A naphthalene diimide bicyclic compound, preparation method and application thereof

Abstract

The present invention discloses a naphthalene diimide bicyclic compound, a preparation method and an application thereof, belonging to the technical fields of organic synthesis and supramolecular chemistry. The naphthalene diimide bicyclic compound exhibits excellent solubility in water. Since the naphthalene diimide bicyclic compound has two highly electron-deficient square cavities, it can encapsulate an electron-rich planar guest, and the formed host-guest complex exhibits a 1:2 binding mode. The host-guest complex of the naphthalene diimide bicyclic compound can exhibit excellent photothermal effect and photothermal stability under irradiation of a 1064nm laser in the NIR-II region, and has good biocompatibility. Therefore, it is further developed as an NIR-II region photothermal agent for efficiently ablating cancer cells and bacteria, confirming its potential application in biomedicine.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and supramolecular chemistry, and particularly relates to a naphthalene diimide bicyclic compound, a preparation method and application thereof. Background Art

[0002] Macrocyclic compounds, due to their unique cyclic molecular structure and excellent host-guest properties, have become a major focus of supramolecular chemistry research. They are also gaining increasing attention in drug delivery and controlled release. The design and development of novel macrocyclic hosts with unique structures and excellent host-guest properties is a persistent and challenging topic in this field.

[0003] The development and application of near-infrared photothermal conversion materials have attracted extensive research and attention over the past few decades, resulting in numerous achievements. However, existing photothermal conversion materials still suffer from drawbacks such as complex synthesis, low biocompatibility, low photothermal conversion efficiency, and poor photothermal stability. In particular, the lack of small-molecule photothermal materials responsive to the second near-infrared region (NIR-II) severely limits their practical application in the biomedical field. Therefore, the development of new, ideal near-infrared photothermal conversion materials that are easy to synthesize, highly efficient, safe, and water-soluble remains an emerging and challenging task. Summary of the Invention

[0004] The purpose of the present invention is to provide a naphthalene diimide bicyclic compound, a preparation method and an application thereof to solve the problems existing in the above-mentioned prior art. The naphthalene diimide bicyclic compound has the application of photothermal sterilization as a NIR-Ⅱ region photothermal agent.

[0005] To achieve the above object, the present invention provides the following solutions:

[0006] The present invention provides a naphthalene diimide bicyclic compound (abbreviated as GBox in English), the general structural formula of which is as follows:

[0007]

[0008] Wherein, R1 is H, CH3 or CH2OH.

[0009] The naphthalene diimide bicyclic compound of the present invention encapsulates guest molecules with different electron-rich degrees, has a host-guest binding pattern of 1:2, and exhibits excellent binding ability. The aqueous solution of the host-guest complex exhibits significant photothermal performance in the NIR-II region. After the naphthalene diimide bicyclic compound encapsulates the guest molecule, it has the effect of thermally ablating cancer cells as a NIR-II region photothermal agent. After the naphthalene diimide bicyclic compound encapsulates the guest molecule, it has the effect of photothermal sterilization as a NIR-II region photothermal agent.

[0010] The present invention provides a simple and practical method for synthesizing a naphthalene diimide bicyclic compound and provides its application in near-infrared photothermal therapy. The naphthalene diimide bicyclic compound exhibits excellent solubility in water; because the naphthalene diimide bicyclic compound has two highly electron-deficient square cavities, it can encapsulate an electron-rich planar guest, and the formed host-guest complex exhibits a 1:2 binding mode; the naphthalene diimide bicyclic host-guest complex can exhibit excellent photothermal effect and photothermal stability under irradiation of a 1064nm laser in the near-infrared region II (NIR-II region), and at the same time has good biocompatibility. Therefore, it is further developed as an NIR-II region photothermal agent for efficient ablation of cancer cells and bacteria, confirming its potential application in biomedicine.

[0011] A method for preparing the naphthalene diimide bicyclic compound, the synthetic route is as follows:

[0012]

[0013] The steps include:

[0014] 1) 4-(Hydroxymethyl)benzonitrile, hydrazine monohydrate, and anhydrous ethanol were mixed and uniformly dispersed, heated, and after the reaction was completed and cooled to room temperature, deionized water was added to precipitate a large amount of white precipitate. The white precipitate was filtered and then washed with deionized water 3-5 times, and dried to obtain a white solid powder, i.e., intermediate A, which was directly used in the next reaction without isolation and purification;

[0015] 2) mixing the unpurified intermediate product A in step 1), 1,4,5,8-naphthalenetetracarboxylic dianhydride, and a solvent, heating and stirring, adding deionized water after the reaction to obtain a yellow precipitate, filtering and then washing with deionized water 3-5 times, drying to obtain a yellow solid crude product, and finally separating by column chromatography to obtain a pure yellow solid powder, i.e., intermediate product B;

[0016] 3) The intermediate product B from step 2) was mixed with a hydrobromic acid solution, heated under reflux with stirring, and after the reaction was completed, the mixture was cooled to room temperature to precipitate a small yellow precipitate. A 5% (mass fraction) aqueous solution of NaHCO3 was then added to precipitate more precipitate. The precipitate was filtered, washed with deionized water 3-5 times, and dried to obtain a yellow solid powder, i.e., the intermediate product C;

[0017] 4) The intermediate product C of step 3), 3,3'-bipyridine or a derivative thereof, and N,N'-dimethylformamide are mixed, heated with stirring, and after the reaction is completed, cooled to room temperature. The suspension after the reaction is centrifuged to obtain a precipitate, which is dissolved in deionized water and added with a saturated aqueous solution of ammonium hexafluorophosphate. The mixture is filtered, washed, and dried to obtain a light yellow solid powder, i.e., a naphthalene diimide bicyclic compound (GBox).

[0018] Preferably, in the preparation method of the naphthalene diimide bicyclic compound, in step 1), the molar volume ratio of 4-(hydroxymethyl)benzonitrile, hydrazine monohydrate (85%, mass fraction) and anhydrous ethanol is 1 mmol: (0.6-1.2) mL: (0.2-0.4) mL;

[0019] The heating temperature is 100-130℃ and the time is 48-80h.

[0020] Preferably, in the preparation method of the naphthalene diimide bicyclic compound, in step 2), the molar volume ratio of 1,4,5,8-naphthalenetetracarboxylic dianhydride, intermediate product A and solvent is 1 mmol: (2.0-4.0) mmol: (10-25) mL;

[0021] The heating temperature is 110-165°C and the time is 12-48 hours;

[0022] Column chromatography was performed with dichloromethane / ethyl acetate (2:1, V / V) as the eluent.

[0023] Preferably, in the method for preparing the naphthalene diimide bicyclic compound, in step 2), the solvent comprises propionic acid, acetic acid, butyric acid or N,N'-dimethylformamide.

[0024] Preferably, in the preparation method of the naphthalene diimide bicyclic compound, in step 3), the heating temperature is 100-115° C. and the time is 12-48 h;

[0025] The mass volume ratio of the intermediate product B to the hydrobromic acid solution is 1 g: (40-70) mL.

[0026] Preferably, in the preparation method of the naphthalene diimide bicyclic compound, in step 3), the hydrobromic acid solution is at least one of a hydrobromic acid acetic acid solution (33%, w / w) and a hydrobromic acid aqueous solution (48%, w / w); when it is a mixture of the two, the hydrobromic acid acetic acid solution (33%, w / w) and the hydrobromic acid aqueous solution (48%, w / w) are mixed in a volume ratio of 1: (0.8-2).

[0027] Preferably, in the preparation method of the naphthalene diimide bicyclic compound, in step 4), the molar ratio of the intermediate product C to 3,3'-bipyridine or its derivative is 1:(2-2.2);

[0028] The heating temperature is 40-100°C and the time is 24-80 hours.

[0029] The reactions in step 2), step 3) and step 4) of the present invention are all carried out in an oxygen-free environment.

[0030] The application of the naphthalene diimide bicyclic compound in the preparation of a photothermal agent for photothermal chemotherapy.

[0031] Application of the naphthalene diimide bicyclic compound in the preparation of near-infrared second-zone photothermal agents.

[0032] The naphthalene diimide bicyclic compound (GBox) of the present invention encapsulates a variety of guest molecules, presenting a 1:2 binding pattern between the host and the guest, and exhibiting excellent binding ability. The host-guest charge transfer (CT) complex formed by the naphthalene diimide bicyclic compound encapsulating the guest molecules can be used as a photothermal agent for photothermal therapy in the NIR-II region, and has applications in thermal ablation of cancer cells and photothermal antibacterial treatment.

[0033] The present invention discloses the following technical effects:

[0034] The naphthalene diimide bicyclic compound prepared by the present invention is a macrocyclic compound with a novel structure and excellent water solubility. The naphthalene diimide bicyclic compound, as an electron-deficient host, can encapsulate electron-rich guests to varying degrees, presenting a host-guest binding pattern of 1:2 and exhibiting excellent binding ability.

[0035] The naphthalene diimide bicyclic compound prepared by the present invention has excellent light absorption properties in the NIR-II region due to the encapsulated guest molecule and good biocompatibility of the host-guest complex, and can be used as a highly efficient NIR-II region photothermal agent for thermal ablation of cancer cells and bacteria.

[0036] The invention has a simple concept, a novel synthesis strategy, and readily available raw materials. It has good universality and can be used to design and synthesize bicyclic compounds with different functions without the need for any template agent. It provides a new approach for the synthesis of water-soluble bicyclic macrocyclic compounds and promotes their potential application in the biomedical field. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0038] Figure 1 The naphthalene diimide bicyclic compound GBox-4 prepared in Example 1 of the present invention is encapsulated with planar guest molecules of varying degrees of electron richness. a) Five planar guest molecules encapsulated by GBox-4. b) UV-vis-NIR spectra of GBox-4 titrated with DAF-OH in H2O (inset: the binding mode of GBox-4 and DAF-OH is 1:2).

[0039] Figure 2The naphthalene diimide bicyclic compound GBox-4 prepared in Example 1 of the present invention was exposed to a laser with a wavelength of 1064 nm (1.0 W cm -2 ) irradiation, heating and cooling curves of aqueous solutions of GBox-4 and DAF-OH, DAF and TTF host-guest complexes, and GBox-4 aqueous solutions and water;

[0040] Figure 3 The naphthalene diimide bicyclic compound GBox-4 prepared in Example 1 of the present invention encapsulates the DAF-OH guest to form a host-guest complex as a NIR-II region photothermal agent for cancer cell thermal ablation. a) is a graph showing different concentrations of GBox-4, and Cell viability after incubation of the complex with Hela cells; b) different concentrations The complex was incubated with HeLa cells and irradiated with 1064 nm laser (1.0 W cm -2 ) is the cell viability; c) is the confocal micrograph of live / dead HeLa cells;

[0041] Figure 4 The photothermal sterilization diagram of the naphthalene diimide bicyclic compound GBox-4 prepared in Example 1 of the present invention encapsulating the DAF-OH guest to form a host-guest complex as a NIR-Ⅱ region photothermal agent, a) is 0.3mM After the complex was incubated with E. coli, the cells were irradiated with 1064 nm laser (1.0 W cm -2 ) thermal image; b) 0.3mM After the complex was incubated with E. coli, the cells were irradiated with 1064 nm laser (1.0 W cm -2 ) after bacterial survival. DETAILED DESCRIPTION

[0042] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0043] It should be understood that the terms described herein are intended only to describe particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges herein, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. The intermediate value within any stated value or stated range, and each smaller range between any other stated value or intermediate value within the stated range, is also encompassed within the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0044] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of any conflict with any incorporated document, the contents of this specification shall prevail.

[0045] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be illustrative only.

[0046] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0047] All experiments in the present invention were repeated three times.

[0048] The room temperature in the present invention refers to 25±2°C.

[0049] Example 1

[0050] A naphthalene diimide bicyclic compound, chemical formula C 66 H 44 N 12 O4 4+ , named GBox-4, its structural formula is:

[0051]

[0052] The reaction equation is as follows:

[0053]

[0054] Specific steps:

[0055] (1) A mixture of 4-(hydroxymethyl)benzonitrile (4 mmol, 532.6 mg), hydrazine monohydrate (85%, mass fraction, 3 mL), and anhydrous ethanol (1 mL) was placed in a 15 mL reactor and dispersed uniformly by ultrasonication. The mixture was heated in an oven at 120°C for 3 days. After the reaction was completed, it was cooled to room temperature at a rate of 5°C / hour. A small amount of white solid material precipitated. Deionized water was added to precipitate a large amount of white precipitate. The white precipitate was filtered, washed with deionized water 3-5 times, and dried to obtain a white solid powder, namely, intermediate A, with a yield of 62%. The product was used directly in the next reaction without separation or purification.

[0056] The intermediate product A was subjected to nuclear magnetic resonance testing, and the data are as follows:

[0057] 1 H NMR (600MHz, DMSO-d6, 298K): δ (ppm) = 7.990 (d, J = 7.8Hz, 4H), 7.479 (d, J = 7.2Hz, 4H), 6.237 (s, 2H), 5.359 (s, 2H), 4.587 (s, 4H); 13 C NMR (150MHz, DMSO-d6, 298K): δ (ppm) = 154.604, 144.514, 128.488, 126.743, 126.014, 63.023.

[0058] (2) 1,4,5,8-naphthalenetetracarboxylic dianhydride (471.99 mg, 1.76 mmol), unpurified intermediate product A (1.20 g, 4.05 mmol) and propionic acid solution (40 mL) were added to a round-bottom flask. The reaction mixture was stirred and refluxed at 155°C for 24 h under nitrogen protection. After the reaction was completed, deionized water (80 mL) was added to obtain a yellow precipitate, which was filtered and washed with deionized water (100 mL) 3-5 times. Drying was performed to obtain a yellow solid crude product. The crude product was separated by column chromatography using dichloromethane / ethyl acetate (2:1, V / V) as the eluent to obtain a yellow solid powder, namely, intermediate product B1.28 g, with a yield of 69.19%.

[0059] The intermediate product B was subjected to nuclear magnetic resonance testing, and the data are as follows:

[0060] 1 H NMR (600MHz, DMSO-d6, 298K): δ (ppm) = 8.828 (s, 4H), 7.597 (d, J = 8.4Hz, 8H), 7.39 9(d,J=8.4Hz,8H),5.050(s,8H),2.318(q,J=7.2Hz,8H),0.979(t,J=7.2Hz,12H); 13 C NMR (150MHz, DMSO-d6, 298K): δ (ppm) = 173.799, 160.547, 153.969, 139.857, 13 3.683,128.858,128.061,127.364,126.047,124.400,64.933,27.086,9.292.

[0061] (3) 300 mg of intermediate B and HBr / acetic acid solution (33% w / w, 20 mL) were added to a round-bottom flask and stirred at reflux at 110°C under nitrogen. The reaction was monitored by thin-layer chromatography. After 18 h, the reaction was stopped and cooled to room temperature. A small amount of yellow precipitate was precipitated. 5 wt% aqueous sodium bicarbonate solution (150 mL) was added to precipitate more. The precipitate was filtered and washed 3-5 times with deionized water (150 mL). It was dried to obtain 210 mg of yellow solid powder, i.e., intermediate C, with a yield of 70%.

[0062] The nuclear magnetic resonance analysis of intermediate product C showed the following data:

[0063] 1 H NMR (600MHz, DMSO-d6, 298K): δ (ppm) = 8.832 (s, 4H), 7.596 (d, J = 7.8Hz, 8H), 7.487 (d, J = 8.4Hz, 8H), 4.654 (s, 8H); 13 CNMR (150MHz, DMSO-d6, 298K): δ (ppm) = 160.512, 153.822, 141.403, 133.685, 130.710, 128.249, 127.545, 126.068, 124.639, 33.638.

[0064] (4) Add the intermediate product C (200 mg, 0.186 mmol), 3,3'-bipyridine (63.85 mg, 0.409 mmol) and N,N-dimethylformamide solvent (90 mL) to a round-bottom flask. Protect with nitrogen to ensure that the reaction is carried out under oxygen-free conditions and stir at 60 ° C for 72 h. After the reaction is completed, cool to room temperature. After the reaction, the suspension in the round-bottom flask is centrifuged to obtain a precipitate. The precipitate is dissolved in deionized water (40 mL) and a saturated aqueous solution of ammonium hexafluorophosphate (10 mL) is added. A precipitate is precipitated and filtered. The precipitate is washed with deionized water 3-5 times and dried to obtain a light yellow solid powder, i.e., the target naphthalene diimide bicyclic compound GBox-4 110 mg, with a yield of 47.68%;

[0065] The data of GBox-4 NMR analysis are as follows:

[0066] 1 H NMR (600MHz, DMSO-d6, 298K): δ (ppm) = 9.658 (s, 4H), 9.428 (d, J = 6Hz, 4H), 8.824 (d, J = 7.8Hz, 4H), 8 .610(s,4H),8.398(m,J=6 / 8.4,4H),7.603(d,J=8.4Hz,8H),7.562(d,J=8.4Hz,8H),5.899(s,8H);13 C NMR (150MHz, DMSO-d6, 298K): δ (ppm) = 162.678, 160.487, 154.162, 145.839, 145.393, 144 .249,137.311,134.436,133.693,129.752,129.139,128.654,125.788,125.448,63.642.

[0067] Example 2

[0068] A naphthalene diimide bicyclic compound, chemical formula C 70 H 52 N 12 O4 4+ , named GBox-5, its structural formula is:

[0069]

[0070] The reaction equation is as follows:

[0071]

[0072] Specific steps:

[0073] (1) A mixture of 4-(hydroxymethyl)benzonitrile (4 mmol, 532.6 mg), hydrazine monohydrate (85%, mass fraction, 3 mL), and anhydrous ethanol (1 mL) was placed in a 15 mL reactor and dispersed uniformly by ultrasonication. The mixture was heated in an oven at 120°C for 3 days. After the reaction was completed, it was cooled to room temperature at a rate of 5°C / hour. A small amount of white solid material precipitated. Deionized water was added to precipitate a large amount of white precipitate. The white precipitate was filtered, washed with deionized water 3-5 times, and dried to obtain a white solid powder, namely, intermediate A, with a yield of 62%. The product was used directly in the next reaction without separation or purification.

[0074] The intermediate product A was subjected to nuclear magnetic resonance testing, and the data are as follows:

[0075] 1 H NMR (600MHz, DMSO-d6, 298K): δ (ppm) = 7.990 (d, J = 7.8Hz, 4H), 7.479 (d, J = 7.2Hz, 4H), 6.237 (s, 2H), 5.359 (s, 2H), 4.587 (s, 4H); 13 C NMR (150MHz, DMSO-d6, 298K): δ (ppm) = 154.604, 144.514, 128.488, 126.743, 126.014, 63.023.

[0076] (2) 1,4,5,8-naphthalenetetracarboxylic dianhydride (471.99 mg, 1.76 mmol), unpurified intermediate product A (1.20 g, 4.05 mmol) and propionic acid solution (40 mL) were added to a round-bottom flask. The reaction mixture was stirred and refluxed at 155°C for 24 h under nitrogen protection. After the reaction was completed, deionized water (80 mL) was added to obtain a yellow precipitate, which was filtered and washed with deionized water (100 mL) 3-5 times. Drying was performed to obtain a yellow solid crude product. The crude product was separated by column chromatography using dichloromethane / ethyl acetate (2:1, V / V) as the eluent to obtain a yellow solid powder, namely, intermediate product B1.28 g, with a yield of 69.19%.

[0077] The intermediate product B was subjected to nuclear magnetic resonance testing, and the data are as follows:

[0078] 1 H NMR (600MHz, DMSO-d6, 298K): δ (ppm) = 8.828 (s, 4H), 7.597 (d, J = 8.4Hz, 8H), 7.39 9(d,J=8.4Hz,8H),5.050(s,8H),2.318(q,J=7.2Hz,8H),0.979(t,J=7.2Hz,12H); 13 C NMR (150MHz, DMSO-d6, 298K): δ (ppm) = 173.799, 160.547, 153.969, 139.857, 13 3.683,128.858,128.061,127.364,126.047,124.400,64.933,27.086,9.292.

[0079] (3) 300 mg of intermediate B and HBr / acetic acid solution (33% w / w, 20 mL) were added to a round-bottom flask and stirred at reflux at 110°C under nitrogen. The reaction was monitored by thin-layer chromatography. After 18 h, the reaction was stopped and cooled to room temperature. A small amount of yellow precipitate was precipitated. 5 wt% aqueous NaHCO3 solution (150 mL) was added to precipitate more. The precipitate was filtered and washed 3-5 times with deionized water (150 mL). It was dried to obtain 210 mg of a yellow solid powder, intermediate C, with a yield of 70%.

[0080] The NMR analysis of intermediate product C showed the following data:

[0081] 1 H NMR (600MHz, DMSO-d6, 298K): δ (ppm) = 8.832 (s, 4H), 7.596 (d, J = 7.8Hz, 8H), 7.487 (d, J = 8.4Hz, 8H), 4.654 (s, 8H); 13CNMR (150MHz, DMSO-d6, 298K): δ (ppm) = 160.512, 153.822, 141.403, 133.685, 130.710, 128.249, 127.545, 126.068, 124.639, 33.638.

[0082] (4) Intermediate product C (200 mg, 0.186 mmol), 3,3'-bipyridine (63.85 mg, 0.409 mmol) and N,N-dimethylformamide solvent (90 mL) were added to a round-bottom flask. The reaction was carried out under nitrogen protection to ensure that the reaction was carried out under oxygen-free conditions and stirred at 60°C for 72 h. After the reaction was completed, the mixture was cooled to room temperature. The suspension in the round-bottom flask was centrifuged to obtain a precipitate. The precipitate was dissolved in deionized water (40 mL) and a saturated aqueous solution of ammonium hexafluorophosphate (10 mL) was added to precipitate. The precipitate was filtered and washed with deionized water 3-5 times and dried to obtain a light yellow solid powder, i.e., the target bicyclic compound GBox-5 (118 mg) with a yield of 37.20%.

[0083] The data of GBox-5 NMR analysis are as follows:

[0084] 1 H NMR (600MHz, DMSO-d6, 298K): δ (ppm) = 9.658 (s, 4H), 9.428 (d, J = 6Hz, 4H), 8.824 (d, J = 7.8Hz, 4 H),8.610(s,4H),7.603(d,J=8.4Hz,8H),7.562(d,J=8.4Hz,8H),5.899(s,8H),2.485(s,12H);

[0085] 13 C NMR (150MHz, DMSO-d6, 298K): δ (ppm) = 162.678, 160.487, 154.162, 145.839, 145.393, 144.249 ,137.311,134.436,133.693,129.752,129.139,128.654,125.788,125.448,63.642,18.355.

[0086] Example 3

[0087] A perylene diimide bicyclic compound, the chemical formula is C 70 H 52 N 12 O8 4+ , named GBox-6, its structural formula is:

[0088]

[0089] The reaction equation is as follows:

[0090]

[0091] Specific steps:

[0092] (1) A mixture of 4-(hydroxymethyl)benzonitrile (4 mmol, 532.6 mg), hydrazine monohydrate (85%, mass fraction, 3 mL), and anhydrous ethanol (1 mL) was placed in a 15 mL reactor and dispersed uniformly by ultrasonication. The mixture was heated in an oven at 120°C for 3 days. After the reaction was completed, it was cooled to room temperature at a rate of 5°C / hour. A small amount of white solid material precipitated. Deionized water was added to precipitate a large amount of white precipitate. The white precipitate was filtered, washed with deionized water 3-5 times, and dried to obtain a white solid powder, namely, intermediate A, with a yield of 62%. The product was used directly in the next reaction without separation or purification.

[0093] The intermediate product A was subjected to nuclear magnetic resonance testing, and the data are as follows:

[0094] 1 H NMR (600MHz, DMSO-d6, 298K): δ (ppm) = 7.990 (d, J = 7.8Hz, 4H), 7.479 (d, J = 7.2Hz, 4H), 6.237 (s, 2H), 5.359 (s, 2H), 4.587 (s, 4H); 13 C NMR (150MHz, DMSO-d6, 298K): δ (ppm) = 154.604, 144.514, 128.488, 126.743, 126.014, 63.023.

[0095] (2) 1,4,5,8-naphthalenetetracarboxylic dianhydride (471.99 mg, 1.76 mmol), unpurified intermediate product A (1.20 g, 4.05 mmol) and propionic acid solution (40 mL) were added to a round-bottom flask. The reaction mixture was stirred and refluxed at 155°C for 24 h under nitrogen protection. After the reaction was completed, deionized water (80 mL) was added to obtain a yellow precipitate, which was filtered and washed with deionized water (100 mL) 3-5 times. Drying was performed to obtain a yellow solid crude product. The crude product was separated by column chromatography using dichloromethane / ethyl acetate (2:1, V / V) as the eluent to obtain a yellow solid powder, namely, intermediate product B1.28 g, with a yield of 69.19%.

[0096] The intermediate product B was subjected to nuclear magnetic resonance testing, and the data are as follows:

[0097] 1H NMR (600MHz, DMSO-d6, 298K): δ (ppm) = 8.828 (s, 4H), 7.597 (d, J = 8.4Hz, 8H), 7.39 9(d,J=8.4Hz,8H),5.050(s,8H),2.318(q,J=7.2Hz,8H),0.979(t,J=7.2Hz,12H); 13 C NMR (150MHz, DMSO-d6, 298K): δ (ppm) = 173.799, 160.547, 153.969, 139.857, 13 3.683,128.858,128.061,127.364,126.047,124.400,64.933,27.086,9.292.

[0098] (3) 300 mg of intermediate B and HBr / acetic acid solution (33% w / w, 20 mL) were added to a round-bottom flask and stirred at 110°C under nitrogen. The reaction was monitored by thin-layer chromatography. The reaction was stopped after 18 h and cooled to room temperature to precipitate a small amount of yellow precipitate. 5 wt% NaHCO3 aqueous solution (150 mL) was added to precipitate more. The precipitate was filtered and washed with deionized water (150 mL) 3-5 times. It was dried to obtain a yellow solid powder, i.e., intermediate C 210 mg, with a yield of 70%;

[0099] The NMR analysis of intermediate product C showed the following data:

[0100] 1 H NMR (600MHz, DMSO-d6, 298K): δ (ppm) = 8.832 (s, 4H), 7.596 (d, J = 7.8Hz, 8H), 7.487 (d, J = 8.4Hz, 8H), 4.654 (s, 8H); 13 CNMR (150MHz, DMSO-d6, 298K): δ (ppm) = 160.512, 153.822, 141.403, 133.685, 130.710, 128.249, 127.545, 126.068, 124.639, 33.638.

[0101] (4) Add the intermediate product C (200 mg, 0.186 mmol), 3,3'-bipyridine (63.85 mg, 0.409 mmol) and N,N-dimethylformamide solvent (90 mL) to a round-bottom flask. Protect with nitrogen to ensure that the reaction is in the absence of oxygen and stir at 60 ° C for 72 h. After the reaction is completed, cool to room temperature. After the reaction, the suspension in the round-bottom flask is centrifuged to obtain a precipitate. The precipitate is dissolved in deionized water (40 mL) and a saturated aqueous solution of ammonium hexafluorophosphate (10 mL) is added. A precipitate is precipitated and filtered. The precipitate is washed with deionized water 3-5 times and dried to obtain a light yellow solid powder, i.e., the target bicyclic compound GBox-6 125 mg, with a yield of 37.98%;

[0102] The data of GBox-6 NMR analysis are as follows:

[0103] 1 H NMR (600MHz, DMSO-d6, 298K): δ (ppm) = 9.658 (s, 4H), 9.428 (d, J = 6Hz, 4H), 8.824 (d, J = 7.8Hz, 4H), 8.6 10(s,4H),7.603(d,J=8.4Hz,8H),7.562(d,J=8.4Hz,8H),5.899(s,8H),5.275(s,4H),4.615(s,8H); 13 C NMR (150MHz, DMSO-d6, 298K): δ (ppm) = 162.678, 160.487, 154.162, 145.839, 145.393, 144.249 ,137.311,134.436,133.693,129.752,129.139,128.654,125.788,125.448,65.055,63.642.

[0104] Test Example 1

[0105] Experimental process of encapsulating planar guest molecules with different degrees of electron richness in the naphthalene diimide bicyclic compound GBox-4: In the UV-visible titration experiment, the guest (DAF, AF, FL, TTF, DAF-OH) solution was gradually added to the GBox-4 solution. Since the binding mode between the host and the guest is 1:2, the resulting host-guest complex is recorded as (For example, the complex of DAF and GBox-4 is recorded as ), recording UV-visible spectra one after another. Stacking the spectra revealed the emergence and enhancement of new absorption bands with the addition of the guest. Nonlinear curve fitting was then used to characterize the binding capacity.

[0106] Figure 2Experimental procedure: Guests (DAF, TTF, DAF-OH) were added to the GBox-4 aqueous solution, and the mixture was ultrasonicated for 30 min to obtain the host-guest complex solution of GBox-4. The host-guest complex solution was then irradiated with a 1064 nm laser (1.0 W cm -2 ) irradiation, while using a thermal imaging camera to record temperature changes. Similar experiments were conducted using pure water and GBox-4 aqueous solution as blank controls.

[0107] Figure 3 Experimental process: In vitro evaluation by cell counting kit (CCK-8) Cell viability of host-guest complexes with and without irradiation. 3 Hela cells were cultured in 100 μL of culture medium for 24 h, and then 0-300 μM host-guest complexes were added and incubated for another 24 h. 1064 nm laser (1.0 W cm -2 After irradiation for 0–10 min, the culture medium was replaced with fresh culture medium containing CCK-8. After an additional 1-hour incubation, absorbance at 450 nm was measured using a microplate reader (EnVision, PerkinElmer). Three independent experiments were performed to determine cell viability.

[0108] Figure 4 Experimental process: 50 μL of E. coli suspension (OD 600 ≈1.2) with 250 μL of 0.36 mM After the host-guest complex solution was incubated at 37°C for 5 min, the E. coli suspension treated with the host-guest complex solution was irradiated with a laser of 1064 nm (1.0 W cm -2 )0-5min, and record the temperature change with infrared thermal imager. Finally, all E. coli suspensions were serially diluted with PBS to 1×10 5 A 100 μL portion of the bacterial dilution was spread onto solid LB agar plates and colonies formed after incubation at 37°C for 14-16 hours were counted. All experiments were performed in triplicate. The proportion of viable bacteria was determined by counting the number of colony-forming units.

[0109] Figure 1 The naphthalene diimide bicyclic compound GBox-4 prepared in Example 1 of the present invention is wrapped with planar guest molecules with different degrees of electron richness. Figure 1 It can be seen that the binding mode between GBox-4 and the guest molecule is 1:2, showing excellent binding ability.

[0110] Figure 2The naphthalene diimide bicyclic compound GBox-4 prepared in Example 1 of the present invention encapsulates DAF-OH, DAF and TTF guest molecules in aqueous solution and exhibits significant photothermal performance in the NIR-II region.

[0111] Figure 3 This is a picture of cancer cell thermal ablation using the naphthalene diimide bicyclic compound GBox-4 encapsulated with DAF-OH guest molecules as a photothermal agent in the NIR-II region. Figure 3 It can be seen that when the host-guest complex and Hela cells are irradiated with 1064nm laser, the thermal ablation effect on cancer cells can reach 90%, and it can be used as a NIR-Ⅱ photothermal agent for thermal ablation of cancer cells.

[0112] Figure 4 This is a photothermal sterilization diagram of the naphthalene diimide bicyclic compound GBox-4 encapsulating the DAF-OH guest molecule prepared in Example 1 of the present invention. Figure 4 It can be seen that when the host-guest complex solution and the E. coli mixed solution are irradiated with a 1064nm laser, the solution temperature can reach 65°C after 5 minutes, and the sterilization rate is as high as 99%. It can be used as an NIR-Ⅱ photothermal agent for antibacterial treatment.

[0113] The embodiments described above are merely descriptions of preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by persons skilled in the art should fall within the scope of protection defined by the claims of the present invention.

Claims

1. Use of a naphthalene diimide bicyclic compound in the preparation of a near-infrared second-region photothermal agent, characterized in that: The general structural formula of the naphthalene diimide bicyclic compound is as follows: Wherein, R1 is H, CH3 or CH2OH.

2. A method for preparing a naphthalene diimide bicyclic compound, characterized in that: The naphthalene diimide bicyclic compound is the naphthalene diimide bicyclic compound according to claim 1, and the synthesis route is as follows: The steps include: 1) 4-(Hydroxymethyl)benzonitrile, hydrazine monohydrate, and anhydrous ethanol were mixed and uniformly dispersed, heated, and after the reaction was completed and cooled to room temperature, deionized water was added to precipitate a white precipitate. The white precipitate was filtered, washed with deionized water, and dried to obtain a white solid powder, i.e., intermediate A; 2) mixing the intermediate product A in step 1), 1,4,5,8-naphthalenetetracarboxylic dianhydride, and a solvent, heating and stirring, adding deionized water after the reaction to obtain a yellow precipitate, filtering and then washing with deionized water, drying to obtain a yellow solid crude product, and finally separating by column chromatography to obtain a pure yellow solid powder, i.e., intermediate product B; 3) The intermediate product B of step 2) was mixed with a hydrobromic acid solution, heated with stirring and refluxed, and after the reaction was completed, cooled to room temperature, and then a NaHCO3 aqueous solution was added, filtered, and the precipitate was washed with deionized water 3-5 times, and dried to obtain a yellow solid powder, i.e., the intermediate product C; 4) The intermediate product C of step 3), 3,3'-bipyridine or a derivative thereof, and N,N'-dimethylformamide are mixed, heated with stirring, and after completion of the reaction, cooled to room temperature. The suspension after the reaction is centrifuged to obtain a precipitate, which is dissolved in deionized water, added with a saturated aqueous solution of ammonium hexafluorophosphate, filtered, washed, and dried to obtain a light yellow solid powder, i.e., a naphthalene diimide bicyclic compound.

3. The method for preparing the naphthalene diimide bicyclic compound according to claim 2, wherein: In step 1), the molar volume ratio of 4-(hydroxymethyl)benzonitrile, 85% by mass of hydrazine monohydrate, and anhydrous ethanol is 1 mmol: (0.6-1.2) mL: (0.2-0.4) mL; The heating temperature is 100-130℃ and the time is 48-80 h.

4. The method for preparing the naphthalene diimide bicyclic compound according to claim 2, wherein: In step 2), the molar volume ratio of 1,4,5,8-naphthalenetetracarboxylic dianhydride, intermediate A, and solvent is 1 mmol: (2.0-4.0) mmol: (10-25) mL; The heating temperature is 110-165°C and the time is 12-48 hours.

5. The method for preparing the naphthalene diimide bicyclic compound according to claim 4, wherein: The solvent is selected from propionic acid, acetic acid, butyric acid or N, N'-dimethylformamide.

6. The method for preparing the naphthalene diimide bicyclic compound according to claim 2, wherein: In step 3), the heating temperature is 100-115° C. and the time is 12-48 h; The mass volume ratio of intermediate product B to hydrobromic acid solution is 1 g: (40-70) mL.

7. The method for preparing the naphthalene diimide bicyclic compound according to claim 6, wherein: In step 3), the hydrobromic acid solution is at least one of a hydrobromic acid-acetic acid solution and a hydrobromic acid aqueous solution.

8. The method for preparing the naphthalene diimide bicyclic compound according to claim 2, wherein: In step 4), the molar ratio of the intermediate product C to 3,3'-bipyridine or its derivative is 1:(2-2.2); The heating temperature is 40-100°C and the time is 24-80 hours.

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