-3.46(m,4H),3.44-3.43(m,4H),3.40-3.39(m,4H),3.29(s,6H),1.31(s,6H)。

Example 7: singlet oxygen yield test

The compounds BODIPY 1, 2, 3,4, 5, 6, Car-BDP and ZnPc are prepared into 2mL of DMF solution (2 mu M), 2mL of singlet oxygen probe DPBF (100 mu M) is absorbed into six different compound solutions to prepare 4mL of solution, an appropriate cut-off wavelength filter (500nm) is selected according to an ultraviolet visible absorption spectrum, a halogen lamp is 30cm away from the solution, ultraviolet visible scanning is carried out respectively at the irradiation time of 10, 20, 30, 40, 50s and 60s, and the absorbance change at 415nm (the maximum absorption wavelength of the DPBF) is recorded, and the results are shown in Table 1.

TABLE 1 singlet oxygen yield test results for compounds of the invention

Compound (I)	1	3	5	2	4	6	Car-BDP	ZnPc
									Φ_Δ	0.45	0.44	0.42	0.13	0.30	0.09	0.36	0.56

。

Example 8 was carried out: in vitro anti-tumor cell activity assay

The antitumor activity of the novel photosensitizer in vitro cells is determined by an MTT method, and the Hela, SW-480 and A549 cells are respectively planted in a 96-well plate by 5000 cells per well and are incubated for 24 hours. Discarding culture solution, adding 100 μ L of photosensitizer with a series of different concentrations into each well, setting 5 multiple wells for each concentration, adding DMEM culture solution without sample into positive control group, adding sterilized pure water into blank control group, incubating for 5h, and irradiating with illumination power of 90mW/cm²The cells were irradiated with a light dose of 54J. After 24h incubation, the medium was aspirated, 100. mu.L of 0.5mg/mL MTT in DMEM was added and incubation continued for 4 h. Absorbing MTT culture solution, adding 100 microliter DMSO into each well, shaking a flat table for 10min, and measuring the OD value (570nm) by a microplate reader;

the results are shown in Table 2, and the results show that the compound in the invention shows better antitumor activity, and is obviously improved compared with the compound Car-BDP, wherein the compounds 2,4 and 6 have the inhibitory activity IC on tumor cells under experimental conditions₅₀The value is less than 2 mu M, and the compound can be further used for preparing an anti-tumor cell photosensitizer as a novel anti-tumor medicament.

Table 2 shows the tumor cell inhibitory activity IC of the compounds of the present invention₅₀Value results (unit: μ M).

TABLE 2

Claims

1. The pyridine-containing BODIPY and quaternary ammonium salt photosensitizer compound is characterized in that the compound is a BODIPY framework compound containing pyridine, carbazole and polyethylene glycol chains and has a structure shown in a general formula (I),

wherein: ar ═

2. The pyridine-containing BODIPY and its quaternary ammonium salt photosensitizer compound according to claim 1, wherein the compound is Compound 1 having the following structure,

3. the pyridine-containing BODIPY and its quaternary ammonium salt photosensitizer compound according to claim 1, wherein the compound is Compound 2 having the following structure,

4. the pyridine-containing BODIPY and its quaternary ammonium salt photosensitizer compound according to claim 1, wherein the compound is Compound 3 having the following structure,

5. the pyridine-containing BODIPY and its quaternary ammonium salt photosensitizer compound according to claim 1, wherein the compound is the compound 4 of the following structure,

6. the pyridine-containing BODIPY and its quaternary ammonium salt photosensitizer compound according to claim 1, wherein the compound is a compound 5 having the following structure,

7. the pyridine-containing BODIPY and its quaternary ammonium salt photosensitizer compound according to claim 1, wherein the compound is a compound 6 having the following structure,

8. use of the pyridine-containing fluoroboron dipyrromethene compound of claim 1 for the preparation of an antitumor photosensitive agent.

9. Use of the pyridine-containing BODIPY compound according to claim 1 for the preparation of a medicament for the treatment of malignant tumors.

10. Use according to claim 9, characterized in that said malignant tumor is a non-specific broad range of tumors selected from the group consisting of gastric, breast, prostate, lung, colon, bladder, ovarian, skin, cervical cancer.