CN114230595A - Positive-charged BODIPY photosensitizer and preparation method and application thereof - Google Patents

Positive-charged BODIPY photosensitizer and preparation method and application thereof Download PDF

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CN114230595A
CN114230595A CN202111581644.0A CN202111581644A CN114230595A CN 114230595 A CN114230595 A CN 114230595A CN 202111581644 A CN202111581644 A CN 202111581644A CN 114230595 A CN114230595 A CN 114230595A
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bodipy
photosensitizer
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孙婷婷
谢志刚
吴起航
文慧
柳时
景遐斌
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Changchun Institute of Applied Chemistry of CAS
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Abstract

The invention relates to several positively charged BODIPY photosensitizers, and a preparation method and application thereof, and belongs to the technical field of photosensitizers. Solves the prior artThe medium BODIPY photosensitizer has poor water solubility, and the photodynamic effect is further enhanced. The structural formula of the positively charged BODIPY photosensitizer is shown as a formula I. The positively charged BODIPY photosensitizer can efficiently generate active oxygen under the condition of illumination, effectively acts on microorganisms such as bacteria and viruses, does not influence the survival of normal cells, does not contain antibiotics or hormones, does not generate drug resistance, has small side effect, is safe, non-toxic and non-irritant, and has wide application space.
Figure DDA0003426263760000011

Description

Positive-charged BODIPY photosensitizer and preparation method and application thereof
Technical Field
The invention belongs to the technical field of photosensitizers, and particularly relates to several positively charged BODIPY photosensitizers, and preparation methods and applications thereof, in particular to application of the positively charged BODIPY photosensitizers in preparation of drugs for resisting microbial infection.
Background
Bacterial resistance is a hotspot of global concern in the 21 st century. The use of antibiotics, as represented by the discovery of penicillin, has extended the average human life by more than 15 years. However, the abuse of antibiotics has led to a significant increase in bacterial resistance, which is a serious threat to human health. It is reported that by 2050, more deaths due to multi-drug resistant (MDR) bacterial infection will be expected than cancer, and will be the main cause of death. Therefore, the development of new antibacterial drugs and therapeutic methods is urgently needed. In addition, as for the current disinfectants, common disinfectants capable of effectively inactivating viruses comprise 75% alcohol, 84-containing disinfectants and the like, wherein the 75% alcohol is flammable, and the 84-containing disinfectants have the defects of toxic chlorine gas release, strong corrosiveness and the like, and are dangerous. Therefore, researchers are continually striving to develop alternative antibacterial and antiviral approaches.
Photodynamic therapy (PDT) is used for antibacterial and antiviral purposes by applying a photosensitizer to the affected area, i.e. the area where the pathogenic microorganisms are located, and then irradiating the area with light of an appropriate wavelength. Photosensitizers interact directly with substrates/solvents under the excitation of light to produce oxygen-containing free radicals (type I reactions) or to produce singlet oxygen (type II reactions). These reactive oxygen species, including oxygen radicals and singlet oxygen, lead to the death of pathogenic microorganisms through lipid peroxidation, membrane damage and organelle damage.
Compared with traditional drug treatment, PDT has the following advantages: (1) can effectively kill most pathogenic microorganisms including viruses, gram-positive bacteria, gram-negative bacteria, yeasts, fungi and parasitic protists; (2) the PDT can destroy the external structure and the internal structure of bacteria, does not generate drug resistance, and is sensitive to photodynamic therapy regardless of multiple treatments or drug-resistant strains. PDT is therefore receiving widespread attention as an alternative to antibiotic therapy, with its non-invasive, spatiotemporal selectivity, low toxic side effects.
PDT contains three elements: photosensitizer, light and oxygen. A highly efficient and safe photosensitizer is key and central to PDT, for which the basic requirements are: the components are single, and the structure is clear; high active oxygen generating efficiency; thirdly, the excretion is quick, and the toxic and side effects are small; fourthly, the water-soluble drug has better water solubility, and is convenient for preparation and administration; fifthly, the medicine can be rapidly taken by pathogenic microorganisms, and the time from the administration to the illumination is short. The requirement of body surface PDT on the illumination depth and the illumination wavelength is relatively low, and the oxygen supply of the superficial layer is also relatively sufficient, so that the light absorption wavelength of the photosensitizer can be selected in a wide range from visible light to near infrared for the PDT of body surface diseases.
In order to make photodynamic therapy more efficient, safe and convenient, and also to find photosensitizers more suitable for PDT in vivo, a number of new photosensitizers with photodynamic properties have been developed. Among them, Boron-dipyrromethene (Boron-dipyrromethene, BODIPY) is the most studied. It is a boron-containing dipyrromethene compound, and the basic skeleton structure is as follows:
Figure BDA0003426263740000021
BODIPY fixes two pyrrole rings through boron bridge bond and methine bridge bondTogether, a rigid coplanar molecular structure is formed, so that the light-absorbing material has the advantages of high extinction coefficient, good illumination stability, insensitivity to chemical environment and the like. H atoms on the aromatic ring of the BODIPY can realize nucleophilic or electrophilic substitution, and the BODIPY is endowed with abundant structures and functions. Firstly, when BODIPY is substituted by heavy atom on pyrrole ring, especially by I or Br at 2-position and 6-position, the triplet population ratio and survival life of photosensitizer excited state can be raised, so that singlet oxygen (C)1O2) The efficiency of production is improved to above 0.8, which is called the "heavy atom effect" of BODIPY. Thus, BODIPY, used in PDT, typically has I or Br substitutions at positions 2 and 6. Secondly, alkyl or conjugated substitution at the pyrrole ring and methine position can reduce the HOMO/LUMO energy gap of the molecule, resulting in a red shift of the absorption peak, which is advantageous for improving the penetration depth and increasing the efficiency of PDT, so BODIPY used in PDT often has such substituent.
Since the cell wall of gram-positive bacteria (G (+)) contains negatively charged teichoic acid, while the outer membrane of gram-negative bacteria (G (-)) is rich in negatively charged Lipopolysaccharide (LPS), many antibacterial drugs can target bacteria through electrostatic interactions. Particularly gram-negative bacteria, which have a strong outer membrane composed of lipopolysaccharide, are generally difficult to penetrate drugs, resulting in difficulty in curing diseases caused by infection thereof. The antibacterial drug with positive charges has strong electrostatic attraction to gram-negative bacteria, and can remarkably improve the antibacterial effect. Therefore, the interaction with bacteria can be enhanced by introducing positive charges into the photosensitizer, thereby enhancing its photodynamic antibacterial effect.
Most of BODIPY photosensitizers have poor water solubility, so that the preparation of the positively charged BODIPY photosensitizer with high active oxygen yield and the preparation of the positively charged BODIPY photosensitizer into water dispersion solve the problem of targeting to bacteria and improve the water solubility of the photosensitizer, and is an urgent need for further improving the curative effect of photodynamic therapy and expanding the range of indications of photodynamic therapy.
Disclosure of Invention
In view of the above, the present invention provides several positive BODIPY photosensitizers, and preparation methods and applications thereof, in order to solve the technical problem of poor water solubility of BODIPY photosensitizers in the prior art, and further enhance the photodynamic effect thereof.
In order to realize the purpose, the following technical scheme is adopted:
the positive BODIPY photosensitizer provided by the invention has the following structural formula:
Figure BDA0003426263740000031
in the formula, R1H or CH3；
R2＝H、CH3、CH＝CH-C6H5Or CH ═ CHC6H4OCH3；
Figure BDA0003426263740000032
Wherein n is 1-11, X-＝I-、Br-、Cl-Or PF6 -；
R4I or Br.
Preferably, the positively charged BODIPY photosensitizer has the structural formula of BODIPY-1 or BODIPY-2:
Figure BDA0003426263740000041
the invention also provides a preparation method of the positive BODIPY photosensitizer with the structural formula of BODIPY-1, which comprises the following steps: reacting compound A with N (CH)3)3Reacting to obtain the BODIPY photosensitizer with quaternary ammonium salt positive electricity;
the structural formula of the compound A is as follows:
Figure BDA0003426263740000042
in the formula, R1H or CH3；
R2＝H、CH3、CH＝CH-C6H5Or CH ═ CHC6H4OCH3；
R4I or Br;
n＝1～11；
X-＝I-、Br-、Cl-or PF6 -。
Preferably, the reaction solvent is ethanol.
The invention also provides a preparation method of the positive BODIPY photosensitizer with the structural formula of BODIPY-2, which comprises the following steps: reacting compound B with P (Ph)3Reacting to obtain a BODIPY compound with quaternary phosphonium salt positive electricity, and reacting with N-iodine/bromosuccinimide to obtain an iodo/bromo BODIPY photosensitizer with quaternary phosphonium salt positive electricity;
the structural formula of the compound B is as follows:
Figure BDA0003426263740000051
in the formula, R1H or CH3；
R2＝H、CH3、CH＝CH-C6H5Or CH ═ CHC6H4OCH3；
n＝1～11；
X-＝I-、Br-、Cl-Or PF6 -。
Preferably, the reaction solvent is acetonitrile.
The invention also provides a water-based dispersion containing the positively charged BODIPY photosensitizer.
Preferably, the final concentration of the positively charged BODIPY photosensitizer in the aqueous dispersion is from 20 to 300. mu.g/mL.
The invention also provides a preparation method of the water-based dispersion liquid, which comprises the following steps:
dissolving a positive BODIPY photosensitizer in an organic solvent to obtain an organic solution, mixing the organic solvent and ultrapure water, stirring at room temperature to remove the organic solvent, centrifuging, and removing precipitates to obtain a supernatant, namely the water-based dispersion liquid.
Preferably, the organic solvent is acetone, methanol, ethanol or dimethyl sulfoxide.
Preferably, the concentration of the positively charged BODIPY photosensitizer in the organic solution is 0.5-2 mg/mL.
Preferably, the volume ratio of the ultrapure water to the organic solution is (5-20): 1.
The invention also provides application of the positively charged BODIPY photosensitizer in preparation of a medicament for resisting microbial infection.
Preferably, the microorganism is one or more of bacteria, viruses and fungi.
The invention also provides the application of the water-based dispersion liquid in preparing a medicament for resisting microbial infection.
Preferably, the microorganism is one or more of bacteria, viruses and fungi.
The principle of the invention is as follows: the solubility of the BODIPY photosensitizer in water and the targeting property of the BODIPY photosensitizer to microorganisms are enhanced by introducing positive charges into the BODIPY photosensitizer, and the uniform and stable dispersion of the BODIPY photosensitizer in water is enhanced by a solvent replacement method (without any auxiliary agent).
Compared with the prior art, the invention has the beneficial effects that:
1. the BODIPY photosensitizer used in the invention has the advantages of simple and clear structure, simple synthesis method and lower production cost.
2. The positive BODIPY photosensitizer prepared by the method has the advantages of higher molar extinction coefficient, lower fluorescence quantum efficiency and higher singlet oxygen generation efficiency. This facilitates their use as PDT photosensitizers. First, lower drug concentrations and doses (20 ng/mL-20. mu.g/mL) can be used, which are much lower (-200 mg/mL) than the currently clinically used 5-aminolevulinic acid (5-ALA). Secondly, the light intensity required by light excitation is about 10-100mW/cm2The range is 5-30min, and the tolerance and compliance of patients are better.
3. The method adopts a solvent replacement method to realize the uniform and stable dispersion of the positively charged BODIPY photosensitizer in water, and the process is simple and quick; besides cheap and easily available acetone, methanol, ethanol, dimethyl sulfoxide and ultrapure water, the method does not use other medicine reagents and has extremely remarkable advantages.
4. The positively charged BODIPY photosensitizer can efficiently generate active oxygen under the illumination condition, effectively acts on microorganisms such as bacteria, viruses and the like, can selectively kill pathogenic microorganisms without influencing the survival of normal cells, does not contain antibiotics or hormones, does not generate drug resistance, has small side effect, is safe, non-toxic and non-irritant, and has wide application space.
5. The positively charged BODIPY photosensitizer has the advantage of adjustable spectrum. Because the BODIPY selected by the invention has strong absorption in the visible light range, the requirement on an excitation light source is reduced, and a common white light or monochromatic light source can be sufficient, so that the body surface PDT method becomes simple, convenient and quick, and a patient can even finish the treatment process at home. The method is favorable for expanding the clinical application range of the BODIPY photosensitizer and bringing higher social and economic benefits.
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In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
In FIG. 1, a and b show the NMR spectrum and mass spectrum, respectively, of BODIPY-1 of example 1.
In FIG. 2, a and b show the NMR spectrum and mass spectrum, respectively, of BODIPY-2 of example 2.
In FIG. 3, a and b show the bactericidal activity of the BODIPY-1 dispersion of example 2 against Staphylococcus aureus in the dark and light conditions, respectively, and c shows the bactericidal activity of the BODIPY-1 dispersion of example 2 against Escherichia coli in the light condition.
In FIG. 4, a and b show the bactericidal activity of the BODIPY-2 dispersion of example 4 against Staphylococcus aureus in dark and light conditions, respectively.
Detailed Description
For a further understanding of the invention, reference will now be made to the preferred embodiments of the invention, but it is to be understood that the description is intended to illustrate further features and advantages of the invention, and not to limit the scope of the claims.
The core structure of the positive BODIPY photosensitizer is iodo/bromo BODIPY substituted by 8-site benzene ring. The structural formula of the positively charged BODIPY photosensitizer is as follows:
Figure BDA0003426263740000071
wherein R is1H or CH3；R2＝H，CH3，CH＝CH-C6H5Or CH ═ CHC6H4OCH3；
Figure BDA0003426263740000072
Figure BDA0003426263740000073
Wherein n is 1 to 11, X-＝I-，Br-，Cl-Or PF6 -；R4I or Br.
In the above technical scheme, preferably, the structural formula of the positively charged BODIPY photosensitizer is BODIPY-1 or BODIPY-2:
Figure BDA0003426263740000081
the positive BODIPY photosensitizer is prepared through a simple chemical reaction, positive charges in different forms are introduced to a substituent at the 8-position of the BODIPY, and photodynamic activity is endowed through an iodine/bromine substitution reaction.
Specifically, the preparation method of the positive BODIPY photosensitizer with the structural formula of BODIPY-1 comprises the following steps:reaction of Compound A with N (CH) in ethanol3)3Reacting to obtain the BODIPY photosensitizer with quaternary ammonium salt positive electricity;
the preparation method of the positive BODIPY photosensitizer with the structural formula of BODIPY-2 comprises the following steps: compound B with P (Ph) in acetonitrile3Reacting to obtain a BODIPY compound with quaternary phosphonium salt positive electricity, and reacting with N-iodine/bromosuccinimide to obtain an iodo/bromo BODIPY photosensitizer with quaternary phosphonium salt positive electricity;
wherein the structural formulas of the compound A and the compound B are respectively as follows:
Figure BDA0003426263740000082
in the formula, R1H or CH3；R2＝H、CH3、CH＝CH-C6H5Or CH ═ CHC6H4OCH3；R4I or Br; n is 1-11; x-＝I-、Br-、Cl-Or PF6 -；
A water-based dispersion of a positively charged BODIPY photosensitizer of the present invention; preferably, the final concentration of the positively charged BODIPY photosensitizer in the aqueous dispersion is 20-300. mu.g/mL.
The preparation method of the water-based dispersion liquid of the positively charged BODIPY photosensitizer comprises the following steps: dissolving the positive BODIPY photosensitizer in an organic solvent to obtain a water-based dispersion liquid. Preferably, the organic solvent is acetone, methanol, ethanol or dimethyl sulfoxide; in the organic solution, the concentration of the positive BODIPY photosensitizer is 0.5-2 mg/mL; the volume ratio of the ultrapure water to the organic solution is (5-20): 1.
The positively charged BODIPY photosensitizer and the water-based dispersion of the present invention are useful in the preparation of a medicament for combating microbial infections. Wherein, the microorganism comprises one or more of bacteria, virus, fungus, actinomycete, rickettsia, mycoplasma, chlamydia and spirochete, and preferably the microorganism is one or more of bacteria, virus and fungus. Specific microbial infections include, but are not limited to: superficial soft tissue infection caused by suppurative pathogenic bacteria, operation incision infection, acne caused by acne bacillus infection, tinea manuum and tinea pedis caused by fungal infection, genital wart, anal wart, flat wart and plantar wart caused by HPV virus infection, herpes caused by HSV virus infection, etc.
The application method of the drug for resisting microbial infection, which is prepared from the positive BODIPY photosensitizer, comprises the steps of coating the drug on an affected part, and irradiating green light or white light with the light intensity of 10-100mW/cm2The illumination time is 5-30 min.
The terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified. In order to make those skilled in the art better understand the technical solution of the present invention, the present invention will be further described in detail with reference to the following embodiments.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art. Materials, reagents, devices, instruments, apparatuses and the like used in the following examples are commercially available unless otherwise specified.
The present invention is further illustrated by the following examples.
Example 1
Synthesis of BODIPY-1
Adding BODIPY-IBr (75mg, 0.1mmol) into a round-bottom flask, adding 15mL of ethanol for dissolving, adding trimethylamine (0.6mL) under stirring at room temperature, refluxing for 24h, and settling with diethyl ether to obtain a product, namely BODIPY-1;
the specific synthetic route is as follows:
Figure BDA0003426263740000101
example 2
Preparation of BODIPY-1 Dispersion
BODIPY-1(1mg) prepared in example 1 was dissolved in 2mL of acetone, and the acetone solution of the dissolved BODIPY-1 was added dropwise to different volumes of ultrapure water under stirring, and the resulting mixed solution was further stirred at room temperature for 8 hours to remove the organic solvent present. Centrifuging, removing precipitate, and collecting supernatant as BODIPY-1 dispersion.
Example 3
Synthesis of BODIPY-2
Adding BODIPY-Br (50mg, 0.1mmol) and triphenylphosphine (28mg, 0.11mmol) into a round-bottom flask, adding 2mL acetonitrile for dissolving, carrying out nitrogen protection, refluxing for 24h, and carrying out ether precipitation to obtain a product, namely BODIPY-TPP.
Adding BODIPY-TPP (27mg, 0.04mmol) and N-iodosuccinimide (NIS, 41mg, 0.18mmol) into a round-bottom flask, adding 10mL of dichloromethane, reacting at room temperature for 7h, and after the reaction is finished, purifying by using dichloromethane and methanol as eluents to obtain a product, namely BODIPY-2;
the specific synthetic route is as follows:
Figure BDA0003426263740000102
example 4
Preparation of BODIPY-2 Dispersion
BODIPY-2(1mg) prepared in example 3 was dissolved in 1mL of acetone, and the acetone solution of the dissolved BODIPY-2 was added dropwise to different volumes of ultrapure water under stirring, and the resulting mixed solution was further stirred at room temperature for 8 hours to remove the organic solvent present. Centrifuging, removing precipitate, and collecting supernatant as BODIPY-2 dispersion.
Nuclear magnetic and mass spectral analyses were performed on BODIPY-1 prepared in example 1 and BODIPY-2 prepared in example 3. The structure and purity of BODIPY-1 (figure 1) and BODIPY-2 (figure 2) were confirmed by NMR hydrogen spectroscopy and mass spectrometry.
The light inactivation efficiency of the BODIPY-1 dispersion prepared in example 2 and the BODIPY-2 dispersion prepared in example 4 was evaluated for Staphylococcus aureus and Escherichia coli. The antibacterial activity of the BODIPY-1 dispersion and the BODIPY-2 dispersion was investigated by growth screening of Staphylococcus aureus or Escherichia coli.
Respectively inoculating staphylococcus aureus and escherichia coli on agar plates,culturing in a constant temperature incubator at 37 ℃ for 12-16h until a single colony grows out. Respectively selecting a single colony to be inoculated in a liquid LB culture medium, and carrying out shake culture at 37 ℃ for 12-16 h. Respectively preparing BODIPY-1 dispersion and BODIPY-2 dispersion with different concentrations, respectively mixing with bacteria (concentration of 105CFU/mL), inoculating to 96-well plate, standing one group in dark for 10min, and irradiating the other group with green light for 10min with light energy density of 7.2J/cm2The dark and light plates were then incubated in an incubator at 37 ℃ for 24h, respectively. The survival rate of the bacteria was calculated by testing the OD values. Each set of experiments was repeated at least three times. The results are shown in FIG. 3 and FIG. 4, and it can be seen that under the condition of illumination, the effective inhibition of Staphylococcus aureus can be realized by lower concentrations of BODIPY-1 and BODIPY-2 (20ng/mL and 0.3 μ g/mL respectively); under the condition of no illumination, the BODIPY-1 and the BODIPY-2 can also realize effective inhibition on staphylococcus aureus. And BODIPY-1 has good inhibition effect on the growth of Escherichia coli under the illumination condition.
It should be understood that the above-described embodiments are merely examples for clarity of description and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither necessary nor exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the spirit or scope of the invention.

Claims (10)

1. The positive BODIPY photosensitizer is characterized by having the following structural formula:
Figure FDA0003426263730000011
in the formula, R1H or CH3；
R2＝H、CH3、CH＝CH-C6H5Or CH ═ CHC6H4OCH3；
Figure FDA0003426263730000012
Wherein n is 1-11, X-＝I-、Br-、Cl-Or PF6 -；
R4I or Br.
2. The positively charged BODIPY photosensitizer of claim 1, having the structural formula BODIPY-1 or BODIPY-2:
Figure FDA0003426263730000013
3. the positively charged BODIPY photosensitizer according to claim 2,
the preparation method of the positive BODIPY photosensitizer with the structural formula of BODIPY-1 comprises the following steps: reacting compound A with N (CH)3)3Reacting to obtain the BODIPY photosensitizer with quaternary ammonium salt positive electricity;
the structural formula of the compound A is as follows:
Figure FDA0003426263730000014
in the formula, R1H or CH3；
R2＝H、CH3、CH＝CH-C6H5Or CH ═ CHC6H4OCH3；
R4I or Br;
n＝1～11；
X-＝I-、Br-、Cl-or PF6 -；
The preparation method of the positive BODIPY photosensitizer with the structural formula of BODIPY-2 comprises the following steps: reacting compound B with P (Ph)3Reacting to obtain the BODIPY compound with quaternary phosphonium salt positive electricity, and reacting with N-Iodine/bromo-succinimide reaction to obtain iodo/bromo BODIPY photosensitizer with quaternary phosphonium salt positive electricity;
the structural formula of the compound B is as follows:
Figure FDA0003426263730000021
in the formula, R1H or CH3；
R2＝H、CH3、CH＝CH-C6H5Or CH ═ CHC6H4OCH3；
n＝1～11；
X-＝I-、Br-、Cl-Or PF6 -。
4. An aqueous dispersion comprising a positively charged BODIPY photosensitizer of claim 1 or 2.
5. The aqueous-based dispersion of claim 4, wherein the final concentration of the positively charged BODIPY photosensitizer in the aqueous-based dispersion is from 20 to 300 μ g/mL.
6. The process for the preparation of the aqueous dispersion according to claim 5, characterized by the following steps:
dissolving a positive BODIPY photosensitizer in an organic solvent to obtain an organic solution, mixing the organic solvent and ultrapure water, stirring at room temperature to remove the organic solvent, centrifuging, and removing precipitates to obtain a supernatant, namely the water-based dispersion liquid.
7. The method of preparing a water-based dispersion according to claim 6,
the organic solvent is acetone, methanol, ethanol or dimethyl sulfoxide;
in the organic solution, the concentration of the positive BODIPY photosensitizer is 0.5-2 mg/mL;
the volume ratio of the ultrapure water to the organic solution is (5-20) to 1.
8. Use of a positively charged BODIPY photosensitizer of claim 1 or 2 in the manufacture of a medicament against microbial infection.
9. Use of the aqueous dispersion of claim 4 in a medicament against microbial infection.
10. Use of a positively charged BODIPY photosensitizer or an aqueous dispersion according to claim 8 or 9, in the manufacture of a medicament against microbial infection, wherein the microorganism is one or more of a bacterium, a virus, a fungus.
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