An organic sound-sensitive agent molecule, and a preparation method and application thereof

Abstract

This invention belongs to the field of biomedical technology and relates to an organic acoustic sensitizer molecule, its preparation method, and its applications. The structure of the organic acoustic sensitizer molecule of this invention is shown in Formula I. The reactive oxygen species (ROS) yield of the organic acoustic sensitizer provided by this invention is significantly higher than that of commercially available acoustic sensitizers. The organic acoustic sensitizer molecule developed by this invention exhibits sufficient ROS generation under ultrasound, making it highly effective for antibacterial and antitumor treatment. The organic acoustic sensitizer molecule I provided by this invention has potential industrial value for preparation as a near-infrared fluorescence imaging material.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to an organic sound-sensitizing agent molecule, its preparation method and application. Background Technology

[0002] The number of cancer patients worldwide is enormous, greatly impacting people's quality of life and safety, causing a heavy burden on families and serious social problems. Therefore, conducting research for cancer treatment has significant social implications.

[0003] Ultrasound has shown great promise in clinical oncology due to its non-invasive nature and high spatiotemporal resolution. Sonodynamic therapy, with its advantages of deep penetration, simple operation, minimal invasiveness, low cost, and high safety, has become a highly attractive treatment method. Sonodynamic therapy uses a sonosensitive agent and ultrasound as an energy source to generate cytotoxic reactive oxygen species (ROS), overcoming the main problems of photodynamic therapy, such as shallow penetration, collateral damage to adjacent tissues, and phototoxicity.

[0004] Most currently available sonodynamic sensitizers are derived from traditional photosensitizers, including organic dyes (such as methylene blue, indocyanine green, and acridine orange), porphyrin derivatives (such as photoporphyrin, hematoporphyrin, and protoporphyrin), and inorganic nanoparticles (such as silicon-based nanoparticles and metal nanoparticles). However, only a few sonodynamic therapy trials have entered the early preclinical stage because existing sonodynamic sensitizers are insufficient in terms of ROS generation capacity, stability under acoustic irradiation, and biocompatibility, resulting in only poor therapeutic effects. Therefore, there is an urgent need to develop effective sonodynamic sensitizers that generate sufficient ROS under ultrasound for therapeutic purposes. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to address the shortcomings of the prior art by providing an organic acoustic molecule, its preparation method and application. The oxygen-containing, sulfur-containing or selenium-containing organic acoustic molecules prepared by the present invention have good ROS generation ability and high anti-tumor efficacy under ultrasound.

[0006] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0007] This invention discloses an organic sound-sensing agent molecule, the structure of which is shown in Formula I:

[0008]

[0009] The organic acoustic sensitizer molecule contains an electron donor structural unit D in its structure;

[0010] Wherein, the electron donor structural unit D is selected from

[0011] R1 and R2 are independently selected from hydrogen or C1-C20 straight-chain alkyl or branched-chain alkyl;

[0012] When both R1 and R2 are hydrogen, the electron donor structural unit D is not...

[0013] R1 and R2 are independently selected from hydrogen or C1-C20 straight-chain alkyl or branched alkyl.

[0014] In some embodiments, preferably, the structure of the organic sound-sensitive agent molecule is as shown in Formula I-1, Formula I-2, or Formula I-3:

[0015]

[0016] R1 and R2 are independently selected from hydrogen or C1-C20 straight-chain alkyl or branched-chain alkyl;

[0017] Wherein, when the structure of the organic sound-sensitive agent molecule is as shown in Formula I-2, R1 and R2 are not both hydrogen.

[0018] In some embodiments, R1 and R2 are independently selected from C1-C20 straight-chain alkyl or branched-chain alkyl.

[0019] In some embodiments, preferably, R1 and R2 are independently selected from C1-C12 straight-chain alkyl or branched-chain alkyl;

[0020] In some embodiments, more preferably, R1 and R2 are independently selected from C4-C12 straight-chain alkyl or branched-chain alkyl;

[0021] In some embodiments, more preferably, R1 and R2 are independently selected from C6-C10 straight-chain alkyl or branched-chain alkyl.

[0022] In some embodiments, most preferably, the organic acoustic sensitizer molecule is selected from compounds with any of the following structures:

[0023]

[0024]

[0025] Furthermore, this invention discloses a method for preparing the above-mentioned organic sound-sensitizing agent molecule, selecting one of the following synthetic routes:

[0026] Synthesis Route 1:

[0027]

[0028] (1) Synthesis of intermediate c: Compound a and compound b undergo aldol condensation and dehydration reaction under the action of acid to obtain intermediate c;

[0029] (2) Synthesis of intermediate e: Compounds c and d undergo N-alkylation reaction under the action of base to obtain intermediate e;

[0030] (3) Synthesis of organic sound-sensitive agent molecule I: Intermediate e and compound f undergo a Stieler reaction in the presence of a palladium catalyst to obtain organic sound-sensitive agent molecule IA;

[0031] Wherein, Z is selected from Br or I;

[0032] The organic acoustic sensitizer molecule contains an electron donor structural unit D in its structure;

[0033] Wherein, the electron donor structural unit D is selected from

[0034] R1 and R2 are independently selected from C1-C20 straight-chain alkyl or branched-chain alkyl;

[0035] or,

[0036] Synthesis Route 2:

[0037]

[0038] Intermediate C was prepared according to synthetic route one. Intermediate C and compound G were subjected to a Stieler reaction in the presence of a palladium catalyst to obtain the organic sound-sensing agent molecule IB.

[0039] Wherein, Z is selected from Br or I;

[0040] The organic acoustic sensitizer molecule contains an electron donor structural unit D in its structure;

[0041] Wherein, the electron donor structural unit D is selected from

[0042] R1 and R2 are independently selected from C1-C20 straight-chain alkyl or branched-chain alkyl.

[0043] In some embodiments, in synthetic route one:

[0044] In step (1), the acid is any one or a combination of hydrochloric acid, sulfuric acid, and p-toluenesulfonic acid; the molar ratio of compound a to compound b is 1.0:(1.0-5.0); the molar ratio of compound a to the acid is 1.0:(0.4-0.6); the solvent used in the aldol condensation dehydration reaction is any one or a combination of glacial acetic acid, methanol, tetrahydrofuran, and dichloromethane.

[0045] In step (2), compound d is a mixture of R1-Z and R2-Z; the base is any one or a combination of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, triethylamine, and pyridine; the molar ratio of compound c to compound d is 1.0:(2.0-5.0); the molar ratio of compound c to the base is 1.0:(2.0-10.0); the solvent used in the N-alkylation reaction is any one or a combination of anhydrous N,N-dimethylformamide, anhydrous acetonitrile, and anhydrous dimethyl sulfoxide; the N-alkylation reaction is carried out under inert gas protection; the reaction temperature of the N-alkylation reaction is 80℃-120℃.

[0046] In step (3), the palladium catalyst is any one or a combination of several of bis(triphenylphosphine)palladium dichloride, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, and tetra(triphenylphosphine)palladium; the molar ratio of intermediate e to compound f is 1.0:(0.8-1.2); the molar ratio of intermediate e to the palladium catalyst is 1.0:(0.05-0.20); the solvent used in the Stieler reaction is any one or a combination of two of anhydrous toluene and anhydrous N,N-dimethylformamide; the Stieler reaction is carried out under inert gas protection; the reaction temperature of the Stieler reaction is 80℃-120℃.

[0047] In some embodiments, preferably in the first synthetic route: in step (1), the acid is hydrochloric acid.

[0048] In some embodiments, preferably in the first synthetic route: in step (1), the molar ratio of compound a to compound b is 1.0:(1.0 to 3.0), more preferably 1.0:(1.0 to 2.0), and even more preferably 1.0:1.0.

[0049] In some embodiments, preferably in synthetic route one: in step (1), the molar ratio of compound a to the acid is 1.0:(0.4 to 0.5).

[0050] In some embodiments, preferably in the first synthetic route: in step (1), the solvent used in the aldol condensation dehydration reaction is glacial acetic acid.

[0051] In some embodiments, preferably in the first synthetic route: in step (1), there are no special requirements for the amount of solvent used in the aldol condensation dehydration reaction, as long as the raw materials are dispersed and / or dissolved evenly.

[0052] In some embodiments, preferably in synthetic route one: in step (1), the reaction temperature of the aldol condensation dehydration reaction is the temperature at which the solvent used is refluxed.

[0053] In some embodiments, preferably in the first synthetic route: in step (2), the base is potassium carbonate.

[0054] In some embodiments, preferably in the first synthetic route: in step (2), the molar ratio of compound c to compound d is 1.0:(2.0 to 3.0), more preferably 1.0:(2.0 to 2.5).

[0055] In some embodiments, preferably, in the first synthetic route: in step (2), the molar ratio of compound c to the base is 1.0:(3.0 to 8.0), more preferably 1.0:(3.0 to 6.0), even more preferably 1.0:(4.0 to 6.0), and most preferably 1.0:5.0.

[0056] In some embodiments, preferably in synthetic route one: in step (2), the solvent used in the N-alkylation reaction is anhydrous N,N-dimethylformamide.

[0057] In some embodiments, preferably in the first synthetic route: in step (2), there are no special requirements for the amount of solvent used in the N-alkylation reaction, as long as the raw materials are dispersed and / or dissolved evenly.

[0058] In some embodiments, in the first synthetic route: in step (2), the N-alkylation reaction is carried out under inert gas protection, preferably under argon protection.

[0059] In some embodiments, preferably in the first synthetic route: in step (2), the N-alkylation reaction is carried out at a temperature of 90°C to 110°C, more preferably 100°C.

[0060] In some embodiments, preferably, in the first synthetic route: in step (3), the palladium catalyst is bis(triphenylphosphine)palladium dichloride.

[0061] In some embodiments, preferably in synthetic route one: in step (3), the molar ratio of intermediate e to compound f is 1.0:1.0.

[0062] In some embodiments, preferably, in the first synthetic route: in step (3), the molar ratio of the intermediate e to the palladium catalyst is 1.0:(0.05-0.15), more preferably 1.0:(0.08-0.12), and even more preferably 1.0:0.10.

[0063] In some embodiments, preferably in synthetic route one: in step (3), the solvent used in the Stieler reaction is anhydrous toluene.

[0064] In some embodiments, preferably in synthetic route one: in step (3), the Stiller reaction is carried out under inert gas protection, preferably under argon protection.

[0065] In some embodiments, preferably in the first synthetic route: in step (3), the Stieler reaction is carried out at a temperature of 90°C to 110°C, more preferably 100°C.

[0066] In some embodiments, in synthetic route two: the palladium catalyst is any one or a combination of several of bis(triphenylphosphine)palladium dichloride, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, and tetra(triphenylphosphine)palladium; the molar ratio of intermediate c to compound g is 1.0:(0.8–1.2); the molar ratio of intermediate c to the palladium catalyst is 1.0:(0.05–0.20); the solvent used in the Stiller reaction is any one or a combination of two of anhydrous toluene and anhydrous N,N-dimethylformamide; the Stiller reaction is carried out under an inert gas atmosphere; the Stiller reaction is carried out at a temperature of 80°C–120°C.

[0067] In some embodiments, preferably in synthetic route two: the palladium catalyst is bis(triphenylphosphine)palladium dichloride.

[0068] In some embodiments, preferably in synthetic route two, the molar ratio of intermediate c to compound g is 1.0:1.0.

[0069] In some embodiments, preferably, in synthetic route two, the molar ratio of intermediate c to palladium catalyst is 1.0:(0.05-0.15), more preferably 1.0:(0.08-0.12), and even more preferably 1.0:0.10.

[0070] In some embodiments, preferably in synthetic route two, the solvent used in the Stieler reaction is anhydrous toluene.

[0071] In some embodiments, preferably in synthetic route two, the Stieler reaction is carried out under an inert gas protection, preferably under an argon protection.

[0072] In some embodiments, preferably in synthetic route two: the Stieler reaction is carried out at a temperature of 90°C to 110°C, more preferably 100°C.

[0073] The application of the aforementioned organic acoustic sensitizer molecules in the preparation of nano-acoustic sensitizer materials is also within the scope of protection of this invention.

[0074] Furthermore, this invention discloses a method for preparing nano-acoustic sensitive agent materials, wherein the above-mentioned organic acoustic sensitive agent molecules are mixed with encapsulating material and a first solvent, and ultrasonically mixed to obtain a dispersion; the dispersion is injected into a second solvent, ultrasonically mixed, the first solvent is removed by rotary evaporation, filtered through a filter membrane, and ultrafiltered through an ultrafiltration tube to obtain the nano-acoustic sensitive agent material.

[0075] In some embodiments, the encapsulating material is phospholipid polyethylene glycol (DSPE-PEG). 2000 The first solvent is tetrahydrofuran; the ultrasonic mixing is performed at a frequency of 25 kHz to 60 kHz; the ultrasonic mixing temperature is 20°C to 35°C, and the ultrasonic time is 5 min to 20 min; the mass ratio of the organic acoustic sensitizer molecules to the encapsulating material is 0.25:(4.0 to 10.0); the concentration of the organic acoustic sensitizer molecules in the dispersion is 0.10 mg / mL to 0.50 mg / mL; the second solvent is deionized water; the volume ratio of the first solvent to the second solvent is 1.0:(7.0 to 12.0); the ultrafiltration is performed using an ultrafiltration tube with a molecular weight cutoff of 100,000, specifically, ultrafiltration is performed 2 to 5 times.

[0076] In some embodiments, preferably, the encapsulating material is phospholipid polyethylene glycol (DSPE-PEG). 2000 The first solvent is tetrahydrofuran; the ultrasonic mixing is performed at a frequency of 35kHz to 45kHz; the ultrasonic mixing temperature is 20℃ to 30℃, and the ultrasonic time is 5min to 20min; the mass ratio of the organic acoustic sensitizer molecules to the encapsulating material is 0.25:(4.0 to 10.0); the concentration of the organic acoustic sensitizer molecules in the dispersion is 0.20mg / mL to 0.30mg / mL; the second solvent is deionized water; the volume ratio of the first solvent to the second solvent is 1.0:(8.0 to 10.0); the ultrafiltration is performed using an ultrafiltration tube with a molecular weight cutoff of 100,000, specifically 2 to 5 times.

[0077] In some embodiments, and more preferably, the encapsulating material is phospholipid polyethylene glycol (DSPE-PEG). 2000 The first solvent is tetrahydrofuran; the ultrasonic mixing is performed at a frequency of 40 kHz; the ultrasonic mixing is performed at a temperature of 25°C for a duration of 5 to 20 minutes; the mass ratio of the organic acoustic sensitizer molecules to the encapsulating material is 0.25:(4.0 to 10.0); the concentration of the organic acoustic sensitizer molecules in the dispersion is 0.25 mg / mL; the second solvent is deionized water; the volume ratio of the first solvent to the second solvent is 1.0:9.0; the ultrafiltration is performed using an ultrafiltration tube with a molecular weight cutoff of 100,000, specifically through three ultrafiltrations.

[0078] In some embodiments, and more preferably, the encapsulating material is phospholipid polyethylene glycol (DSPE-PEG). 2000 The first solvent is tetrahydrofuran; the ultrasonic mixing is performed at a frequency of 40 kHz; the ultrasonic mixing is performed at a temperature of 25°C for a duration of 5 to 20 minutes; the mass ratio of the organic acoustic sensitizer molecules to the encapsulating material is 0.25:4.0; the concentration of the organic acoustic sensitizer molecules in the dispersion is 0.25 mg / mL; the second solvent is deionized water; the volume ratio of the first solvent to the second solvent is 1.0:9.0; the ultrafiltration is performed using an ultrafiltration tube with a molecular weight cutoff of 100,000, specifically through three ultrafiltrations.

[0079] The nano-acoustic sensitive agent materials prepared by the above-described preparation method are also within the scope of protection of this invention.

[0080] The application of the aforementioned organic acoustic sensitizer molecules or the aforementioned nano-acoustic sensitizer materials in the preparation of antitumor drugs is also within the scope of protection of this invention, and / or the application of the aforementioned organic acoustic sensitizer molecules or the aforementioned nano-acoustic sensitizer materials in the preparation of antibacterial drugs is also within the scope of protection of this invention, and / or the application of the aforementioned organic acoustic sensitizer molecules or the aforementioned nano-acoustic sensitizer materials in the preparation of cosmetic products with antibacterial effects is also within the scope of protection of this invention, and / or the application of the aforementioned organic acoustic sensitizer molecules or the aforementioned nano-acoustic sensitizer materials in the preparation of cosmetic products with anti-inflammatory effects is also within the scope of protection of this invention, and / or the application in the preparation of near-infrared fluorescence imaging materials is also within the scope of protection of this invention.

[0081] Specifically, the application of the aforementioned organic acoustic sensitizer molecules or the aforementioned nano acoustic sensitizer materials in the preparation of antitumor drugs specifically refers to the application of the aforementioned organic acoustic sensitizer molecules or the aforementioned nano acoustic sensitizer materials in the preparation of anti-colon tumor drugs.

[0082] Specifically, the application of the aforementioned organic acoustic sensitizer molecules or the aforementioned nano-acoustic sensitizer materials in the preparation of antibacterial drugs is specifically the application of the aforementioned organic acoustic sensitizer molecules or the aforementioned nano-acoustic sensitizer materials in the preparation of drugs against Gram-positive bacteria and / or Gram-negative bacteria, and more specifically the application of the aforementioned organic acoustic sensitizer molecules or the aforementioned nano-acoustic sensitizer materials in the preparation of drugs against methicillin-resistant Staphylococcus aureus and / or against Pseudomonas aeruginosa and / or against Escherichia coli.

[0083] Specifically, the above-mentioned organic acoustic sensitizer molecules or the above-mentioned nano acoustic sensitizer materials are used in the preparation of cosmetic products with antibacterial effects or in the preparation of cosmetic products with anti-inflammatory effects. The cosmetic products are mainly used to treat skin diseases caused by bacterial infections, such as acne.

[0084] Beneficial effects:

[0085] (1) Under the same ultrasonic conditions, the reactive oxygen yield of the organic acoustic sensitizer provided by the present invention is much higher than that of commercially available acoustic sensitizers (e.g., methylene blue).

[0086] (2) Most currently available sonosensitive agents are derived from traditional photosensitizers. However, only a few sonodynamic therapy trials have entered the early preclinical stage because existing sonosensitive agents have insufficient ROS generation capacity, resulting in poor therapeutic effects. The organic sonosensitive agent molecule developed in this invention has sufficient ROS generation under ultrasound, which can be used efficiently for antibacterial and antitumor therapy.

[0087] (3) The organic acoustic sensor molecule I provided by the present invention has potential industrial value in preparing it as a near-infrared fluorescence imaging material. Attached Figure Description

[0088] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0089] Figure 1 The image shows the ultraviolet-visible absorption spectrum of organic acoustic sensitizer molecule I.

[0090] Figure 2 The fluorescence emission spectrum of organic acoustic sensor molecule I is shown.

[0091] Figure 3 The plot shows the particle size distribution data of NO, NS, and NSe in the obtained nanoparticles.

[0092] Figure 4 The diagram shows the reactive oxygen species generation capacity of different nanoparticles NX (X = O, S or Se).

[0093] Figure 5 Diagrams showing the inhibition of tumor cell activity by different nanoparticles NX (X = O, S, or Se).

[0094] Figure 6 The image shows the anti-tumor effect of NSe in the CT26 mouse tumor model.

[0095] Figure 7 The antibacterial effects of different nanoparticles NX (X = O, S or Se) are shown in the diagram. Detailed Implementation

[0096] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0097] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0098] The organic sonosensitive agent molecular structure design provided by this invention is based on electron donor (furan, thiophene, selenophene) and electron acceptor (IID) units. By controlling the corresponding electron donor through single-atom engineering, an ADA structure organic sonosensitive agent molecule is constructed, and an organic sonosensitive agent molecule with high singlet oxygen generation capacity is optimized to realize sonodynamic therapy of tumors.

[0099] Example 1: Preparation of organic sound-sensitizing agent molecule (IID)2-O

[0100]

[0101] (1) Synthesis of intermediate c: Under inert gas protection, compound a (2.26 g, 10.00 mmol) and compound b (1.33 g, 10.00 mmol) were dissolved in glacial acetic acid (60 mL), and concentrated hydrochloric acid (0.4 mL, 4.7 mmol) was added as a catalyst. The reaction system was subjected to aldol condensation and dehydration reaction under reflux for 48 hours. After the reaction was completed, the mixture was cooled to room temperature, and the resulting solid was filtered. The filter cake was washed successively with water, anhydrous ethanol, and ethyl acetate. The resulting solid was dried under vacuum to give a deep red intermediate c, with a yield of approximately 90%.

[0102] 1H NMR data for intermediate C: 1 H NMR (400MHz, DMSO-d6) δ10.96(d,J=41.6Hz,2H),9.02(d,J=26.8Hz,2H),7.35(s,1H),7.17(s,1H),6.96(d,J=10.9Hz,2H),6.82(s,1H).

[0103] (2) Synthesis of intermediate e-1: Compound c (2.05 g, 6.02 mmol) and dry potassium carbonate (4.15 g, 30.10 mmol) were dissolved in ultradry N,N-dimethylformamide (DMF, 50 mL) under argon protection by injecting 1-bromo-2-ethylhexane (compound d-1, 2.57 g, 13.23 mmol). The reaction system was stirred at 100 °C for N-alkylation overnight. After the reaction was completed, the mixture was poured into water, the organic phase was extracted with dichloromethane (DCM), washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration to remove the solvent, the resulting dark red solid was purified by silica gel column chromatography (eluent: DCM: petroleum ether = 2:3) to give intermediate e-1 in approximately 40% yield.

[0104] 1H NMR data for intermediate e-1:1 H NMR(400MHz,Chloroform-d)δ9.12(s,1H),9.04(s,1H),7.34(s,1H),7.13(s,1H),7.03( s,1H),6.87(s,1H),6.74(s,1H),3.61(s,4H),1.82(s,2H),1.29(s,16H),0.91(s,12H).

[0105] (3) Synthesis of compound I-1-1: Under an argon atmosphere, intermediate e-1 (5.00 mmol), 10 mol% of bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2), and an equimolar amount of 1,1'-(2,5-furandiyl)bis[1,1,1-trimethyltin] (compound f-1, 5.00 mmol) were dissolved in anhydrous toluene (20 mL). The reaction mixture was stirred overnight at 100 °C to carry out the Stieler reaction. After the reaction was completed, the product was purified by silica gel column chromatography (eluent: DCM: petroleum ether = 3:1) to give the target product I-1-1, denoted as (IID)2-O.

[0106] 1H NMR data for compound (IID)2-O: 1 ¹H NMR (400MHz, Chloroform-d) δ 9.21 (s, 1H), 9.15–9.13 (m, 1H), 7.32 (s, 6H), 7.06 (s, 2H), 7.04 (s, 1H), 6.90 (s, 1H), 6.87 (s, 1H), 6.77 (s, 3H), 3.73 (s, 8H), 1.85 (s, 4H), 1.43 (s, 32H), 0.93 (s, 24H); MALDI-TOF:calcd for compound (IID)₂-O. 68 H 84 N4O5[M]:1037.44,found:1037.831.

[0107] Example 2: Preparation of organic sound-sensitizing agent molecule (IID)2-S

[0108]

[0109] In the preparation of the organic sound-sensitive agent molecule (IID)2-S, the intermediate e-1 used is prepared in the same way as in Example 1.

[0110] Synthesis of compound I-2-1: Under an argon atmosphere, intermediate e-1 (5.00 mmol), 10 mol% of bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2), and an equimolar amount of 1,1'-(2,5-thiophenediyl)bis[1,1,1-trimethyltin] (compound f-2, 5.00 mmol) were dissolved in anhydrous toluene (20 mL). The reaction mixture was stirred overnight at 100 °C. After the reaction was completed, the product was purified by silica gel column chromatography (eluent: DCM:petroleum ether = 3:1) to give the target product I-2-1, denoted as (IID)2-S.

[0111] 1H NMR data for compound (IID)2-S: 1 ¹H NMR (400MHz, Chloroform-d) δ 9.20 (s, 1H), 9.17–9.14 (m, 1H), 7.44 (s, 2H), 7.33 (s, 5H), 7.02 (s, 5H), 6.79 (s, 2H), 3.75 (s, 8H), 1.86 (s, 4H), 1.38 (s, 32H), 0.96 (s, 24H); MALDI-TOF for compound (IID)2-S: calcd. for C 68 H 84 N4O4S[M]:1053.50,found:1053.108.

[0112] Example 3: Preparation of organic sound-sensitive agent molecule (IID)2-Se

[0113]

[0114] In the preparation of the organic sound-sensitive agent molecule (IID)2-Se, the intermediate e-1 is prepared in the same way as in Example 1.

[0115] Synthesis of compound I-3-1: Under an argon atmosphere, intermediate e-1 (5.00 mmol), 10 mol% of bis(triphenylphosphine)palladium dichloride (Pd(PPh3)2Cl2), and an equimolar amount of 1,1'-(2,5-selenophenidine)bis[1,1,1-trimethyltin] (compound f-3, 5.00 mmol) were dissolved in anhydrous toluene (20 mL). The reaction mixture was stirred overnight at 100 °C. After the reaction was completed, the product was purified by silica gel column chromatography (eluent: DCM:petroleum ether = 3:1) to give the target product I-3-1, denoted as (IID)2-Se.

[0116] 1H NMR data for compound (IID)2-Se: 1¹H NMR (400 MHz, Chloroform-d) δ 9.20 (s, 1H), 9.14 (s, 1H), 7.75–7.67 (m, 4H), 7.34 (s, 6H), 7.05 (s, 2H), 6.78 (s, 2H), 3.68 (s, 8H), 1.91 (s, 4H), 1.26 (s, 32H), 0.97 (s, 24H); MALDI-TOF for compound (IID)2-Se: calcd. for C 68 H 84 N4O4Se[M]:1100.57,found:1101.346.

[0117] Example 4: Characterization of the optical properties of organic acoustic sensor molecules. The specific experimental methods are as follows.

[0118] To characterize the optical properties of the organic acoustic sensor molecules described in this invention, their ultraviolet-visible absorption and fluorescence emission spectra were measured at room temperature according to the following steps. All measurements were performed using optical-grade quartz cuvettes (optical path 1.0 cm). Baseline calibration was performed using the same solvent before each measurement.

[0119] Organic acoustic sensitizer molecules I (IID)₂-O prepared in Example 1, IID)₂-S prepared in Example 2, and IID)₂-Se prepared in Example 3, respectively, were dissolved in a selected solvent (one or more combinations of degassed methanol, acetonitrile, tetrahydrofuran, or mixtures thereof, depending on the specific implementation) to prepare a solution. A blank was prepared using the solvent and baseline subtraction was performed. A UV-Vis spectrophotometer was used to scan the sample in the wavelength range of 300 nm–800 nm. The absorption spectra of the samples were recorded, the wavelength of the main absorption peak λmax was determined, and the absorbance was normalized. The fluorescence emission spectra were measured using a fluorescence spectrometer. During measurement, the excitation wavelength was fixed at the sample absorption peak (λex = 600 nm, slit width 5 nm).

[0120] Figure 1 The image shows the UV-Vis absorption spectrum of organic acoustic sensitizer molecule I, with λmax at 600 nm.

[0121] Figure 2 The image shows the fluorescence emission spectrum of organic acoustic sensitizer molecule I. Under 600 nm excitation, the fluorescence emission λem is 780 nm.

[0122] Experimental results show that the organic acoustic sensor molecule I provided by this invention has potential industrial value in preparing it as a near-infrared fluorescence imaging material.

[0123] Example 5: Preparation of nanoparticles loaded with organic sound-sensing agent molecules, the specific method is as follows.

[0124] At an ultrasonic frequency of 40 kHz and an ultrasonic temperature of 25 °C, compounds I-1-1 (prepared in Example 1, 250 μg), I-2-1 (prepared in Example 2, 250 μg), I-3-1 (prepared in Example 3, 250 μg), and phospholipid polyethylene glycol DSPE-PEG were respectively added. 2000 (MW = 2300, 4 mg) was dissolved in 1 mL of tetrahydrofuran to ensure homogeneous mixing (ultrasonication for 5-20 min), then rapidly injected into 9 mL of deionized water and subjected to continuous sonication (40 kHz, 25 °C) for 10 min. The THF was then evaporated using a rotary evaporator, filtered through a 0.22 μM aqueous membrane, and ultrafiltered three times using an ultrafiltration tube with a molecular weight cutoff of 100,000 to finally obtain DSPE-PEG. 2000 Nanoparticles encapsulating organic sound-sensing agent molecules, denoted as NO, NS, and NSe, have an encapsulation rate of 80%–90%.

[0125] Figure 3 The image shows the particle size distribution data of NO, NS, and NSe in the obtained nanoparticles. The particle size distribution of the nanoparticles is around 90 nm.

[0126] Example 6: The performance of NX (X = O, S or Se) prepared according to the experimental method of Example 5 was evaluated. The specific experimental method is as follows.

[0127] NX (X = O, S or Se) and methylene blue (MB) were ultrasonically treated using a 1MHz ultrasonic instrument with a duty cycle of 50% and an ultrasonic time of 5 minutes.

[0128] The reactive oxygen species generation capacity of different NX (X = O, S or Se) is as follows: Figure 4 As shown in the figure, NX (X = O, S or Se) has a superior ability to generate ROS compared to the commercially available sound sensitizer methylene blue (MB); and due to the heavy atom effect, the reactive oxygen species generation ability of selenium-containing organic sound sensitizer molecules is more significant.

[0129] Example 7: In vitro performance evaluation of NX (X = O, S or Se), the specific experimental method is as follows.

[0130] Based on Example 6, the in vitro performance of NX (X = O, S, or Se) was evaluated. Specifically, mouse colon cancer cell line (CT26 cells) were cultured in RPMI-1640 medium (commercially purchased) supplemented with 10% fetal bovine serum and 1% penicillin + streptomycin at 37°C and 5% CO2, followed by inoculation with 1*10 cells per well. 6CT26 cells were seeded into six-well plates. After cell adhesion, NX (X = O, S, or Se, prepared according to the experimental method in Example 5) was added to final concentrations of 10 μg / mL, 20 μg / mL, 30 μg / mL, 40 μg / mL, and 50 μg / mL. After incubation for 4 hours, the supernatant was discarded and replaced with 1 mL of fresh RPMI-1640 medium. The cells were then sonicated (1 MHz, 1 min), and tumor cell viability was assessed using the MTT assay.

[0131] Figure 5 The graph shows the activity of tumor cells in different groups, with the horizontal axis representing different concentrations and the vertical axis representing cell viability. The graph shows that the antitumor effect was better with NX (X=O, S, or Se) compared to the control group (without NX, X=O, S, or Se), indicating lower activity of CT26 cells in this group. The mechanism is that organic acoustic sensitizer molecules generate reactive oxygen species (ROS) under ultrasound treatment. Excessive ROS levels lead to oxidative damage to tumor cells, thus enhancing the antitumor efficacy. Furthermore, due to the heavy atom effect, the sonodynamic effect of selenium-containing organic acoustic sensitizer molecules is more significant.

[0132] Example 8: In vivo capacity assessment of NSe, the specific experimental method is as follows.

[0133] Based on Example 7, the in vivo performance of the NSe group, which showed the best effect among NX (X = O, S, or Se), was evaluated. Specifically, mouse colon cancer cell lines (CT26 cells) were cultured in RPMI-1640 medium (commercially purchased) supplemented with 10% fetal bovine serum and 1% penicillin + streptomycin at 37°C and 5% CO2, and seeded into culture dishes until the cell density reached 80-90%. To establish a tumor model, 6-8 week old female Balb / c mice were selected, and the adherent CT26 cells were prepared into a single-cell suspension using PBS (pH = 7.4, 0.01M) with trypsin. 5*10 cells were subcutaneously injected into each mouse. 6 One cell. Wait for the tumor to grow to 50 mm in volume. 3 PBS (pH = 7.4, 0.01M) or NSe (prepared according to the experimental method in Example 5) at a final concentration of 200 μg / mL was injected via the tail vein, with an administration volume of 200 μL. After 48 h of blood circulation, the mouse tumors were subjected to ultrasound treatment (1 MHz, 2 min). After ultrasound treatment, the tumor volume was recorded: tumor volume V = long diameter of the tumor a * short diameter of the tumor b 2 *0.5.

[0134] Figure 6The antitumor effects of different drugs in Balb / c mice are shown, with the horizontal axis representing the number of days after treatment and the vertical axis representing tumor volume. The figure shows that, compared to the control group (PBS group, ultrasound only, without sonosensitive agent injection), NSe treatment has a significant tumor-suppressing effect. The mechanism is that organic sonosensitive agent molecules generate reactive oxygen species under ultrasound treatment; when their content is too high, it leads to oxidative damage to tumor cells, inhibiting tumor growth.

[0135] Example 9: The antibacterial effect of NX (X = O, S or Se), the specific experimental method is as follows.

[0136] With 1*10 per hole 5 Methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Escherichia coli were inoculated into 6-well plates. Each well was treated with either NX (X = O, S, or Se, prepared according to the method in Example 5) or PBS to a final concentration of 20 μg / mL. After incubation for 1 hour, the plates were sonicated (1 MHz, 1 min). Following sonication, the plates were cultured at 37°C until the bacterial growth in the PBS-treated wells reached 1*10⁻⁶. 8 The turbidity of the bacteria was assessed by measuring OD600.

[0137] Figure 7 The antibacterial effects of different groups in the tests are shown, with the horizontal axis representing different bacterial groups and the vertical axis representing bacterial turbidity. In the antibacterial experiments, the antibacterial effects of NO, NS, and NSe against methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Escherichia coli were investigated. Compared with the control group PBS, all treatment groups showed varying degrees of antibacterial activity, with the turbidity change showing a pattern of NO > NS > NSe. This trend indicates that all three nanoparticles can inhibit bacterial growth under ultrasound, but NSe has the highest antibacterial efficiency. NSe generates more ROS under ultrasound, leading to more significant bacterial cell membrane disruption and growth inhibition. These results demonstrate that organic sonic sensitizers exhibit antibacterial properties in a variety of Gram-positive and Gram-negative bacterial strains and have the potential for further development into broad-spectrum antibacterial agents.

[0138] This invention provides an organic sound-sensitive agent molecule, its preparation method, and its application. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. An organic sound-sensing agent molecule, characterized in that, The structure of the organic acoustic sensor molecule is shown in Formula I: The organic acoustic sensitizer molecule contains an electron donor structural unit D in its structure; Wherein, the electron donor structural unit D is selected from R1 and R2 are independently selected from hydrogen or C1-C20 straight-chain alkyl or branched-chain alkyl; When both R1 and R2 are hydrogen, the electron donor structural unit D is not...

2. The organic acoustic sensitizer molecule according to claim 1, characterized in that, The structure of the organic acoustic sensitizer molecule is shown in Formula I-1, Formula I-2 or Formula I-3: R1 and R2 are independently selected from hydrogen or C1-C20 straight-chain alkyl or branched-chain alkyl; Wherein, when the structure of the organic sound-sensitive agent molecule is as shown in Formula I-2, R1 and R2 are not both hydrogen.

3. The organic acoustic sensitizer molecule according to claim 1 or 2, characterized in that, R1 and R2 are independently selected from C1-C20 straight-chain alkyl or branched-chain alkyl; Preferably, R1 and R2 are independently selected from C1-C12 straight-chain alkyl or branched-chain alkyl; More preferably, R1 and R2 are independently selected from C4-C12 straight-chain alkyl or branched-chain alkyl; More preferably, R1 and R2 are independently selected from C6-C10 straight-chain alkyl or branched-chain alkyl.

4. The organic sound-sensing agent molecule according to any one of claims 1 to 3, characterized in that, The organic acoustic sensor molecule is selected from compounds with any of the following structures:

5. A method for preparing the organic sound-sensitive agent molecule according to any one of claims 1 to 4, characterized in that, Choose one of the following synthesis routes: Synthesis Route 1: (1) Synthesis of intermediate c: Compound a and compound b undergo aldol condensation and dehydration reaction under the action of acid to obtain intermediate c; (2) Synthesis of intermediate e: Compounds c and d undergo N-alkylation reaction under the action of base to obtain intermediate e; (3) Synthesis of organic sound-sensitive agent molecule I: Intermediate e and compound f undergo a Stieler reaction in the presence of a palladium catalyst to obtain organic sound-sensitive agent molecule IA; Wherein, Z is selected from Br or I; The organic acoustic sensitizer molecule contains an electron donor structural unit D in its structure; Wherein, the electron donor structural unit D is selected from R1 and R2 are independently selected from C1-C20 straight-chain alkyl or branched-chain alkyl; or, Synthesis Route 2: Intermediate C was prepared according to synthetic route one. Intermediate C and compound G were subjected to a Stieler reaction in the presence of a palladium catalyst to obtain the organic sound-sensing agent molecule IB. Wherein, Z is selected from Br or I; The organic acoustic sensitizer molecule contains an electron donor structural unit D in its structure; Wherein, the electron donor structural unit D is selected from 6. The preparation method according to claim 5, characterized in that, In synthetic route one: In step (1), the acid is any one or a combination of hydrochloric acid, sulfuric acid, and p-toluenesulfonic acid; the molar ratio of compound a to compound b is 1.0:(1.0-5.0); the molar ratio of compound a to the acid is 1.0:(0.4-0.6); the solvent used in the aldol condensation dehydration reaction is any one or a combination of glacial acetic acid, methanol, tetrahydrofuran, and dichloromethane. In step (2), compound d is a mixture of R1-Z and R2-Z; the base is any one or a combination of potassium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, triethylamine, and pyridine; the molar ratio of compound c to compound d is 1.0:(2.0-5.0); the molar ratio of compound c to the base is 1.0:(2.0-10.0); the solvent used in the N-alkylation reaction is any one or a combination of anhydrous N,N-dimethylformamide, anhydrous acetonitrile, and anhydrous dimethyl sulfoxide; the N-alkylation reaction is carried out under inert gas protection; the reaction temperature of the N-alkylation reaction is 80℃-120℃. In step (3), the palladium catalyst is any one or a combination of several of bis(triphenylphosphine)palladium dichloride, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, and tetra(triphenylphosphine)palladium; the molar ratio of intermediate e to compound f is 1.0:(0.8-1.2); the molar ratio of intermediate e to the palladium catalyst is 1.0:(0.05-0.20); the solvent used in the Stieler reaction is any one or a combination of two of anhydrous toluene and anhydrous N,N-dimethylformamide; the Stieler reaction is carried out under inert gas protection; the reaction temperature of the Stieler reaction is 80℃-120℃.

7. The preparation method according to claim 5, characterized in that, In synthetic route two: the palladium catalyst is any one or a combination of several of bis(triphenylphosphine)palladium dichloride, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride, and tetra(triphenylphosphine)palladium; the molar ratio of intermediate c to compound g is 1.0:(0.8–1.2); the molar ratio of intermediate c to the palladium catalyst is 1.0:(0.05–0.20); the solvent used in the Stiller reaction is any one or a combination of two of anhydrous toluene and anhydrous N,N-dimethylformamide; the Stiller reaction is carried out under an inert gas atmosphere; the Stiller reaction is carried out at a temperature of 80°C–120°C.

8. The use of the organic acoustic sensitizer molecule according to any one of claims 1 to 4 in the preparation of nano-acoustic sensitizer materials.

9. A method for preparing a nano-acoustic sensor material, characterized in that, The organic sound-sensitive agent molecule described in any one of claims 1 to 4 is mixed with an encapsulating material and a first solvent, and ultrasonically mixed to obtain a dispersion; the dispersion is injected into a second solvent, ultrasonically mixed, the first solvent is removed by rotary evaporation, filtered through a filter membrane, and ultrafiltered through an ultrafiltration tube to obtain the nano-sound-sensitive agent material.

10. The preparation method according to claim 9, characterized in that, The encapsulating material is phospholipid polyethylene glycol (DSPE-PEG). 2000 The first solvent is tetrahydrofuran; the ultrasonic mixing is performed at a frequency of 25 kHz to 60 kHz; the ultrasonic mixing temperature is 20°C to 35°C, and the ultrasonic time is 5 min to 20 min; the mass ratio of the organic acoustic sensitizer molecules to the encapsulating material is 0.25:(4.0 to 10.0); the concentration of the organic acoustic sensitizer molecules in the dispersion is 0.10 mg / mL to 0.50 mg / mL; the second solvent is deionized water; the volume ratio of the first solvent to the second solvent is 1.0:(7.0 to 12.0); the ultrafiltration is performed using an ultrafiltration tube with a molecular weight cutoff of 100,000, specifically, ultrafiltration is performed 2 to 5 times.

11. The nano-acoustic sensitive agent material prepared by the preparation method according to any one of claims 9 to 10.

12. The use of the organic acoustic sensitizer molecule according to any one of claims 1 to 4 or the nano acoustic sensitizer material according to claim 11 in the preparation of antitumor drugs, and / or in the preparation of antibacterial drugs, and / or in the preparation of cosmetic products with antibacterial effects, and / or in the preparation of cosmetic products with anti-inflammatory effects, and / or in the preparation of near-infrared fluorescence imaging materials.

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