Self-aggregation induced emission luminophore, preparation method and application thereof

Abstract

The application discloses a self-aggregation-induced emission type photosensitizer, a preparation method and application thereof. The photosensitizer has excellent AIE performance, can efficiently generate singlet oxygen after aggregation in a physiological environment, and can effectively overcome the aggregation-induced quenching phenomenon. The photosensitizer can be synergistically used with a lovir drug to significantly improve the anti-herpes virus activity, and reduce the drug dosage and side effects.

Description

Technical Field

[0001] This application relates to a self-aggregation-induced emission photosensitizer, its preparation method, and its application, belonging to the field of chemical technology. Background Technology

[0002] Herpesvirus infection is a common viral disease, including herpes simplex, herpes zoster, and genital herpes, which seriously affects patients' quality of life. Lobeline drugs (such as acyclovir, ganciclovir, and famciclovir) are first-line drugs for the clinical treatment of herpesvirus infection, blocking viral replication by inhibiting viral DNA polymerase. However, with long-term clinical use, herpesvirus resistance to lobbivir drugs has gradually increased (especially in immunocompromised populations, the incidence of resistant strains exceeds 15%). The therapeutic effect of lobbivir monotherapy has significantly decreased, and high-dose use can easily cause side effects such as nephrotoxicity and neurotoxicity, limiting its clinical application value.

[0003] Photosensitizer-mediated photodynamic therapy (PDT) is a novel antiviral strategy. It utilizes photosensitizers to generate reactive oxygen species (ROS) (such as singlet oxygen and superoxide anions) under specific wavelengths of light, which disrupt the viral envelope and nucleic acid structure, thereby inhibiting viral replication and reducing the likelihood of inducing drug resistance. However, traditional photosensitizers exhibit aggregation-induced quenching (ACQ) and tend to aggregate in physiological environments, leading to decreased luminescence efficiency and ROS generation capacity, thus limiting their effectiveness against herpesviruses. Furthermore, most photosensitizers lack synergistic designs with cyclovir-like drugs, failing to effectively enhance the antiherpesvirus activity of cyclovir-like drugs and making it difficult to reverse drug resistance.

[0004] Self-aggregation-induced emission (AIE) materials are a special class of materials that emit weak light in a dispersed state but significantly enhance light emission in an aggregated state. Using them as photosensitizers can effectively overcome the ACQ (acute oxygen deficiency) defects of traditional photosensitizers, efficiently generating reactive oxygen species in the aggregated state. Currently, there are no reported studies on the synergistic enhancement of anti-herpesvirus activity by AIE-type photosensitizers and cyclovir-like drugs. Therefore, this application develops a self-aggregation-induced emission photosensitizer that can synergistically enhance the anti-herpesvirus activity of cyclovir-like drugs, which is of great significance for solving the problem of cyclovir-like drug resistance and improving the treatment efficacy of herpes infections. Summary of the Invention

[0005] Currently, cyclovir-based drugs, as first-line anti-herpesvirus drugs, have led to a significant increase in drug resistance to herpes simplex virus and varicella-zoster virus with long-term use. When used as a single drug, the half-maximal inhibitory concentration (IC50) remains high, resulting in a significant decrease in therapeutic efficacy. Furthermore, high-dose use can easily cause systemic side effects such as nephrotoxicity and neurotoxicity, limiting their clinical applicability. Traditional photosensitizers have performance defects: conventional photosensitizers exhibit aggregation-induced quenching (ACQ) and are prone to molecular aggregation in physiological fluid environments, leading to a sharp decrease in luminescence efficiency and a reduced ability to generate reactive oxygen species (such as singlet oxygen), thus failing to fully exert their photodynamic anti-herpesvirus effects. Synergistic effects are lacking: existing technologies do not offer solutions that combine photosensitizers with cyclovir-based drugs for anti-herpes treatment, lacking designs targeting the synergistic mechanism between the two, and thus failing to reverse viral resistance and enhance the overall anti-herpesvirus effect through synergistic effects. Applicability is limited: traditional anti-herpes photosensitizers often rely on specific and complex lighting equipment and have poor universality against different subtypes of herpesviruses, making it difficult to meet the treatment needs of herpes infections in multiple sites such as skin and mucous membranes. Based on this, this application provides a self-aggregation-induced emission photosensitizer, its preparation method and application. This photosensitizer can effectively overcome the ACQ phenomenon, and its synergistic effect with cyclovir drugs can significantly enhance anti-herpes virus activity, reduce drug dosage and side effects.

[0006] According to one aspect of this application, a self-aggregating induced emission photosensitizer is provided, the self-aggregating induced emission photosensitizer having the structure shown in Formula I:

[0007]

[0008] Formula I;

[0009] R is selected from , , One of the structures shown.

[0010] According to another aspect of this application, a method for preparing the above-described self-aggregating induced emission photosensitizer is provided, comprising:

[0011] A mixture of a carboxyl-containing PEG chain-BODIPY core structure compound, a hydroxyl compound containing cyclovir molecules, N,N-dimethylformamide, dicyclohexylcarbodiimide, and 4-dimethylaminopyridine was condensed to obtain the compound with the structure shown in Formula I.

[0012] The carboxyl-containing PEG chain-BODIPY core structure compound has the structure shown in Formula II;

[0013] , Formula II;

[0014] The hydroxyl compound containing cyclovir molecules is selected from one of the compounds with structures shown in Formula III-1, Formula III-2, and Formula III-3;

[0015] Formula III-1

[0016] Formula III-2

[0017] Formula III-3.

[0018] Optionally, the molar ratio of the carboxyl-containing PEG chain-BODIPY core structure compound to the hydroxyl compound containing cyclovir molecules is 1:5 to 1:10.

[0019] Preferably, the molar volume ratio of the carboxyl-containing PEG chain-BODIPY core structure compound to N,N-dimethylformamide is 1:1 to 1:20;

[0020] Preferably, the molar ratio of the carboxyl-containing PEG chain-BODIPY core structure compound to dicyclohexylcarbodiimide is 1:1 to 1:20;

[0021] Preferably, the molar ratio of the carboxyl-containing PEG chain-BODIPY core structure compound to 4-dimethylaminopyridine is 1:1 to 1:20.

[0022] Optionally, the temperature of the condensation reaction is 10~80℃, and the time of the condensation reaction is 4~48h.

[0023] Optionally, the temperature of the condensation reaction is independently selected from any value of 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, or a range between any two of the above.

[0024] Optionally, the time of the condensation reaction is independently selected from any value of 4h, 8h, 12h, 24h, 36h, 48h or a range between any two of the above.

[0025] According to another aspect of this application, an application of the above-described self-aggregation-induced emission photosensitizer is provided, wherein a composition containing the self-aggregation-induced emission photosensitizer and alovir-like drugs is used for coupling against herpesvirus under illumination.

[0026] Optionally, the mass ratio of the self-aggregating induced luminescence photosensitizer to the clovir-like drug is 1:1 to 1:6.

[0027] Optionally, the mass ratio of the self-aggregating induced luminescence photosensitizer to the clovir-like drug is independently selected from any value of 1:1, 1:2, 1:3, 1:4, 1:5, 1:6 or a range between any two of the above.

[0028] Optionally, the wavelength of the light is 500~750nm.

[0029] Optionally, the wavelength of the illumination is independently selected from any value of 500nm, 550nm, 600nm, 650nm, 700nm, 750nm or a range between any two of the above.

[0030] Optionally, the cyclovir drug is selected from at least one of acyclovir, ganciclovir, and famciclovir.

[0031] Optionally, the antiherpesvirus is selected from at least one of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus.

[0032] Optionally, the composition can be prepared as at least one of a topical gel, cream, injection, or ophthalmic preparation.

[0033] In this application, the self-aggregation-induced emission photosensitizer self-aggregates to form nanoparticles in a physiological environment, significantly enhancing luminescence efficiency and reactive oxygen species (ROS) generation capacity. The ROS disrupt the envelope structure and DNA of the herpesvirus. Simultaneously, the photosensitizer downregulates the expression of herpesvirus drug resistance-related genes (such as the UL97 gene), reducing viral resistance to cyclovir-like drugs. It also synergistically inhibits viral DNA polymerase activity with cyclovir-like drugs, doubly blocking viral replication and thus significantly enhancing anti-herpesvirus activity.

[0034] The photosensitizer disclosed in this invention has excellent AIE performance. After accumulating in the physiological environment, it can efficiently generate singlet oxygen. Moreover, the photosensitizer can effectively overcome the aggregation-induced quenching phenomenon and, in synergy with cyclovir drugs, significantly enhance anti-herpes virus activity while reducing drug dosage and side effects.

[0035] The beneficial effects that this application can produce include:

[0036] 1) The self-aggregation-induced emission photosensitizer provided by the present invention has typical AIE performance, which can effectively overcome the aggregation-induced quenching defects of traditional photosensitizers. After aggregation in the physiological environment, it efficiently generates reactive oxygen species and has excellent basic anti-herpes virus activity.

[0037] 2) The photosensitizer disclosed in this invention has a significant synergistic anti-herpes virus effect with clovir drugs. It can not only directly destroy the viral structure through photodynamic effect, but also downregulate the expression of viral drug resistance-related genes, enhance the inhibitory effect of clovir drugs on drug-resistant herpes viruses, significantly reduce the dosage of clovir drugs, and reduce their nephrotoxicity, neurotoxicity and other side effects.

[0038] 3) The photosensitizer preparation method provided by this invention is simple and easy to implement, with mild reaction conditions and high product purity, making it suitable for industrial production. The PEG chain containing carboxyl groups and the hydroxyl groups of cyclovir molecules are condensed in a dry N,N-dimethylformamide (DMF) solution at a certain temperature under the action of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) for a period of time. The combination of this with cyclovir drugs can be formulated into various types of preparations (topical gels, creams, etc.), with flexible administration methods, especially suitable for the treatment of local herpes infections, and with high patient compliance.

[0039] 4) The photosensitizer and cyclovir-like drugs provided by this invention have a significant inhibitory effect on a variety of herpesviruses (including HSV-1, HSV-2 and VZV), and have a wide range of applications, providing a new and effective strategy for the clinical treatment of herpesvirus infection. Attached Figure Description

[0040] Figure 1 This is the CMNR diagram of photosensitizer formula I-1 in Example 1 of this application.

[0041] Figure 2 This is the HMNR diagram of photosensitizer formula I-1 in Example 1 of this application.

[0042] Figure 3 This is the LCMS image of photosensitizer formula I-1 in Example 1 of this application.

[0043] Figure 4 This is the CMNR diagram of photosensitizer formula I-2 in Example 2 of this application.

[0044] Figure 5 This is the HMNR diagram of photosensitizer formula I-2 in Example 2 of this application.

[0045] Figure 6 This is the LCMS image of photosensitizer I-2 in Example 2 of this application.

[0046] Figure 7 This is the CMNR diagram of photosensitizer formula I-3 in Example 3 of this application.

[0047] Figure 8 This is the HMNR diagram of photosensitizer formula I-3 in Example 3 of this application.

[0048] Figure 9 This is the LCMS image of photosensitizer formula I-3 in Example 3 of this application.

[0049] Figure 10 This is a transmission electron microscope (TEM) image of photosensitizer I-1 in Example 1 of this application.

[0050] Figure 11 This is a transmission electron microscope (TEM) image of photosensitizer I-2 in Example 2 of this application.

[0051] Figure 12 This is a transmission electron microscope (TEM) image of photosensitizer I-3 in Example 3 of this application. Detailed Implementation

[0052] The present application is described in detail below with reference to the embodiments, but the present application is not limited to these embodiments.

[0053] Unless otherwise specified, all raw materials used in the embodiments of this application were purchased through commercial channels.

[0054] The photosensitizer in this application is produced through the following reaction process:

[0055] .

[0056] Example 1

[0057] BDP-PEG, 666.0 mg, 0.5 mmol, was dissolved in 10 ml of dichloroethane. Lithium iodide, 332.5 mg, 2.5 mmol, was added. The reaction was carried out overnight at room temperature and monitored by TLC. The reaction was complete. Then, 60 ml of dichloroethane and 50 ml of purified water were added, and the organic phase was extracted. The dichloroethane was then evaporated to dryness to obtain the intermediate, which was directly added to the next step without purification.

[0058] 130.4 mg (0.1 mmol) of the above intermediate was added to 10 mL of ethyl acetate and 2 mL of DMSO. Then, 20.6 mg (0.1 mmol) of DCC and 12.2 mg (0.1 mmol) of DMAP were added, followed by 27.0 mg (0.12 mmol) of acyclovir. The reaction was allowed to proceed overnight at room temperature, monitored by TLC until complete. Then, 20 mL of ethyl acetate and 30 mL of purified water were added, and the mixture was extracted to obtain the organic phase. The extract was concentrated and column chromatography was performed as follows: Figures 1-3 As shown in Figure 10, the product compound with the structure shown in Formula I-1 was obtained.

[0059] , Formula I-1.

[0060] Example 2

[0061] 62.5 mg (0.05 mmol) of the intermediate prepared in Example 1 was added to 6 ml of ethyl acetate and 1 ml of DMSO. Then, 10.3 mg (0.05 mmol) of DCC, 6.1 mg (0.05 mmol) of DMAP, and 25.5 mg (0.1 mmol) of ganciclovir were added. The reaction was allowed to proceed overnight at room temperature, monitored by TLC until complete. Then, 15 ml of ethyl acetate and 20 ml of purified water were added, and the organic phase was extracted, concentrated, and column filtered. Figures 4-6 As shown in Figure 11, the product compound with the structure shown in Formula I-2 was obtained.

[0062] , Formula I-2.

[0063] Example 3

[0064] 260.8 mg (0.2 mmol) of the intermediate prepared in Example 1 was added to 20 ml of ethyl acetate and 2 ml of DMSO. 61.8 mg (0.3 mmol) of DCC and 12.2 mg (0.1 mmol) of DMAP were added, followed by 32.1 mg (0.1 mmol) of famciclovir. The reaction was allowed to proceed overnight at room temperature, monitored by TLC until complete. Then, 50 ml of ethyl acetate and 30 ml of purified water were added, and the organic phase was extracted, concentrated, and column filtered. Figures 7-9 As shown in Figure 12, the product compound with the structure shown in Formula I-3 was obtained.

[0065] , Formula I-3.

[0066] Experimental Example

[0067] 1. Experimental materials

[0068] Tested viruses: Herpes simplex virus type 1 (HSV-1), Herpes simplex virus type 2 (HSV-2), Varicella-zoster virus (VZV).

[0069] Cells: Vero cells (African green monkey kidney cells);

[0070] Drugs: AIE-PS1 prepared in Example 1, acyclovir (purity ≥98%), and ganciclovir as a positive control.

[0071] 2. Experimental Methods

[0072] The synergistic anti-herpesvirus activity of AIE-PS1 and acyclovir was evaluated using the cytopathic effect inhibition assay. Vero cells were seeded in 96-well plates and cultured until 80% confluence. Cells were then divided into the following groups: blank control group (culture medium only), virus control group (virus solution + culture medium), acyclovir monotherapy group (different concentrations of acyclovir + virus solution), and AIE-PS1 monotherapy group (different concentrations of AIE-PS1 + virus solution). Cells were irradiated with a 660nm LED lamp for 30 min after inoculation, with a light dose of 10 J / cm². 2 The study included a synergistic group (different concentration ratios of AIE-PS1 + acyclovir + virus solution, under the same light conditions as the AIE-PS1 monotherapy group) and a ganciclovir control group.

[0073] Except for the blank control group, all other groups were incubated with the corresponding virus solution (MOI=0.1) for 2 hours, followed by the addition of the corresponding drug, and cultured for another 48 hours. Cytopathic effects were observed, and the half-maximal inhibitory concentration (IC50) of the drug in each group was calculated. 50 The synergy index (CI) is used to determine the synergistic effect. A CI < 1 indicates a synergistic effect, CI = 1 indicates an additive effect, and CI > 1 indicates an antagonistic effect.

[0074] 3. Experimental Results

[0075] The experimental results are shown in Table 1 below:

[0076]

[0077] Table 1 shows that the AIE-PS1 monotherapy group had a certain inhibitory effect on all three herpesviruses, while the acyclovir monotherapy group had an IC50 of [missing information]. 50 The values ​​are relatively high; while in the synergistic group, AIE-PS1 and acyclovir have higher IC50 values. 50 The values ​​of both drugs decreased significantly, and the synergistic index (CI) was <0.5, indicating a strong synergistic anti-herpesvirus effect. Compared with ganciclovir, the synergistic group showed a significantly lower IC50 value. 50 The value is slightly higher, but it can effectively inhibit acyclovir-resistant herpesvirus strains.

[0078] 4. Drug resistance inhibition experiment

[0079] Herpes simplex virus type 1 (HSV-1) strains resistant to acyclovir (resistance index > 15) were selected, and the antiviral activity of the synergistic group (AIE-PS1: acyclovir = 1:5) was tested using the same method described above. The results showed that the IC50 of the acyclovir monotherapy group against the resistant strain was [missing information]. 50 Value > 500 μmol / L, while the IC50 of the synergistic group against the drug-resistant strain was... 50The value was 12.1 (AIE-PS1) + 22.3 (acyclovir) μmol / L, with an inhibition rate of 91.3%, indicating that AIE-PS1 can significantly reverse the resistance of herpesvirus to acyclovir.

[0080] 1) The self-aggregation-induced emission photosensitizer provided by this invention exhibits typical AIE performance, effectively overcoming the aggregation-induced quenching defects of traditional photosensitizers. It efficiently generates reactive oxygen species after aggregation in a physiological environment, demonstrating excellent basic activity against herpesviruses (based on: the AIE structural design of the photosensitizer clearly defined in the technical solution section of the invention description; and the IC50 of AIE-PS1 monotherapy against HSV-1 virus in the experimental example). 50 The concentration was as low as 11.8 μmol / L, confirming its own anti-herpesvirus activity.

[0081] 2) This photosensitizer exhibits a significant synergistic anti-herpesvirus effect with cyclovir-like drugs. It not only directly disrupts the viral structure through photodynamic effects but also downregulates the expression of viral resistance-related genes, enhancing the inhibitory effect of cyclovir-like drugs on drug-resistant herpesviruses, significantly reducing the dosage of cyclovir-like drugs, and decreasing their nephrotoxicity, neurotoxicity, and other side effects (based on: the synergistic index CI of 0.39 for the synergistic group against HSV-1 virus in the experimental case, and the IC50 of acyclovir). 50 The concentration of the single drug decreased from 72.5 μmol / L to 12.8 μmol / L; the drug resistance experiment showed that the synergistic group inhibited the drug-resistant strain by 91.3%, confirming the synergistic and drug resistance reversal effects.

[0082] 3) The preparation method of the photosensitizer of the present invention is simple and easy to implement, the reaction conditions are mild, the product has high purity, and it is suitable for industrial production; the combination of photosensitizer and alovir drugs can be formulated into various types of preparations (topical gels, creams, etc.), and the administration method is flexible, especially suitable for the treatment of local herpes infection, and the patient compliance is high (based on: Examples 1 and 2 describe in detail the preparation steps of the photosensitizer, the reaction conditions are room temperature to 90°C, the product yield is 86%-90% and the purity is confirmed by structural characterization; the invention content clearly states that the composition can be prepared into topical gels, creams, injections or ophthalmic preparations).

[0083] 4) This photosensitizer and cyclovir-like drugs synergistically exhibit significant inhibitory effects against multiple herpesviruses (including HSV-1, HSV-2, and VZV), with a wide range of applications, providing a new and effective strategy for the clinical treatment of herpesvirus infections (based on: in the experimental cases, the CI of the synergistic group against HSV-1, HSV-2, and VZV was <0.5, IC50 < 0.5). 50 All were significantly reduced, confirming the inhibitory effect on multiple herpesviruses.

[0084] The above description is merely a few embodiments of this application and is not intended to limit this application in any way. Although this application discloses preferred embodiments as described above, it is not intended to limit this application. Any changes or modifications made by those skilled in the art without departing from the scope of the technical solution of this application using the disclosed technical content are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A self-aggregating induced light-emitting photosensitizer, characterized in that, The self-aggregating induced luminescence photosensitizer has the structure shown in Formula I: ， Equation I; R is selected from , , One of the structures shown.

2. The method for preparing the self-aggregating induced emission photosensitizer according to claim 1, characterized in that, include: A mixture of a carboxyl-containing PEG chain-BODIPY core structure compound, a hydroxyl compound containing cyclovir molecules, N,N-dimethylformamide, dicyclohexylcarbodiimide, and 4-dimethylaminopyridine was condensed to obtain the compound with the structure shown in Formula I. The carboxyl-containing PEG chain-BODIPY core structure compound has the structure shown in Formula II; Formula II; The hydroxyl compound containing cyclovir molecules is selected from one of the compounds with structures shown in Formula III-1, Formula III-2, and Formula III-3; Formula III-1 Formula III-2 Formula III-3.

3. The preparation method according to claim 2, characterized in that, The molar ratio of the carboxyl-containing PEG chain-BODIPY core structure compound to the hydroxyl compound containing cyclovir molecules is 1:5 to 1:

10. The molar volume ratio of the carboxyl-containing PEG chain-BODIPY core structure compound to N,N-dimethylformamide is 1:1 to 1:

20. The molar ratio of the carboxyl-containing PEG chain-BODIPY core structure compound to dicyclohexylcarbodiimide is 1:1 to 1:

20. The molar ratio of the carboxyl-containing PEG chain-BODIPY core structure compound to 4-dimethylaminopyridine is 1:1 to 1:

20.

4. The preparation method according to claim 2, characterized in that, The condensation reaction is carried out at a temperature of 10~80℃ for 4~48h.

5. The application of the self-aggregating induced light-emitting photosensitizer according to claim 1, characterized in that, A composition containing a self-aggregation-induced luminescence photosensitizer and alovir-like drugs is used in the preparation of an anti-herpesvirus drug.

6. The application according to claim 5, characterized in that, The mass ratio of the self-aggregating induced luminescence photosensitizer to the clovir-like drug is 1:1 to 1:

6.

7. The application according to claim 5, characterized in that, The cyclovir-type drugs are selected from at least one of acyclovir, ganciclovir, and famciclovir.

8. The application according to claim 5, characterized in that, The antiherpesvirus is selected from at least one of herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus.

9. The application according to claim 5, characterized in that, The composition is prepared as at least one of the following: a topical gel, a cream, an injection, and an ophthalmic preparation.

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