A class of heptamethine cyanine photoacoustic molecules, preparation and application thereof

Abstract

The present application relates to a kind of based on heptamethine cyanine molecule, its preparation method and application, belong to medical technology field.Compounds B1-3, C1 and C3 can specifically examine nitroreductase, be activated by nitroreductase and photoacoustic signal is enhanced.Introducing heavy atom, significantly improve photo-thermal conversion efficiency and intersystem crossing, promote photothermal therapy and photodynamic therapy.Compound C1 shows specific tumor killing effect and obvious photoacoustic signal in vivo by excellent synergistic PTT / PDT effect, provides a general strategy for cancer photoacoustic diagnosis and enhanced phototherapy.Compound C3 realizes staphylococcus aureus in situ pneumonia photoacoustic imaging for the first time, and can detect bacteria in tumor with high sensitivity and specificity, provides a promising new method for early detection of deep bacterial infection in vivo.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a class of heptamethine cyanine molecules for precise photoacoustic imaging and treatment of cancer and photoacoustic imaging of bacterial infection, as well as a preparation method and application thereof. Background Art

[0002] Cancer is a major global health problem, with 19.3 million new cases and 10 million cancer-related deaths worldwide in 2020. [1] In order to develop more effective and accurate cancer treatments, researchers around the world have been working to address this challenge. Traditional cancer treatments, such as surgery, radiotherapy, and chemotherapy, have disadvantages such as immune system damage, drug resistance, and killing of normal cells. [2-5] Therefore, alternative and tolerable cancer treatment strategies are urgently needed. Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a promising cancer treatment method that converts light energy into local hyperthermia to induce heat shock or generates cytotoxic reactive oxygen species (ROS) to ablate cancer cells. [6 -10]. However, as a non-invasive treatment strategy, phototherapy is limited by the limitations of light irradiation, including low toxicity to normal tissues, killing a variety of cells including multidrug-resistant cancers, and stimulating the body's immune response by inducing cell apoptosis or necrosis.

[11] Photosensitizers (PSs) are an important component of phototherapy. Although inorganic materials have excellent photothermal conversion efficiency and photostability, their poor biodegradability and long-term toxicity limit their clinical translation. [1 2 ,13] Therefore, organic photosensitizers with biocompatibility and low cytotoxicity have been developed to enhance the efficacy of phototherapy. [6 , 14 - 16] .

[0003] Bacterial infections are also a major medical and public health problem worldwide

[17] Optical imaging is an effective tool for observing and evaluating the pathogenesis and progression of bacterial-related diseases in biomedical research.

[18] However, due to limitations in penetration depth and light scattering, existing optical imaging methods are mainly limited to skin infections. Currently, the most commonly used methods for clinical pneumonia infection imaging include X-rays, CT, and MRI. However, these techniques often lack specificity and have difficulty distinguishing different types of pneumonia infections.

[19] Therefore, there is an urgent need for rapid, accurate, and real-time molecular imaging strategies to visualize bacteria in deep tissues. Photoacoustic imaging is based on the absorption of pulsed laser light. The absorbed photons release energy in the form of heat, which then vibrate and relax to generate pressure waves, which produce detectable sound waves.

[20] With the development of organic photoacoustic contrast agents, photoacoustic imaging has shown great potential in diagnosing deep tissue bacterial infections because they can provide more specific and sensitive information about the infection site and severity.

[21] .

[0004] Cyanine derivatives have excellent biosafety, high molar extinction coefficients, and deep tissue penetration depths and are considered to be excellent potential candidates for the development of organic photosensitizers and photoacoustic contrast agents. [22-25] Due to the intrinsic targeting of positively charged cyanine derivatives to mitochondria and the sensitivity of mitochondria to heat shock [26-28] The present invention designed and synthesized a class of nitroreductase (NTR)-activated photoacoustic molecules, which utilize the photoinduced electron transfer (PeT) mechanism to improve the photothermal conversion efficiency of PTT. The incorporation of heavy atoms into the cyanine chromophore can effectively promote the intersystem crossing rate and ROS generation of PDT, which is used to synergistically and effectively kill cancer cells. We attached the prostate-specific membrane antigen (PSMA)-specific targeting group KUE (Lys-urea-Glu) to the photoacoustic molecule to enhance the catalytic activity of NTR, achieve in vivo tumor detection by prostate cancer (PCa)-specific photoacoustic imaging, and efficiently kill cancer cells through synergistic PTT / PDT. This strategy provides an effective tool for specific diagnosis and phototherapy of cancer. At the same time, we attached a neomycin fragment to the photoacoustic molecule to achieve bacterial-specific targeting, which was used for the first time for photoacoustic imaging of pneumonia induced by Staphylococcus aureus in situ and tumor-homing bacteria in vivo. It can be used as a visualization tool for evaluating bacterial infection treatment and monitoring bacteria in tumor cells. Summary of the Invention

[0005] The technical problem solved by the present invention is to provide a compound or a pharmaceutically acceptable salt thereof, a preparation method thereof and an application thereof.

[0006] In order to solve the technical problems of the present invention, the present invention provides the following technical solutions:

[0007] In a first aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof:

[0008]

[0009] R1 is independently selected from hydrogen atoms and R2 is independently selected from hydroxyl, and X is independently selected from O, S, and Se.

[0010] Furthermore, the compound of the present invention is selected from:

[0011]

[0012] The second aspect of the technical solution of the present invention is to provide a method for preparing the compound or a pharmaceutically acceptable salt thereof according to the first aspect, characterized in that it comprises the following steps:

[0013]

[0014] Wherein: R1, R2, and X are as defined in any one of claims 1 to 4;

[0015] (1) Add 4-(Boc-amino)phenol or p-aminothiophenol or 4,4'-diselenanediyldiphenylamine, compound 1, base and solvent to a round-bottom flask, react at a set temperature and stirring conditions, after the reaction is completed, extract the reaction solution, concentrate under reduced pressure and purify to obtain I or further react with p-nitrobenzylchloroformate, base and solvent under argon protection under anhydrous conditions at room temperature, extract the reaction solution after the reaction is completed, concentrate under reduced pressure and purify to obtain I;

[0016] (2) adding I prepared in step (1), a condensing agent, a base, a ligand and a solvent to a round-bottom flask, reacting under anhydrous conditions under argon protection at room temperature, extracting the reaction solution after completion of the reaction, concentrating under reduced pressure and purifying, and then reacting with trifluoroacetic acid at room temperature, concentrating under reduced pressure and purifying to obtain II; or reacting I prepared in step (1) with di-tert-butyl dicarbonate, a base and a solvent under anhydrous conditions under argon protection at room temperature, extracting the reaction solution after completion of the reaction, concentrating under reduced pressure and purifying, and then reacting the obtained compound with a condensing agent, a base, a ligand and a solvent under anhydrous conditions under argon protection at room temperature, extracting the reaction solution after completion of the reaction, concentrating under reduced pressure and purifying, and then reacting with trifluoroacetic acid at room temperature, concentrating under reduced pressure and purifying to obtain II.

[0017] The third aspect of the technical solution of the present invention is to provide the use of the compound or a pharmaceutically acceptable salt thereof described in the first aspect in the preparation of a photosensitizer.

[0018] The fourth aspect of the technical solution of the present invention is to provide the use of the compound or a pharmaceutically acceptable salt thereof described in the first aspect in the preparation of photoacoustic imaging and therapeutic drugs for prostate cancer at the in vitro, cellular or in vivo levels.

[0019] The fifth aspect of the technical solution of the present invention is to provide the use of the compound or pharmaceutically acceptable salt thereof described in the first aspect in the preparation of in vitro, cellular or in vivo levels of pneumonia induced by bacteria in situ and photoacoustic imaging of tumor-homing bacteria in vivo, wherein the bacteria is Staphylococcus aureus. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 Shown are the absorption and emission spectra of compounds A1-3, B1-3, and C1-4.

[0021] Figure 2 This indicates that compounds C1 and C3 were reduced by nitroreductase in the presence of β-nicotinamide adenine dinucleotide disodium salt hydrate, and the fluorescence intensity gradually decreased.

[0022] Figure 3 This indicates that compounds B1-3 and C1 have strong ability to generate active oxygen.

[0023] Figure 4 This indicates that compounds A1-3, B1-3, C1, and C2 all have excellent photothermal generation capabilities.

[0024] Figure 5 Compound C1 has obvious phototoxicity to C4-2 cells and very low dark toxicity.

[0025] Figure 6 This indicates that compound C1 significantly inhibits tumor growth after irradiation with light, can be used to treat tumors, and is a good phototherapeutic agent.

[0026] Figure 7 This indicates that compound C3 can be used to specifically target bacteria without affecting tumor cells. The photoacoustic signal gradually increases in a time-dependent manner, which can distinguish bacteria from tumors and be used for photoacoustic imaging of bacteria in tumor tissues. DETAILED DESCRIPTION

[0027] Example 1 Preparation steps of compound A1:

[0028]

[0029] Preparation Example 1, Preparation of Compound 3

[0030] Compound 2 (46.3 mg, 0.22 mmol) was dissolved in ultra-dry N,N-dimethylformamide (1.5 mL). Sodium hydride (60% dispersion in mineral oil, 7.1 mg, 0.30 mmol) was slowly added under argon at 0°C. After stirring at room temperature for 10 minutes, compound 1 (100 mg, 0.15 mmol) was added to the above system, and the reaction system was stirred at 40°C for 3 hours. After completion of the reaction, the reaction system was diluted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure column chromatography (4% MeOH / CH2Cl2) to obtain compound 3 as a green solid, 73.5 mg, with a yield of 58.6%.

[0031] Preparation Example 2, Preparation of Compound A1

[0032] Compound 3 (55.0 mg, 0.065 mmol) was added to trifluoroacetic acid and stirred at room temperature for 20 minutes. The reaction system was diluted with dichloromethane and concentrated under reduced pressure. This was repeated five times to remove the trifluoroacetic acid. The residue was purified by medium-pressure column chromatography (5% MeOH / CH2Cl2) to afford Compound A1 as a bluish-black solid (43.7 mg, 90.1% yield). 1 H NMR (600MHz, CD3OD-d4): δ8.05(dd,J=14.2,8.5Hz,2H),7.40-7.36(m,4H),7.25(dd,J=8.0,4.7Hz,2H ),7.21(q,J=7.1Hz,2H),6.90(d,J=8.6Hz,2H),6.76(d,J=8.7Hz,2H),6.13(dd,J=14.2,7.7Hz,2H),4 .13(q,J=7.2Hz,2H),4.09(t,J=7.5Hz,2H),2.73(t,J=6.3Hz,4H),2.30(t,J=7.3Hz,2H),2.05-2.01( m,2H),1.83-1.79(m,2H),1.71-1.66(m,2H),1.50-1.44(m,2H),1.39(s,12H),1.36(t,J=7.3Hz,3H). 13C NMR (150MHz, CD3OD-d4): δ177.63,173.50,173.29,166.52,154.85,143.93,143.61,1 43.16,142.64,142.46,129.77,129.73,126.13,126.03,123.57,123.52,123.41,123. 37,118.26,116.22,111.84,111.64,100.64,100.40,50.29,50.24,44.79,40.01,34. 91,28.24,28.13,27.94,27.39,25.78,25.27,25.21,22.51,12.31.HRMS(ESI)m / z:[M] + The theoretical value is C 44 H 52 N3O3 + ,670.4003; the measured value is 670.3999.

[0033] Example 2 Preparation steps of compound A2:

[0034]

[0035] Preparation Example 3, Preparation of Compound A2

[0036] Compound 1 (100 mg, 0.15 mmol) was dissolved in ultra-dry N,N-dimethylformamide (1.5 mL), and compound 4 (92.3 mg, 0.74 mmol) was added under argon. After stirring at room temperature for 2 hours, the reaction system was diluted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure column chromatography (4% MeOH / CH2Cl2) to obtain compound A2 as a blue-black solid, 75 mg, with a yield of 74%. 1 H NMR (400MHz, CD3OD-d4): δ8.72 (dd, J=13.9, 8.3Hz, 2H), 7.43–7.40 (m, 3H), 7. 38-7.35(m,3H),7.29-7.27(m,3H),7.25-7.20(m,3H),6.29(dd,J=13.6,10.2H z,2H),4.19-4.11(m,4H),2.78(s,4H),2.29(t,J=7.1Hz,2H),2.03–2.00(m,2 H),1.83–1.78(m,2H),1.70-1.63(m,2H),1.46(s,14H),1.36(t,J=6.7Hz,3H). 13C NMR (100MHz, DMSO-d6): δ174.28,171.72,171.55,150.49,145.34,144.99,142.07,141 .61,141.19,140.99,133.16,133.08,128.54,128.50,127.53,124.96,124.85,122.40, 122.35,118.94,111.27,111.14,101.48,101.41,59.72,48.79,48.71,43.49,33.47,27 .27,27.16,26.65,25.79,25.65,24.15,20.72,20.42,14.04,12.16.HRMS(ESI)m / z:[M] + The theoretical value is C 44 H 52 N3O2S + ,686.3775; the measured value is 686.3771.

[0037] Example 3 Preparation steps of compound A3:

[0038]

[0039] Preparation Example 4, Preparation of Compound A3

[0040] Compound 5 (280.3 mg, 0.82 mmol) was dissolved in ethanol (16 mL), and sodium borohydride (108.5 mg, 2.87 mmol) was added portionwise at 0°C under argon. After stirring at 0°C for 15 minutes, citric acid was added to the reaction system, and the reaction was continued at 0°C for 10 minutes. A solution of compound 1 (1 g, 1.48 mmol) in ultra-dry N,N-dimethylformamide (24 mL) was then added to the reaction system. The reaction was stirred at room temperature for 2 hours. Upon completion, the reaction system was diluted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure column chromatography (5% MeOH / CH2Cl2) to afford 524 mg of compound A3 as a bluish-black solid in a 78.6% yield. 1H NMR (500MHz, CD3OD-d4): δ8.85-8.80(m,2H),7.47(d,J=8.7Hz,2H),7.44(t,J=6.3Hz,2H),7.41- 7.38(m,2H),7.29(t,J=7.9Hz,2H),7.28-7.23(m,4H),6.30(dd,J=14.2,11.0Hz,2H),4.19(q,J= 7.1Hz,2H),4.15(t,J=7.4Hz,2H),2.81(t,J=7.3Hz,4H),2.31(t,J=7.3Hz,2H),2.07-2.02(m,2H ),1.87-1.81(m,2H),1.72-1.66(m,2H),1.52(s,12H),1.51-1.46(m,2H),1.39(t,J=7.2Hz,3H). 13 C NMR (150MHz, CD3OD-d4): δ177.21,173.98,173.84,155.34,150.80,150.38,143.62,143. 12,142.76,142.56,135.30,135.20,131.07,129.87,129.83,126.47,126.34,123.48,123 .43,122.64,122.56,112.09,111.94,102.40,102.26,50.55,50.47,44.93,40.22,34.60, 31.13,28.14,28.06,28.03,27.75,27.70,27.36,25.65,22.33,12.45.HRMS(ESI)m / z:[M] + The theoretical value is C 44 H 52 N3O2Se + ,734.3219; the measured value is 734.3220.

[0041] Example 4 Preparation steps of compound B1-3:

[0042]

[0043] Preparation Example 5, Preparation of Compound B1

[0044] Compound A1 (50 mg, 0.075 mmol) and compound 6 (24.1 mg, 0.11 mmol) were dissolved in ultra-dry dichloromethane (0.75 mL). N,N-diisopropylethylamine (13 μL, 0.11 mmol) was added to the system under argon protection. The reaction was complete after stirring at room temperature for 30 minutes. The reaction system was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure column chromatography (4% MeOH / CH2Cl2) to obtain compound B1 as a green solid (31.6 mg, 49.9% yield). 1 H NMR (600MHz, CDCl3): δ9.13(s,1H),8.15(d,J=8.3Hz,2H),7.92(d,J=14.0Hz,2H),7.70(d,J=8.5Hz,2H),7.59(d,J=8.3Hz,2 H),7.33(q,J=7.6Hz,2H),7.25(s,2H),7.18(q,J=7.3Hz,2H),7.05(d,J=8.0Hz,1H),7.01(d,J=7.9Hz,1H),6.96(d,J=8.6Hz ,2H),5.98(d,J=14.4Hz,1H),5.88(d,J=14.0Hz,1H),5.24(s,2H),4.00-3.96(m,4H),2.69(t,J=6.2Hz,2H),2.65(t,J=6.2H z,2H),2.46(t,J=7.1Hz,2H),2.05-2.01(m,2H),1.80-1.75(m,2H),1.67-1.63(m,2H),1.38(t,J=7.2Hz,3H),1.33(s,14H). 1 3C NMR (150MHz, CDCl3): δ172.80,171.29,165.41,155.89,154.04,147.51,144.58,143.12,142.26,142 .18,141.78,141.19,140.96,134.00,128.90,128.86,128.72,128.03,125.52,125.08,123.79,122. 78,122.53,122.46,122.36,121.28,114.78,110.80,109.94,100.01,98.74,64.96,49.55,49.13,44 .75,39.22,34.50,29.84,28.01,27.97,27.06,26.25,24.59,24.46,21.21,12.24.HRMS(ESI)m / z:[M]+ The theoretical value is C 52 H 57 N4O7 + ,849.4222; the measured value is 849.4193.

[0045] Preparation Example 6, Preparation of Compound B2

[0046] Compound A2 (75 mg, 0.11 mmol) and compound 6 (35.3 mg, 0.16 mmol) were dissolved in ultra-dry dichloromethane (1.1 mL). N,N-diisopropylethylamine (28.5 μL, 0.16 mmol) was added to the system under argon protection. The reaction was complete after stirring at room temperature for 5 minutes. The reaction system was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure column chromatography (4% MeOH / CH2Cl2) to obtain compound B2 as a gray-green solid (27.5 mg, 29.1% yield). 1 H NMR (600MHz, CDCl3): δ8.76(d,J=43.6Hz,2H),8.13(d,J=8.8Hz,2H),7.53(d,J=8.8Hz,4H),7. 35(t,J=7.7Hz,2H),7.30(t,J=6.3Hz,2H),7.21(s,2H),7.10(d,J=8.8Hz,2H),7.08-7.03(m,2H ),6.08(d,J=47.9Hz,2H),5.20(s,2H),4.02(s,4H),2.68(s,4H),2.36(t,J=7.2Hz,2H),2.02-1 .99(m,2H),1.83-1.80(m,2H),1.67-1.62(m,2H),1.50(s,6H),1.46(s,6H),1.42-1.37(m,5H). 13CNMR (150MHz, CDCl3): δ173.28,171.67,153.75,153.66,147.53,147.42,146.27,144.33,142.10,14 1.83,141.31,141.23,137.15,134.31,133.81,130.44,128.92,128.78,128.04,126.92,125.65,125. 19,123.77,122.52,122.45,120.34,110.93,110.11,101.60,100.25,65.05,49.66,49.31,44.62,39 .31,34.20,31.37,28.06,28.04,27.18,26.48,26.44,26.30,24.50,20.87,12.29.HRMS(ESI)m / z:[M] + The theoretical value is C 52 H 57 N4O6S + ,865.3993; the measured value is 865.3995.

[0047] Preparation Example 7, Preparation of Compound B3

[0048] Compound A3 (500 mg, 0.68 mmol) and compound 6 (220 mg, 1.02 mmol) were dissolved in ultra-dry dichloromethane (6.8 mL). N,N-diisopropylethylamine (128 μL, 1.02 mmol) was added to the system under argon protection. The reaction was complete after stirring at room temperature for 30 minutes. The reaction system was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure column chromatography (6% MeOH / CH2Cl2) to obtain compound B3 as a gray-green solid (226 mg, 32.0% yield). 1 H NMR (600MHz, CDCl3): δ8.78(s,2H),8.13(d,J=8.0Hz,2H),7.53(d,J=7.2Hz,4H ),7.36(s,2H),7.31(t,J=6.0Hz,2H),7.22-7.17(m,4H),7.06(d,J=23.6Hz,2H ),6.10(d,J=56.3Hz,2H),5.20(s,2H),4.04(s,4H),2.73(s,4H),2.39(s,2H), 2.01(s,2H),1.85(s,2H),1.66(s,2H),1.54(s,6H),1.49(s,6H),1.43(s,5H). 13CNMR (150MHz, CDCl3): δ173.40,171.58,156.64,153.72,150.61,149.18,147.54,144.32,142. 07,141.87,141.27,137.71,134.81,134.45,129.29,128.95,128.80,128.12,125.68,125.16,1 23.81,122.57,122.50,120.69,111.05,110.15,101.90,100.39,65.10,49.66,49.30,44.88,3 9.71,34.32,31.37,29.84,28.09,27.30,27.19,26.40,24.61,21.20,12.52.HRMS(ESI)m / z:[M] + The theoretical value is C 52 H 57 N4O6Se + ,913.3438; the measured value is 913.3439.

[0049] Example 5 Preparation steps of compound C1:

[0050]

[0051] Preparation Example 8, Preparation of Compound 9

[0052] Compound 7 (180 mg, 0.28 mmol) and compound 8 (122.8 mg, 0.25 mmol) were dissolved in ultra-dry tetrahydrofuran (2.5 mL). 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (143.6 mg, 0.38 mmol) and N,N-diisopropylethylamine (87.8 μL, 0.50 mmol) were added. The system was stirred at room temperature under argon for 2 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The residue was purified by medium-pressure column chromatography (4% MeOH / CH2Cl2) to obtain compound 9 as a colorless oil (271 mg, 96.1% yield).

[0053] Preparation Example 9, Preparation of Compound 10

[0054] Compound 9 (271 mg, 0.24 mmol) was dissolved in acetonitrile (7.5 mL), diethylamine (2.5 mL, 24.21 mmol) was added and the reaction was allowed to proceed at room temperature for 40 minutes under argon protection. After the reaction was completed, the reaction solvent was distilled under reduced pressure, and the residue was purified by column chromatography (10% MeOH / CH2Cl2) to obtain compound 10 as a colorless oil, 64 mg, in a yield of 29.5%. 1 H NMR (400 MHz, CDC13): δ 7.87 (s, 2H), 7.61 (s, 1H), 4.33 (dd, J = 8.8, 4.9 Hz, 1H), 4.23 (dd, J = 7.7, 4.4 Hz, 1H), 4.07 (s, 2H), 3.89 (s, 2H), 3.74-3.65 (m, 28H), 3.29 (s, 2H), 3.19 (s, 2H), 2.41-2.27 (m, 2H), 2.10-2.00 (m, 1H), 1.89-1.82 (m, 1H), 1.80-1.67 (m, 2H), 1.60-1.51 (m, 2H), 1.44 (s, 18H), 1.42 (s, 9H), 1.32-1.20 (m, 2H). 13 C NMR (150 MHz, CDC13): δ 172.79, 172.68, 172.46, 170.52, 157.69, 81.60, 81.30, 80.46, 70.88, 70.67, 70.52, 70.44, 70.40, 70.32, 70.28, 70.19, 70.16, 70.03, 67.05, 53.78, 53.02, 40.69, 38.32, 31.90, 31.83, 29.11, 28.55, 28.24, 28.18, 22.51. HRMS (ESI) m / z: [M+H] + Calculated for C 42 H 81 N4O 16 + 897.5642; Found 897.5631.

[0055] Preparation of compound C1

[0056] Compound B3 (24.4 mg, 0.026 mmol) was dissolved in ultra-dry dichloromethane (1 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.2 mg, 0.032 mmol), 1-hydroxybenzotriazole (4.3 mg, 0.032 mmol), and N,N-diisopropylethylamine (5.6 μL, 0.032 mmol) were added under argon. After reacting at room temperature for 20 minutes, compound 10 (24 mg, 0.026 mmol) was added to the above system and the reaction continued at room temperature for 4 hours. After completion of the reaction, the reaction system was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was used directly in the next step without further purification.

[0057] The above residue (40 mg, 0.022 mmol) and triethylsilane (64 μL, 0.402 mmol) were dissolved in dichloromethane (440 μL). Trifluoroacetic acid (410 μL, 5.357 mmol) was slowly added dropwise, and the reaction system was stirred at room temperature for 11 hours. After completion of the reaction, the reaction system was diluted with dichloromethane and concentrated under reduced pressure. This was repeated five times to remove the trifluoroacetic acid. The residue was purified by HPLC to obtain Compound C1 as a gray-green solid (12 mg). The total yield over two steps was 27.7%. 1H NMR(600MHz,DMSO-d6):δ12.49(s,3H),9.89(s,1H),8.70(dd,J=14.1,3.0Hz,2H),8.22(d,J=8.7Hz,2H),7.82(t,J=5.7Hz,1H),7.66(t,J=5.9Hz,1H),7.63(d,J=8.6Hz,2H),7.54(dd,J=7.4,4.9Hz,2H),7.41-7.38(m,6H),7.28(d,J=8.8Hz,2H),7.25-7.22(m,2H),6.33-6.28(m,4H),5.24(s,2H),4.21(q,J=7.2Hz,2H),4.15(t,J=7.5Hz,2H),4.10(td,J=8.3,5.2Hz,1H),4.04(td,J=8.1,5.2Hz,1H),3.84(s,2H),3.55(s,4H),3.52(s,4H),3.50-3.48(m,22H),3.16(q,J=5.9Hz,2H),3.07(q,J=6.9Hz,2H),2.75(q,J=6.3Hz,4H),2.29-2.18(m,2H),2.06(t,J=7.3Hz,2H),2.02-1.96(m,1H),1.94-1.89(m,3H),1.74-1.67(m,3H),1.66-1.61(m,1H),1.57-1.52(m,4H),1.48(s,12H),1.43-1.38(m,2H),1.37-1.32(m,2H),1.28(t,J=7.1Hz,3H). 13C NMR (150MHz, DMSO-d6): δ174.51,174.14,173.71,171.95,171.80,171.57,168.99,157.25,152.94,152.92,148.43,148.13,147.05,144.4 2,142.07,141.63,141.20,141.02,137.51,133.59,133.55,129.65,1 28.97,128.57,128.52,128.44,124.96,124.88,124.75,123.58,122. 47,122.41,119.67,111.29,111.14,101.53,101.39,70.22,69.93,6 9.76,69.71,69.56,69.51,69.15,64.52,52.26,51.62,48.81,48.74, 43.55,38.41,37.93,34.99,31.78,29.88,28.91,27.55,27.19,27.09,26.71,26.22,25.76,24.85,22.56,20.63,12.19.HRMS(ESI)m / z:[M] + The theoretical value is C 82 H 111 N8O 21 Se + ,1623.7024; the measured value is 1623.7024.

[0058] Example 6 Preparation steps of compound C2:

[0059]

[0060] Preparation Example 11, Preparation of Compound 11

[0061] Compound A3 (50 mg, 0.068 mmol) was dissolved in ethanol (1.6 mL), and di-tert-butyl dicarbonate (18.8 μL, 0.082 mmol) was added under argon. After reacting at room temperature for 12 hours, the solvent was removed by distillation under reduced pressure. The residue was dissolved in dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure column chromatography (6% MeOH / CH2Cl2) to obtain compound 11 as a gray-green solid (35.1 mg, 56.5% yield). 1H NMR (600MHz, CDCl3): δ8.79 (dd, J=23.3, 13.8Hz, 2H), 7.38-7.30 (m, 6H), 7.22 (t, J=7.4Hz, 1H), 7.21-7.18 (m, 3H ),7.11(d,J=8.0Hz,1H),7.05(d,J=7.9Hz,1H),6.99(s,1H),6.19(d,J=14.1Hz,1H),6.05(d,J=13.9Hz,1H),4.0 5-4.02(m,4H),2.71(dt,J=21.1,5.9Hz,4H),2.47(t,J=6.7Hz,2H),2.02-1.99(m,2H),1.86-1.81(m,2H),1.76- 1.71(m,2H),1.54(s,6H),1.52(s,6H),1.50-1.48(m,2H),1.45(s,9H),1.41(t,J=7.0Hz,3H).HRMS(ESI)m / z:[M] + The theoretical value is C 49 H 60 N3O4Se + ,834.3744; the measured value is 834.3740.

[0062] Preparation Example 12, Preparation of Compound C2

[0063] Compound 11 (28.6 mg, 0.034 mmol) was dissolved in ultra-dry dichloromethane (1.4 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.2 mg, 0.037 mmol), 1-hydroxybenzotriazole (5.1 mg, 0.037 mmol), and N,N-diisopropylethylamine (6.5 μL, 0.037 mmol) were added under argon. After reacting at room temperature for 20 minutes, compound 10 (28 mg, 0.031 mmol) was added to the above system and the reaction was continued at room temperature for 5 hours. After completion of the reaction, the reaction system was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was used directly in the next step without further purification.

[0064] The above residue (45.8 mg, 0.027 mmol) and triethylsilane (77 μL, 0.481 mmol) were dissolved in dichloromethane (540 μL). Trifluoroacetic acid (637 μL, 6.416 mmol) was slowly added dropwise, and the reaction system was stirred at room temperature for 4 hours. After the reaction was completed, the reaction system was diluted with dichloromethane and concentrated under reduced pressure. This was repeated five times to remove the trifluoroacetic acid. The residue was purified by HPLC to obtain compound C2 as a gray-green solid (14.3 mg). The total yield for the two steps was 30.1%. 1H NMR(600MHz,DMSO-d6):δ8.76(dd,J=14.1,5.5Hz,2H),7.82(t,J=5.7Hz,1H),7.66(t,J=5.9Hz,1H),7.56(dd,J=7.4,5.0Hz,2H),7.41-7.38(m,4H),7.26-7.23(m,2H),7.12(d,J=8.6Hz,2H),6.63(d,J=7.9Hz,2H),6.3-6.27(m,4H),4.21(q,J=7.3,6.8Hz,2H),4.15(t,J=7.4Hz,2H),4.10(td,J=8.3,5.2Hz,1H),4.04(td,J=8.0,5.2Hz,1H),3.85(s,2H),3.55(s,4H),3.52(s,4H),3.50-3.49(m,22H),3.16(q,J=5.9Hz,2H),3.07(q,J=6.8Hz,2H),2.72(q,J=6.5Hz,4H),2.29-2.18(m,2H),2.07(t,J=7.3Hz,2H),2.02-1.85(m,4H),1.74-1.67(m,3H),1.66-1.61(m,1H),1.57-1.50(m,16H),1.43-1.38(m,2H),1.37-1.34(m,2H),1.29(t,J=7.2Hz,3H). 13 C NMR(150MHz,DMSO-d6):δ174.51,174.14,173.71,171.96,171.74,171.51,168.99,157.26,154.48,148.69,148.40,142.11,141.66,141.19,141.01,133.58,133.51,130.05,129.65,128.57,128.52,124.92,124.84,122.45,122.40,117.05,111.25,111.09,101.43,101.28,70.23,69.93,69.77,69.71,69.57,69.51,69.15,52.27,51.63,48.81,48.75,43.52,38.41,37.93,34.99,31.78,31.30,29.88,28.91,27.55,27.26,27.16,26.69,26.21,25.77,24.86,22.56,20.68,12.17.HRMS(ESI)m / z:[M] + 理论值为C74 H 106 N7O 17 Se + ,1444.6805; the measured value is 1444.6814.

[0065] Example 7 Preparation steps of compound C3:

[0066]

[0067] Preparation Example 13, Preparation of Compound C3

[0068] Compound B1 (13 mg, 0.015 mmol) was dissolved in ultra-dry dichloromethane (1.2 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.63 mg, 0.045 mmol), 1-hydroxybenzotriazole (6.08 mg, 0.045 mmol), and N,N-diisopropylethylamine (5.8 mg, 0.045 mmol) were added under argon protection. After reacting at room temperature for 30 minutes, compound 12 (22 mg, 0.018 mmol) was added to the above system and the reaction was continued at room temperature for 2 hours. After completion of the reaction, the reaction system was diluted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was used directly in the next step without further purification.

[0069] The above residue was dissolved in trifluoroacetic acid (600 μL), and the reaction system was stirred at room temperature for 15 minutes. After completion of the reaction, the reaction system was diluted with dichloromethane and concentrated under reduced pressure. This was repeated five times to remove the trifluoroacetic acid. The residue was purified by HPLC to obtain compound C3 as a green solid (19 mg). The total yield over two steps was 85.9%. 1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.34(s,6H),8.25(d,J=8.5Hz,2H),8.20-8.10(m,6H),8.06(s,6H),7.91-7.76(m,6H),7.67(d,J=8.5Hz,3H),7.56-7.46(m,4H),7.43-7.38(m,2H),7.36(d,J=7.8Hz,1H),7.29(d,J=8.1Hz,1H),7.26-7.22(m,1H),7.19(t,J=7.4Hz,1H),7.11(d,J=9.0Hz,2H),6.22(d,J=14.3Hz,1H),6.12(d,J=14.1Hz,1H),5.77-5.66(m,1H),5.26(s,2H),5.21(s,1H),5.02(s,1H),4.27-4.23(m,1H),4.22-4.16(m,2H),4.15-4.07(m,4H),4.06-3.99(m,3H),3.97-3.88(m,3H),3.78(t,J=8.8Hz,1H),3.55(s,1H),3.50(d,J=7.9Hz,1H),3.43(t,J=9.4Hz,1H),3.38-3.30(m,1H),3.29-3.19(m,6H),3.13(s,3H),3.02(s,1H),2.77-2.62(m,4H),2.36(s,1H),2.23-2.11(m,2H),1.93(s,2H),1.81-1.70(m,2H),1.70-1.62(m,2H),1.59-1.52(m,2H),1.38(dd,J=13.4,7.5Hz,2H),1.30(s,12H),1.26(s,3H); 13C NMR(100MHz,DMSO-d6)δ173.57,171.66,170.87,162.79,158.80,158.47 ,155.08,153.11,147.05,144.56,142.05,141.52,141.39,141.15,140. 81,140.31,133.43,128.56,128.44,128.34,125.03,124.56,123.59,12 2.49,121.56,121.43,120.86,120.16,117.88,115.18,114.95,114.56, 111.18,110.81,108.49,100.30,99.56,95.52,93.67,84.12,80.01,77.81,73.57,72.35,70.92,70.69,70.09,67.86,67.32,66.87,64.45,53.40,51.08,49.41,48.74,48.63,48.38,43.37,40.99,35.20,27.98,27.28,27.08,26.70,26.11,24.95,23.67,20.66,12.14. HRMS (ESI): m / z theoretical value is C 75 H 102 N 11 O 18 + :1444.7399[M] + ; The measured value is 1444.7421.

[0070] Example 8 Preparation steps of compound C4:

[0071]

[0072] Preparation Example 14, Preparation of Compound C4

[0073] Compound 3 (19 mg, 0.0248 mmol) was dissolved in ultra-dry dichloromethane (0.33 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.3 mg, 0.033 mmol), 1-hydroxybenzotriazole (4.5 mg, 0.033 mmol), and N,N-diisopropylethylamine (4.3 mg, 0.033 mmol) were added under argon protection. After reacting at room temperature for 30 minutes, compound 12 (20 mg, 0.0165 mmol) was added to the above system and the reaction was continued at room temperature for 2 hours. After completion of the reaction, the reaction system was diluted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was used directly in the next step without further purification.

[0074] The above residue was dissolved in trifluoroacetic acid (760 μL), and the reaction system was stirred at room temperature for 15 minutes. After completion of the reaction, the reaction system was diluted with dichloromethane and concentrated under reduced pressure. This was repeated five times to remove the trifluoroacetic acid. The residue was purified by HPLC to obtain compound C4 as a green solid (14.1 mg). The total yield over two steps was 44%. 1 H NMR(400MHz, DMSO-d6)δ8.11–7.98(m,2H),7.40(dd,J=7.8,2.8Hz,2H),7.38-7.34(m,2H),7.29-7 .24(m,1H),7.22(d,J=3.9Hz,1H),7.21-7.16(m,2H),6.90(d,J=2.0Hz,1H),6.89(s,1H),6.78(s,1 H),6.76(s,1H),6.12(dd,J=23.7,14.2Hz,2H),5.66(d,J=3.4Hz,1H),5.36(d,J=5.3Hz,1H),5.29( s,1H),4.43-4.36(m,1H),4.31-4.24(m,1H),4.23-4.18(m,1H),4.16(s,1H),4.15-4.11(m,2H),4. 09(d,J=6.9Hz,2H),4.07-4.01(m,2H),3.90-3.83(m,1H),3.76(s,2H),3.70(d,J=2.5Hz,1H),3.66 (s,3H),3.62-3.53(m,2H),3.41(s,2H),3.40-3.36(m,2H),3.35(s,1H),3.25-3.21(m,1H),3.20-3 .03(m,4H),2.80-2.68(m,4H),2.32-2.20(m,3H),2.08-1.95(m,3H),1.85-1.75(m,2H),1.74-1.60 (m,4H),1.51-1.42(m,3H),1.39(s,9H),1.36(s,3H),1.34(s,2H),1.29(s,2H),1.25-1.20(m,2H). 13CNMR(100MHz,DMSO-d6)δ176.69,173.61,173.10,166.47,154.83,144.24,143.70,143.56,143.29,143.08,142.68,14 2.39,129.79,129.70,126.27,125.90,123.52,123.49,123.43,123.38,118.28,116.20,111.80,111.69,100.66,100. 34,97.35,83.26,80.48,77.97,75.66,74.70,73.28,72.15,70.97,70.65,69.31,55.69,52.95,51.59,50.39,50.13,44.82,41.96,41.87,41.71,40.09,36.91,28.28,28.10,27.77,26.70,25.27,25.18,22.51,12.36. HRMS (ESI): m / z theoretical value is C 67 H 97 N 10 O 14 + :1265.7180[M] + ; The measured value is 1265.7253.

[0075] Pharmacological experiments

[0076] Experimental Example 1: Absorption and emission spectra of compounds A1-3, B1-3 and C1-4

[0077] Compounds A1-3, B1-3 and C1-4 were dissolved in dimethyl sulfoxide and the absorption and normal emission spectra of the compounds were measured by microplate reader. Figure 1 .

[0078] Experimental Example 2: Compound C1 and C3 reduction experiment by nitroreductase

[0079] Compound C1 was dissolved in 0.05 M tris (pH = 7.4, containing 1.5% dimethyl sulfoxide), and β-nicotinamide adenine dinucleotide disodium salt hydrate (500 μM) and nitroreductase (10 μg / mL) were added sequentially. The emission spectrum of the compound was immediately monitored (excitation wavelength 740 nm). Compound C1 (5 μM) was immediately reduced by nitroreductase (10 μg / mL), and the fluorescence intensity gradually decreased with the extension of incubation time. Figure 2 .

[0080] Compound C3 was dissolved in 0.05 M Tris-HCl buffer (pH = 7.4, containing 1.5% dimethyl sulfoxide), and β-nicotinamide adenine dinucleotide disodium salt hydrate (500 μM) and nitroreductase (2 μg / mL) were added successively. The emission spectrum of the compound was monitored immediately (excitation wavelength 740 nm). Compound C3 (10 μM) was reduced by nitroreductase (2 μg / mL) immediately, and the fluorescence intensity decreased gradually with the extension of incubation time, up to 6 times. See Figure 1. Figure 2 .

[0081] Experimental Example 3: Activity oxygen production ability of compounds A1-3, B1-3 and C1-2

[0082] 2', 7'-dichlorodihydrofluorescein diacetate (DCFH-DA) was used as an activity oxygen indicator. First, DCFH-DA solution (0.5 mL, 1 mM dissolved in ethanol) was mixed with sodium hydroxide solution (2 mL, 10 mM dissolved in water), stirred at room temperature for 30 minutes, and then diluted with phosphate buffer (1x, pH 7.4) to a final concentration of 40 μM. Compounds A1-3, B1-3 and C1-2 (1 μL, 5 mM) were added to the DCFH solution to obtain a compound concentration of 10 μM. Under irradiation of 785 nm laser (200 mW / cm 2 , 1 min), the fluorescence emission spectrum under 480 nm excitation was measured every 10 seconds. Compounds B1-3 and C1 both had strong activity oxygen production ability. See Figure 2. Figure 3 .

[0083] Experimental Example 4: Determination of photothermal properties of compounds A1-3, B1-3 and C1-2

[0084] The compounds were diluted with dimethyl sulfoxide to a final concentration of 20 μM, and irradiated with 785 nm laser (800 mW / cm 2 , 7 min) in a quartz dish. At the same time, the solution temperature was recorded every 30 s with an infrared thermal imager. The results showed that compounds A1-3, B1-3 and C1-2 all had strong photothermal production ability, and the temperature increased by 16.7, 17.4, 14.3 and 15.5 °C, respectively, under irradiation of 785 nm laser (800 mW / cm 2 ) for 7 minutes. See Figure 3. Figure 4

[0085] Experimental Example 5: Determination of phototoxicity and dark toxicity of compound C1

[0086] The cell survival rate was determined by CCK-8 method. C4-2 cells (5 x 10 4cells / mL, 100 μL) were inoculated in 96-well plates and cultured at 37°C, 5% CO2, normoxia (21% O2) or hypoxia (1% O2) for 24 hours. For phototoxicity experiments, cells were treated with compound C1 at concentrations of 2.5 μM, 5 μM, 10 μM and 20 μM, respectively. After culture at 37°C, 5% CO2, normoxia and hypoxia for 2 hours, the cells were illuminated with an 808 nm laser (800 mW / cm 2 ) for 5 minutes, and then continue to culture under normoxic and hypoxic conditions for 22 hours. For dark toxicity, the cells were treated with compound C1 at concentrations of 2.5μM, 5μM, 10μM and 20μM, and cultured at 37°C, 5% CO2 for 24 hours under normoxic and hypoxic conditions, respectively. 20μL CCK8 was added to each well, and then cultured at 37°C, 5% CO2 for 1 hour. The absorption OD value of each group was measured on a microplate reader, and the wavelength was set to 450nm. According to the OD value of each well, the cell survival rate was calculated by the formula. The formula is as follows: Cell survival rate (%) = (OD of experimental group / OD of control group) × 100%. Compound C1 has obvious phototoxicity to C4-2 cells and very low dark toxicity. See Figure 5 .

[0087] Experimental Example 6: Phototherapeutic effect of compound C1 on C4-2 tumor-bearing mice.

[0088] BALB / c-nude male mice aged 6-8 weeks and weighing an average of 20 g were injected subcutaneously in the left upper limb shoulder with a C4-2 cell suspension (200 μL, approximately 2×10 6 cells). The mice were divided into 4 groups: (1) saline group; (2) saline + light group; (3) compound C1 group; (4) compound C1 + light group. 3 Afterwards, compound C1 (20 μM, 50 μL) or saline (50 μL) was injected into the tumor. One hour later, the tumor was illuminated with a 785 nm laser (800 mW / cm 2 ) irradiated the tumor area for 5 minutes, after which the mouse weight and tumor volume were measured. Dosing was continued every three days for 18 days. Tumor volume = 1 / 2 × length × width × height. The results showed that compound C1 significantly inhibited tumor growth after illumination and can be used to treat tumors, making it a promising phototherapeutic agent. Figure 6 .

[0089] Experimental Example 7: Compound C3 is used for photoacoustic imaging of bacteria in tumor tissue.

[0090] BALB / c-nude male mice aged 6-8 weeks and weighing an average of 20 g were injected subcutaneously at the end of the left hind limb with a PANC1 cell suspension (approximately 5-6 × 10 7 cells), with tumor volume growing to 500 mm 3, intratumoral injection of Staphylococcus aureus (1×10 9 CFU) were injected intratumorally, followed by intratumoral injection of compound C3 (100 μL, 20 μM). Small animal photoacoustic imaging monitoring (excitation wavelength 785 nm) was performed at 0.5 h and 2 h, respectively. The results showed that compound C3 can be used to specifically target bacteria without affecting tumor cells. The photoacoustic signal gradually increased in a time-dependent manner, which can distinguish bacteria from tumors and is used for photoacoustic imaging of bacteria in tumor tissue. Figure 7 .

[0091] References

[0092] [1]SUNG H,FERLAY J,SIEGEL RL,et al.Global Cancer Statistics 2020:GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36Cancers in185Countries[J].CACancer J Clin,2021,71(3):209-49.

[0093] [2]CHEN

[0094] [3]GALLETTI G,LEACH BI,LAM L,et al.Mechanisms of resistance tosystemic therapy in metastatic castration-resistant prostate cancer[J].CancerTreat Rev,2017,57:16-27.

[0095] [4] MARTINI A, GANDAGLIA G, FOSSATI N, et al. Defining Clinically Meaningful Positive Surgical Margins in Patients Undergoing Radical Prostatectomy for Localised Prostate Cancer [J]. Eur Urol Oncol, 2021, 4(1): 42-8.

[0096] [5] VOZENIN M C, BOURHIS J, DURANTE M. Towards clinical translation of FLASH radiotherapy [J]. Nat Rev Clin Oncol, 2022, 19(12): 791-803.

[0097] [6] LI K, XU S, XIONG M, et al. Molecular engineering of organic-based agents for in situ bioimaging and phototherapeutics [J]. Chem Soc Rev, 2021, 50(21): 11766-84.

[0098] [7] XIE Z, FAN T, AN J, et al. Emerging combination strategies with phototherapy in cancer nanomedicine [J]. Chem Soc Rev, 2020, 49(22): 8065-87.

[0099] [8] XU C, YE R, SHEN H, et al. Molecular Motion and Nonradiative Decay: Towards Efficient Photothermal and Photoacoustic Systems [J]. Angew Chem Int Ed Engl, 2022, 61(30): e202204604.

[0100] [9]ZHANG J,NING L,HUANG J,et al.Activatable molecular agents forcancer theranostics[J].Chem Sci,2019,11(3):618-30.

[0101]

[10] ZHAO H,LI N,MAC,et al.An AIE probe for long-term plasma membraneimaging and membrane-targeted photodynamic therapy [J].Chinese ChemicalLetters,2023,34(4).

[0102]

[11] PHAM T C,NGUYEN V N,CHOI Y,et al.Recent Strategies to DevelopInnovative Photosensitizers for Enhanced Photodynamic Therapy[J].Chem Rev,2021,121(21):13454-619.

[0103]

[12] GOURDON L,CARIOU K,GASSER G.Phototherapeutic anticancerstrategies with first-row transition metal complexes:a critical review[J].Chem Soc Rev,2022,51(3):1167-95.

[0104]

[13] LI X,YANG M,CAO J,et al.H-Aggregates of Prodrug-HemicyanineConjugate for Enhanced Photothermal Therapy and Sequential Hypoxia-ActivatedChemotherapy[J].ACS Materials Letters,2022,4(4):724-32.

[0105]

[14] CHEN W, WANG Z, TIAN M, et al. Integration of TADF Photosensitizer as "Electron Pump" and BSA as "Electron Reservoir" for Boosting Type I Photodynamic Therapy [J]. J Am Chem Soc, 2023, 145(14): 8130-40.

[0106]

[15] HU W, PRASAD P N, HUANG W. Manipulating the Dynamics of Dark Excited States in Organic Materials for Phototheranostics [J]. Acc Chem Res, 2021, 54(3): 697-706.

[0107]

[16] LI H, KIM Y, JUNG H, et al. Near-infrared (NIR) fluorescence-emitting small organic molecules for cancer imaging and therapy [J]. Chem Soc Rev, 2022, 51(21): 8957-9008.

[0108]

[17] ZLITNI A, GOWRISHANKAR G, STEINBERG I, et al. Maltotriose-based probes for fluorescence and photoacoustic imaging of bacterial infections [J]. Nature communications, 2020, 11(1): 1250.

[0109]

[18] HUANG Y, CHEN W, CHUNG J, et al. Recent progress in fluorescent probes for bacteria [J]. Chem Soc Rev, 2021, 50(13): 7725-44.

[0110]

[19] DEFRES S,MARWICK C,NATHWANI D.MRSAas a cause of lung infectionincluding airway infection,community-acquired pneumonia and hospital-acquiredpneumonia[J].The European respiratory journal,2009,34(6):1470-6.

[0111]

[20] KNOX H J,CHAN J.Acoustogenic Probes:ANew Frontier inPhotoacoustic Imaging[J].Acc Chem Res,2018,51(11):2897-905.

[0112]

[21] LIU Y,TENG L,YIN B,et al.Chemical Design of ActivatablePhotoacoustic Probes for Precise Biomedical Applications[J].Chem Rev,2022,122(6):6850-918.

[0113]

[22] LI L,HAN X,WANG M,et al.Recent advances in the development ofnear-infrared organic photothermal agents[J].Chemical Engineering Journal,2021,417.

[0114]

[23] LIU Y,BHATTARAI P,DAI Z,et al.Photothermal therapy andphotoacoustic imaging via nanotheranostics in fighting cancer[J].Chem SocRev,2019,48(7):2053-108.

[0115]

[24] VICKERMAN B M,ZYWOT E M,TARRANT T K,et al.Takingphototherapeutics from concept to clinical launch[J].Nat Rev Chem,2021,5(11):816-34.

[0116]

[25] ZHAO X,LIU J,FAN J,et al.Recent progress in photosensitizers forovercoming the challenges of photodynamic therapy:from molecular design toapplication[J].Chem Soc Rev,2021,50(6):4185-219.

[0117]

[26] LUO S,TAN X,FANG S,et al.Mitochondria-Targeted

[0118] Small-Molecule Fluorophores for Dual Modal Cancer Phototherapy

[0119] [J].Advanced Functional Materials,2016,26(17):2826-35.

[0120]

[27] XU Z,ZHANG M-X,XU Y,et al.The visualization of lysosomal

[0121] and mitochondrial glutathione via near-infrared fluorophore and in

[0122] vivo imaging application[J].Sensors and Actuators B:Chemical,

[0123] 2019,290:676-83.

[0124]

[28] ZOU Y,LI M,XIONG T,et al.ASingle Molecule Drug Targeting

[0125] Photosensitizer for Enhanced Breast Cancer Photothermal Therapy

[0126] [J].Small,2020,16(18):e1907677。

Claims

1. A compound represented by formula II or a pharmaceutically acceptable salt thereof: R1 is independently selected from R2 is independently selected from and X is independently selected from O, S, and Se.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from:

3. Use of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof in the preparation of a photosensitizer.

4. Use of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof in the preparation of photoacoustic imaging and therapeutic drugs for prostate cancer at the in vitro, cellular or in vivo levels.

5. Use of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof in the preparation of a photoacoustic imaging agent for bacteria-induced pneumonia in situ and tumor-homing bacteria in vivo at the in vitro, cellular or in vivo levels.

6. Use according to claim 5, characterized in that The bacterium is Staphylococcus aureus.

7. A method for preparing the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, characterized in that: Its preparation method is: Wherein: R1, R2, and X are as defined in any one of claims 1-2; (1) Add 4-(Boc-amino)phenol or p-aminothiophenol or 4,4'-diselenanediyldiphenylamine, compound 1, base and solvent to a round-bottom flask, react at a set temperature and stirring conditions, after the reaction is completed, extract the reaction solution, concentrate under reduced pressure and purify to obtain I or further react with p-nitrobenzylchloroformate, base and solvent under argon protection under anhydrous conditions at room temperature, extract the reaction solution after the reaction is completed, concentrate under reduced pressure and purify to obtain I; (2) adding I prepared in step (1), a condensing agent, a base, a ligand and a solvent to a round-bottom flask, reacting under anhydrous conditions under argon protection at room temperature, extracting the reaction solution after completion of the reaction, concentrating under reduced pressure and purifying, and then reacting with trifluoroacetic acid at room temperature, concentrating under reduced pressure and purifying to obtain II; or reacting I prepared in step (1) with di-tert-butyl dicarbonate, a base and a solvent under anhydrous conditions under argon protection at room temperature, extracting the reaction solution after completion of the reaction, concentrating under reduced pressure and purifying, and then reacting the obtained compound with a condensing agent, a base, a ligand and a solvent under anhydrous conditions under argon protection at room temperature, extracting the reaction solution after completion of the reaction, concentrating under reduced pressure and purifying, and then reacting with trifluoroacetic acid at room temperature, concentrating under reduced pressure and purifying to obtain II.

Images