A triplet photosensitizer molecule with near-infrared absorption and efficient generation of singlet oxygen, its preparation method and application.

Abstract

This invention relates to a triplet photosensitizer molecule with near-infrared absorption and efficient singlet oxygen generation, its preparation method, and its applications. Under a nitrogen atmosphere, the bilateral bromide of the A2 electron-withdrawing unit and the single-sided tin compound of the D1 and D2 electron-donating units undergo a Stille coupling reaction in an anhydrous toluene system under a commercially available tetra(triphenylphosphine)palladium catalyst at a temperature of 100-140°C for 6-24 hours to yield the intermediate D1-A2-D2. Under a nitrogen atmosphere, the D1-A2-D2 intermediate is reacted with phosphorus oxychloride in anhydrous DMF solution. The reaction was carried out at a temperature of 70-90℃ for 8-24h to obtain the bilateral aldehyde intermediate CHO-D1-A2-D2-CHO. Under a nitrogen atmosphere, the CHO-D1-A2-D2-CHO intermediate was heated with the A1 electron-withdrawing unit and piperidine in chloroform solution to carry out a Knoevenagel condensation reaction at a temperature of 50-65℃ for 8-24h to obtain the product shown in formula (1). The triplet photosensitizer molecule of the present invention has a simple structure, does not contain transition metals, and has good biocompatibility.

Description

Technical Field

[0001] This invention belongs to the field of functional materials technology, and in particular to a triplet photosensitizer molecule with near-infrared absorption and the ability to efficiently generate singlet oxygen, as well as its preparation method and application. Background Technology

[0002] In recent years, photodynamic therapy (PDT) has attracted widespread attention from scientists as a novel cancer treatment method due to its advantages such as being non-invasive, easy to operate, highly selective, and having low toxicity. PDT utilizes light to excite triplet photosensitizers enriched in tumor tissue, sensitizing oxygen molecules within the tissue to produce reactive oxygen species, thereby inducing apoptosis and necrosis of tumor cells. Specifically, the triplet photosensitizer, upon light excitation, reaches its singlet excited state, and through intersystem crossing, generates a triplet excited state. This triplet excited state can then undergo intermolecular energy transfer with oxygen molecules, producing highly reactive singlet oxygen that oxidizes intracellular biological components, subsequently causing apoptosis and necrosis, thus achieving the therapeutic goal. For better application in biotherapy, a good triplet photosensitizer should possess the following properties: low biotoxicity; high efficiency in intersystem crossing; strong absorption in the near-infrared band; and a long triplet excited state lifetime. In particular, infrared light has relatively deep penetrating power, enabling it to penetrate biological tissues to achieve better PDT therapeutic effects. Therefore, highly efficient triplet photosensitizers with near-infrared light absorption have profound significance for promoting the development of life sciences.

[0003] Currently, triplet photosensitizers mainly include inorganic nanomaterials, porphyrin derivatives, transition metal complexes, cyanine dyes, fluoroboron pyrrole derivatives, and other small organic molecules. Compared with inorganic nanomaterials and transition metal complexes, organic triplet photosensitizers have advantages such as high biocompatibility and good degradability, and their synthetic routes are simple and inexpensive. However, in most reported studies (e.g., the article Heavy-atom-free π-twisted photosensitizers for fluorescence bioimaging and photodynamic therapy, DOI: 10.1039 / D4TB01014K), highly efficient organic triplet photosensitizers mostly have distorted structures, resulting in shorter absorption wavelengths, generally less than 600 nm, making it difficult to penetrate deep into the skin to reach internal organs, thus limiting the tumor treatment sites. Near-infrared light has high penetration depth and low damage to biological tissues, but there are relatively few types of organic triplet photosensitizers that absorb in the near-infrared region, limiting the range of excitation wavelengths and their application in photodynamic therapy.

[0004] Therefore, the development of biocompatible, highly efficient organic triplet photosensitizers with near-infrared absorption has become an urgent research and problem to be solved. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a triplet photosensitizer molecule with near-infrared absorption and the ability to efficiently generate singlet oxygen, as well as its preparation method and application. Compared with traditional photosensitizers, the novel organic triplet photosensitizer has an efficient intersystem crossing process and a long triplet lifetime. It can efficiently generate singlet oxygen using near-infrared light irradiation, enabling near-infrared light-excited photodynamic therapy and improving the efficacy of tumor treatment.

[0006] The technical problem solved by this invention is achieved through the following technical solution:

[0007] A triplet photosensitizer molecule with near-infrared absorption and the ability to efficiently generate singlet oxygen has the structural formula shown in formula (1):

[0008]

[0009] In the formula (1), A1 and A2 are electron-withdrawing units, and D1 and D2 are electron-donating units.

[0010] Furthermore, the electron-withdrawing unit A1 in formula (1) is selected from any one of the structural formulas shown in formulas (2-1) to (2-4):

[0011]

[0012] In formulas (2-1) and (2-2), X is selected from any one of the following groups: hydrogen, fluorine, chlorine, bromine, and iodine.

[0013] Furthermore, in equation (1), D1 and D2 are electron-donating units selected from any of the same or different structural formulas shown in equations (3-1) to (3-8):

[0014]

[0015] In formulas (3-1) to (3-6), R1, R2, R3, and R4 may be the same or different, and each is independently selected from any one of the following groups: hydrogen, alkyl, alkoxy, alkylthio, and silyl.

[0016] Wherein, the alkyl, alkoxy, alkylthio, and silyl groups are straight-chain or branched chains with 1-16 carbon atoms.

[0017] Furthermore, in equation (1), the electron-withdrawing unit A2 is selected from any of the structural formulas shown in equations (4-1) to (4-5) below.

[0018]

[0019] In formulas (4-1) to (4-4), R5 and R6 may be the same or different, and each is independently selected from any one of the following groups: hydrogen, alkyl, alkoxy, alkylthio;

[0020] Wherein, the alkyl, alkoxy, alkylthio, and silyl groups are straight-chain or branched chains with 1-16 carbon atoms.

[0021] Moreover, it can be any one of the following structures (5-1) to (5-6):

[0022]

[0023] A method for preparing a triplet photosensitizer molecule with near-infrared absorption and capable of efficiently generating singlet oxygen, characterized by the following steps:

[0024]

[0025] Moreover, it includes the following steps:

[0026] S1. Under a nitrogen atmosphere, the bilateral bromide of the electron-withdrawing unit A2 and the unilateral tin compounds of the electron-donating units D1 and D2 undergo a Stille coupling reaction in an anhydrous toluene system under a commercially available tetra(triphenylphosphine)palladium catalyst at a temperature of 100-140℃ for a time of 6-24h to obtain intermediate D1-A2-D2.

[0027] S2. Under a nitrogen atmosphere, the D1-A2-D2 intermediate reacts with phosphorus oxychloride in anhydrous DMF solution at a reaction temperature of 70-90℃ for 8-24h to obtain the bilateral aldehyde intermediate CHO-D1-A2-D2-CHO.

[0028] S3. Under a nitrogen atmosphere, the CHO-D1-A2-D2-CHO intermediate, A1 electron-withdrawing unit, and piperidine were heated in chloroform solution to carry out a Knoevenagel condensation reaction at a temperature of 50-65℃ and a reaction time of 8-24h to obtain the product shown in formula (1).

[0029] Furthermore, the molar ratio of the bilateral bromide, the unilateral tin compound, and the tetra(triphenylphosphine)palladium is 1:2-2.5:0.05-0.2;

[0030] The molar ratio of the D1-A2-D2 intermediate to phosphorus oxychloride is 1:2-2.5:0.05-0.2;

[0031] The molar ratio of the CHO-D1-A2-D2-CHO intermediate to the A1 electron-withdrawing unit is 1:2-2.5:0.05-0.2;

[0032] In step S1, the reaction temperature is 110-120℃ and the reaction time is 6-12h;

[0033] In step S2, the reaction temperature is 75-85℃ and the reaction time is 12-18h;

[0034] In step S3, the reaction temperature is 55-60℃ and the reaction time is 12-18h.

[0035] The application of a triplet photosensitizer molecule with near-infrared absorption that can efficiently generate singlet oxygen, or its nanoparticle form, as a singlet oxygen generating reagent.

[0036] The application of a triplet photosensitizer molecule with near-infrared absorption and capable of efficiently generating singlet oxygen, or its nanoparticle formulation, in photodynamic therapy.

[0037] The advantages and positive effects of this invention are:

[0038] 1. The triplet photosensitizer molecule described in this invention has a simple structure, requires few synthesis steps, does not contain transition metals, is inexpensive, and has good biocompatibility.

[0039] 2. The triplet photosensitizer molecule of the present invention has a structure in which electron donors and electron acceptors are alternately connected, which can effectively redshift the absorption spectrum and extend the absorption spectrum of the molecule to the near-infrared region. By changing different electron donors and electron acceptors, the intersystem crossing and triplet quantum yield of the molecule can be regulated, thereby prolonging the triplet lifetime and increasing the singlet oxygen yield. The molecule can generate singlet oxygen under near-infrared light irradiation, which has application prospects in photodynamic therapy.

[0040] 3. The near-infrared light excited by the triplet photosensitizer molecules described in this invention has better biological tissue penetration than ultraviolet and visible light, causing less damage to biological tissues. The material has the advantages of near-infrared absorption and high singlet oxygen production, which has great application value for photodynamic therapy in vivo.

[0041] 4. This invention proposes a design and synthesis strategy for an organic triplet photosensitizer molecule that does not contain transition metal elements and exhibits near-infrared absorption. Compared with traditional photosensitizers, the novel organic triplet photosensitizer has an efficient intersystem crossing process and a long triplet lifetime. It can efficiently generate singlet oxygen using near-infrared light irradiation, enabling near-infrared light-excited photodynamic therapy and improving the efficacy of tumor treatment. Attached Figure Description

[0042] Figure 1 The absorption spectra of formulas (5-1) and (5-2) in chloroform solution are shown in the embodiments of the present invention.

[0043] Figure 2 This is a diagram of singlet oxygen generated in solution according to formula (5-1) in an embodiment of the present invention.

[0044] Figure 3 This is a diagram of singlet oxygen generated in solution according to formula (5-2) in an embodiment of the present invention. Detailed Implementation

[0045] The present invention will be further described in detail below through specific embodiments. These embodiments are merely descriptive and not limiting, and should not be construed as limiting the scope of protection of the present invention. Unless otherwise specified, all materials described are available from publicly available commercial sources.

[0046] A method for preparing a triplet photosensitizer molecule with near-infrared absorption and capable of efficiently generating singlet oxygen, comprising the following steps:

[0047]

[0048] Under a nitrogen atmosphere, the bilateral bromide (1 equivalent) of the electron-withdrawing unit of A2 and the unilateral tin compound (2.2 equivalent) of the electron-donating units of D1 and D2 undergo a Stille coupling reaction in an anhydrous toluene system under heating with commercially available tetra(triphenylphosphine)palladium (0.1 equivalent) as catalysis to give intermediate D1-A2-D2.

[0049] Furthermore, under a nitrogen atmosphere, the D1-A2-D2 intermediate (1 equivalent) and phosphorus oxychloride (10 equivalents) were reacted in anhydrous DMF solution to synthesize the bilateral aldehyde intermediate CHO-D1-A2-D2-CHO;

[0050] Next, under a nitrogen atmosphere, the CHO-D1-A2-D2-CHO intermediate (1 equivalent) was subjected to a Knoevenagel condensation reaction with an A1 electron-withdrawing unit (4 equivalents) and piperidine (0.2 mL) in chloroform solution and heated to obtain the product shown in formula (1).

[0051] Example 1

[0052] A method for preparing a triplet photosensitizer molecule with near-infrared absorption and efficient singlet oxygen generation is disclosed in this embodiment. The synthesis of the electron donor-acceptor type triplet photosensitizer material of formula (5-1) includes the following steps:

[0053] Synthesize according to the following reaction equation:

[0054]

[0055] Synthesis of S1 and Intermediate 1: Under nitrogen protection, starting material 1 (5.5 g, 10 mmol) was dissolved in 200 mL of ethanol. NaBH4 (3.03 g, 80 mmol) was added in portions under an ice-water bath. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the solvent was removed by vacuum distillation. Then, 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried with anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography using a 2:1 (v / v) mixture of petroleum ether and dichloromethane as the eluent to obtain the yellow oily intermediate 1.

[0056] Synthesis of S2 and Intermediate 2: Under nitrogen protection, intermediate 1 (2.61 g, 5 mmol) was dissolved in 30 mL of glacial acetic acid. 10 mL of sodium nitrite (0.41 g, 6 mmol) aqueous solution was added in an ice-water bath. The mixture was then stirred at room temperature for 1 h. After the reaction was completed, the solvent was removed by vacuum distillation. 100 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried with anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography using a 1:50 volume ratio of ethanol to dichloromethane mixture as the eluent to obtain the colorless oily intermediate 2.

[0057] Synthesis of S3 and Intermediate 3: Under nitrogen protection, intermediate 2 (2.13 g, 4 mmol), potassium carbonate (2.76 g, 20 mmol), and 1-bromo-2-butyloctane (3.0 g, 12 mmol) were added to 50 mL of LMF solution. The reaction mixture was stirred overnight at 90 °C. After the reaction was completed, the mixture was filtered and the filtrate was collected. The solvent was removed by vacuum distillation. The crude product was purified by column chromatography. A mixture of petroleum ether and dichloromethane in a volume ratio of 3:1 was used as the eluent to obtain the colorless oily intermediate 3.

[0058] Synthesis of S4 and Intermediate 4: Under nitrogen protection, intermediate 3 (671 mg, 1 mmol), starting material 2 (1.32 g, 2.2 mmol), and tetrakis(triphenylphosphine)palladium (115.6 mg, 0.1 mmol) were added to 20 mL of dry toluene solution. The mixture was stirred at 110 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature. The reaction solution was poured into potassium fluoride aqueous solution and extracted three times with dichloromethane. The organic phase was collected, dried with anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography using a 1:8 volume ratio of ethanol and dichloromethane as the eluent to obtain the orange oily product intermediate 4. Among them, starting material 2 was tributyl(6-(2-butyloctyl)thieno[3,2-B]thieno-2-yl)stanane.

[0059] Synthesis of S5 and intermediate 5: Under nitrogen protection, intermediate 4 (677 mg, 0.6 mmol) was added to 20 mL of anhydrous DMF solution. Phosphorus oxychloride (920 mg, 6 mmol) was added dropwise under an ice-water bath and stirring was continued for 1 h. The reaction solution was then heated to 80 °C and stirred overnight. After the reaction was completed, the reaction solution was poured into 100 mL of water, and the pH was adjusted to neutral by adding saturated sodium carbonate aqueous solution. After extraction with dichloromethane three times, the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography using a 1:2 volume ratio of petroleum ether and dichloromethane mixture as the eluent to obtain red powder intermediate 5.

[0060] S6. Synthesis of Formula (5-1): Under nitrogen protection, intermediate 5 (118 mg, 0.1 mmol), starting material 3 (92 mg, 0.4 mmol), and piperidine (0.2 mL) were added to 20 mL of chloroform solution and stirred overnight at 60 °C. After the reaction was completed, the mixture was cooled to room temperature, the solvent was removed by vacuum distillation, and then 5 mL of chloroform was added to dissolve the product. The solution was then poured into 50 mL of methanol and filtered to obtain the crude product. The crude product was purified by column chromatography using a mixture of petroleum ether and dichloromethane at a volume ratio of 1:2 as the eluent to obtain the dark blue product of Formula (5-1). Among them, starting material 3 is 5,6-difluoro-3-(dicyanomethylene)indone.

[0061] Example 2

[0062] A method for preparing a triplet photosensitizer molecule with near-infrared absorption and efficient singlet oxygen generation is disclosed. This embodiment describes the synthesis of an electron donor-acceptor type triplet photosensitizer material of formula (5-2), comprising the following steps:

[0063] Synthesize according to the following reaction equation:

[0064]

[0065] Synthesis of S1 and Intermediate 6: Under nitrogen protection, intermediate 3 (671 mg, 1 mmol), starting material 4 (1.42 g, 2.2 mmol), and tetrakis(triphenylphosphine)palladium (115.6 mg, 0.1 mmol) were added to 20 mL of dry toluene solution. The mixture was stirred at 110 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature. The reaction solution was poured into an aqueous potassium fluoride solution and extracted three times with dichloromethane. The organic phase was collected, dried with anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography using ethanol and dichloromethane in a volume ratio of 1:8 as the eluent to obtain the orange oily product intermediate 6. Among them, starting material 4 was tributyl(6-(2-butyloctyl)selenophenol[3,2-B]thiophen-2-yl)stanane.

[0066] Synthesis of S2 and intermediate 7: Under nitrogen protection, intermediate 6 (734 mg, 0.6 mmol) was added to 20 mL of anhydrous DMF solution. Phosphorus oxychloride (920 mg, 6 mmol) was added dropwise in an ice-water bath and stirring was continued for 1 h. The reaction solution was then heated to 80 °C and stirred overnight. After the reaction was completed, the reaction solution was poured into 100 mL of water, and the pH was adjusted to neutral by adding saturated sodium carbonate aqueous solution. After extraction with dichloromethane three times, the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by column chromatography using petroleum ether and dichloromethane in a volume ratio of 1:2 as eluent to obtain red powder intermediate 7.

[0067] Synthesis of S3, Formula (5-2): Under nitrogen protection, intermediate 7 (128 mg, 0.1 mmol), starting material 3 (92 mg, 0.4 mmol), and piperidine (0.2 mL) were added to 20 mL of chloroform solution and stirred overnight at 60 °C. After the reaction was completed, the mixture was cooled to room temperature, the solvent was removed by vacuum distillation, and then 5 mL of chloroform was added to dissolve the product. The solution was then poured into 50 mL of methanol and filtered to obtain the crude product. The crude product was purified by column chromatography using petroleum ether and dichloromethane in a volume ratio of 1:2 as eluents to obtain the dark blue product of Formula (5-2).

[0068] Example 3

[0069] The absorption spectra of the electron donor-acceptor triplet photosensitizer materials of formulas (5-1) and (5-2) synthesized in Examples 1 and 2 were measured in chloroform solution using a visible-ultraviolet absorption spectrometer. The absorption spectra are shown below. Figure 1 As shown in the figure, the absorption wavelength range of the material in organic solution is mainly 500-770nm. Among them, the maximum absorption peak of material formula (5-1) is 680nm and the maximum absorption peak of material formula (5-2) is 695nm, indicating that the material has strong absorption in the visible and near-infrared light regions.

[0070] Example 4

[0071] The generation of singlet oxygen in the electron donor-acceptor triplet photosensitizer materials of formulas (5-1) and (5-2) synthesized in Examples 1 and 2 was detected using a singlet oxygen scavenger (DPBF), comprising the following steps:

[0072] S1. Prepare chloroform solutions of formula (5-1) and formula (5-2) respectively. Use the chloroform solution of formula (5-1) as the mother solution A1 and the chloroform solution of formula (5-2) as the mother solution A2. The concentration of both mother solution A1 and mother solution A2 is 0.001 mmol / mL.

[0073] S2. Prepare a chloroform solution of DPBF with a concentration of 0.001 mmol / mL as stock solution B.

[0074] S3. Take 0.005 mL of mother liquor A1, dilute it with chloroform solvent until the absorbance at 600 nm is about 0.2, then add mother liquor B to make the absorbance at 415 nm about 1, and obtain a mixture containing formula (5-1) and DPBF.

[0075] S4. Take 0.005 mL of mother solution A2, dilute it with chloroform solvent until the absorbance at 600 nm is about 0.2, then add mother solution B to make the absorbance at 415 nm about 1, to obtain a mixture containing formula (5-2) and DPBF.

[0076] S5. Under light-protected conditions, irradiate the mixture containing formula (5-1) and DPBF, and the mixture containing formula (5-2) and DPBF with 600nm light respectively, and detect the decrease in the intensity of the DPBF absorption peak at irradiation times of 0 seconds, 30 seconds, 60 seconds, 90 seconds, 120 seconds, 150 seconds, 180 seconds, 210 seconds, and 240 seconds, thereby realizing the detection of the singlet oxygen generation state.

[0077] The diagram shows the singlet oxygen generated in solution by the electron donor-acceptor type triplet photosensitizer material of formula (5-1). Figure 2 As shown in the figure, the DPBF absorption peak intensity at 415 nm decreased from 1.00 to 0.95 within 240 seconds, indicating that material formula (5-1) has the ability to generate singlet oxygen.

[0078] The diagram shows the singlet oxygen generated in solution by the electron donor-acceptor type triplet photosensitizer material of formula (5-2). Figure 3 As shown in the figure, the DPBF absorption peak intensity at 415 nm decreased from 1.14 to 0.58 within 240 seconds, indicating that material formula (5-2) has the ability to generate singlet oxygen. Comparison shows that the efficiency of singlet oxygen generation by material formula (5-2) is 11.2 times that of formula (5-1), making it a potential triplet photosensitizer with near-infrared absorption and efficient singlet oxygen generation.

[0079] Although embodiments of the invention have been disclosed for illustrative purposes, those skilled in the art will understand that various substitutions, variations, and modifications are possible without departing from the spirit and scope of the invention and the appended claims. Therefore, the scope of the invention is not limited to the contents disclosed in the embodiments.

Claims

1. A triplet photosensitizer molecule with near-infrared absorption and capable of efficiently generating singlet oxygen, characterized in that: It can be any of the following structures: 。 2. The application of the triplet photosensitizer molecule with near-infrared absorption and capable of efficiently generating singlet oxygen as described in claim 1 in the preparation of a singlet oxygen generating reagent.

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