CN108715591A - Near infrared absorption porphyrin compound as photosensitizer and its application - Google Patents

Abstract

The present invention provides a compound, or a metal complex thereof, represented by formula (I). The compound described in the present invention can be used as a porphyrin photosensitizer, and the synthetic tetraphenylporphyrin is used as a matrix to change its absorption wavelength by reducing hydrogenation. In addition, the compound of the present invention also improves the hydrophilicity of the porphyrin compound by introducing polyethylene glycol (PEG) and cyclodextrin.

Description

Near-infrared absorbing porphyrin compounds used as photosensitizers and applications thereof

technical field

The invention relates to the field of biomedicine, in particular to a class of near-infrared absorbing porphyrin compounds used as photosensitizers and applications thereof.

Background technique

Cancer is one of the major diseases affecting human health, and millions of people die of cancer every year. So far, chemotherapy and radiotherapy are still the most important treatment methods besides surgery, but they cause serious toxic and side effects to the human body while killing tumor cells, and the dose-limiting toxicity of the drug makes the drug effect even less obvious.

In recent years, photodynamic therapy (Photodynamic therapy, PDT) has gradually become one of the important methods for clinical diagnosis and treatment of cancer. Compared with other traditional treatments for cancer (such as surgery, chemotherapy, and radiotherapy), photodynamic therapy has irreplaceable advantages such as specific selectivity and less invasiveness to the human body, making it an emerging means of cancer treatment.

Photodynamic therapy is a new technology that uses photodynamic effect for disease diagnosis and treatment. Its basic elements are photosensitizer, oxygen and light source (commonly used laser). It uses a light source of appropriate wavelength to excite the photosensitizer absorbed by the tissue, and the photosensitizer in the excited state transfers energy to the surrounding oxygen to generate highly active reactive oxygen species (ROS). Reactive oxygen species can destroy tumor cells, induce stagnation of tumor blood vessels, and promote necrosis of malignant tumor tissues, thereby achieving the purpose of treating tumors.

Since photosensitizers only produce cytotoxicity in response to light of specific types and wavelengths, photodynamic therapy is relatively capable of selectively killing local primary and recurrent tumor cells, with little or no damage to healthy tissues and little toxicity. Due to the characteristics of few side effects, it is especially suitable for the elderly and frail patients who cannot be operated or need intravenous chemotherapy. Especially for those patients with advanced tumors who are ineffective or dangerous with traditional treatment methods, photodynamic therapy is an ideal method. Therefore, the development of photodynamic therapy may bring new opportunities for future cancer treatment.

In the process of photodynamic therapy, photosensitizers, as energy carriers and reaction bridges, are crucial decisive factors in photodynamic therapy. The type of photosensitizer, toxicity, sensitization efficiency, and its selective localization and aggregation at the target site all have an important impact on photodynamic therapy. According to the requirements of phototherapy itself, an ideal photosensitizer drug should have the following characteristics: (1) strong absorption in the red light region (600-900nm); (2) high triplet quantum yield; (3) in the presence of oxygen Under the conditions, the excited triplet photosensitizer can generate reactive oxygen species through photosensitive reaction, especially singlet oxygen; (4) high selectivity; (5) high toxicity and low dark toxicity; (6) can be quickly removed from normal tissues Clear etc.

Photosensitizers currently in clinical use or in the research stage include porphyrins, phthalocyanines, fullerenes, fluorobodipyrroles, phenothiazines, methylene blue and metal oxides. Among them, porphyrin and its derivatives have the best PDT due to their large π-bonded conjugated ring, strong absorption in the red region of visible light, strong light penetration ability, and high quantum yield of singlet oxygen. The conditions that the drug should meet are photosensitizers that are the earliest and most widely used in tumor treatment.

In past research and clinical use, porphyrin and its derivatives have been widely used as photosensitizers for clinical diagnosis and treatment of malignant tumors, especially hematoporphyrin and photosensitizer. Porphyrin photosensitizers not only exist in nature with their unique biological activity, but also have a special affinity with cancer cells because of their unique structure. They can be used as photosensitizers and anticancer drugs for detecting cancer in medical research. With the deepening of people's research on porphyrins, photodynamic therapy with porphyrin photosensitizers as the core has gradually become the fourth mature cancer treatment method after surgery, radiotherapy and chemotherapy. In recent years, with the continuous deepening of research on porphyrins, the research on the design, synthesis and application of functional molecules using the unique structure and properties of porphyrins has received extensive attention in the fields of chemistry, biology, and medicine. focus on.

In addition to oxygen, the tissue penetration depth of excitation light is another key parameter of photodynamic therapy. The achievable depth of photodynamic therapy depends on the penetration depth of the excitation light, which is highly dependent on the absorption and scattering properties of the tissue. Since the penetration depth of light is very different in different tissues. In contrast, the penetration depth is related to the wavelength of light in most tissues.

However, in traditional photodynamic therapy, the photosensitizer is usually excited by short-wavelength light, so its poor tissue penetration ability becomes the Achilles' heel in the treatment of deep tumors.

Studies have shown that: when the light absorption of the photosensitizer in photodynamic therapy is in the infrared/near-infrared region, it ensures deeper penetration and less attenuation during tissue propagation, which can effectively increase photodynamic therapy for deeper tumors, Improve the effect of photodynamic therapy. What's more, due to its own low light intensity, the phototoxicity to normal cells and living organisms is also reduced.

However, currently known porphyrin-based photosensitizers only have strong absorption in the red region of visible light. Therefore, designing and synthesizing porphyrin-based photosensitizers with strong absorption in the infrared/near-infrared region to increase the depth of light penetration into tissues during treatment is a problem that needs to be solved today.

Contents of the invention

One object of the present invention is to provide a class of porphyrin compounds that can be used as photosensitizers, using synthetic tetraphenylporphyrin as a precursor, and changing its absorption wavelength by reductive hydrogenation. In addition, the compound of the present invention also improves the hydrophilicity of the porphyrin compound by introducing polyethylene glycol (PEG) and cyclodextrin.

In order to solve the above problems, the present invention provides a compound, or a metal complex thereof, represented by formula (I):

Wherein, R ₁ , R ₂ , R ₃ and R ₄ are independently -H, -OH, -NH ₂ , Polyethylene glycol chain or β-cyclodextrin group; R ₅ is polyethylene glycol chain or β-cyclodextrin group.

In one embodiment of the present invention, the metal complex is represented by formula (I-M):

Wherein, R ₁ , R ₂ , R ₃ and R ₄ are independently -H, -OH, -NH ₂ , Polyethylene glycol chain or β cyclodextrin group; R ₅ is polyethylene glycol chain or β cyclodextrin group; M is Zn, Mn, Fe or Pt.

In an embodiment of the present invention, the formula (I) is selected from the structures in the following formulas (I-1) to (I-5):

Wherein, Ra is -OH, -NH ₂ ; Rb is polyethylene glycol chain or β-cyclodextrin group.

In one embodiment of the present invention, the metal complexes of the compounds of the formulas (I-1) to (I-5) are represented by the formulas (I-1-M) to (I-5-M):

Wherein, Ra is -OH, -NH ₂ ; Rb is polyethylene glycol chain or β-cyclodextrin group; M is Zn, Mn, Fe or Pt.

In one embodiment of the present invention, the compounds that can be used as porphyrin photosensitizers are represented by formulas (I-1)~(I-5) and formulas (I-1-M)~(I-5-M) Show.

In one embodiment of the present invention, the polyethylene glycol chain is represented by formula (i): where n is 48.

In a preferred embodiment of the present invention, the metal complex is represented by formula (I-M-1):

Wherein, Rb is a polyethylene glycol chain or a β-cyclodextrin group.

In a preferred embodiment of the present invention, the compounds used as porphyrin photosensitizers are compounds 1-6, or metal complexes M1-M6 thereof.

Wherein, n is 48, and M is Zn, Mn, Fe or Pt. And preferably, the M is Zn, and n is 48.

The present invention also provides a porphyrin photosensitizer, the porphyrin photosensitizer uses any one of the above-mentioned compounds or metal complexes thereof as an active ingredient; or, the porphyrin photosensitizer is any one of the above compounds or its metal complexes; alternatively, the porphyrin photosensitizer comprises any one of the above-mentioned compounds or its metal complexes.

Experiments show that the absorption wavelength and maximum absorption wavelength of the porphyrin photosensitizer obtained in the present invention are all greater than 730nm, located in the near-infrared region, and can further penetrate deeply into biological tissues. At the same time, the synthesis process of the compound of the invention is simple and cheap, and has the characteristics of easy functionalization, low toxic and side effects, obvious phototoxicity and the like. Therefore, the porphyrin photosensitizer described in the present invention has potential application in photodynamic therapy.

In the present invention, by modifying the porphyrin ring itself, tetraphenylporphyrin is used as a parent, and its absorption wavelength is changed by reductive hydrogenation, so that the obtained compound has a longer maximum absorption wavelength, a higher High singlet oxygen yield, obvious phototoxicity and low dark toxicity. In addition, in the present invention, polyethylene glycol (PEG) and cyclodextrin are introduced into the tetraphenylporphyrin matrix to improve the hydrophilicity of the compound, so that the obtained porphyrin photosensitizer is expected to be used in photodynamic therapy. be applied in.

Description of drawings

Fig. 1 is the ultraviolet-visible light absorption spectrum of compound 1;

Fig. 2 is the ultraviolet-visible light absorption spectrum of compound 2;

Fig. 3 is the ultraviolet-visible light absorption spectrum of compound 3;

Fig. 4 is the ultraviolet-visible light absorption spectrum of compound 4;

Fig. 5 is the ultraviolet-visible light absorption spectrum of compound 5;

Fig. 6 is the ultraviolet-visible light absorption spectrum of compound 6;

Fig. 7 is the ¹ O that porphyrin photosensitizer ₁ produces under light condition on capture agent DPBF ultraviolet-visible light absorption;

Fig. 8 is the change of the maximum absorption value of ultraviolet-visible light of DPBF with the illumination time under illumination conditions;

Fig. 9 is the cell dark toxicity of porphyrin photosensitizer 5 and porphyrin photosensitizer measured by MTT method;

Fig. 10 is the cell phototoxicity of porphyrin photosensitizer 5 and porphyrin photosensitizer determined by MTT method.

Detailed ways

The following describes the preferred embodiments of the present invention with reference to the accompanying drawings to prove that the present invention can be implemented. The embodiments can fully introduce the present invention to those skilled in the art, making its technical content clearer and easier to understand. The present invention can be embodied in many different forms of embodiments, and the protection scope of the present invention is not limited to the embodiments mentioned herein.

In the embodiment of the present invention, the hydrogen nuclear magnetic resonance spectrum ( ¹ HNMR) was measured on a Bruker AV400 Spectrophotometer with a working frequency of 400 MHz, tetramethylsilane was used as an internal standard, and samples were dissolved in deuterated chloroform.

Embodiment 1. Compound 1 and porphyrin photosensitizer 1

In this example, compound 1 is provided, which can be used as porphyrin photosensitizer 1. The compound 1 structure is

The synthetic route of the compound 1 is:

The specific preparation method of the compound 1 comprises the following steps:

(1) Benzaldehyde and pyrrole in a molar ratio of 1:1 were refluxed in propionic acid at 140°C for 4 hours. After cooling, methanol was added to crystallize. After filtration and separation by silica gel column chromatography, 5,10,15,20- Tetraphenylporphyrin (TPP);

Weigh benzaldehyde (10.6g, 0.1mol) and 200mL propionic acid into a 500mL three-necked flask, stir and dissolve at room temperature, and then connect the condenser to reflux. Freshly distilled pyrrole (7 mL, 0.1 mol) was then added dropwise under nitrogen protection. The reaction mixture was heated to reflux for an additional 4 h, then cooled to room temperature. Then propionic acid was concentrated by distillation under reduced pressure, 150 mL of methanol was added after cooling, and a purple solid was precipitated at low temperature (-20°C) overnight, and a purple crude product was obtained by suction filtration and washed with methanol. Finally, using chloroform/methanol (95:5, v/v) as the eluent, the product was purified by silica gel column chromatography, and the product was 5,10,15,20-tetraphenylporphyrin (TPP), and the yield was 25%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.88 (m, 8H, β-CH), 8.21 (m, 8H, 5, 10, 15, 20-Ar-oH), 7.75 (m, 12H, 10, 15,20-Ar-m-and pH),-2.77(s,2H,-NH-).

(2) Under nitrogen protection, anhydrous potassium carbonate and 5,10,15,20-tetraphenylporphyrin (TPP) obtained in step (1) were dissolved in anhydrous pyridine. Subsequently, p-toluenesulfonyl hydrazide was added, and the mixture was refluxed at 105° C. and protected from light for 24 hours. After the reaction is over, add p-toluenesulfonylhydrazide again under the protection of nitrogen. After reacting at room temperature for 8 hours, add ethyl acetate and water to reflux for 1 hour. After the solution is cooled, the organic phase is saturated with 2mol/L hydrochloric acid, phosphoric acid, and water respectively. Washing and extracting with sodium bicarbonate solution, drying, and rotary evaporating to remove the solvent, and separating the obtained crude product through solid silica gel column chromatography to obtain compound 1, which is the porphyrin photosensitizer compound 1 that absorbs near-infrared light according to the present invention;

Under nitrogen protection, anhydrous potassium carbonate (1.1g, 8mmol) and 5,10,15,20-tetraphenylporphyrin (TPP, 0.5g, 0.8mmol) obtained in step (1) were dissolved in 40mL of anhydrous in pyridine. Then p-toluenesulfonyl hydrazide (1.5 g, 8 mmol) was added, and the mixture was refluxed at 105° C. and protected from light for 24 h. After the reaction was completed and cooled, p-toluenesulfonylhydrazide (1.5 g, 8 mmol) was added again under the protection of nitrogen. After 8 hours of reaction at room temperature, ethyl acetate/water (2:1, 300 mL) was added and refluxed for 1 hour. After the solution was cooled, the organic phase was Wash and extract with 2mol/L hydrochloric acid, 68% phosphoric acid solution, water and saturated sodium bicarbonate solution successively for 3 times, the solution is dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation. The obtained crude product was separated by solid silica gel column chromatography using dichloromethane/n-hexane (1:1, v/v) as eluent. Compound 1 was obtained after vacuum drying, which is a porphyrin photosensitizer compound 1 that absorbs near-infrared light, and the yield was 65%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.52-8.02 (m, 4H, β-CH), 7.88-7.69 (m, 8H, 5, 10, 15, 20-Ar-oH), 7.65-7.52 ( m,12H,5,10,15,20-Ar-m-and pH), 4.13-3.96(m,8H,β-CH ₂ ), -1.38and-1.42(s,2H,-NH-).

Embodiment 2. Compound 2 and porphyrin photosensitizer 2

In this example, compound 2 is provided, which can be used as porphyrin photosensitizer 2. The structure of the compound 2 is

The synthetic route of the compound 2 is:

The specific preparation method of the compound 2 comprises the following steps:

(1) According to the molar ratio of p-hydroxybenzaldehyde: benzaldehyde: pyrrole is 1:3:4 (that is, p-hydroxybenzaldehyde: benzaldehyde: pyrrole = 1:3:4), in propionic acid at 140 ° C Reflux reaction for 4 hours, after cooling, add methanol to crystallize, filter, and obtain 5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin (TPP-OH) after separation by silica gel column chromatography;

(2) Under nitrogen protection, anhydrous potassium carbonate and 5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin (TPP-OH) obtained in step (1) were dissolved in in water pyridine. Subsequently, p-toluenesulfonyl hydrazide was added, and the mixture was refluxed at 105° C. and protected from light for 24 hours. After the reaction is over, add p-toluenesulfonylhydrazide again under the protection of nitrogen. After reacting at room temperature for 8 hours, add ethyl acetate and water to reflux for 1 hour. After the solution is cooled, the organic phase is saturated with 2mol/L hydrochloric acid, phosphoric acid, and water respectively. Washing and extracting with sodium bicarbonate solution, drying, and then rotary evaporating to remove the solvent, and separating the obtained crude product through solid silica gel column chromatography to obtain compound 2, which is the porphyrin photosensitizer compound 2 that absorbs near-infrared light according to the present invention;

Under nitrogen protection, anhydrous potassium carbonate (1.1g, 8mmol) and 5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin (TPP-OH, 0.8 mmol) was dissolved in 40 mL of anhydrous pyridine. Then p-toluenesulfonyl hydrazide (1.5 g, 8 mmol) was added, and the mixture was refluxed at 105° C. and protected from light for 24 h. After the reaction was completed and cooled, p-toluenesulfonylhydrazide (1.5g, 8mmol) was added again under the protection of nitrogen. After 8 hours of reaction at room temperature, ethyl acetate/water (2:1, 300mL) was added and refluxed for 1 hour. After the solution was cooled, the organic phase was Wash and extract with 2mol/L hydrochloric acid, 68% phosphoric acid solution, water and saturated sodium bicarbonate solution successively for 3 times, the solution is dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation. The obtained crude product was separated by solid silica gel column chromatography using dichloromethane/n-hexane (1:1, v/v) as eluent. Compound 2 was obtained after vacuum drying, which is the porphyrin photosensitizer 2 absorbing near-infrared light, and the yield was 70%.

Embodiment 3. Compound 3 and porphyrin photosensitizer 3

In this example, compound 3 is provided, which can be used as porphyrin photosensitizer 3. The structure of the compound 3 is

The synthetic route of the compound 3 is:

The specific preparation method of the compound 3 comprises the following steps:

(1) Benzaldehyde and pyrrole in a molar ratio of 1:1 were refluxed in propionic acid at 140°C for 4 hours. After cooling, methanol was added to crystallize. After filtration and separation by silica gel column chromatography, 5,10,15,20- Tetraphenylporphyrin (TPP);

Weigh benzaldehyde (10.6g, 0.1mol) and 200mL propionic acid into a 500mL three-necked flask, stir and dissolve at room temperature, and then connect the condenser to reflux. Freshly distilled pyrrole (7 mL, 0.1 mol) was then added dropwise under nitrogen protection. The reaction mixture was heated to reflux for an additional 4 h, then cooled to room temperature. Then propionic acid was concentrated by distillation under reduced pressure, 150 mL of methanol was added after cooling, and a purple solid was precipitated at low temperature (-20°C) overnight, and a purple crude product was obtained by suction filtration and washed with methanol. Finally, using chloroform/methanol (95:5, v/v) as the eluent, the product was purified by silica gel column chromatography, and the product was 5,10,15,20-tetraphenylporphyrin (TPP), and the yield was 25%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.88 (m, 8H, β-CH), 8.21 (m, 8H, 5, 10, 15, 20-Ar-oH), 7.75 (m, 12H, 10, 15,20-Ar-m-and pH),-2.77(s,2H,-NH-).

(2) The 5,10,15,20-tetraphenylporphyrin (TPP) obtained in step (1) was dissolved in trifluoroacetic acid, and sodium nitrite was added to react at room temperature for 5 minutes, and then quenched by adding water. Then, the organic phase was washed and extracted with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dried and evaporated to remove the solvent, and separated by silica gel column chromatography to obtain 5,10-bis(4-nitrophenyl)-15,20 - mixtures of diphenylporphyrin and 5,15-bis(4-nitrophenyl)-10,20-diphenylporphyrin;

Weigh the 5,10,15,20-tetraphenylporphyrin (TPP, 0.8g, 1.3mmol) obtained in step (1) into a 100mL round bottom flask, add 50mL trifluoroacetic acid and stir at room temperature for 15min to fully dissolve it . Then sodium nitrite (0.74g, 10.6mmol) was weighed and added into the reaction flask, mixed and stirred for 6 minutes. Afterwards, the reaction solution was transferred to 150 mL of ice water to quench the reaction, and the organic phase was extracted with dichloromethane (3×100 mL), and then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively to extract the organic phase for 3 times. After drying with sodium sulfate water and filtering, after spin-drying the solvent, the crude product was purified through a silica gel column using dichloromethane/petroleum ether (2:1, v/v) as the eluent to obtain 5,10-bis(4-nitrate phenyl)-15,20-diphenylporphyrin and 5,15-bis(4-nitrophenyl)-10,20-diphenylporphyrin, after vacuum drying, 0.48g of purple mixed product was obtained , the yield was 60%.

5,10-bis(4-nitrophenyl)-15,20-diphenylporphyrin: ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.91(d, 4H, β-CH), 8.82(d ,4H,β-CH),8.69(m,6H,15,20-Ar-m-and pH),8.39(m,4H,15,20-Ar-oH),8.12 (m,4H,5,10 -Ar-oH), 7.70 (m, 4H, 5, 10-Ar-m-and pH), -2.79 (s, 2H, -NH-).

5,15-bis(4-nitrophenyl)-10,20-diphenylporphyrin: ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.90(d,4H, β-CH), 8.77(d ,4H,β-CH),8.65(m,6H,15,20-Ar-m-and pH),8.41(m,4H,15,20-Ar-oH),8.20 (m,4H,5,10 -Ar-oH), 7.81 (m, 4H, 5, 10-Ar-m-and pH), -2.79 (s, 2H, -NH-).

(3) Under argon protection, the 5,10-bis(4-nitrophenyl)-15,20-diphenylporphyrin obtained in step (2) was mixed with 5,15-bis(4-nitro Add concentrated hydrochloric acid to the mixture of phenyl)-10,20-diphenylporphyrin and stir for 30 minutes, then add stannous chloride and react at 65°C for 2 hours. After the reaction is cooled, water is added to quench the reaction, and ammonia water is added until the pH value of the solution is equal to about 8. Then, wash and extract the organic phase with saturated sodium chloride solution, dry and evaporate to remove the solvent, and obtain 5,15-bis(4-aminophenyl)-10,20-diphenylporphyrin (NH ₂ -TPP-NH ₂ );

Weigh the 5,10-bis(4-nitrophenyl)-15,20-diphenylporphyrin and 5,15-bis(4-nitrophenyl)-10,20-diphenylporphyrin obtained in step (2) Diphenylporphyrin (0.7g, 1mmol) was added to a 100mL Schlenk bottle, under the protection of argon, 30mL of concentrated hydrochloric acid was added to the bottle and stirred for 20min, then stannous chloride (2.2g, 10mmol) was added. The balloon was kept under pressure and reacted at 65°C for 2h. After the reaction, transfer the reaction solution to 100mL ice water to quench the reaction, add ammonia water to neutralize to a pH value of about 8, use dichloromethane as the extractant, and extract the organic phase with saturated sodium chloride solution, and dry it with anhydrous sodium sulfate The solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography using dichloromethane/acetone (50/1: v/v) as eluent to obtain 5,15-bis(4-aminophenyl)-10,20 - Diphenylporphyrin. Yield 22.1%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.89(d,4H,β-CH),8.82(d,4H,β-CH),8.21(m,4H,15,20-Ar-oH),8.01 (m,4H,5,10-Ar-oH),7.79(m,6H,15,20-Ar-m-andp-H),7.06(m,4H,5,10-Ar-mH),4.05( s,4H,-NH ₂ ),-2.78(s,2H,-NH-).

(4) Under nitrogen protection, anhydrous potassium carbonate and 5,15-bis(4-aminophenyl)-10,20-diphenylporphyrin (NH ₂ -TPP-NH ₂ ) Dissolve in anhydrous pyridine. Subsequently, p-toluenesulfonyl hydrazide was added, and the mixture was refluxed at 105° C. and protected from light for 24 hours. After the reaction is over, add p-toluenesulfonylhydrazide again under the protection of nitrogen. After reacting at room temperature for 8 hours, add ethyl acetate and water to reflux for 1 hour. After the solution is cooled, the organic phase is saturated with 2mol/L hydrochloric acid, phosphoric acid, and water respectively. Washing and extracting with sodium bicarbonate solution, drying and rotary evaporation to remove the solvent, and separating the obtained crude product through solid silica gel column chromatography to obtain compound 3, which is the porphyrin photosensitizer compound 3 that absorbs near-infrared light according to the present invention;

Under nitrogen protection, anhydrous potassium carbonate (1.1g, 8mmol) and 5,15-bis(4-aminophenyl)-10,20-diphenylporphyrin (0.51g, 0.8mmol), dissolved in 40mL of anhydrous pyridine. Then p-toluenesulfonyl hydrazide (1.5 g, 8 mmol) was added, and the mixture was refluxed at 105° C. and protected from light for 24 h. After the reaction was completed and cooled, p-toluenesulfonylhydrazide (1.5g, 8mmol) was added again under the protection of nitrogen. After 8 hours of reaction at room temperature, ethyl acetate/water (2:1, 300mL) was added and refluxed for 1 hour. After the solution was cooled, the organic phase was Wash and extract with 2mol/L hydrochloric acid, 68% phosphoric acid solution, water and saturated sodium bicarbonate solution successively for 3 times, the solution is dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation. The obtained crude product was separated by solid silica gel column chromatography using dichloromethane/n-hexane (2:1, v/v) as eluent. Compound 3 was obtained after vacuum drying, that is, compound 3, a porphyrin photosensitizer that absorbs near-infrared light. The yield was 75%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.66-8.08(m, 4H, β-CH), 8.11-7.92(m, 4H, 15, 20-Ar-oH), 7.82-7.76(m, 4H, 5,10-Ar-oH),7.67-7.51(m,6H,15,20-Ar-m-and pH),7.01-6.92(m,4H,5,10-Ar-mH),4.24-4.06( m, 8H, β- _CH2 ), 4.02 (s, 4H, _-NH2 ), -1.38 and -1.43 (s, 2H, -NH-).

Embodiment 4. Compound 4 and porphyrin photosensitizer 4

In this example, compound 4 is provided, which can be used as porphyrin photosensitizer 4. The structure of the compound 4 is

The synthetic route of the compound 4 is:

The specific preparation method of the compound 4 comprises the following steps:

(1) p-Hydroxybenzaldehyde and pyrrole in a molar ratio of 1:1 were refluxed in propionic acid at 140°C for 4 hours. After cooling, methanol was added to crystallize, filtered, and separated by silica gel column chromatography to obtain 5,10,15, 20-Tetrahydroxyphenylporphyrin (TPP-(OH) ₄ );

(2) Under nitrogen protection, anhydrous potassium carbonate and 5,10,15,20-tetrahydroxyphenylporphyrin (TPP-(OH) ₄ ) obtained in step (1) were dissolved in anhydrous pyridine. Subsequently, p-toluenesulfonyl hydrazide was added, and the mixture was refluxed at 105° C. and protected from light for 24 hours. After the reaction is over, add p-toluenesulfonylhydrazide again under the protection of nitrogen. After reacting at room temperature for 8 hours, add ethyl acetate and water to reflux for 1 hour. After the solution is cooled, the organic phase is saturated with 2mol/L hydrochloric acid, phosphoric acid, and water respectively. Washing and extracting with sodium bicarbonate solution, drying and rotary evaporation to remove the solvent, and separating the obtained crude product by solid silica gel column chromatography to obtain compound 4, which is the porphyrin photosensitizer compound 4 that absorbs near-infrared light according to the present invention;

Under nitrogen protection, anhydrous potassium carbonate (1.1g, 8mmol) and 5,10,15,20-tetrahydroxyphenylporphyrin (TPP-(OH) ₄ , 0.8mmol) obtained in step (1), Dissolved in 40mL of anhydrous pyridine. Then p-toluenesulfonyl hydrazide (1.5 g, 8 mmol) was added, and the mixture was refluxed at 105° C. and protected from light for 24 h. After the reaction was completed and cooled, p-toluenesulfonylhydrazide (1.5g, 8mmol) was added again under the protection of nitrogen. After 8 hours of reaction at room temperature, ethyl acetate/water (2:1, 300mL) was added and refluxed for 1 hour. After the solution was cooled, the organic phase was Wash and extract with 2mol/L hydrochloric acid, 68% phosphoric acid solution, water and saturated sodium bicarbonate solution successively for 3 times, the solution is dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation. The obtained crude product was separated by solid silica gel column chromatography using dichloromethane/n-hexane (2:1, v/v) as eluent. Compound 4 was obtained after vacuum drying, which is porphyrin photosensitizer compound 4 that absorbs near-infrared light. The yield was 65%.

Embodiment 5. Compound 5 and porphyrin photosensitizer 5

In this example, compound 5 is provided, which can be used as porphyrin photosensitizer 5. The structure of the compound 5 is

The synthetic route of described compound 5 is:

The specific preparation method of the compound 5 comprises the following steps:

(1) Benzaldehyde and pyrrole in a molar ratio of 1:1 were refluxed in propionic acid at 140°C for 4 hours. After cooling, methanol was added to crystallize. After filtration and separation by silica gel column chromatography, 5,10,15,20- Tetraphenylporphyrin (TPP);

Weigh benzaldehyde (10.6g, 0.1mol) and 200mL propionic acid into a 500mL three-necked flask, stir and dissolve at room temperature, and then connect the condenser to reflux. Freshly distilled pyrrole (7 mL, 0.1 mol) was then added dropwise under nitrogen protection. The reaction mixture was heated to reflux for an additional 4 h, then cooled to room temperature. Then propionic acid was concentrated by distillation under reduced pressure, 150 mL of methanol was added after cooling, and a purple solid was precipitated at low temperature (-20°C) overnight, and a purple crude product was obtained by suction filtration and washed with methanol. Finally, using chloroform/methanol (95:5, v/v) as the eluent, the product was purified by silica gel column chromatography, and the product was 5,10,15,20-tetraphenylporphyrin (TPP), and the yield was 25%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.88 (m, 8H, β-CH), 8.21 (m, 8H, 5, 10, 15, 20-Ar-oH), 7.75 (m, 12H, 10, 15,20-Ar-m-and pH),-2.77(s,2H,-NH-).

(2) The 5,10,15,20-tetraphenylporphyrin (TPP) obtained in step (1) was dissolved in trifluoroacetic acid, and sodium nitrite was added to react at room temperature for 5 minutes, and then quenched by adding water. Then, the organic phase was washed and extracted with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dried and evaporated to remove the solvent, and separated by silica gel column chromatography to obtain 5,10-bis(4-nitrophenyl)-15,20 - mixtures of diphenylporphyrin and 5,15-bis(4-nitrophenyl)-10,20-diphenylporphyrin;

Weigh the 5,10,15,20-tetraphenylporphyrin (TPP, 0.8g, 1.3mmol) obtained in step (1) into a 100mL round bottom flask, add 50mL trifluoroacetic acid and stir at room temperature for 15min to fully dissolve it . Then sodium nitrite (0.74g, 10.6mmol) was weighed and added into the reaction flask, mixed and stirred for 6 minutes. Afterwards, the reaction solution was transferred to 150 mL of ice water to quench the reaction, and the organic phase was extracted with dichloromethane (3×100 mL), and then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively to extract the organic phase for 3 times. After drying with sodium sulfate water and filtering, after spin-drying the solvent, the crude product was purified through a silica gel column using dichloromethane/petroleum ether (2:1, v/v) as the eluent to obtain 5,10-bis(4-nitrate phenyl)-15,20-diphenylporphyrin and 5,15-bis(4-nitrophenyl)-10,20-diphenylporphyrin, after vacuum drying, 0.48g of purple mixed product was obtained , the yield was 60%.

5,10-bis(4-nitrophenyl)-15,20-diphenylporphyrin: ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.91(d, 4H, β-CH), 8.82(d ,4H,β-CH),8.69(m,6H,15,20-Ar-m-and pH),8.39(m,4H,15,20-Ar-oH),8.12 (m,4H,5,10 -Ar-oH), 7.70 (m, 4H, 5, 10-Ar-m-and pH), -2.79 (s, 2H, -NH-).

5,15-bis(4-nitrophenyl)-10,20-diphenylporphyrin: ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.90(d,4H, β-CH), 8.77(d ,4H,β-CH),8.65(m,6H,15,20-Ar-m-and pH),8.41(m,4H,15,20-Ar-oH),8.20 (m,4H,5,10 -Ar-oH), 7.81 (m, 4H, 5, 10-Ar-m-and pH), -2.79 (s, 2H, -NH-).

(3) Under argon protection, the 5,10-bis(4-nitrophenyl)-15,20-diphenylporphyrin obtained in step (2) was mixed with 5,15-bis(4-nitro Add concentrated hydrochloric acid to the mixture of phenyl)-10,20-diphenylporphyrin and stir for 30 minutes, then add stannous chloride and react at 65°C for 2 hours. After the reaction is cooled, water is added to quench the reaction, and ammonia water is added until the pH value of the solution is equal to about 8. Then, wash and extract the organic phase with saturated sodium chloride solution, dry and evaporate to remove the solvent, and obtain 5,15-bis(4-aminophenyl)-10,20-diphenylporphyrin (NH ₂ -TPP-NH ₂ );

Weigh the 5,10-bis(4-nitrophenyl)-15,20-diphenylporphyrin and 5,15-bis(4-nitrophenyl)-10,20-diphenylporphyrin obtained in step (2) Diphenylporphyrin (0.7g, 1mmol) was added to a 100mL Schlenk bottle, under the protection of argon, 30mL of concentrated hydrochloric acid was added to the bottle and stirred for 20min, then stannous chloride (2.2g, 10mmol) was added. The balloon was kept under pressure and reacted at 65°C for 2h. After the reaction, transfer the reaction solution to 100mL ice water to quench the reaction, add ammonia water to neutralize to a pH value of about 8, use dichloromethane as the extractant, and extract the organic phase with saturated sodium chloride solution, and dry it with anhydrous sodium sulfate The solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography using dichloromethane/acetone (50/1: v/v) as eluent to obtain 5,15-bis(4-aminophenyl)-10,20 - Diphenylporphyrin. Yield 22.1%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.89(d,4H,β-CH),8.82(d,4H,β-CH),8.21(m,4H,15,20-Ar-oH),8.01 (m,4H,5,10-Ar-oH),7.79(m,6H,15,20-Ar-m-andp-H),7.06(m,4H,5,10-Ar-mH),4.05( s,4H,-NH ₂ ),-2.78(s,2H,-NH-).

(4) Dissolve propyne bromide and 5,15-bis(4-aminophenyl)-10,20-diphenylporphyrin (NH ₂ -TPP-NH ₂ ) obtained in step (3) in dimethyl Formamide (DMF), and adding anhydrous potassium carbonate, reacted at 80°C for 24h. After cooling, the organic phase was washed and extracted with saturated sodium chloride solution, dried and evaporated to remove the solvent, and separated by silica gel column chromatography to obtain 5,15-bis(4-propynylaniline)-10,20-diphenylporphyrin (≡ -TPP-≡);

Under nitrogen protection, anhydrous potassium carbonate (221 mg, 1.6 mmol) and 5,15-bis(4-aminophenyl)-10,20-diphenylporphyrin (100 mg, 0.16 mmol) was dissolved in 20mL DMF and fully dissolved. Then 2 mL of a DMF solution of propyne bromide (190 mg, 1.6 mmol) was added and reacted at 80° C. for 24 h. After cooling, use dichloromethane as the extractant and saturated sodium chloride solution to wash and extract the organic phase. After drying, the solvent is removed by rotary evaporation. Dichloromethane is used as the eluent for silica gel column chromatography to obtain 5,15-bis(4-propynyl aniline)-10,20-diphenylporphyrin. The yield was 91%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.89(d,4H,β-CH),8.82(d,4H,β-CH),8.21(m,4H,15,20-Ar-oH),8.01 (m,4H,5,10-Ar-oH),7.79(m,6H,15,20-Ar-m-and pH),7.06(m,4H,5,10-Ar-mH),3.75(s , 4H, -NH-CH ₂ -C≡), 2.51 (s, 2H, -C≡CH), -2.78 (s, 2H, -NH-).

(5) Under the protection of nitrogen, the 5,15-bis(4-propynylaniline)-10,20-diphenylporphyrin (≡-TPP-≡) obtained in step (4) was dissolved in dichloromethane and methanol in a mixed solution, then add zinc acetate to react at room temperature for 6 hours, wash and extract the organic phase with saturated sodium chloride solution, dry and then evaporate to remove the solvent to obtain zinc-containing 5,15-bis(4-propynylaniline)-10 ,20-Diphenylporphyrin;

Under nitrogen protection, the 5,15-bis(4-propynylaniline)-10,20-diphenylporphyrin (100mg, 0.14mmol) obtained in step (4) was dissolved in a mixture of dichloromethane and methanol solution, then add zinc acetate (257mg 1.4mmol) to react at room temperature for 6h, wash and extract the organic phase with saturated sodium chloride solution, dry and remove the solvent by rotary evaporation to obtain zinc-containing 5,15-bis(4-propynylaniline)- 10,20-Diphenylporphyrin. The yield was 97%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.89 (d, 4H, β-CH), 8.82 (d, 4H, β-CH), 8.21 (m, 4H, 15, 20-Ar-oH), 8.01 (m,4H,5,10-Ar-oH),7.79(m,6H,15,20-Ar-m-and pH),7.06(m,4H,5,10-Ar-mH),3.75(s , 4H, -NH-CH ₂ -C≡), 2.51 (s, 2H, -C≡CH).

(6) Under the protection of nitrogen, monoazide polyethylene glycol monomethyl ether (PEG-N ₃ ) and the zinc-containing 5,15-bis(4-propynylaniline)-10 obtained in step (5) Dissolve 20-diphenylporphyrin in dimethylformamide (DMF), ventilate for 30 minutes, add pentamethyldiethylenetriamine (PMDETA) and cuprous bromide under the protection of nitrogen, fully stir to dissolve, and react at 50°C 48h. After the reaction was completed and cooled, the organic phase was washed and extracted with saturated sodium chloride solution, dried and then evaporated to remove the solvent, purified by dialysis and freeze-dried, and separated by silica gel column chromatography to obtain double PEG-modified TPP;

Under the protection of nitrogen, monoazide polyethylene glycol monomethyl ether (PEG-N ₃ , 1.04g, 0.52mmol) and the zinc-containing 5,15-bis(4-propynylaniline) obtained in step (5) -10,20-diphenylporphyrin (100mg, 0.13mmol) was dissolved in 10mL dimethylformamide (DMF), and after aeration for 30min, PMDETA (90mg, 0.52mmol) and cuprous bromide were added under nitrogen protection (75mg, 0.52mmol) was fully stirred and dissolved, and reacted at 50°C for 48h. After the reaction was completed and cooled, the extracted organic phase was washed with saturated sodium chloride solution, dried and evaporated to remove the solvent, and then the unreacted reagent was removed by dialysis (MWCO=3500Da) according to the molecular weight. After lyophilization, dichloromethane/methanol (30:1, v/v) was used as the eluent to pass through the column to obtain double PEG-modified TPP (PEG-TPP-PEG), with a yield of 77%.

(7) Under nitrogen protection, anhydrous potassium carbonate and the double PEG-modified TPP obtained in step (6) were dissolved in anhydrous pyridine. Subsequently, p-toluenesulfonyl hydrazide was added, and the mixture was refluxed at 105° C. and protected from light for 24 hours. After the reaction is over, add p-toluenesulfonylhydrazide again under the protection of nitrogen. After reacting at room temperature for 8 hours, add ethyl acetate and water to reflux for 1 hour. After the solution is cooled, the organic phase is saturated with 2mol/L hydrochloric acid, phosphoric acid, and water respectively. Washing and extracting with sodium bicarbonate solution, drying, and then rotary evaporating to remove the solvent, and separating the obtained crude product through solid silica gel column chromatography to obtain compound 5, which is the porphyrin photosensitizer compound 5 that absorbs near-infrared light according to the present invention;

The double PEG-modified TPP (0.8 mmol) and anhydrous potassium carbonate (1.1 g, 8 mmol) obtained in step (6) were dissolved in 40 mL of anhydrous pyridine under nitrogen protection. Then p-toluenesulfonyl hydrazide (1.5 g, 8 mmol) was added, and the mixture was refluxed at 105° C. and protected from light for 24 h. After the reaction was completed and cooled, p-toluenesulfonylhydrazide (1.5g, 8mmol) was added again under the protection of nitrogen. After 8 hours of reaction at room temperature, ethyl acetate/water (2:1, 300mL) was added and refluxed for 1 hour. After the solution was cooled, the organic phase was Wash and extract with 2mol/L hydrochloric acid, 68% phosphoric acid solution, water, and saturated sodium bicarbonate solution successively for three times, and the solution is dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation. The obtained crude product was separated by solid silica gel column chromatography using dichloromethane/methanol (30:1, v/v) as eluent. Compound 5 was obtained after vacuum drying, that is, compound 5, a porphyrin photosensitizer that absorbs near-infrared light. Yield is 54%

Embodiment 6. Compound 6 and porphyrin photosensitizer 6

In this example, compound 6 is provided, which can be used as porphyrin photosensitizer 6. The structure of the compound 6 is

The synthetic route of described compound 6 is:

The specific preparation method of the compound 6 comprises the following steps:

(1) Benzaldehyde and pyrrole in a molar ratio of 1:1 were refluxed in propionic acid at 140°C for 4 hours. After cooling, methanol was added to crystallize. After filtration and separation by silica gel column chromatography, 5,10,15,20- Tetraphenylporphyrin (TPP);

Weigh benzaldehyde (10.6g, 0.1mol) and 200mL propionic acid into a 500mL three-necked flask, stir and dissolve at room temperature, and then connect the condenser to reflux. Freshly distilled pyrrole (7 mL, 0.1 mol) was then added dropwise under nitrogen protection. The reaction mixture was heated to reflux for an additional 4 h, then cooled to room temperature. Then propionic acid was concentrated by distillation under reduced pressure, 150 mL of methanol was added after cooling, and a purple solid was precipitated at low temperature (-20°C) overnight, and a purple crude product was obtained by suction filtration and washed with methanol. Finally, using chloroform/methanol (95:5, v/v) as the eluent, the product was purified by silica gel column chromatography, and the product was 5,10,15,20-tetraphenylporphyrin (TPP), and the yield was 25%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.88 (m, 8H, β-CH), 8.21 (m, 8H, 5, 10, 15, 20-Ar-oH), 7.75 (m, 12H, 10, 15,20-Ar-m-and pH),-2.77(s,2H,-NH-).

(2) The 5,10,15,20-tetraphenylporphyrin (TPP) obtained in step (1) was dissolved in trifluoroacetic acid, and sodium nitrite was added to react at room temperature for 5 minutes, and then quenched by adding water. Then, the organic phase was washed and extracted with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dried and evaporated to remove the solvent, and separated by silica gel column chromatography to obtain 5,10-bis(4-nitrophenyl)-15,20 - mixtures of diphenylporphyrin and 5,15-bis(4-nitrophenyl)-10,20-diphenylporphyrin;

Weigh the 5,10,15,20-tetraphenylporphyrin (TPP, 0.8g, 1.3mmol) obtained in step (1) into a 100mL round bottom flask, add 50mL trifluoroacetic acid and stir at room temperature for 15min to fully dissolve it . Then sodium nitrite (0.74g, 10.6mmol) was weighed and added into the reaction flask, mixed and stirred for 6 minutes. Afterwards, the reaction solution was transferred to 150 mL of ice water to quench the reaction, and the organic phase was extracted with dichloromethane (3×100 mL), and then washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively to extract the organic phase for 3 times. After drying with sodium sulfate water and filtering, after spin-drying the solvent, the crude product was purified through a silica gel column using dichloromethane/petroleum ether (2:1, v/v) as the eluent to obtain 5,10-bis(4-nitrate phenyl)-15,20-diphenylporphyrin and 5,15-bis(4-nitrophenyl)-10,20-diphenylporphyrin, after vacuum drying, 0.48g of purple mixed product was obtained , the yield was 60%.

5,10-bis(4-nitrophenyl)-15,20-diphenylporphyrin: ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.91(d, 4H, β-CH), 8.82(d ,4H,β-CH),8.69(m,6H,15,20-Ar-m-and pH),8.39(m,4H,15,20-Ar-oH),8.12 (m,4H,5,10 -Ar-oH), 7.70 (m, 4H, 5, 10-Ar-m-and pH), -2.79 (s, 2H, -NH-).

5,15-bis(4-nitrophenyl)-10,20-diphenylporphyrin: ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.90(d,4H, β-CH), 8.77(d ,4H,β-CH),8.65(m,6H,15,20-Ar-m-and pH),8.41(m,4H,15,20-Ar-oH),8.20 (m,4H,5,10 -Ar-oH), 7.81 (m, 4H, 5, 10-Ar-m-and pH), -2.79 (s, 2H, -NH-).

(3) Under argon protection, the 5,10-bis(4-nitrophenyl)-15,20-diphenylporphyrin obtained in step (2) was mixed with 5,15-bis(4-nitro Add concentrated hydrochloric acid to the mixture of phenyl)-10,20-diphenylporphyrin and stir for 30 minutes, then add stannous chloride and react at 65°C for 2 hours. After the reaction is cooled, water is added to quench the reaction, and ammonia water is added until the pH value of the solution is equal to about 8. Then, wash and extract the organic phase with saturated sodium chloride solution, dry and evaporate to remove the solvent, and obtain 5,15-bis(4-aminophenyl)-10,20-diphenylporphyrin (NH ₂ -TPP-NH ₂ );

Weigh the 5,10-bis(4-nitrophenyl)-15,20-diphenylporphyrin and 5,15-bis(4-nitrophenyl)-10,20-diphenylporphyrin obtained in step (2) Diphenylporphyrin (0.7g, 1mmol) was added to a 100mL Schlenk bottle, under the protection of argon, 30mL of concentrated hydrochloric acid was added to the bottle and stirred for 20min, then stannous chloride (2.2g, 10mmol) was added. The balloon was kept under pressure and reacted at 65°C for 2h. After the reaction, transfer the reaction solution to 100mL ice water to quench the reaction, add ammonia water to neutralize to a pH value of about 8, use dichloromethane as the extractant, and extract the organic phase with saturated sodium chloride solution, and dry it with anhydrous sodium sulfate The solvent was spin-dried, and the crude product was separated and purified by silica gel column chromatography using dichloromethane/acetone (50/1: v/v) as eluent to obtain 5,15-bis(4-aminophenyl)-10,20 - Diphenylporphyrin. Yield 22.1%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.89(d,4H,β-CH),8.82(d,4H,β-CH),8.21(m,4H,15,20-Ar-oH),8.01 (m,4H,5,10-Ar-oH),7.79(m,6H,15,20-Ar-m-andp-H),7.06(m,4H,5,10-Ar-mH),4.05( s,4H,-NH ₂ ),-2.78(s,2H,-NH-).

(4) Dissolve propyne bromide and 5,15-bis(4-aminophenyl)-10,20-diphenylporphyrin (NH ₂ -TPP-NH ₂ ) obtained in step (3) in dimethyl Formamide (DMF), and adding anhydrous potassium carbonate, reacted at 80°C for 24h. After cooling, the organic phase was washed and extracted with saturated sodium chloride solution, dried and evaporated to remove the solvent, and separated by silica gel column chromatography to obtain 5,15-bis(4-propynylaniline)-10,20-diphenylporphyrin (≡ -TPP-≡);

Under nitrogen protection, anhydrous potassium carbonate (221 mg, 1.6 mmol) and 5,15-bis(4-aminophenyl)-10,20-diphenylporphyrin (100 mg, 0.16 mmol) was dissolved in 20mL DMF and fully dissolved. Then 2 mL of a DMF solution of propyne bromide (190 mg, 1.6 mmol) was added and reacted at 80° C. for 24 h. After cooling, use dichloromethane as the extractant and saturated sodium chloride solution to wash and extract the organic phase. After drying, the solvent is removed by rotary evaporation. Dichloromethane is used as the eluent for silica gel column chromatography to obtain 5,15-bis(4-propynyl aniline)-10,20-diphenylporphyrin. The yield was 91%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.89(d,4H,β-CH),8.82(d,4H,β-CH),8.21(m,4H,15,20-Ar-oH),8.01 (m,4H,5,10-Ar-oH),7.79(m,6H,15,20-Ar-m-and pH),7.06(m,4H,5,10-Ar-mH),3.75(s , 4H, -NH-CH ₂ -C≡), 2.51 (s, 2H, -C≡CH), -2.78 (s, 2H, -NH-).

(5) Under the protection of nitrogen, the 5,15-bis(4-propynylaniline)-10,20-diphenylporphyrin (≡-TPP-≡) obtained in step (4) was dissolved in dichloromethane and methanol in a mixed solution, then add zinc acetate to react at room temperature for 6 hours, wash and extract the organic phase with saturated sodium chloride solution, dry and then evaporate to remove the solvent to obtain zinc-containing 5,15-bis(4-propynylaniline)-10 ,20-Diphenylporphyrin;

Under nitrogen protection, the 5,15-bis(4-propynylaniline)-10,20-diphenylporphyrin (100mg, 0.14mmol) obtained in step (4) was dissolved in a mixture of dichloromethane and methanol solution, then add zinc acetate (257mg 1.4mmol) to react at room temperature for 6h, wash and extract the organic phase with saturated sodium chloride solution, dry and remove the solvent by rotary evaporation to obtain zinc-containing 5,15-bis(4-propynylaniline)- 10,20-Diphenylporphyrin. The yield was 97%. ¹ H NMR (400MHz, CDCl ₃ ), δppm: 8.89 (d, 4H, β-CH), 8.82 (d, 4H, β-CH), 8.21 (m, 4H, 15, 20-Ar-oH), 8.01 (m,4H,5,10-Ar-oH),7.79(m,6H,15,20-Ar-m-and pH),7.06(m,4H,5,10-Ar-mH),3.75(s , 4H, -NH-CH ₂ -C≡), 2.51 (s, 2H, -C≡CH).

(6) Under the protection of nitrogen, the monoazide β-cyclodextrin (CD-N ₃ ) and the zinc-containing 5,15-bis(4-propynylaniline)-10,20-bis obtained in step (5) Phenylporphyrin was dissolved in dimethylformamide (DMF), ventilated for 30 minutes, then under nitrogen protection, pentamethyldiethylenetriamine (PMDETA) and cuprous bromide were added, stirred and dissolved, and reacted at 50°C for 48 hours. After the reaction is finished and cooled, the organic phase is washed and extracted with saturated sodium chloride solution, dried and evaporated to remove the solvent, purified by dialysis and freeze-dried to obtain bicyclodextrin-modified TPP;

Under the protection of nitrogen, monoazide β-cyclodextrin (CD-N ₃ , 603mg, 0.52mmol) and the zinc-containing 5,15-di(4-propynylaniline)-10,20 obtained in step (5) -Diphenylporphyrin (100mg, 0.13mmol) was dissolved in 10mL dimethylformamide (DMF), and after 30min of ventilation, PMDETA (90mg, 0.52mmol) and cuprous bromide (75mg, 0.52mmol) were added under nitrogen protection mmol) was fully stirred and dissolved, and reacted at 50°C for 48h. After the reaction was completed and cooled, the extracted organic phase was washed with saturated sodium chloride solution, dried and evaporated to remove the solvent, and then the unreacted reagents were removed by dialysis (MWCO=1 000Da) according to the molecular weight. After lyophilization, dichloromethane/methanol (40:1, v/v) was used as the eluent to pass through the column to obtain dicyclodextrin-modified TPP (CD-TPP-CD), with a yield of 68%.

(7) Under nitrogen protection, anhydrous potassium carbonate and the bicyclodextrin-modified TPP obtained in step (6) were dissolved in anhydrous pyridine. Subsequently, p-toluenesulfonyl hydrazide was added, and the mixture was refluxed at 105° C. and protected from light for 24 hours. After the reaction is over, add p-toluenesulfonylhydrazide again under the protection of nitrogen. After reacting at room temperature for 8 hours, add ethyl acetate and water to reflux for 1 hour. After the solution is cooled, the organic phase is saturated with 2mol/L hydrochloric acid, phosphoric acid, and water respectively. Washing and extracting with sodium bicarbonate solution, drying and rotary evaporation to remove the solvent, and separating the obtained crude product through solid silica gel column chromatography to obtain compound 6, which is the porphyrin photosensitizer compound 6 that absorbs near-infrared light according to the present invention;

The bicyclodextrin-modified TPP (CD-TPP-CD, 0.8 mmol) and anhydrous potassium carbonate (1.1 g, 8 mmol) obtained in step (6) were dissolved in 40 mL of anhydrous pyridine under nitrogen protection. Then p-toluenesulfonyl hydrazide (1.5 g, 8 mmol) was added, and the mixture was refluxed at 105° C. and protected from light for 24 h. After the reaction was completed and cooled, p-toluenesulfonylhydrazide (1.5 g, 8 mmol) was added again under the protection of nitrogen. After 8 hours of reaction at room temperature, ethyl acetate/water (2:1, 300 mL) was added and refluxed for 1 hour. After the solution was cooled, the organic phase was Wash and extract with 2mol/L hydrochloric acid, 68% phosphoric acid solution, water and saturated sodium bicarbonate solution successively for 3 times, the solution is dried over anhydrous sodium sulfate, and the solvent is removed by rotary evaporation. The obtained crude product was separated by solid silica gel column chromatography using dichloromethane/methanol (40:1, v/v) as eluent. Compound 6 was obtained after vacuum drying, which is the porphyrin photosensitizer Compound 6 that absorbs near-infrared light. The yield was 49%.

Embodiment 7. Verification experiment

1. Light absorption characteristics

The ultraviolet-visible absorption spectra of compounds 1 to 6 in Examples 1 to 6 were measured with an ultraviolet-visible spectrophotometer produced by Thermo Fisher Scientific Co., Ltd. The instrument model is Evolution 220UV-Vis, and the spectral scanning range is from 300 nm to 800 nm. The ultraviolet-visible absorption spectra shown in Figures 1 to 6 were obtained, thereby obtaining the light absorption characteristics of the porphyrin photosensitizer 1 to porphyrin photosensitizer 6 of the present invention.

2. The performance of generating singlet oxygen

Using DPBF as the singlet oxygen scavenger, the generation of singlet oxygen under light was measured, and the effect of ¹ O ₂ (singlet oxygen) produced by porphyrin photosensitizer 1 on the scavenger DPBF UV- A schematic diagram of the influence of visible light absorption, and a schematic diagram of the variation of the maximum ultraviolet-visible light absorption value of DPBF with illumination time under illumination conditions shown in FIG. 8 .

3. Cell dark toxicity and cell phototoxicity;

In order to further study the application of the porphyrin photosensitizer of the present invention in photodynamic therapy, the inventors also conducted in vitro cell experiments. Taking human lung cancer cell A549 as the research object, the cytotoxicity was tested by MTT method, and the absorbance was measured by a spectrophotometric microplate reader.

Taking A549 cells as the research object, the cytotoxicity of porphyrin photosensitizer 5 and porphyrin photosensitizer 6 (maximum porphyrin concentration 40 μg/mL) under no light conditions and light conditions was measured by MTT method, and the results shown in Figure 9 were obtained. Cellular dark toxicity of porphyrin photosensitizer 5 and porphyrin photosensitizer 6, and cellular phototoxicity of porphyrin photosensitizer 5 and porphyrin photosensitizer 6 as described in FIG. 10 . As shown in Figure 9 and Figure 10, the experimental results show that: under no light conditions, porphyrin photosensitizer 5 and porphyrin photosensitizer 6 of the present invention have no cytotoxicity, and the cell survival rate is more than 90%; Under light conditions, both the porphyrin photosensitizer 5 and the porphyrin photosensitizer 6 of the present invention exhibit obvious cytotoxicity, and the cell survival rate at the highest concentration in the experiment of the two compounds is not higher than 35%.

The above is only a preferred embodiment of the present invention, it should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, and these improvements and modifications should also be considered Be the protection scope of the present invention.

Claims (7)

1. A compound, or a metal complex thereof, shown in formula (I): Wherein, R ₁ , R ₂ , R ₃ and R ₄ are independently -H, -OH, -NH ₂ , Polyethylene glycol chain or β-cyclodextrin group; R ₅ is polyethylene glycol chain or β-cyclodextrin group. 2. compound as claimed in claim 1, is characterized in that, described polyethylene glycol chain is shown in formula (i): Among them, n is 48. 3. porphyrin photosensitizer as claimed in claim 1, is characterized in that, described formula (I) is selected from the structure in following formula (I-1)～(I-5): Wherein, Ra is a hydroxyl group or an amino group; Rb is a polyethylene glycol chain or a β-cyclodextrin group. 4. compound as claimed in claim 1, is characterized in that, described metal complex is shown in formula (I-M): Wherein, M is Zn, Mn, Fe or Pt. 5. compound as claimed in claim 4, is characterized in that, described metal complex is shown in formula (I-M-1): Wherein, Rb is a polyethylene glycol chain or a β-cyclodextrin group. 6. The compound according to claim 1, wherein the compound is compound 1-6, or a metal complex thereof: Among them, n is 48. 7. A porphyrin-based photosensitizer comprising any one of the compounds or metal complexes as claimed in claims 1 to 5.