A near-infrared photothermal agent and its preparation method and application

Abstract

The present invention relates to a near-infrared photothermal agent and its preparation method and application. The prepared target compound exhibits good water solubility; the UV-visible-near-infrared absorption spectrum shows that the absorption peak of its aqueous solution is located at 947 nm; it has strong near-infrared second-zone light absorption ability, and the photothermal conversion efficiency under 1060 nm light excitation reaches 42.3%, showing good results in the test of in vitro photothermal therapy. 2 ) Laser irradiation effectively inhibited tumor growth and achieved good photothermal therapy effects.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a near-infrared photothermal agent and a preparation method and application thereof. Background Art

[0002] Malignant tumors are serious diseases that threaten human health and life, and are a leading cause of death worldwide. Traditional treatments, such as surgery, chemotherapy, and radiotherapy, are invasive and have significant toxic side effects. The search for and discovery of new therapies and drugs for treating tumors is a major challenge.

[0003] Photothermal therapy is a therapy that uses the heat released by the non-radiative relaxation of photosensitizers in an excited state. It has attracted much attention due to its low toxicity and non-invasive treatment methods. Compared with the near-infrared region I (650-1000nm), the near-infrared region II (1000-1700nm) has a stronger ability to penetrate biological tissues. In terms of the tolerance of biological tissues to light, the maximum allowable exposure of 1064nm light (1.0W / cm 2 ) is significantly higher than 808nm (0.33W / cm 2 ), which enables near-infrared II phototherapy to achieve fewer side effects or stronger therapeutic effects. Currently, most reported photothermal agents and therapies have difficulty utilizing near-infrared II light, and the development of photothermal agents and therapies excited by near-infrared II light is urgently needed.

[0004] Organic small molecule photothermal agents have attracted considerable attention in recent years due to their advantages, including good biocompatibility, ease of metabolism, ease of separation and purification, and defined chemical structures. However, these agents generally suffer from weak or no absorption in the near-infrared region II, low photothermal conversion efficiency, and poor water solubility. Summary of the Invention

[0005] The purpose of the present invention is to provide a near-infrared photothermal agent with high light conversion efficiency, good water solubility and low biological toxicity and a preparation method thereof, and also to provide its application in inhibiting tumors and preparing drugs for inhibiting tumors.

[0006] The present invention adopts the following technical solutions:

[0007] A compound with the general formula:

[0008]

[0009] Among them, R 1 , R 2 Each is independent R 3 , R 4 Each is independent Halogen, hydroxyl, amino; R 5for halogen.

[0010] As a preferred general formula, R 1 , R 2 , R 3 , R 4 Both R 5 for Specifically, the structural formula of the above compound is:

[0011]

[0012] A method for preparing the above compound (IR-P1P), the synthetic route of which is:

[0013]

[0014]

[0015] Specifically, the process includes the following steps:

[0016] S1, anisole, 4-bromobenzoyl chloride and aluminum chloride were added to dichloromethane, reacted at 0°C for 1.5 h, quenched with dilute hydrochloric acid, extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain compound 1. The structure of compound 1 is as follows:

[0017]

[0018] In S1, the molar ratio of anisole, 4-bromobenzoyl chloride, and aluminum chloride is 1.5:1:1.5.

[0019] S2, compound 1 and aluminum chloride were dissolved in toluene, refluxed for 1.5 h, quenched with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain compound 2. The structure of compound 2 is as follows:

[0020]

[0021] In S2, the molar ratio of compound 1 and aluminum chloride is 1:2.

[0022] S3, compound 2, 1,6-dibromohexane and potassium carbonate were added to acetonitrile, reacted at 60°C for 12 hours, the solvent was evaporated under reduced pressure, and the mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and recrystallized from ethanol to obtain compound 3. The structure of compound 3 is as follows:

[0023]

[0024] In S3, the molar ratio of compound 2, 1,6-dibromohexane, and potassium carbonate is 1:3:3.

[0025] S4, titanium tetrachloride was slowly added dropwise to a zinc powder / tetrahydrofuran system pre-cooled at -78°C, and after reflux for 2 hours, a tetrahydrofuran solution of compound 3, benzophenone, and pyridine was added. The reaction was continued under reflux for 6 hours, and a 10% potassium carbonate aqueous solution was added. The mixture was filtered through celite, and the tetrahydrofuran was evaporated and then extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography using petroleum ether as eluent to obtain compound 4. The structure of compound 4 is as follows:

[0026]

[0027] In S4, the molar ratio of compound 3, benzophenone, zinc powder, titanium tetrachloride, and pyridine is 1:1.2:5:2.5:1.3.

[0028] S5, compound 4 was dissolved in tetrahydrofuran. Under nitrogen protection, n-butyl lithium was slowly added dropwise at -78°C. After 1.5 hours, tributyltin chloride was added. The reaction was allowed to react at room temperature for 10 hours. The solvent was then evaporated under reduced pressure. Petroleum ether was added, and the mixture was sonicated for 1 minute before filtration. The filtrate was evaporated to dryness to obtain crude compound 5. The structure of compound 5 is as follows:

[0029]

[0030] In S5, the molar ratio of compound 4, n-butyl lithium, and tributyltin chloride is 1:2:2.1.

[0031] S6, compound 6, 1-Boc-pyrrole-2-boronic acid, and tetrakis(triphenylphosphine)palladium were dissolved in toluene, and an aqueous solution of ethanol and potassium carbonate was added. The mixture was reacted at 100°C under nitrogen for 10 hours. The solvent was evaporated under reduced pressure, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was separated and purified by silica gel column chromatography using petroleum ether / dichloromethane as the eluent to obtain compound 7. The structure of compound 7 is as follows:

[0032]

[0033] In S6, the molar ratio of compound 6, 1-Boc-pyrrole-2-boric acid, potassium carbonate, and tetrakis(triphenylphosphine)palladium is 1:3.5:7:0.05; and the volume ratio of petroleum ether and dichloromethane is 2:1.

[0034] S7, compound 7 was dissolved in tetrahydrofuran and precooled to -40°C under nitrogen protection. N-bromosuccinimide was slowly added in batches, stirred for 30 minutes, and then reacted at 0°C for 4 hours. The solvent was evaporated under reduced pressure, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was separated and purified by silica gel column chromatography using petroleum ether / dichloromethane as the eluent to obtain compound 8. The structure of compound 8 is as follows:

[0035]

[0036] In S7, the molar ratio of compound 7 and N-bromosuccinimide is 1:2.1; and the volume ratio of petroleum ether and dichloromethane is 2.5:1.

[0037] S8, crude compound 5, compound 8, and bis(triphenylphosphine)palladium dichloride were dissolved in toluene and reacted at 100°C for 12 hours under nitrogen. The solvent was evaporated under reduced pressure, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was separated and purified by silica gel column chromatography using petroleum ether / dichloromethane as the eluent to obtain compound 9. The structure of compound 9 is as follows:

[0038]

[0039] In S8, the molar ratio of compound 8 and bis(triphenylphosphine)palladium dichloride is 1:0.2; the volume ratio of petroleum ether and ethyl acetate is 8:1

[0040] S9, compound 9 was dissolved in a trifluoroacetic acid / dichloromethane mixture and stirred at room temperature for 3 h. The trifluoroacetic acid was evaporated under reduced pressure and extracted with dichloromethane. The organic phases were combined and washed sequentially with water, saturated sodium bicarbonate solution, and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness to obtain compound 10. The structure of compound 10 is as follows:

[0041]

[0042] In S9, the molar ratio of compound 9 to trifluoroacetic acid is 1:250; and the volume ratio of trifluoroacetic acid to dichloromethane is 1:1.

[0043] S10, compound 10 was dissolved in pyridine at 90°C for 3 h, centrifuged, and the supernatant was discarded. The precipitate was ultrasonically washed with ether several times and dried in vacuo to obtain IR-P1P, whose structure is as follows:

[0044]

[0045] In S10, the volume ratio of compound 10 and pyridine is a molar ratio of 1:850.

[0046] A use of the compound of the general formula in photothermal therapy of tumors.

[0047] A use of the above-mentioned general formula compound in the preparation of a near-infrared photothermal agent.

[0048] A near-infrared photothermal agent has a structure represented by general formula I or IR-P1P.

[0049] The beneficial effects of the present invention are as follows: the near-infrared photothermal agent IR-P1P based on benzobisthiadiazole dyes has good water solubility, and the UV-visible-near-infrared absorption spectrum shows that the absorption peak of its aqueous solution is located at 947nm, with strong near-infrared second region light absorption ability, low biological toxicity, and the photothermal conversion efficiency under 1060nm light excitation reaches 42.3%. 2 ) Laser irradiation at a safe dose induced cell apoptosis, effectively inhibited tumor growth, and achieved good photothermal therapy effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 This is the nuclear magnetic spectrum of the near-infrared photothermal agent IR-P1P prepared in Example 10.

[0051] Figure 2 This is the mass spectrum of IR-P1P.

[0052] Figure 3 is the normalized visible-near infrared absorption curve of IR-P1P aqueous solution.

[0053] Figure 4 The IR-P1P aqueous solution described in Example 11 was exposed to a 1060 nm laser (1.0 W / cm 2 ) and the linear fit of the natural logarithm of time and driving temperature under irradiation.

[0054] Figure 5 These are the results of the cytotoxicity experiment of IR-P1P described in Example 12. DETAILED DESCRIPTION

[0055] The following examples will help to understand the present invention, but the content of the present invention is not limited to the examples.

[0056] All reagents used in the present invention are commercially available. Nuclear magnetic resonance spectra were measured using an Oxford Spectroscopy BUXI-I NMR spectrometer, and mass spectra were measured using a Bruker Daltonik Apex Ultra Fourier transform ion cyclotron resonance ultrahigh resolution mass spectrometer. Ultraviolet-visible-near-infrared (UV-Vis-NIR) absorption spectra were measured on a Shimadzu UV-3600 spectrometer, and infrared thermal imaging information was captured using a Fluke Ti401PRO thermal imager.

[0057] Example 1 Synthesis of Compound 1

[0058]

[0059] 9.000 g (41 mmol, 1 eq) of 4-bromobenzoyl chloride and 8.200 g (61.5 mmol, 1.5 eq) of aluminum trichloride were added to 100 mL of dichloromethane. 6.650 g (61.5 mmol, 1.5 eq) of anisole was added dropwise at 0°C and allowed to react for 1.5 h. After completion of the reaction, the mixture was quenched with 2.0 mol / L aqueous hydrochloric acid (30 mL) and then extracted with dichloromethane. The organic phases were combined and washed sequentially with water, saturated sodium bicarbonate solution, and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness and dried under vacuum. Compound 1 (11.300 g) was obtained as a white solid in a 94% yield.

[0060] 1 H NMR (400MHz, CDCl3) δ7.80 (d, J = 8.8 Hz, 2H), 7.69-7.54 (m, 4H), 6.97 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H).

[0061] Example 2 Synthesis of Compound 2

[0062]

[0063] 5.00 g (17.2 mmol, 1 eq) of compound 1 was dissolved in 100 mL of toluene and precooled to 0°C for 10 min. 4.58 g (34.4 mmol, 2 eq) of aluminum chloride was added, stirred for 5 min, and then heated to reflux for 1 h. The mixture was allowed to cool, and 50 mL of 1.0 mol·L hydrochloric acid solution and 100 mL of water were added. The mixture was stirred at room temperature for 10 min, extracted with ethyl acetate, and the combined organic phases were washed sequentially with water, saturated sodium bicarbonate solution, and saturated brine, then dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness and dried under vacuum. 4.31 g of crude product was obtained as a reddish-brown solid, which was used directly in the next step without purification.

[0064] 1H NMR (400MHz, DMSO-d6) δ 10.50 (s, 1H), 7.74 (d, J = 8.4Hz, 2H), 7.65 (d, J = 8.6Hz, 2H), 7.60 (d, J = 8.4Hz, 2H), 6.90 (d, J = 8.6Hz, 2H).

[0065] Example 3 Synthesis of Compound 3

[0066]

[0067] 15.83 g (57.1 mmol, 1 eq) of compound 2 and 41.81 g (171.4 mmol, 3 eq) of 1,6-dibromohexane were dissolved in 100 mL of acetonitrile. 23.68 g (171.4 mmol, 3 eq) of potassium carbonate was added and the mixture was allowed to react at 60°C for 12 h. The solvent was evaporated under reduced pressure, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and recrystallized from ethanol. This afforded 16.03 g of compound 3 as a pink solid in a 64% yield.

[0068] 1 H NMR (400MHz, CDCl3) δ7.81-7.76(m,2H),7.65-7.59(m,4H),6.97-6.93(m,2H),4.05(t ,J=6.4Hz,2H),3.43(t,J=6.7Hz,2H),1.95-1.80(m,4H),1.53(dt,J=7.3,3.5Hz,4H).

[0069] Example 4 Synthesis of Compound 4

[0070]

[0071] 7.43 g (113.6 mmol, 5 eq) of zinc powder and 250 mL of anhydrous tetrahydrofuran were added to a 500 mL three-necked round-bottom flask with a condenser. After nitrogen protection, the mixture was precooled at -78 ° C for 10 min, and 6.24 mL (10.77 g, 56.8 mmol, 2.5 eq) of titanium tetrachloride was slowly added dropwise. After 0.5 h, the mixture was placed at room temperature for 10 min, heated to reflux for 2 h, and precooled to 0 ° C. 2.38 mL (2.34 g, 29.6 mmol, 1.3 eq) of pyridine and 80 mL of anhydrous tetrahydrofuran solution containing 10.00 g (22.7 mmol, 1 eq) of compound 3 and (27.3 mmol, 1.2 eq) 4.97 g of benzophenone were added to the system. After nitrogen protection, the mixture was heated to reflux for 6 h. After the reaction was completed, 150 mL of 10% potassium carbonate solution was added, and the mixture was filtered through a celite bed. The tetrahydrofuran was evaporated and extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was isolated and purified by silica gel column chromatography using petroleum ether as eluent to obtain 5.35 g of compound 4 as a golden solid in a 40% yield.

[0072] 1 H NMR (400MHz, DMSO-d6) δ7.31(d,J=8.5Hz,2H),7.18–7.08(m,6H),6.97(dd,J=9.6,3.8Hz,4H),6.89(d,J=8.4Hz,2H),6.84(d,J=8.7H z,2H),6.68(d,J=8.8Hz,2H),3.86(t,J=6.4Hz,2H),3.52(t,J=6.7Hz,2H),1.86–1.74(m,2H),1.71–1.60(m,2H),1.47–1.33(m,4H). 13 C NMR (101MHz, DMSO) δ157.30,143.21,143.09,142.75,140.25,138.95,134.68,132.80,131.89,130.68,13 0.62,130.52,127.90,127.84,126.57,126.49,119.61,113.77,67.13,35.03,32.13,28.48,27.25,24.63.

[0073] Example 5 Synthesis of Compound 5

[0074]

[0075] Weigh 2.00 g (3.4 mmol, 2 eq) of compound 4 and dissolve it in 40 mL of anhydrous tetrahydrofuran. Precool the mixture to -78°C for 10 min under nitrogen. Slowly add 2.70 mL (6.8 mmol, 2 eq) of 2.5 mol / L n-butyllithium dropwise. After 1.5 h, slowly add 2.33 g (7.1 mmol, 2.1 eq) of tributyltin chloride dropwise. Stir at room temperature for 10 h after the addition is complete. Evaporate the solvent under reduced pressure. Add 40 mL of petroleum ether, sonicate for 1 min, filter, and evaporate the filtrate to dryness to obtain 3.95 g of crude product, which is set aside without purification.

[0076] Example 6 Synthesis of Compound 7

[0077]

[0078] 500 mg (1.42 mmol, 1 eq) of compound 6, 1.05 g (4.97 mmol, 3.5 eq) of 1-Boc-pyrrole-2-boronic acid, and 83 mg (71 μmol, 0.05 eq) of tetrakis(triphenylphosphine)palladium were dissolved in 16 mL of toluene. 2 mL of ethanol and 1.37 g (9.94 mmol, 7 eq) of potassium carbonate in 2 mL of water were added. The mixture was reacted at 100°C under nitrogen for 10 h. The solvent was evaporated under reduced pressure, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was isolated and purified by silica gel column chromatography using petroleum ether / dichloromethane (v / v = 2 / 1) as the eluent to obtain 680 mg of compound 7 as a blue solid in a 48% yield.

[0079] 1 H NMR (400MHz, CDCl3) δ7.62-7.58(m,1H),7.26(s,3H),6.92-6.89(m,1H),6.50(t,J=3.3Hz,1H),1.23(s,9H).HRMS(ESI):m / z calcd.for C 24 H 25 N6O4S2 + [M+H] + 525.1374,found525.1362.

[0080] Example 7 Synthesis of Compound 8

[0081]

[0082] 1.39 g (2.65 mmol, 1 eq) of compound 7 was dissolved in 60 mL of anhydrous tetrahydrofuran and precooled at -40°C for 10 min under nitrogen. 988 mg (5.65 mmol, 2.1 eq) of N-bromosuccinimide was added portionwise. The mixture was stirred for 30 min and then reacted at 0°C for 4 h. The solvent was evaporated under reduced pressure, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was separated and purified by silica gel column chromatography using petroleum ether / dichloromethane (v / v = 2.5 / 1) as eluent to obtain 1.38 g of compound 7 as a blue solid in a 77% yield.

[0083] 1 H NMR (400MHz, CDCl3) δ6.94 (d, J = 3.7Hz, 2H), 6.58 (d, J = 3.7Hz, 2H), 1.27 (s, 18H). 13 C NMR (101MHz, CDCl3) δ152.04,148.40,129.57,119.30,116.65,85.29,27.63.

[0084] Example 8 Synthesis of Compound 9

[0085]

[0086] 3.95 g of crude compound 5, 775 mg (1.14 mmol, 1 eq) of compound 8, and 119 mg (227 μmol, 0.2 eq) of bis(triphenylphosphine)palladium dichloride were dissolved in 40 mL of toluene and reacted at 100°C for 12 h under nitrogen. The solvent was evaporated under reduced pressure, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was separated and purified by silica gel column chromatography using petroleum ether / ethyl acetate (v / v = 8 / 1) as the eluent to obtain 460 g of compound 9 as a blue solid in a 23% yield.

[0087] 1 H NMR (400MHz, DMSO-d6) δ7.24–7.08(m,16H),7.08–7.01(m,8H),6.99(d,J=7.1Hz,4H),6.94–6.85(m,6H),6.71(d,J=8.6Hz,4H),6.46(d,J=3 .5Hz,2H),3.88(t,J=6.2Hz,4H),3.53(t,J=6.7Hz,4H),1.80(p,J=6.7Hz,4H),1.67(p,J=13.2,7.1Hz,4H),1.48–1.34(m,8H),1.00(s,18H).

[0088] Example 9 Synthesis of Compound 10

[0089]

[0090] 290 mg of compound 9 was dissolved in 3 mL of dichloromethane, pre-cooled at 0°C for 5 min, and 3 mL (250 eq) of trifluoroacetic acid was slowly added dropwise. The mixture was stirred at room temperature for 3 h. The trifluoroacetic acid was removed under reduced pressure, and the mixture was extracted with dichloromethane. The combined organic phases were washed sequentially with water, saturated sodium bicarbonate solution, and saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness and dried under vacuum. 150 mg of crude compound 10 was obtained as a brown solid.

[0091] Example 10 Synthesis of IR-P1P

[0092]

[0093] 80 mg of crude compound 10 was dissolved in 4 mL (850 eq) of pyridine and reacted at 90°C for 3 h. The mixture was centrifuged, the supernatant was discarded, and the precipitate was ultrasonically washed with ether several times and dried in vacuo to obtain 62 mg of IR-P1P as a brown solid.

[0094] 1 H NMR (400MHz, DMSO-d6) δ11.85(s,2H),9.09(d,J=5.7Hz,4H),8.60(t,J=7.7Hz,2H),8.15(t ,J=6.9Hz,4H),7.86(s,2H),7.61(d,J=8.0Hz,4H),7.24-7.10(m,12H),7.10-6.98(m,12H), 6.93(d,J=8.6Hz,6H),6.71(d,J=8.6Hz,4H),4.60(t,J=7.5Hz,4H),3.88(t,J=6.2Hz,4H), 2.00-1.89(m,4H),1.73-1.62(m,4H),1.50-1.38(m,4H),1.38-1.28(m,4H).HRMS(ESI):m / z calcd.for C 88 H 76 N8O2S2 2+ [M-2Br] 2+ 670.2761,found670.2763.

[0095] Example 11 Calculation of photothermal curve and photothermal conversion efficiency of IR-P1P

[0096] The power density of the nanostructured carbon nanotubes at 1060 nm (1.0 W / cm 2 ) irradiation, the temperature change of 100 μmol / L aqueous solution of IR-P1P (irradiation for 600 s, then naturally cooled to room temperature, and the temperature information was recorded every 30 s by an infrared thermal imager) and the photothermal conversion efficiency (η) was calculated. The measurement results are shown in Figure 4 As shown, the photothermal conversion efficiency of IR-P1P is 42.3%.

[0097] Example 12 Evaluation of the dark toxicity and phototoxicity of IR-P1P using the human liver cancer cell line HepG2

[0098] Cytotoxicity Assessment: HepG2 cells (10,000 cells per well) were seeded in 96-well plates and cultured at 37°C in a 5% CO2 incubator for 24 hours. The cells were then incubated with DMEM high-glucose complete medium containing varying concentrations of IR-P1P for 24 hours. Cell viability was determined using a standard MTT assay relative to control cells.

[0099] Cell phototoxicity evaluation: HepG2 cells (10,000 cells per well) were seeded in 96-well plates and cultured in a 5% CO2 incubator at 37°C for 24 hours. The cells were incubated with DMEM high-glucose complete medium containing different concentrations of IR-P1P for 6 hours and then irradiated with a 1060 nm laser (1.0 W / cm 2 The cells were irradiated for 5 min and incubated for 18 h. The cell viability was determined by standard MTT assay relative to that of the control group.

[0100] The test results are as follows Figure 5 As shown in Table 1. Analysis of the data of the non-illumination group showed that as the concentration of IR-P1P increased, even at a concentration of up to 200 μmol / L, the cell activity was still high, indicating that the photothermal agent has low biological toxicity. Analysis of the data of the illumination group showed that as the concentration of IR-P1P increased, the cell activity gradually decreased. At a concentration of 200 μmol / L, the cell activity was as low as 23%. At 1060 nm (1.0 W / cm 2 ) Laser irradiation at a safe dose effectively induced cell apoptosis, significantly inhibited tumor growth, and achieved good photothermal therapy effects.

[0101] Table 1

[0102]

[0103] Note: L- means no light irradiation, L+ means 1060nm laser irradiation for 5 minutes with a power density of 1.0W / cm 2

[0104] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. The general formula is The compound in, R 1 , R 2 Each independently R 3 , R 4 Each independently Halogen, hydroxyl, amino; R 5 for 2. The compound according to claim 1, characterized in that In the general formula, R 1 , R 2 , R 3 , R 4 Both R 5 for 3. A method for preparing a compound as claimed in claim 2, characterized in that: Its synthetic route is:

4. The preparation method according to claim 3, characterized in that: It specifically includes the following steps: S1, anisole, 4-bromobenzoyl chloride and aluminum chloride are added to dichloromethane, and the reaction is completed at 0°C, and then extraction is performed. The organic phase is washed and dried, and the solvent is evaporated under reduced pressure to obtain compound 1; S2, compound 1 and aluminum chloride are dissolved in toluene, refluxed, extracted after the reaction is completed, the organic phase is washed and dried, and the solvent is evaporated under reduced pressure to obtain compound 2; S3, compound 2, 1,6-dibromohexane and potassium carbonate are added to acetonitrile, reacted at 60°C, the solvent is evaporated under reduced pressure, extraction is performed, the organic phase is washed and dried, the solvent is evaporated under reduced pressure, and recrystallization is performed to obtain compound 3; S4, titanium tetrachloride is slowly added dropwise to a zinc powder / tetrahydrofuran system precooled at -78°C, and after refluxing for 2 hours, a tetrahydrofuran solution of compound 3, benzophenone and pyridine is added, and the reflux reaction is continued for 6 hours, and a 10% potassium carbonate aqueous solution is added, filtered through diatomaceous earth, tetrahydrofuran is evaporated and then extracted with water, the organic phase is washed and dried, and the solvent is evaporated under reduced pressure; the crude product is separated and purified to obtain compound 4; S5, compound 4 was dissolved in tetrahydrofuran, and n-butyl lithium was slowly added dropwise under nitrogen protection at -78°C precooling, and tri-n-butyltin chloride was added. The reaction was carried out at room temperature, and the solvent was evaporated under reduced pressure; petroleum ether was then added, and the mixture was filtered after ultrasonication, and the filtrate was evaporated to dryness to obtain a crude product of compound 5; S6, compound 6, 1-Boc-pyrrole-2-boric acid and tetrakis(triphenylphosphine)palladium are dissolved in toluene, ethanol and an aqueous solution of potassium carbonate are added, reacted at 100°C under nitrogen protection, the solvent is evaporated under reduced pressure, extracted, the organic phases are combined, washed, dried, and the organic phases are concentrated to dryness, and the crude product is separated and purified to obtain compound 7; S7, compound 7 was dissolved in tetrahydrofuran, precooled to -40°C under nitrogen protection, N-bromosuccinimide was slowly added in batches, stirred, and reacted at 0°C, the solvent was evaporated under reduced pressure, extracted, the organic phases were combined, washed, dried, and the organic phase was concentrated to dryness, and the crude product was separated and purified to obtain compound 8; S8, the crude compound 5, compound 8 and bis(triphenylphosphine)palladium dichloride were dissolved in toluene, reacted at 100°C under nitrogen protection, the solvent was evaporated under reduced pressure, extracted, the organic phases were combined, washed, dried, the organic phase was concentrated to dryness, and the crude product was separated and purified to obtain compound 9; S9, compound 9 is dissolved in a trifluoroacetic acid / dichloromethane mixed solution, stirred at room temperature, trifluoroacetic acid is evaporated under reduced pressure, extracted, the organic phases are combined, washed, dried, and the organic phase is concentrated to dryness to obtain compound 10; S10, compound 10 was dissolved in pyridine at 90°C for reaction, centrifuged, the supernatant was discarded, the precipitate was ultrasonically washed with ether, and vacuum dried to obtain the target compound.

5. The preparation method according to claim 4, characterized in that: In steps S1 to S4 and S6 to S8, the organic phase is washed with saturated brine and dried over anhydrous sodium sulfate.

6. The preparation method according to claim 4, characterized in that: In step S9, the organic phase is washed with water, saturated sodium bicarbonate solution, and saturated brine in sequence, and dried over anhydrous sodium sulfate.

7. The preparation method according to claim 4, characterized in that: In steps S4, S6 to S8, the crude product is separated and purified using silica gel column chromatography.

8. Use of the compound according to claim 1 or 2 in the preparation of a drug for treating tumors, characterized in that: The tumor is liver cancer.

9. Use of the compound as claimed in claim 1 or 2 in the preparation of a near-infrared photothermal agent.

10. A near-infrared thermal agent, characterized in that: Its general formula is as shown in claim 1 or 2.

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