N-aryl croconic acid cyanine compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of compound medicines, and relates to an N-aryl croconic acid cyanine compound with a structure shown as a general formula (I), the N-aryl croconic acid cyanine compound is obtained by heating a croconic acid compound shown as a formula (II) and a diphenylamine derivative shown as a formula (III) to perform dehydration condensation reaction, and the product structure has a donor-acceptor-donor conjugated structure. The compound is stable in structure, has good light capture capability, has reactive oxygen species generation capability and photothermal conversion capability under laser irradiation, has photodynamic performance and photothermal performance, is non-toxic to cells, has good biocompatibility, and can be used as a photosensitizer in photothermal and photodynamic combined treatment of tumors.

Description

Technical Field

[0001] The invention belongs to the technical field of compound medicines and relates to an N-aryl crotonyl cyanine compound and a preparation method and application thereof. Background Art

[0002] Cancer has always been a serious threat to human life and health. Traditional treatment methods, such as chemotherapy, radiotherapy and surgery, have certain shortcomings. While achieving the purpose of treatment, they also cause certain harm to the human body. Phototherapy, as a non-invasive treatment method, is more competitive than traditional treatment methods. Phototherapy mainly includes photothermal therapy and photodynamic therapy. Photothermal therapy uses photosensitizers to convert light energy into heat energy, thereby causing high-temperature death of cancer cells. Photodynamic therapy uses light energy to cause photosensitizers to undergo intersystem crossing from singlet to triplet states to produce highly cytotoxic reactive oxygen species, thereby inhibiting cancer cells to a certain extent. Phototherapy is far less damaging to surrounding healthy tissues than traditional treatment methods, and has the advantages of low toxicity, high specificity and no drug resistance. At present, common photosensitizers are divided into inorganic materials and organic materials. Inorganic materials are difficult to metabolize in the human body and have poor biocompatibility, while organic materials can significantly make up for these defects of inorganic materials. Organic small molecule photosensitizers have good stability and biocompatibility and are considered to be ideal materials for phototherapy. Therefore, the development of organic compounds with photothermal or photodynamic properties is of certain significance in cancer therapeutics.

[0003] Photothermal therapy and photodynamic therapy are compensatory in treatment, and combined treatment may have a therapeutic effect of "1+1>2". Since the tumor microenvironment is an oxygen-deficient environment, the addition of photothermal effect can accelerate blood flow, thereby improving the oxygen supply of tissues and increasing the production of reactive oxygen species, which is beneficial to photodynamic therapy; at the same time, the photodynamic effect can inhibit the expression of heat shock proteins, thereby reducing the heat resistance of tumor cells, which is beneficial to photothermal therapy. Therefore, the development of organic compounds with both photothermal and photodynamic effects as drugs has important clinical application significance in tumor treatment. Summary of the invention

[0004] In view of this, the purpose of the present invention is to provide an N-aryl-type crotonyl cyanine compound and its preparation method and application. The compound has a stable structure, good light absorption ability, and has a significant temperature increase and generation of active oxygen species after laser irradiation, and has photodynamic properties and photothermal properties.

[0005] In order to achieve the above object, the present invention provides the following technical solutions:

[0006] 1. An N-aryl-type crotonyl cyanine compound having a molecular structure shown in the following general formula (I):

[0007] Wherein R1 and R2 are independently selected from hydrogen atom, methyl, methoxy,

[0008] Ethyl, isopropyl, tert-butyl, phenyl or 1,1,2-triphenyl-vinyl.

[0009] Furthermore, the N-aryl-type crotonyl cyanine compound, the compound represented by the general formula (I) is a compound of formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), and formula (XI).

[0010]

[0011]

[0012] Furthermore, R1 is selected from methyl and methoxy.

[0013] The N-aryl crotonate cyanine compound of the molecular structure of the general formula (I) provided by the present invention comprises a crotonate group and a diphenylamine derivative group in the compound structure, wherein the crotonate part serves as a strong electron-withdrawing group to form a conjugated system with the diphenylamine derivative electron-donating groups on both sides, and has good light absorption capacity; the N-aryl crotonate cyanine compound converts light energy into heat energy under illumination, has good photothermal properties, and can be used for photothermal treatment of tumors; at the same time, the N-aryl crotonate cyanine compound can also generate active oxygen species after illumination, has good photodynamic performance, and can also be used for photodynamic treatment of tumors.

[0014] 2. A method for preparing an N-aryl-type crotonyl cyanine compound, comprising the following steps:

[0015] The compound of formula (II) and the compound of formula (III) are added to an organic solvent in a molar ratio of 1:2 to 4, and a dehydration condensation reaction is carried out by heating to obtain the N-aryl-type crotonyl cyanine compound;

[0016] The compound of formula (II) has the following molecular structure:

[0017]

[0018] The compound of formula (III) has the following molecular structure:

[0019] Wherein R1 and R2 are independently selected from hydrogen atom, methyl, methoxy, ethyl,

[0020] isopropyl, tert-butyl, phenyl or 1,1,2-triphenyl-vinyl.

[0021] In the preparation method of the N-aryl-type crotonyl cyanine compound, a purification step is further included after the condensation reaction.

[0022] In the further preparation method of the N-aryl-type crotonyl cyanine compound, the organic solvent is a mixed solvent of toluene and n-butanol.

[0023] Preferably, the volume ratio of toluene to n-butanol is 1:1 to 3:1.

[0024] Preferably, the reaction temperature of the dehydration condensation reaction is 100-130° C., and the reaction time is 10-20 hours.

[0025] Preferably, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:2.

[0026] Preferably, the purification is performed by silica gel column chromatography, slurry filtration and / or thin layer chromatography.

[0027] Preferably, the purification is to remove the reaction solution solvent, subject the solid substance to silica gel column chromatography, then elute with an organic solvent, collect the eluate, remove the organic solvent in the eluate, pulp the obtained solid or prepare thin layer chromatography, and obtain the N-aryl-type crotonyl cyanine compound after suction filtration or solvent removal.

[0028] Preferably, the organic solvent is a mixed solvent of dichloromethane and methanol.

[0029] Preferably, the eluent is a mixed solvent of dichloromethane and methanol in a volume ratio of 200:0.5-200:5.

[0030] Preferably, the solvent selected for pulping is a mixed solvent of ethyl acetate and methanol.

[0031] Preferably, the solvent used in the preparation of thin layer chromatography is a mixed solvent of dichloromethane and methanol, or a mixed solvent of dichloromethane and ethyl acetate.

[0032] 3. The invention also provides the use of N-aryl crotonyl cyanine compounds in the preparation of tumor therapeutic drugs.

[0033] Preferably, the drug is a photothermal therapy photosensitizer;

[0034] Preferably, the drug is a photodynamic therapy photosensitizer;

[0035] Preferably, the drug is a photosensitizer for photothermal therapy synergistic with photodynamic therapy.

[0036] The beneficial effects of the present invention are as follows: the N-aryl-type crotonyl cyanine compound of the molecular structure of the general formula (I) provided by the present invention has a DAD (donor-acceptor-donor) conjugated structure constructed by a crotonyl group and a diphenylamine derivative group. Experiments have shown that the structure not only has good light absorption ability, but also has active oxygen species generation ability and photothermal conversion ability under illumination conditions, has both photodynamic performance and photothermal performance, is non-toxic to cells, has good biocompatibility, and can be used as a photosensitizer in the photothermal and photodynamic combined treatment of tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to make the purpose, technical solution and beneficial effects of the present invention clearer, the present invention provides the following drawings for illustration:

[0038] Figure 1 Absorption spectra of DMSO solutions of compounds IV, V, VI, and VII.

[0039] Figure 2 This is a thermal infrared imaging diagram of the temperature change of the DMSO solution of compound IV at different concentrations and different light powers after irradiation with a 660nm laser.

[0040] Figure 3 This is the photothermal stability diagram of compound V in DMSO solution.

[0041] Figure 4 It is the temperature rise and fall curve of the DMSO solution of compound VI and the negative natural logarithm relationship between time and temperature in the natural cooling stage.

[0042] Figure 5 This is a temperature change diagram of the DMSO solution of compound VII after irradiation with 660nm laser at different concentrations and different light powers.

[0043] Figure 6 This is a graph showing the active oxygen generation ability of DMSO solutions of compounds IV, V, VI, and VII.

[0044] Figure 7 The dark toxicity and phototoxicity of compound IV on 4T1 cells. DETAILED DESCRIPTION

[0045] Now, various exemplary embodiments of the present invention are described in detail in conjunction with the accompanying drawings. This detailed description should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as commonly understood by conventional technicians in the field of the present invention. The raw materials, reagents or devices used in the following examples, unless otherwise specified, can be obtained from conventional commercial sources, or can be obtained by existing known methods. Although the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein can also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe methods and / or materials related to the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail. Regarding the "comprising", "including", "having", "containing" and the like used herein, they are all open terms, that is, they mean including but not limited to.

[0046] Example 1

[0047] An N-aryl-type crotonyl cyanine compound has a molecular structure shown in the following formula (IV):

[0048]

[0049] The preparation method of the N-aryl-type crotonyl cyanine compound of formula (IV) comprises the following steps:

[0050] 1. Under argon conditions, add 4.11 g (10 mmol) of 1-(4-bromophenyl)-1,2,2-triphenylethylene, 2.46 g (20 mmol) of 4-methoxyaniline, 39.00 μL (0.16 mmol) of tri-tert-butylphosphine, 128.00 mg (0.16 mmol) of tri(dibenzylideneacetone)dipalladium, and 1.92 g (20 mmol) of sodium tert-butoxide into a round-bottom flask, and add anhydrous toluene as solvent. The mixture was heated to reflux at 110°C for 24 hours, then cooled to room temperature, and the solvent was removed under reduced pressure; extracted with dichloromethane and water, the organic layer was collected, an appropriate amount of anhydrous sodium sulfate was added for drying, and after concentration, it was further purified by column chromatography (the eluent was petroleum ether: dichloromethane in a volume ratio of 3:1) to obtain 4-methoxy-N-(4-(1,2,2-triphenylethylene)phenyl)aniline (compound of formula (III-1)), a yellow powder solid (2.51 g, yield 55%). 1H NMR (400MHz,CDCl3,ppm)δ7.15-6.98(m,17H,Ar-H),6.87-6.80(m,4H,Ar-H),6.64(d,J=8.4Hz,2H,Ar-H),3.78(s,3H,OCH3). The compound of formula (III-1) CAS:2407147-57-1, the structural formula is as follows:

[0051]

[0052] 2. Weigh 907.16 mg (2 mmol) of the above-prepared 4-methoxy-N-(4-(1,2,2-triphenylethylene)phenyl)aniline and 142.07 mg (1 mmol) of 4,5-dihydroxycyclopent-4-ene-1,2,3-trione (compound of formula (II)) and add them to a two-necked flask, add 6 mL of toluene and 6 mL of n-butanol, and heat under reflux at 120° C. for 12 hours. After the reaction is completed, stop heating, cool the reaction solution to room temperature, remove the solvent under reduced pressure, and obtain a crude product by column chromatography (eluent is dichloromethane: methanol volume ratio = 200: 1). The crude product is slurried with a mixed solvent of ethyl acetate and methanol (ethyl acetate: methanol volume ratio = 1: 6), and filtered and dried to obtain a brown powder solid (83.8 mg, 8%), and obtain an N-aryl-type oxadiazine compound having a molecular structure of formula (IV). 1 H NMR (400MHz, CDCl3, ppm) δ7.19–6.74 (m, 46H, Ar-H), 3.82 (s, 6H, OCH3). 13 C NMR (100MHz, CDCl3, ppm) δ179.0,159.6,143.4,143.2,143.0,142.2,139.8,131.5,131. 4,127.8,127.8,127.7,127.3,126.9,126.7,125.5,114.0,77.4,77.3,77.1,76.7,55.6. HRMS(ESI) + m / z:[M+H] + calcd.C 71 H 53 N2O5 + ,1013.3949; found,1013.3934.

[0053]

[0054] Example 2

[0055] An N-aryl crotonate cyanine compound having a molecular structure as shown in the following formula (V):

[0056]

[0057] The preparation method of the above-mentioned N-aryl-type crotonyl cyanine compound comprises the following steps:

[0058] Bis(4-methoxyphenyl)amine: CAS number: 101-70-2.

[0059] Weigh 458.56 mg (2 mmol) of bis(4-methoxyphenyl)amine and 142.07 mg (1 mmol) of 4,5-dihydroxycyclopent-4-ene-1,2,3-trione (compound of formula (II)) and add them to a two-necked flask, add 5 mL of toluene and 5 mL of n-butanol, and heat under reflux at 120°C for 12 hours. After the reaction is completed, stop heating, cool the reaction solution to room temperature, remove the solvent under reduced pressure, and obtain a crude product by column chromatography (the eluent is dichloromethane: methanol volume ratio = 40:1). The crude product is recrystallized using dichloromethane and methanol, filtered and dried to obtain a light brown solid (84.7 mg, 15%), and an N-aryl-type crotonyl cyanine compound having a molecular structure of formula (V) is obtained. 1 H NMR (400MHz, CDCl3, ppm) δ6.98 (dd, J=21.9, 8.5Hz, 8H, Ar-H), 6.85 (dd, J=14.9, 8.6Hz, 8H, Ar-H), 3.83 (d, J=4.9Hz, 12H, OCH3). 13 C NMR (100MHz, CDCl3, ppm) δ179.0,170.4,159.6,153.5,136.0,135.5,127.4,127.2,114.2,114.0,77.4,77.3,77.1,76.8,55.6,55.5. HRMS(ESI) + m / z:[M+H] + calcd.C 33 H 29 N2O7 + ,565.1969;found,565.1954.

[0060] Example 3

[0061] An N-aryl crotonate cyanine compound has a molecular structure shown in the following formula (VI):

[0062]

[0063] The preparation method of the above-mentioned N-aryl-type crotonyl cyanine compound comprises the following steps:

[0064] 4-Methoxy-N-(p-tolyl)aniline CAS number: 39253-43-5.

[0065] Weigh 1.28 g (6 mmol) of 4-methoxy-N-(p-tolyl)aniline and 0.43 g (3 mmol) of 4,5-dihydroxycyclopent-4-ene-1,2,3-trione (compound of formula (II)) and add them to a two-necked flask, add 15 mL of toluene and 15 mL of n-butanol, and heat under reflux at 120°C for 14 hours. After the reaction is completed, stop heating, cool the reaction solution to room temperature, remove the solvent under reduced pressure, and obtain a solid by column chromatography (the eluent is dichloromethane: methanol volume ratio = 150: 1) to obtain a crude product. The crude product is washed with petroleum ether, and then slurried with a mixed solvent of ethyl acetate and methanol (ethyl acetate: methanol volume ratio = 1: 3) and filtered to obtain a black solid (110 mg, 7%), to obtain an N-aryl-type oxadiazine compound having a molecular structure of formula (VI). 1 HNMR (400MHz, DMSO-d6, ppm) δ7.27–6.81(m,16H,Ar-H),3.79(s,6H,-OCH3),2.34(s,6H,-CH3). 13 C NMR (101MHz, CDCl3, ppm) δ179.0,159.7,140.0,138.8,129.6,127.5,126.0,125.8,114.2,114.0,55.5,21.4. HRMS(ESI) + m / z:[M+H] + calcd.C 33 H 29 N2O5 + ,533.2071found,533.2055.

[0066] Example 4

[0067] An N-aryl crotonate cyanine compound has a molecular structure shown in the following formula (VII):

[0068]

[0069] The preparation method of the above-mentioned N-aryl-type crotonyl cyanine compound comprises the following steps:

[0070] 4,4'-Dimethyldiphenylamine CAS number: 620-93-9.

[0071] Weigh 1.18 g (6 mmol) of 4,4'-dimethyldiphenylamine and 0.43 g (3 mmol) of 4,5-dihydroxycyclopent-4-ene-1,2,3-trione (compound of formula (II)) into a two-necked flask, add 15 mL of toluene and 15 mL of n-butanol, and heat under reflux at 120°C for 14 hours. After the reaction is completed, stop heating, cool the reaction solution to room temperature, remove the solvent under reduced pressure, and obtain a solid by column chromatography (the eluent is dichloromethane: methanol volume ratio = 150: 1) to obtain a crude product. The crude product is washed with petroleum ether, and then slurried with a mixed solvent of ethyl acetate and methanol (ethyl acetate: methanol volume ratio = 1: 5), and filtered and dried to obtain a black solid (99 mg, 7%), and an N-aryl-type oxadiazine compound having a molecular structure of formula (VII) is obtained. 1 HNMR (400MHz, DMSO-d6, ppm) δ7.18 (d, J = 7.8 Hz, 8H, Ar-H), 7.03 (d, J = 7.9 Hz, 8H, Ar-H), 2.34 (s, 12H, -CH3). 13 C NMR (101MHz, CDCl3, ppm) δ179.0,169.9,155.1,140.5,139.9,138.8,129.6,129.4,126.1,125.9,21.4. HRMS(ESI) + m / z:[M+H] + calcd.C 33 H 29 N2O3 + ,501.2173,found,501.2155.

[0072] Example 5

[0073] An N-aryl-type crotonyl cyanine compound has a molecular structure shown in the following formula (VIII):

[0074]

[0075] The preparation method of the above-mentioned N-aryl-type crotonyl cyanine compound comprises the following steps:

[0076] 4-Methyldiphenylamine CAS number: 620-84-8.

[0077] Weigh 1.10 g (6 mmol) of 4-methyldiphenylamine and 0.43 g (3 mmol) of 4,5-dihydroxycyclopent-4-ene-1,2,3-trione (compound of formula (II)) into a two-necked flask, add 15 mL of toluene and 15 mL of n-butanol, and heat under reflux at 120°C for 12 hours. After the reaction is completed, stop heating, cool the reaction solution to room temperature, remove the solvent under reduced pressure, and obtain a solid by column chromatography (eluent is dichloromethane: methanol volume ratio = 400: 1) to obtain a crude product. The crude product is further purified by preparative thin layer chromatography (developing solvent is dichloromethane: methanol volume ratio = 200: 1) to obtain an N-aryl-type oxadiazine compound having a molecular structure of formula (VIII). 1 H NMR (400MHz, CDCl3, ppm) δ7.37–7.34(m,6H),7.10–6.86(m,12H),2.40–2.36(m,6H). HRMS(ESI) + m / z:[M+H] + calcd.C 31 H 25 N2O3 + ,473.1860,found:473.1850.

[0078] Example 6

[0079] An N-aryl crotonate cyanine compound has a molecular structure shown in the following formula (IX):

[0080]

[0081] The preparation method of the above-mentioned N-aryl-type crotonyl cyanine compound comprises the following steps:

[0082] N-phenyl-4-benzidine CAS No.: 32228-99-2

[0083] Weigh 1.47 g (6 mmol) of N-phenyl-4-benzidine and 0.43 g (3 mmol) of 4,5-dihydroxycyclopent-4-ene-1,2,3-trione (compound of formula (II)) into a two-necked flask, add 15 mL of toluene and 15 mL of n-butanol, and heat under reflux at 120° C. for 12 hours. After the reaction is completed, stop heating, cool the reaction solution to room temperature, remove the solvent under reduced pressure, and purify the obtained solid by repeated preparative thin-layer chromatography (volume ratio of dichloromethane: ethyl acetate = 30:1) to obtain an N-aryl-type oxadiazine compound having a molecular structure of formula (IX). 1H NMR (400MHz, CDCl3, ppm) δ7.53–7.48(m,8H),7.37–7.29(m,12H),7.10–7.04(m,8H). HRMS(ESI) + m / z:[M+H] + calcd.C 41 H 29 N2O3 + ,597.2173,found:597.2155.

[0084] Example 7

[0085] An N-aryl crotonate cyanine compound having a molecular structure as shown in the following formula (X):

[0086]

[0087] The preparation method of the above-mentioned N-aryl-type crotonyl cyanine compound comprises the following steps:

[0088] Bis(4-isopropylphenyl)amine CAS number: 63451-41-2.

[0089] Weigh 0.76 g (3 mmol) of bis(4-isopropylphenyl)amine and 0.21 g (1.5 mmol) of 4,5-dihydroxycyclopent-4-ene-1,2,3-trione (compound of formula (II)) and add them to a two-necked flask, add 7.5 mL of toluene and 7.5 mL of n-butanol, connect a condenser, and heat to reflux at 120° C. for 12 hours. After the reaction is completed, stop heating, cool the reaction solution to room temperature, remove the solvent under reduced pressure, and obtain a crude product by column chromatography (eluent is dichloromethane: methanol volume ratio = 200: 1). The obtained crude product is purified by repeated preparative thin layer chromatography (dichloromethane: methanol volume ratio = 100: 1) to obtain an N-aryl-type crotonyl cyanine compound having a molecular structure of formula (X). 1 HNMR (400MHz, CDCl3, ppm) δ7.53–7.48(m,8H),7.37–7.29(m,12H),7.10–7.04(m,8H). HRMS(ESI) + m / z:[M+H] + calcd.C 41 H 29 N2O3 + ,613.3425,found:613.3411.

[0090] Example 8

[0091] An N-aryl crotonate cyanine compound has a molecular structure shown in the following formula (XI):

[0092]

[0093] The preparation method of the above-mentioned N-aryl-type crotonyl cyanine compound comprises the following steps:

[0094] Bis(4-tert-butylphenyl)amine CAS No. 4627-22-9.

[0095] Weigh 1.69 g (6 mmol) of bis(4-tert-butylphenyl)amine and 0.43 g (3 mmol) of 4,5-dihydroxycyclopent-4-ene-1,2,3-trione (compound of formula (II)) and add them to a two-necked flask, add 15 mL of toluene and 15 mL of n-butanol, connect a condenser, and heat to reflux at 120°C for 12 hours. After the reaction is completed, stop heating, cool the reaction solution to room temperature, remove the solvent under reduced pressure, and obtain a crude product by column chromatography (eluent: dichloromethane). The obtained crude product is purified by repeated preparative thin-layer chromatography (developing solvent: dichloromethane) to obtain an N-aryl-type crotonyl cyanine compound having a molecular structure of formula (XI).

[0096] 1 HNMR (400MHz, CDCl3) δ7.39–7.28(m,8H),7.03–6.92(m,8H),1.32–1.28(m,36H). HRMS(ESI) + m / z:[M+H] + calcd.C 45 H 53 N2O3 + ,669.4051,found:669.4035.

[0097] Example 9 Photothermal properties of compounds IV, V, VI, and VII

[0098] By changing the concentration of compound IV, V, VI, VII solution and laser power, the temperature change of the solution is detected and the photothermal conversion efficiency of the compound is calculated. Compound IV, V, VI, VII is prepared into a mother solution with a concentration of 1 mg / mL with DMSO, and then diluted with DMSO to a compound solution of the required concentration. Figure 1 The absorption spectra of DMSO solutions (20 μM) of compounds IV, V, VI, and VII were obtained by irradiating with a 660 nm laser to increase the temperature, and a near-infrared imager was used to detect the real-time temperature changes. Figure 2 This is a thermal infrared imaging diagram of the temperature change of the DMSO solution of compound IV at different concentrations and different light powers after irradiation with a 660nm laser. Figure 3 The photothermal stability of Compound V in DMSO solution is shown. Figure 4The temperature rise and fall curves of the DMSO solution of compound VI (50 mg / ml) are shown, and the time and temperature in the natural cooling stage show a negative natural logarithmic relationship. Figure 5 The temperature change of the DMSO solution of compound VII at different concentrations and different light powers after irradiation with 660 nm laser is shown.

[0099] The test showed that the temperature of compound IV, V, VI, and VII systems increased with the increase of irradiation time, solution concentration, and laser power. When the laser power was fixed at 1 W / cm 2 When the concentration of compound IV system is 7.8125μg / mL, the system temperature can be increased to 60℃, and the photothermal conversion efficiency is 25%; when the concentration of compound V system is 25μg / mL, the system temperature can be increased to 76℃, and the photothermal conversion efficiency is 36%; when the concentration of compound VI system is 50μg / mL, the system temperature can be increased to 85℃, and the photothermal conversion efficiency is 36%; when the concentration of compound VII system is 50μg / mL, the system temperature can be increased to 90℃, and the photothermal conversion efficiency is 32%. These results all show that this type of compound has good photothermal conversion performance and can be used for tumor photothermal therapy.

[0100] Example 10 Photodynamic properties of compounds IV, V, VI, and VII

[0101] Add the probe 2',7'-dichlorofluorescein diacetate (DCFH) for detecting reactive oxygen species to the solution of compound IV, V, VI, and VII, and detect the change in fluorescence intensity after irradiation with 660nm laser. The greater the change in fluorescence intensity, the stronger the ability to generate reactive oxygen species. Compound IV, V, VI, and VII were prepared into a 100μM test substance solution with DMSO, and the DCFH probe was prepared into a 30μM working solution with PBS buffer. The test substance solution was mixed with the working solution and irradiated with 100mW / cm 2 The fluorescence intensity was recorded every 10 seconds. Figure 6 As shown, compared with the blank control group, the solutions of compounds IV, V, VI, and VII all generated reactive oxygen species, among which compound IV had the strongest ability to generate reactive oxygen species.

[0102] Example 11 Dark toxicity and phototoxicity of compound IV

[0103] Compound IV was prepared into nanoparticles using nanoprecipitation to increase its water solubility. 4T1 cells were seeded in 96-well plates (1×10 4 / well), incubated in a 37 ° C, 5% CO2 incubator for 24 hours until the cells adhered to the wall, discarded the old culture medium, and prepared compound IV nano solution (500μg / mL, 250μg / mL, 125μg / mL, 62.5μg / mL, 31.25μg / mL, 15.625μg / mL) in serum-free culture medium, and added 100μL to each well. One row was a group, and each group had 6 replicates. The dark group continued to culture for 24 hours. After 24 hours of drug addition, the laser group discarded the supernatant and washed with PBS until there was no residue, and irradiated with 660nm laser (1.0W / cm 2 , 1 min / well) 10 min later, 100 μL of fresh serum-free medium was added to each well and cultured for 4 h. Then, the cell viability of both groups was determined by the standard MTT method. The experimental results are shown in Figure 7 shown. Figure 7 Figure a shows the effect of different concentrations of compound IV nanosolution on 4T1 cell viability under dark conditions; Figure 7 Figure b shows the effect of different concentrations of compound IV nanosolution on 4T1 cell viability under light conditions. Figure 7 Figure a shows that in the concentration range of 15.625–500 μg / mL of the compound IV nanosolution, when there is no laser irradiation, 4T1 cells still maintain a high activity. Even when the concentration of the compound IV nanosolution is as high as 500 μg / mL, the cell survival rate is still as high as 86%, indicating that the compound IV nanosolution has good biocompatibility. Figure 7 Figure b shows that under laser irradiation, cell viability decreases with the increase of the concentration of compound IV nanosolution. When the concentration of compound IV nanosolution is 500 μg / mL, cell viability is significantly inhibited, proving that compound IV nanosolution has excellent tumor killing ability.

[0104] Finally, it should be noted that the above description is only a preferred embodiment of the present invention. Under the guidance of the present invention, ordinary technicians in this field can make various changes in form and details without violating the purpose and claims of the present invention. Such changes are all within the scope defined by the claims of the present invention.

Claims

1. An N-aryl-type crotonyl cyanine compound, characterized in that: It has the molecular structure shown in the following general formula (I): wherein R1 and R2 are independently selected from hydrogen atom, methyl, methoxy, ethyl, isopropyl, tert-butyl, phenyl or 1,1,2-triphenyl-vinyl.

2. The N-aryl-type crotonocyanine compound according to claim 1, characterized in that: R1 is selected from methyl and methoxy.

3. The method for preparing the N-aryl-type crotonyl cyanine compound according to claim 1, characterized in that: The steps include: The compound of formula (II) and the compound of formula (III) are added to an organic solvent in a molar ratio of 1:2 to 4, and a dehydration condensation reaction is carried out by heating to obtain the N-aryl-type crotonyl cyanine compound; The compound of formula (II) has the following molecular structure: The compound of formula (III) has the following molecular structure: wherein R1 and R2 are independently selected from hydrogen atom, methyl, methoxy, ethyl, isopropyl, tert-butyl, phenyl or 1,1,2-triphenyl-vinyl.

4. The method for preparing the N-aryl-type crotonyl cyanine compound according to claim 3, characterized in that: The condensation reaction is followed by a purification step.

5. The method for preparing the N-aryl-type crotonyl cyanine compound according to claim 3, characterized in that: The organic solvent is a mixed solvent of toluene and n-butanol.

6. The method for preparing the N-aryl-type crotonyl cyanine compound according to claim 5, characterized in that: The volume ratio of toluene to n-butanol is 1:1 to 3:

1.

7. The method for preparing the N-aryl-type crotonyl cyanine compound according to claim 3, characterized in that: The reaction temperature of the dehydration condensation reaction is 100-130° C., and the reaction time is 10-20 hours.

8. The method for preparing an N-aryl-type crotonyl cyanine compound according to claim 4, characterized in that: The purification is performed by silica gel column chromatography, slurry filtration or / and thin layer chromatography.

9. The method for preparing an N-aryl-type crotonyl cyanine compound according to claim 8, characterized in that: The purification comprises removing the reaction solution solvent, subjecting the solid substance to silica gel column chromatography, eluting with an organic solvent, collecting the eluate, removing the organic solvent in the eluate, slurrying the obtained solid or preparing a thin layer chromatography, and filtering or removing the solvent to obtain the N-aryl-type crotonyl cyanine compound.

10. Use of the N-aryl crotonyl cyanine compound according to claim 1 or 2 in the preparation of tumor therapeutic drugs.

Images