CN111689937A - Hydrogen peroxide activated aspirin visual prodrug and preparation method and application thereof - Google Patents

Hydrogen peroxide activated aspirin visual prodrug and preparation method and application thereof Download PDF

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CN111689937A
CN111689937A CN202010716794.7A CN202010716794A CN111689937A CN 111689937 A CN111689937 A CN 111689937A CN 202010716794 A CN202010716794 A CN 202010716794A CN 111689937 A CN111689937 A CN 111689937A
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aspirin
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王鹏
徐艳琪
夏丽丽
崔梦园
任翔宇
刘天广
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China Pharmaceutical University
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Abstract

The invention discloses a hydrogen peroxide activated aspirin visual prodrug, a preparation method and application thereof, and salicylic acid is used as hydrogen peroxide (H)2O2) A novel responsive group, aspirin, is incorporated into the pyranonitrile (DCM) dye structure, synthesizing a novel hydrogen peroxide-responsive aspirin prodrug (DA). The prodrug molecule is substituted with H2O2Activating and releasing active aspirin, and can be used for endogenous and exogenous H2O2Has high selectivity cell imaging. Prodrug DA can be used as an effective tool for tracking H in vivo system2O2Associated pathological reactions, and aspirin which is cleaved after the reactionAnd also has potential prospect in the aspect of being applied to the treatment of related diseases as a therapeutic drug.
Figure DDA0002598476720000011

Description

Hydrogen peroxide activated aspirin visual prodrug and preparation method and application thereof
Technical Field
The invention relates to a prodrug, a preparation method and application thereof, in particular to a hydrogen peroxide activated aspirin visualized prodrug, a preparation method and application thereof.
Background
The design concept of prodrugs is based on the accepted theory that protection-deprotection of reactive groups during organic chemical synthesis is to avoid unwanted side reactions. Prodrugs are known drugs that are masked by a specific protecting group that can be cleaved by a specific target molecule that is overexpressed in the diseased cell, releasing the active drug. Prodrugs have been developed in that they can improve specific targeting and thereby reduce side effects. In addition, other undesirable characteristics of the drug may be improved, such as poor solubility and low cellular absorption.
Aspirin, a classic non-steroidal anti-inflammatory drug, has been widely used in fever, pain and inflammatory diseases. In addition, many studies have shown that chronic administration of aspirin can effectively reduce the incidence of cancer, delay the malignant process, reduce the risk of tumor metastasis, and thus reduce the cancer mortality. Indeed, preclinical studies have shown that aspirin is able to inhibit tumor growth in animal models of various cancers. Recent studies found that aspirin inhibited tumor metastasis and angiogenesis by targeting Heparanase (HPSE). Heparanase is a carcinogenic extracellular matrix enzyme and has important significance for the cleavage of the glycosidase heparan sulfate chain in mammals. Aspirin can inhibit tumor metastasis, angiogenesis and growth in a heparanase-dependent manner at millimolar concentrations by binding directly to the heparanase Glu225 region and inhibiting enzymatic activity. Meanwhile, clinical research finds that aspirin serving as an inhibition epitope can enter the active site of heparanase to inhibit the expression of the heparanase. However, high doses of aspirin cause some adverse effects, particularly with varying degrees of gastroduodenal mucosal damage, including erosion, ulceration and bleeding. More importantly, the application of free aspirin is hindered by the defects of low efficiency of targeting to tumor sites, instability in vivo and easy removal.
To date, several aspirin prodrugs are being explored, primarily with the advantage of reducing the side effects of aspirin. For example, Huang et al, which use aspirin as a lead, directly conjugated to galactose, did have lower cytotoxicity than aspirin alone, with a galactose-linked prodrug. However, they lack signaling reporters and do not provide effective information to monitor the progress of drug release. Therefore, it is of great interest to develop aspirin prodrugs coupled to fluorophore conjugates that can track the uptake of the prodrug in vivo and visualize the release process of the activated drug in the tumor.
The reported fluorophores including coumarins, naphthalimides, xanthines, etc., have limited their use for in vivo imaging due to their short wavelength, insufficient penetration into skin and subcutaneous tissue, and other drawbacks.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a hydrogen peroxide activated aspirin visualized prodrug, the molecule can be specifically activated by hydrogen peroxide to release a drug molecule aspirin, and the visualization of drug release and the quantification of hydrogen peroxide can be realized through the opening of a fluorescent group DCM. The invention also aims to provide a preparation method of the prodrug. It is a further object of the present invention to provide such prodrugs in p-H2O2Responsive detection of and cellular endogenous and exogenous H2O2To an imaging system of (1).
The technical scheme is as follows: the hydrogen peroxide activated aspirin visual prodrug has a structural formula shown in a formula (I):
Figure BDA0002598476700000021
the preparation method of the hydrogen peroxide activated aspirin visualized prodrug comprises the following steps:
(1) placing 2- (2-methyl-4H-chromium-4-methylene) malononitrile and 4-hydroxybenzaldehyde into a three-neck flask filled with anhydrous toluene, adding piperidine and acetic acid under the protection of nitrogen, heating and refluxing, and purifying a reaction solution to obtain a compound DCM-OH, wherein the structural formula is as follows:
Figure BDA0002598476700000022
(2) dissolving aspirin in dry dichloromethane in a three-neck flask, and adding catalyst pyridine under the protection of nitrogen; placing a three-necked flask in an ice bath, dropwise adding thionyl chloride into the mixed solution after cooling, stirring in the ice bath, then stirring the reaction solution at room temperature until the color of the reaction solution becomes yellow, and rotationally evaporating the solvent to obtain a compound a;
(3) the obtained compound a was added to a solution of DCM-OH in anhydrous dichloromethane, followed by addition of triethylamine, the mixture was stirred at room temperature, and the reaction solution was purified to obtain compound (I), i.e., prodrug DA.
The hydrogen peroxide activated aspirin visualized prodrug is in the para-H2O2The use in the detection of responsiveness of (1).
The application comprises the following steps:
and (3) co-incubating the hydrogen peroxide activated aspirin visual prodrug DA with hydrogen peroxide solutions with different concentrations in a PBS (phosphate buffer solution) containing DMSO (dimethyl sulfoxide), and taking out the reaction solution after the co-incubation is finished to measure the ultraviolet absorption spectrum or the fluorescence emission spectrum of the reaction solution.
The hydrogen peroxide activated aspirin visualized prodrug has endogenous and exogenous H in cells2O2To an imaging system of (1).
Has the advantages that: compared with the prior art, the invention has the following remarkable characteristics: (1) from the change of fluorescence intensity before and after response, H can be rapidly detected2O2And the aim of rapid detection is fulfilled. (2) The prodrug is relatively simple to synthesize and is compatible with H2O2Response toIs based on H2O2Catalyzing hydrolysis of the ester bond to release the fluorophores DCM and aspirin. (3) The prodrug is characterized by no fluorescence per se but can react with H2O2After the rapid reaction, obvious fluorescence enhancement is generated, thereby realizing H2O2And (4) selective and rapid detection. Therefore, the invention can be used as an effective tool for tracking the in-vivo system and H2O2Related pathological reactions, and the salicylic acid part disconnected after the reaction has potential prospect of being applied to the aspect of tumor treatment as a therapeutic drug.
Drawings
FIG. 1 shows prodrugs DA and H2O2Response mass spectrogram of the reacted solution;
FIG. 2 shows prodrugs DA and H2O2Fluorescence emission spectrum of the reacted solution;
FIG. 3 shows the fluorescence intensity of prodrug DA (10. mu.M) in PBS buffer as a function of H2O2(0-400 μ M) concentration trend and linear relationship;
FIG. 4 is an image of HepG2 live cells of prodrug DA under different conditions.
Detailed Description
Example 1
Preparation of prodrug DA
1. The preparation steps are as follows:
(1) synthesis of fluorophore: o-hydroxyacetophenone (2.5g, 18.3mmol) was weighed into a 100mL round-bottomed flask, 30mL of ethyl acetate was measured and added to the round-bottomed flask, then sodium (2.0g, 85mmol) was added to the flask, and the mixture was stirred at room temperature for 2.5 h. After the reaction, the residue was filtered, dissolved in water, and acidified to neutral with acetic acid. Spin-dry on a rotary evaporator to give compound 1.
Figure BDA0002598476700000031
Compound 1(1.0g, 5.6mmol) was weighed into a 100mL round bottom flask and acetic acid (30mL) was added to the flask and refluxed for 0.5h in the presence of 2.0mL sulfuric acid, then the reaction mixture was poured into crushed ice, neutralized with sodium carbonate and extracted with dichloromethane. Finally the solvent was removed and recrystallized from ethanol to give gray solid 2.
Figure BDA0002598476700000041
Compound 2(1.0g, 6.2mmol) was weighed into 10.0mL of acetic anhydride containing malononitrile (0.5g, 7.5 mmol). After refluxing for 13h, concentration under reduced pressure gave a mixture. The concentrated mixture was then added to a round bottom flask containing water (30mL) and refluxed for 0.5 h. Finally, crude product is obtained by filtration, and the crude product is recrystallized from ethanol to obtain gray solid 3.
Figure BDA0002598476700000042
Weighing the compound 3(100.0mg, 0.48mmol) and 4-hydroxybenzaldehyde (52.3mg, 0.48mmol) and placing in a three-neck flask containing 30.0mL of anhydrous toluene, adding piperidine (1.0mL) and acetic acid (0.5mL) under the protection of nitrogen, heating to 120 ℃ for refluxing for 13h, and performing rotary drying through a rotary evaporator to obtain the target product DCM-OH.
Figure BDA0002598476700000043
(2) Prodrug molecule: aspirin (5.0g, 27mmol) was weighed out and dissolved in dry dichloromethane (100mL) in a three-necked flask, and the catalyst pyridine (2.30mL) was added under nitrogen. The three-necked flask was placed in an ice bath, thionyl chloride (3.2mL) was slowly added dropwise to the mixture after cooling with a syringe, and after stirring in the ice bath for 20min, the reaction was stirred vigorously at room temperature for 6h until the color of the reaction became yellow. The solvent was spun off on a rotary evaporator to give a yellow solid, compound a.
Figure BDA0002598476700000051
(3) Target compound DA: the obtained compound a (75mg, 0.38mmol) was added to a solution of DCM-OH (100mg, 0.32mmol) in anhydrous dichloromethane (7.5mL) at 0 deg.C, followed by the addition of three drops of Triethylamine (TEA). The mixture was stirred at room temperature overnight, and finally, the solvent was removed by a rotary evaporator and purified to give compound DA.
Figure BDA0002598476700000052
3. Prodrug DA solution and different concentration gradients H2O2Preparation of the solution
We prepared solutions of prodrug DA at different concentrations using PBS solution (pH 7.4 with 50% DMSO); use of distilled water to prepare H with different concentrations2O2A solution; the DCM-OH solution is obtained from DA and H2O2Obtained after reaction.
Weighing 4.7mg of prodrug DA, dissolving in 10mL of DMSO solution, and preparing into standard solution with the concentration of 1 mM; similarly, 3.1mg of the fluorophore DCM-OH is dissolved in 10mL of DMSO solution to prepare a standard solution with the concentration of 1 mM; and diluting the hydrogen peroxide standard solution into mother liquor with different concentrations to prepare the standard solution. 4mL EP tubes were taken, 2mL PBS (10mM, pH 7.4) buffer and 40 μ L prodrug DA standard (10 μ M) were added to the tubes, and then different concentrations of H were added2O2The standard solution was added to the reaction system, and the volume of the reaction system was adjusted to 4mL with a DMSO solution.
Example 2
Prodrugs DA and H2O2Response mass spectrum of solution after reaction.
This example relates to prodrug DA solutions and H2O2The preparation procedure of the solution was the same as in example 1, and the other specific procedures were as follows: to the prodrug DA solution (10. mu.M) prepared in example 1 was added H2O2The solution (400. mu.M) was incubated in PBS (10mM, pH 7.4, 50% DMSO) for 30min at 37 ℃ in a constant temperature shaker, and CH was added to the solution2Cl2And extracting and collecting an organic layer. The solution was removed by rotary evaporator to give a tea brown solid whose structure was characterized by mass spectrometry. As shown in FIG. 1, a peak of DCM-OH appeared in the solution after the reaction,this result indicates that H2O2Catalyzing hydrolysis of the ester bond to release the fluorophore DCM.
Example 3
This example relates to prodrug DA solutions and H2O2The preparation procedure of the solution was the same as in example 1, and the other specific procedures were as follows: to a reaction system PBS buffer (10mM, pH 7.4, 50% DMSO) containing prodrug DA (10 μ M) was added H at various concentrations2O2The solution (0-400. mu.M) was incubated in a constant temperature shaker at 37 ℃ for 30 min. Fluorescence measurements of the solutions were performed on an Edinburgh FS5 fluorescence spectrometer at room temperature. Under the excitation of 560nm wavelength, the slit width is set as 5.0/7.0nm, and the fluorescence emission spectrum of the solution in the 600-850nm wave band is collected. As shown in fig. 2, prodrug DA showed almost no fluorescence emission. Addition of H2O2Then, the prodrug DA solution has a clear fluorescence emission peak at 705 nm. This result indicates that H is added2O2The change in the spectral properties of the prodrug DA solution then facilitates the generation of DCM-OH.
Example 4
This example relates to prodrug DA solutions and H2O2The preparation procedure of the solution was the same as in example 1, and the other specific procedures were as follows: to the prodrug DA solution prepared in example 1, H was added at various concentrations2O2The solution (0-400. mu.M) was incubated in a constant temperature shaker at 37 ℃ for 30 min. Fluorescence measurements of the solutions were performed on an Edinburgh FS5 fluorescence spectrometer at room temperature. Under the excitation of 560nm wavelength, the slit width is set as 5.0/7.0nm, and the fluorescence emission spectrum of the solution in the 600-850nm wave band is collected. As shown in FIG. 3, we can see that the fluorescence intensity curve of DA is dependent on H2O2In addition, the detection limit is calculated to be as low as 1.9 × 10-8And M. The prodrug DA has high sensitivity and can be used for detecting endogenous hydrogen peroxide in a biological system.
Example 5
The preparation procedure of the prodrug DA solution in this example is the same as that in example 1, and the other specific steps are as follows: HepG2 cells were arranged in three groups. Respectively without additional treatment group and lipopolysaccharide(Lipopolysaccharide, LPS) inducer and plus H2O2Induction group cells in logarithmic growth phase were digested, centrifuged, and prepared in 10% FBS-containing DMEM medium to 4 × 105Cell/well Density, the cell suspension was added to laser confocal culture dishes, 1mL of cell suspension was added per dish in 5% CO2Adherent monolayers were formed by overnight incubation in 37 ℃ incubator and lipopolysaccharide (LPS, 10. mu.g mL) was added when cell density reached 60% -70% respectively-1) Inducing for half an hour and adding H2O2Solution (100 μ M) was induced for half an hour, the other group was left untreated, then three groups were incubated for half an hour in an incubator with 10 μ LDA (1mM) DMSO solution, the mixture was removed, washed three times with PBS, and fixed with 4% paraformaldehyde. And finally, performing cell imaging by using an FV-1000 laser confocal microscope. As shown in fig. 4, HepG2 cells in the control group were treated with prodrug DA only, showing weak fluorescent signal. Through H2O2Or LPS-pretreated HepG2 cells were incubated with DA (10. mu.M) in a 37 ℃ cell incubator for 30min, and strong intracellular fluorescence was observed. Thus, the prodrug DA can be converted to endogenous and exogenous H in living cells2O2Effective activation and has good application prospect in the fields of biology and medicine.

Claims (5)

1. A hydrogen peroxide activated aspirin visualization prodrug having the structural formula shown in formula (I):
2. a method of preparing a hydrogen peroxide activated aspirin visualization prodrug as claimed in claim 1, comprising the steps of:
(1) placing 2- (2-methyl-4H-chromium-4-methylene) malononitrile and 4-hydroxybenzaldehyde into a three-neck flask filled with anhydrous toluene, adding piperidine and acetic acid under the protection of nitrogen, heating and refluxing, and purifying a reaction solution to obtain a compound DCM-OH, wherein the structural formula is as follows:
Figure FDA0002598476690000012
(2) dissolving aspirin in dry dichloromethane in a three-neck flask, and adding catalyst pyridine under the protection of nitrogen; placing a three-necked flask in an ice bath, dropwise adding thionyl chloride into the mixed solution after cooling, stirring in the ice bath, then stirring the reaction solution at room temperature until the color of the reaction solution becomes yellow, and rotationally evaporating the solvent to obtain a compound a;
(3) the obtained compound a was added to a solution of DCM-OH in anhydrous dichloromethane, followed by addition of triethylamine, the mixture was stirred at room temperature, and the reaction solution was purified to obtain compound (I), i.e., prodrug DA.
3. The hydrogen peroxide activated aspirin visualization prodrug of claim 1 in para-H2O2The use in the detection of responsiveness of (1).
4. Use according to claim 3, characterized in that it comprises the following steps:
and (3) co-incubating the hydrogen peroxide activated aspirin visual prodrug DA with hydrogen peroxide solutions with different concentrations in a PBS (phosphate buffer solution) containing DMSO (dimethyl sulfoxide), and taking out the reaction solution after the co-incubation is finished to measure the ultraviolet absorption spectrum or the fluorescence emission spectrum of the reaction solution.
5. The hydrogen peroxide activated aspirin visualization prodrug of claim 1 in cells with endogenous and exogenous H2O2To an imaging system of (1).
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Cited By (1)

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CN112608329A (en) * 2020-12-28 2021-04-06 桂林南药股份有限公司 Artemisinin derivative and preparation method and application thereof

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CN108395460A (en) * 2018-01-31 2018-08-14 广州医科大学 A kind of weary oxygen activation adriamycin prodrug and preparation method thereof
CN111349108A (en) * 2020-03-09 2020-06-30 中国科学院长春应用化学研究所 Aspirin derivative and preparation method, medicine and application thereof

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CN106924749A (en) * 2017-05-16 2017-07-07 西南大学 A kind of preparation method of the targeting small molecule prodrugs of pH responses and Synergistic treatment
CN107266483A (en) * 2017-06-08 2017-10-20 浙江工业大学 A kind of hydrogen peroxide that responds kills photaesthesia targeting anti-tumor prodrug of tumour cell and preparation method and application
CN108129468A (en) * 2018-01-29 2018-06-08 四川理工学院 A kind of aspirin derivatives and its preparation method and application
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112608329A (en) * 2020-12-28 2021-04-06 桂林南药股份有限公司 Artemisinin derivative and preparation method and application thereof
CN112608329B (en) * 2020-12-28 2022-02-18 桂林南药股份有限公司 Artemisinin derivative and preparation method and application thereof

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