Method for preparing aromatic benzene propargyl ketone through light induction and biological application of aromatic benzene propargyl ketone

Abstract

The invention discloses a method for preparing aromatic benzene propargyl ketone through light induction and biological application, and belongs to the technical field of organic synthesis and biological medicine. Aromatic benzene propargyl alcohol is converted into the aromatic benzene propargyl ketone under the light induction condition; functional groups are changed before and after light induction, hydroxyalkyne without reaction activity is converted into carbonyl alkyne with click reaction activity, fluorescence enhancement can be achieved, and the method can be used for imaging and tracing; in addition, the aromatic benzene propargyl ketone can react with amino-containing compounds or biological macromolecules, so that the killing of tumor cells is realized. According to the method, light is used as a starting switch, reaction conditions are simple, controllability is good, no additional catalyst is needed, large-scale production is easy, and the method has wide application prospects in the aspects of polypeptide or protein marking, tumor resistance and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and biomedicine, and specifically relates to a method for preparing aromatic phenylpropynyl ketone by light induction and its biological application. Background Art

[0002] Cancer is one of the most common diseases in the world, with high morbidity and mortality rates. It is a major public health problem worldwide. It not only seriously affects the quality of life and life expectancy of patients, but also has a profound impact on medical resources and social economy. Chemotherapy is one of the most widely used cancer treatments in clinical practice. It can effectively inhibit tumor proliferation and metastasis in the early stage of treatment. However, as the course of treatment increases, many patients will develop drug resistance. In order to solve this problem, the only way to passively increase the dose is to increase the dose in clinical practice. However, increasing the dose often leads to increased toxic side effects of chemotherapy drugs on normal cells. Therefore, it is crucial to achieve site-specific activation of chemotherapy drugs at the lesion site for the further development of chemotherapy.

[0003] Patent document with publication number CN101500557A discloses the synthesis of nitrofuran compounds (such as nifurtimox) and their use in treating cancer and inhibiting angiogenesis. The structural formula of the nitrofuran compound is as follows: The compound can be delivered by liposomes, and the liposomes can be targeted to specific tissues by coupling with specific ligands such as sugars, glycolipids or proteins; the patent document with publication number CN108451939A discloses the use of 2,4-dinitrobenzenesulfonamide compounds for preparing drugs for treating cervical cancer, and 2,4-dinitrobenzenesulfonamide compounds achieve targeted cancer therapy by inhibiting the activity of thioredoxin reductase. However, the above compounds themselves cannot be activated at the lesion site.

[0004] As an external stimulation signal, light has the characteristics of simple manipulation, high resolution, low invasiveness and spatiotemporal controllability. It is currently widely used in the biomedical field. By utilizing light with high spatiotemporal controllability and combining it with the in situ nature of chemical reactions, a photochemical reaction system is constructed for the targeted activation of chemotherapeutic drugs at the tumor site, which can provide a new idea for the chemotherapy of tumors. Summary of the invention

[0005] In order to overcome the shortcomings of the prior art, the present invention provides a method for light-induced preparation of aromatic phenylpropynyl ketone and its biological application.

[0006] The specific technical solutions adopted are as follows:

[0007] A method for preparing aromatic phenylpropargyl ketone by light induction, comprising: converting aromatic phenylpropargyl alcohol represented by formula (I) into aromatic phenylpropargyl ketone represented by formula (II) under light induction conditions;

[0008]

[0009] In formula (I) to formula (II), R1 is a light absorption regulating group independently selected from phenyl, naphthyl, substituted phenyl, aromatic amine or a heteroaromatic ring group containing at least one nitrogen, oxygen or sulfur atom.

[0010] The inventors have discovered that aromatic phenylpropargyl alcohol with a structural formula as shown in formula (I) can be converted into aromatic phenylpropargyl ketone with a structural formula (II) under light-induced conditions; the change of functional groups before and after light-induction (the hydroxyl alkyne without reaction activity is converted into the carbonyl alkyne with click reaction activity) can achieve fluorescence enhancement and can be used for imaging and tracing; and aromatic phenylpropargyl ketone can react with amino-containing compounds or biological macromolecules to kill tumor cells.

[0011] Furthermore, in the substituted phenyl group, the substituent is a methoxy group, an alkylamino group, a carbazolyl group, a phenoxazine group, a naphthylamino group or a triphenylvinyl group.

[0012] Furthermore, the aromatic amine group is a diphenylamine group, a triphenylamine group or a dipyridylamine group.

[0013] Further, the heteroaromatic ring group containing at least one nitrogen, oxygen or sulfur atom is a thienyl, pyridyl, furyl, carbazolyl, phenothiazinyl, phenoxazinyl, phenothiazinephenyl, dithienyl, thienocyclopentadienyl, 9,10-dihydro-9,9-dimethylacridinyl, 9,10-dihydro-9,9-diphenylacridinyl, 10-H-spiro[acridine-9,9'-fluorene]yl, diphenylaminethienyl, dithienyl, fusedthienyl or thienocyclopentadienyl.

[0014] It should be noted that R1 is a light absorption regulating group, and its main function is to regulate the ultraviolet-visible light-near infrared absorption of the molecule. By replacing different R1s, the molecule can have different absorptions, so that different lights can be used to excite the aromatic phenylpropargyl alcohol shown in formula (I) to be converted into the aromatic phenylpropargyl ketone shown in formula (II); but the real protein / peptide labeling and tumor cell killing effects are achieved by the conversion of the non-reactive hydroxyl alkyne into the click-reactive carbonyl alkyne after light induction.

[0015] Preferably, the conditions for light induction are irradiation under ultraviolet light or white light for ≥2s, further irradiation for ≥1min, and further irradiation for ≥10min; the wavelength range of ultraviolet light is 365nm-460nm; the wavelength range of white light is 400nm-1000nm.

[0016] More preferably, the power density during UV or white light irradiation is 5-200 mW cm -2 .

[0017] Optionally, the aromatic phenylpropynyl alcohol shown in formula (I) is prepared by the following method:

[0018] (1) Compound and 5-bromo-2-nitrobenzaldehyde are heated to 60-80° C. in an inert gas atmosphere to carry out Suzuki reaction for 6-24 hours, and after the reaction, post-processed to obtain a nitrobenzaldehyde derivative; R1 is as defined above;

[0019] (2) preparing an organic solution of a nitrobenzaldehyde derivative, adding a Grignard reagent under ice bath conditions, and reacting for 2-6 hours under an inert gas atmosphere. After the reaction is completed, post-treatment is performed to obtain an aromatic phenylpropargyl alcohol having a structural formula as shown in formula (I).

[0020] Specifically, in step (1), the compound The molar ratio of 5-bromo-2-nitrobenzaldehyde to 1:1.5-2 is 1:1.5; the inert gas atmosphere is nitrogen atmosphere, and a catalyst and an auxiliary agent are also added during the Suzuki reaction;

[0021] Furthermore, the catalyst is preferably Pd(PPh3)4, and the auxiliary agent is preferably CsCO3.

[0022] Specifically, in step (2), the Grignard reagent is ethynylmagnesium bromide, and the molar ratio of the nitrobenzaldehyde derivative to ethynylmagnesium bromide is 1:1.2-2; and the inert gas atmosphere is a nitrogen atmosphere.

[0023] Preferably, the organic solvent for dissolving the nitrobenzaldehyde derivative is selected from tetrahydrofuran.

[0024] The present invention also provides a compound, which is aromatic phenylpropargyl alcohol or aromatic phenylpropargyl ketone. The structural formula of aromatic phenylpropargyl alcohol is shown in formula (I), the structural formula of aromatic phenylpropargyl ketone is shown in formula (II), and R1 is defined as above.

[0025] The present invention also provides the method for preparing aromatic phenylpropynyl ketone by light induction or the application of the compound in preparing tumor therapeutic drugs.

[0026] Preferably, the tumor therapeutic drug comprises nanoparticles, and the nanoparticle component comprises aromatic phenylpropargyl alcohol with a structural formula as shown in formula (I). Under light-induced conditions, the nanoparticles convert the aromatic phenylpropargyl alcohol with a structural formula as shown in formula (I) into aromatic phenylpropargyl ketone with a structural formula (II) to exert a tumor therapeutic effect.

[0027] More preferably, the aromatic phenylpropargyl alcohol having the structural formula (I) is mixed with a surfactant and co-precipitated to prepare the nanoparticles.

[0028] The present invention also provides the method for preparing aromatic phenylpropynyl ketone by light induction or the use of the compound in preparing a polypeptide or protein fluorescent labeling reagent.

[0029] Preferably, the aromatic phenylpropargyl alcohol with the structural formula shown in formula (I) is contacted with a polypeptide or protein, and under light-induced conditions, the aromatic phenylpropargyl alcohol with the structural formula shown in formula (I) is converted into the aromatic phenylpropargyl ketone with the structural formula (II) to play a fluorescent labeling role.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] (1) The present invention utilizes a light-induced method to convert aromatic phenylpropargyl alcohol into aromatic phenylpropargyl ketone, using light as a starting switch, and has good spatiotemporal response properties. Compared with the current synthesis methods of phenylpropargyl ketone derivatives, the method of the present invention has simple reaction conditions, does not require an external catalyst, and is easy to mass produce.

[0032] (2) The light-induced conversion of aromatic phenylpropargyl alcohol into aromatic phenylpropargyl ketone in the present invention can be used for in situ treatment of tumors, and the biologically inactive aromatic phenylpropargyl alcohol can be delivered to the tumor lesion site, so that it can be site-specifically activated into biologically active aromatic phenylpropargyl ketone under light conditions for the treatment of tumors. Compared with the characteristic that photodynamic therapy requires the participation of oxygen, the present invention adopts the strategy of in situ generation of active substances, which shows better therapeutic effects under hypoxic conditions and has broad application prospects in cancer treatment.

[0033] (3) The aromatic phenylpropargyl alcohol / aromatic phenylpropargyl ketone in the present invention can be used for fluorescent labeling of proteins or polypeptides, overcoming the shortcoming of biological macromolecules being non-fluorescent, and can be used for cell imaging and tracing. In addition, the changes in functional groups before and after illumination can also achieve fluorescence enhancement of the compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 This is the UV-visible absorption spectrum of NTYOL molecules in dichloromethane solution under different illumination times.

[0035] Figure 2 This is the fluorescence emission spectrum of NTYOL molecules in dichloromethane solution under different illumination times.

[0036] Figure 3 This is the SDS-PAGE result of BSA-NSTYONE obtained after NTYOL labeled BSA with light.

[0037] Figure 4This is the SDS-PAGE result of NTYOL labeling intracellular proteins after illumination.

[0038] Figure 5 The figure shows the dark toxicity and phototoxicity evaluation results of NTYOL and crystal violet (CV) on 4T1 cells under normoxic conditions.

[0039] Figure 6 The figure shows the dark toxicity and phototoxicity evaluation results of NTYOL and crystal violet (CV) in 4T1 cells under hypoxic conditions.

[0040] Figure 7 Figure A shows the killing evaluation results of NTYOL NPs on mouse 4T1 solid tumors, and Figure B shows the biosafety evaluation results of NTYOL NPs on model mice. DETAILED DESCRIPTION

[0041] The present invention will be further described below in conjunction with the examples and accompanying drawings. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The operating methods of the following examples that do not specify specific conditions are usually performed under normal conditions or under conditions recommended by the manufacturer. The content that is not described in detail in this specification sheet belongs to the prior art known to professionals in the field. The experimental materials used in the following examples, if not otherwise specified, can be purchased by conventional biochemical reagent companies.

[0042] Example 1

[0043]

[0044] Synthesis of 4-nitro-4'-(1,2,2-triphenylvinyl)-[1,1'-biphenyl]-3-carboxaldehyde (NTC): 4,4,5,5-tetramethyl-2-(4-(1,2,2-triphenylvinyl)phenyl)-1,3,2-dioxaborane (916 mg, 2 mmol), 5-bromo-2-nitrobenzaldehyde (690 mg, 3 mmol), Pd(PPh3)4 (60 mg, 0.1 mmol) and CsCO3 (489 mg, 3 mmol) were added to a 100 ml two-necked bottle in sequence, and nitrogen was introduced-evacuated-nitrogen was introduced for 3 cycles (10 minutes each), and then the pre-degassed tetrahydrofuran / water mixed solution was injected into the reaction bottle. Then it was heated to 80°C and reacted for 12 hours. After the reaction, the product was extracted with dichloromethane / water (the volume ratio of dichloromethane to water was 1 / 1), dried over anhydrous magnesium sulfate for 2 hours, and separated and purified by column chromatography to obtain yellow solid NTC (722 mg) with a yield of 75%.

[0045] The characterization results of compound NTC are as follows:

[0046] 1 H NMR (500MHz, Chloroform-d) δ10.50 (s, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 2. 1Hz,1H),7.87(dd,J=8.5,2.1Hz,1H),7.41(d,J=8.5Hz,2H),7.18–7.02(m,17H).

[0047] 13 C NMR (101MHz, CDCl3) δ188.5,147.8,146.9,145.4,143.4,143.3,139.8,135.2,132.3,131 .3,131.3,131.3,131.2,127.9,127.9,127.7,127.6,126.8,126.7,126.7,126.6,125.3.

[0048] Example 2

[0049]

[0050] Synthesis of compound 1-(4-nitro-4'-(1,2,2-triphenylvinyl)-[1,1'-biphenyl]-3-yl)prop-2-yn-1-ol (NTYOL): 4-nitro-4'-(1,2,2-triphenylvinyl)-[1,1'-biphenyl]-3-carboxaldehyde NTC (960 mg, 2 mmol) prepared in Example 1 was added to a 50 mL dry round-bottom flask, and nitrogen was introduced-evacuated-introduced for 3 cycles (10 minutes each), and then pre-degassed tetrahydrofuran (10 mL) was injected into the reaction bottle. Then, under ice bath conditions, a solution of ethynylmagnesium bromide in tetrahydrofuran (6 mL, the molar ratio of ethynylmagnesium bromide to NTYOL was about 2:1) was slowly injected into the reaction bottle with a syringe and reacted for 3 hours. After stopping the reaction, saturated ammonium chloride solution was added to quench the reaction, extracted with dichloromethane / water (the volume ratio of dichloromethane to water was 1 / 1), dried over anhydrous magnesium sulfate for 2 hours, and separated and purified by column chromatography to obtain 0.91 g of golden solid NTYOL with a yield of 90%.

[0051] The characterization results of compound NTYOL are as follows:

[0052] 1H NMR(400MHz,Chloroform-d)δ8.12(d,J=1.7Hz,1H),8.07(d,J=8.5Hz,1H),7.65(dd,J =8.5,1.9Hz,1H),7.40(d,J=8.3Hz,2H),7.19–7.01(m,17H),6.08(s,1H),2.64(s,1H).

[0053] 13 C NMR (101MHz, CDCl3) δ146.7,146.4,145.0,143.6,143.5,142.1,140.1,136.1,135.7,132.3,131.5 ,131.5,131.4,128.01,127.96,127.8,127.8,127.5,126.9,126.8,126.8,126.7,81.6,75.3,61.6.

[0054] Example 3

[0055]

[0056] Synthesis of compound 1-(4-nitroso-4'-(1,2,2-triphenylvinyl)-[1,1'-biphenyl]-3-yl)prop-2-yn-1-one (NSTYONE): 1-(4-nitro-4'-(1,2,2-triphenylvinyl)-[1,1'-biphenyl]-3-yl)prop-2-yn-1-ol NTYOL (507 mg, 1 mmol) prepared in Example 2 was added to a 100 mL dry round-bottom flask, and 30 mL of dichloromethane was added. The mixture was heated to 40 ℃ under a 410 nm ultraviolet lamp (10 mW cm -2 ) was irradiated for 1 h. After the reaction was stopped, the solvent was removed by rotary evaporator, and column chromatography was used for separation and purification to obtain 200 mg of yellow solid NSTYONE with a yield of 40%.

[0057] The characterization results of compound NSTYONE are as follows:

[0058] 1 H NMR(500MHz,Chloroform-d)δ8.03(d,J=8.5Hz,1H),7.84(d,J=2.0Hz,1H),7.80 (dd,J=8.5,2.0Hz,1H),7.38(d,J=8.4Hz,2H),7.18–7.02(m,17H),3.46(s,1H).

[0059] 13C NMR (101MHz, CDCl3) δ175.9,146.4,145.9,145.3,143.3,143.2,142.1,139.8,135.1 ,134.8,132.3,131.2,130.1,127.9,127.7,126.8,126.7,126.6,125.0,82.1,80.1.

[0060] During the above reaction, the reaction was dynamically monitored using ultraviolet absorption spectroscopy and fluorescence emission spectroscopy. Figure 1 It can be seen from the UV absorption spectrum that with the increase of illumination time, the absorption peak of the raw material NTYOL at 350nm is significantly weakened; when illuminated for 1 minute, the absorption peaks at 310nm and 390nm become significantly higher, and with the extension of illumination time, the absorption gradually red-shifts, which is consistent with the UV absorption position of the product NSTYONE. Therefore, the changes in the UV absorption spectrum can be used to dynamically monitor the occurrence of the reaction.

[0061] At the same time, the fluorescence emission spectra of NTYOL at different illumination times were collected, and its fluorescence intensity (I) was tested and compared with the fluorescence intensity of NTYOL before illumination (I0). The results are as follows: Figure 2 As shown in the figure, with the increase of illumination time, the fluorescence of the reaction system also showed a significant enhancement.

[0062] Example 4

[0063] Taking advantage of the property of aromatic phenylpropargyl alcohol that can be converted into aromatic phenylpropargyl ketone that can react with amino groups under light conditions, bovine serum albumin was modified, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) experiments were used to verify that the bovine serum albumin was modified and endowed with the natural protein fluorescent properties.

[0064] Modification of BSA (BSA-NSTYONE): 30 mg of bovine serum albumin (BSA) was added to a 50 mL single-mouth bottle and then completely dissolved in 2 mL of water. Then, 5 mg of 1-(4-nitro-4'-(1,2,2-triphenylvinyl)-[1,1'-biphenyl]-3-yl)prop-2-yn-1-ol (NTYOL) dissolved in 1 mL of tetrahydrofuran was added and the mixture was illuminated under white light (400 nm-1000 nm, 40 mW cm -2 ) under irradiation conditions, react at room temperature for 30 minutes, then open the lid and stir overnight to completely evaporate tetrahydrofuran, remove the solvent water using a freeze dryer, and obtain 20 mg of a light yellow solid. As a control experiment, the same operation was performed without light irradiation to obtain BSA+NTYOL.

[0065] Weigh 0.2 mg of standard bovine serum albumin BSA, 0.5 mg of BSA+NTYOL (NTYOL group), and 0.5 mg of BSA-NSTYONE (NTYOL+L group) and dissolve them in 1 mL (0.5 mol L -1 , pH 6.8) Tris-hydrochloric acid buffer or distilled water, perform SDS-PAGE experiment and fluorescent gel imaging characterization, prepare the sample to be tested, place the sample to be tested on the bottom plate of the fluorescent gel imager, select the combination channel imaging of the excitation wavelength 400nm and the emission wavelength receiving filter 530nm. Adjust the focus and take pictures. Put the film after the fluorescent gel imaging into a large culture dish for staining, use 0.25% Coomassie brilliant blue dye solution, stain for 1h. Discard the dye solution, rinse the gel surface with distilled water several times, then add the decolorizing solution for diffusion decolorization, and change the decolorizing solution frequently until the protein band is clear.

[0066] Then place the protein strip on the bottom plate of the fluorescent gel imager and select the white light field. Adjust the focus and take a photo. Figure 3 The SDS-PAGE results showed that at the band with a molecular weight slightly lower than 70KDa, under ultraviolet light, an obvious fluorescent band could be seen in BSA-NSTYONE (NTYOL+L group), while BSA+NTYOL (NTYOL group) had no fluorescence, proving that NTYOL and bovine serum protein can be successfully coupled under illumination conditions, and this coupling method can give natural proteins fluorescent properties.

[0067] Example 5

[0068] By utilizing the property of aromatic phenylpropargyl alcohol that can be converted into aromatic phenylpropargyl ketone that can react with amino groups under light conditions, intracellular proteins can be labeled, and the feasibility of this method can be verified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) experiments.

[0069] Intracellular protein labeling: Mouse breast cancer 4T1 cells were cultured in a cell culture dish. After the cells were completely attached to the wall, the original complete medium was aspirated and the complete medium containing NTYOL (4 μM) was added. The cells were cultured for another 2 h. The culture dish was then placed under a white light lamp for 20 min (light power density 40 mW cm -2 ). Then continue to culture for 2 hours. Collect the cells in the culture dish, add cell lysis solution to lyse the cells, extract the protein in the cells, and process them for later use (NTYOL+L group). As a control experiment, the same operation was performed without adding light (NTYOL group).

[0070] Perform SDS-PAGE experiment according to the steps in Example 4, place the protein band corresponding to the cell protein extracted in the above steps on the bottom plate of the fluorescent gel imager, select the white light field, adjust the focus and take pictures. Figure 4 The SDS-PAGE results showed that there was no obvious difference under the white light field; under the fluorescence field, the protein with only NTYOL added (NTYOL group) had no obvious fluorescence emission under the fluorescence field, but the protein with NTYOL added showed obvious fluorescence emission under the fluorescence field after 20 minutes of white light irradiation (NTYOL+L group), indicating that this strategy can successfully achieve the labeling of intracellular proteins.

[0071] Example 6

[0072] The light-induced bioactivity of aromatic phenylpropargyl alcohols was used to kill hypoxic tumors, and mouse breast cancer 4T1 cells were used as model cells to study their light / dark toxicity.

[0073] 4T1 cells were cultured at 1×10 4 After culturing for 24 hours in a 96-well plate, DMEM complete medium containing NTYOL at concentrations of 0 μM, 0.5 μM, 1 μM, 2 μM, 4 μM, and 8 μM was added, and the cells were placed in a hypoxic bag (the oxygen content in the bag was below 0.1 and the carbon dioxide content was 5%) or in a cell culture incubator under normal culture conditions (oxygen content 21% and carbon dioxide concentration 5%) for 12 hours. The 96-well plate was then placed under a white light lamp (light power density 40 mW cm -2 ) After 20 minutes of illumination, continue to culture in the original culture environment for 12 hours. Remove the supernatant, add 100mL of MTT and culture for 2 hours, terminate the culture, aspirate the culture medium in the well, add 100μL of dimethyl sulfoxide to each well, place it on a shaker and shake at a low speed for 10 minutes to fully dissolve the crystals, and detect the OD value with an enzyme marker. According to the same operation, the same cell phototoxicity and dark toxicity test was performed on crystal violet (CV), a currently recognized oxygen-independent photodynamic type I photosensitizer.

[0074] Figure 5 (normoxia) and Figure 6 (Hypoxic conditions) shows the results of the toxicity evaluation of NTYOL and CV on 4T1 cells. Under the same normal conditions, compared with CV, NTYOL exhibits lower dark cytotoxicity and higher phototoxicity. In addition, under the same hypoxic conditions, the photosensitizer CV almost loses its photodynamic effect due to the extreme lack of oxygen under hypoxic conditions. In contrast, NTYOL still has low dark cytotoxicity under hypoxic conditions. It is worth noting that after irradiation with white light, the biological activity of the molecule is significantly improved, and it has a high cell killing ability, so that it still has high phototoxicity under hypoxic conditions.

[0075] Example 7

[0076] Preparation of NTYOL nanoparticles (NTYOL NPs): Compound NTYOL (1 mg) and DSPE-PEG 2000 According to the mass ratio of 1:3, it was dissolved in 1 mL of tetrahydrofuran under ultrasonic dispersion to obtain a mixed solution, and then the uniform mixed solution was quickly added to ultrapure water (10 mL), and further ultrasonically treated with a probe ultrasonicator at 30% output (rated power 125 W) for 3 minutes, and then purified by dialysis (molecular weight cutoff 3.5 kDa) for 2 days to remove the organic solvent and remove free small molecules, and then the nanoparticles were collected and concentrated by a centrifugal filter for further use.

[0077] Example 8

[0078] The light-induced biological activity of aromatic phenylpropargyl alcohols is used to kill tumors in vivo.

[0079] (1) Tumor model construction: Female BABL / c mice (5-6 weeks old) were housed in a standard SPF experimental animal room. 4T1 cells (1×10 6 cfu / mL) was injected subcutaneously on the right back of each mouse to establish the mouse primary tumor subcutaneous model. About 7 days later, when the tumor volume grew to about 100mm 3 Mice can be used for experiments.

[0080] (2) Model mice were randomly divided into four groups (n = 5), including PBS group, PBS+L group, NTYOL NPs group, and NTYOLNPs+L group, and different treatments were given by tail vein administration (150 μL, NTYOL NPs concentration was 5 mg mL -1 ). 36 h after administration, the mice in the illumination group were placed under a white light lamp for 30 min (power density 150 mW cm -2 The time of tail vein administration was recorded as day -1, the time of light treatment was recorded as day 0, the weight and tumor volume of the mice were recorded on the day of light treatment, and the weight and tumor size of the mice were recorded and counted every 2 days thereafter. Figure 7 As shown in A and B, the average tumor volume of the NTYOL NPs+L group was significantly lower than that of the other treatment groups, and no weight difference was found among the groups in the weight growth curve of the mice, indicating that the injection of the nanoparticles had no obvious physiological toxicity to the mice. This indicates that the nanoparticles can kill tumor cells under light conditions, thereby significantly inhibiting the growth of tumor cells, and at the same time have good normal cell biosafety.

[0081] The embodiments described above provide a detailed description of the technical solutions of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, supplements or similar substitutions made within the scope of the principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing aromatic phenylpropynyl ketone by light induction, characterized in that: Under light-induced conditions, the aromatic phenylpropargyl alcohol represented by formula (I) is converted into the aromatic phenylpropargyl ketone represented by formula (II); In formula (I) to formula (II), R1 is a light absorption regulating group independently selected from phenyl, naphthyl, substituted phenyl, aromatic amine or a heteroaromatic ring group containing at least one nitrogen, oxygen or sulfur atom.

2. The method according to claim 1, characterized in that In the substituted phenyl group, the substituent is methoxy, alkylamino, carbazolyl, phenoxazine, naphthylamino or triphenylvinyl; and / or, the aromatic amine group is a diphenylamine group, a triphenylamine group or a dipyridylamine group; And / or, the heteroaromatic ring group containing at least one nitrogen, oxygen or sulfur atom is a thienyl, pyridyl, furyl, carbazolyl, phenothiazinyl, phenoxazinyl, phenothiazinephenyl, bithienyl, thienocyclopentadienyl, 9,10-dihydro-9,9-dimethylacridinyl, 9,10-dihydro-9,9-diphenylacridinyl, 10-H-spiro[acridine-9,9'-fluorene]yl, diphenylaminethienyl, bithienyl, fusedthienyl or thienocyclopentadienyl.

3. The method according to claim 1, characterized in that: The conditions for light induction were irradiation with ultraviolet light or white light for ≥ 2 s.

4. The method according to claim 1, characterized in that: The aromatic phenylpropynyl alcohol shown in formula (I) is prepared by the following method: (1) Compound and 5-bromo-2-nitrobenzaldehyde are heated to 60-80° C. in an inert gas atmosphere to carry out Suzuki reaction for 6-24 hours, and after the reaction, post-processed to obtain a nitrobenzaldehyde derivative; R1 is as defined above; (2) preparing an organic solution of a nitrobenzaldehyde derivative, adding a Grignard reagent under ice bath conditions, reacting for 2-6 hours under an inert gas atmosphere, and after the reaction, post-treating to obtain an aromatic phenylpropargyl alcohol represented by formula (I).

5. A compound, characterized in that The compound is aromatic phenylpropargyl alcohol or aromatic phenylpropargyl ketone, the structural formula of aromatic phenylpropargyl alcohol is shown in formula (I), the structural formula of aromatic phenylpropargyl ketone is shown in formula (II), and R1 is defined as above; 6. Use of the method according to any one of claims 1 to 4 or the compound according to claim 5 in the preparation of tumor therapeutic drugs.

7. The use according to claim 6, characterized in that: The tumor therapeutic drug comprises nanoparticles, wherein the nanoparticle component comprises aromatic phenylpropargyl alcohol as shown in formula (I), and under light-induced conditions, the aromatic phenylpropargyl alcohol as shown in formula (I) is converted into aromatic phenylpropargyl ketone as shown in formula (II) to exert its effect.

8. The use according to claim 7, characterized in that: The aromatic phenylpropargyl alcohol represented by formula (I) is mixed with a surfactant and co-precipitated to prepare the nanoparticles.

9. Use of the method according to any one of claims 1 to 4 or the compound according to claim 5 in the preparation of a fluorescent labeling reagent for a polypeptide or protein.

10. The use according to claim 9, characterized in that: The aromatic phenylpropargyl alcohol represented by formula (I) is brought into contact with a polypeptide or a protein. Under light-induced conditions, the aromatic phenylpropargyl alcohol represented by formula (I) is converted into the aromatic phenylpropargyl ketone represented by formula (II) to play a fluorescent labeling role.

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