CN113214297A - Organic boron photosensitizer based on aggregation-induced emission and application thereof in treating multiple drug-resistant bacterial infection - Google Patents
Organic boron photosensitizer based on aggregation-induced emission and application thereof in treating multiple drug-resistant bacterial infection Download PDFInfo
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- CN113214297A CN113214297A CN202010058421.5A CN202010058421A CN113214297A CN 113214297 A CN113214297 A CN 113214297A CN 202010058421 A CN202010058421 A CN 202010058421A CN 113214297 A CN113214297 A CN 113214297A
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- photosensitizer
- dma
- organoboron
- organic boron
- multiple drug
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Abstract
The invention relates to an organic boron photosensitizer based on aggregation-induced emission, a preparation method thereof and application thereof in photodynamic therapy for multi-drug-resistant bacterial infection. The series of organic boron photosensitizers synthesized by the invention based on aggregation-induced emission are easy to synthesize, show good aggregated state luminescence and active oxygen generation characteristics, are used as photosensitizers for labeling and photodynamic treatment of multiple drug-resistant bacteria infection, and have important significance and value in the technical field of biological medicine.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to an organic boron photosensitizer based on aggregation-induced emission characteristics, a preparation method thereof and application thereof in the treatment of multiple drug-resistant bacterial infection.
Background
Multi-drug resistant bacteria (MDR bacteria), also known as multidrug resistant microorganisms, occur as a result of bacterial mutation and overuse of antibacterial drugs, and refer to bacteria that are resistant (one or more) to three or more classes (different in structure or mechanism of action) of antibacterial drugs simultaneously. The problem of nosocomial infections caused by bacterial resistance and multidrug-resistant bacteria is becoming more and more serious. Over the past 30 years, due to bacterial mutation, abuse of antibacterial drugs and other problems, drug resistant strains have increased and spread, and even fully resistant bacteria have emerged that have developed full resistance to commonly used antibacterial drugs. With current development, the problem of bacterial resistance has become a significant public health and social problem. The major risk factors for multiple drug resistant bacterial infections often occur in Intensive Care Units (ICU), long term hospitalized patients, former recipients of antibacterial medications, during intubation or invasive procedures (catheters, central venous catheters, nasogastric tubes, artificial airways + mechanical ventilation), and the use of immunosuppressive agents. Clinically common multi-drug resistant bacteria include methicillin-resistant staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extended-spectrum beta-lactamase (ESBLs) -producing bacteria, carbapenem-resistant enterobacteriaceae (CRE, including NDM-1 and KPC-producing enterobacteriaceae), carbapenem-resistant acinetobacter baumannii (CR-AB), multi-drug-resistant pseudomonas aeruginosa (MDR-PA), multi-drug-resistant mycobacterium tuberculosis (MDR-TB), Clostridium Difficile (CD), and the like. Infection caused by multiple drug-resistant bacteria is characterized by complexity, difficult treatment and the like, and mainly infects respiratory systems, urinary systems, blood systems, operation parts and the like. In recent years, multidrug-resistant bacteria have become important pathogenic bacteria for nosocomial infections.
An aggregation-induced emission (AIE) type fluorescent material hardly emits light in a solution, and enhances light emission in an aggregated state or under a solid thin film. Recent studies report that the AIE luminescent materials (AIE molecules, AIE fluorophores, aiegens) in the aggregation state greatly reduce the non-radiative energy loss of the unimolecular state due to the intramolecular motion limitation, and at the same time, the increase of the matching ratio between the singlet state and the triplet state energy level due to aggregation is favorable for the exciton of the excited state to cross over from the singlet state to the T triplet state via intersystem crossing (ISC), thereby improving the generation efficiency of Reactive Oxygen Species (ROS), which is referred to as aggregation-induced ROS-generation. The molecular material constructed based on AIE characteristics has an aggregation-induced intersystem crossing mechanism different from the limitation of the traditional fluorescent probe, can realize the simultaneous enhancement of fluorescence quantum yield and photodynamic effect, and is further favorable to be used as a photosensitizer with high efficiency for photodynamic therapy (PDT) for multi-drug resistant bacterial infection. The AIE type photosensitizer can effectively reduce the abuse of antibiotics through the photodynamic treatment of multiple drug-resistant bacteria infection, can achieve the functions of killing multiple drug-resistant bacteria, protecting tissues and the like, and has important significance and value as the technical field of new generation biological medicines.
Disclosure of Invention
The invention aims to provide an organic boron photosensitizer with aggregation-induced emission characteristics, a preparation method and application thereof, and solves the problems of clinical drug resistance of multi-drug-resistant bacteria, poor inhibition or killing of the multi-drug-resistant bacteria and the like in the prior art.
The technical scheme adopted by the invention for solving the technical problem is as follows: an organic boron photosensitizer based on aggregation-induced emission characteristics, wherein the structural formula of the organic boron photosensitizer is shown as formula I:
wherein Ar is1And Ar2Each independently selected from the group of any of the following structural formulae:
wherein R is1The number of substitutions may be from 1 to 5 and is independently selected from H, CF3Cyano (CN), Nitro (NO)2) One of halogen, hydroxyl, amine, optionally substituted alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, acyl, aryl, heterocyclyl, heteroaryl, heterocycloalkyl, monoalkylamine, or dialkylamino; r2Independently selected from one of H, alkyl, optionally substituted alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, aryl, heterocyclyl, heteroaryl, heterocycloalkyl, monoalkylamino, or dialkylamino; x is independently selected from one of halide, acetate, dihydrogen phosphate, hydrogen sulfate, tetrafluoroborate, hexafluorophosphate and sulfoacid.
In the organoboron photosensitizer of the present invention, Ar is1And Ar2Each independently selected from the group of any of the following structural formulae:
in the organoboron photosensitizer of the present invention, Ar is1And Ar2Each independently selected from:
in the organic boron photosensitizer, the organic boron photosensitizer is represented by the structural formula I':
in the organoboron photosensitizer of the present invention, the organoboron photosensitizer is selected from one of the following structural formulas:
it is preferable that R is represented by1The number of substitutions may be from 1 to 5 and is independently selected from H, CF3、CN、NO2Halogen, C1-8 alkyl, C1-8 alkoxy, C1-8 alkylthio, C3-7 cycloalkyl, C3-7 cycloalkyloxy, aryl, heterocyclyl, heteroaryl, N-alkylpiperazinyl, morpholino, or C1-6 dialkylamino; r2Independently selected from H, alkyl, optionally substituted C1-8 alkyl, C1-8 alkoxy, C1-8 alkynyl, C3-7 cycloalkyl, aryl. More preferably, R is as defined above1The number of substitutions may be from 1 to 5 and is independently selected from H, CF3CN, halogen, C1-4 alkoxy, N-methylpiperazinyl, morpholino or C1-4 dialkylamino.
The invention also provides a preparation method of the organic boron photosensitizer, which comprises the following steps:
the preparation method comprises the following steps:
s1, Condensation reaction (Condensation reaction) of acylhydrazone ligand: placing a compound with a structural formula shown in a formula I-1 and a hydrazide compound shown in a formula II-1 in an ethanol solvent, and heating and refluxing to obtain an intermediate product with a structural formula shown in a formula I-2;
s2, boronization reaction: the intermediate, Allyltrimethylsilane (ATMS), and Boron trifluoride etherate (BF) were combined3OEt2) Placing the organic boron photosensitizer in a dry Dichloroethane (DCE) solvent and a nitrogen environment, and refluxing to obtain the final product of the structural formula shown in the formula I.
Preferably, after the mixture obtained in step S1 is cooled to room temperature, the obtained solid is filtered and washed with an organic solvent (e.g., ethanol) to obtain an intermediate product.
Further, the filtrate of step S1 is subjected to vacuum concentration to obtain a crude product, and then an organic solvent (such as ethanol) is added for washing, and then the pure intermediate product is obtained by filtration, thereby improving the yield of the intermediate product.
Preferably, the mixture obtained by the reaction in step S2 is cooled to room temperature, the crude product obtained is concentrated under reduced pressure, and after washing with a cold organic solvent (such as methanol), the organic boron photosensitizer is obtained by filtration.
More preferably, the filtrate obtained in step S2 is subjected to vacuum concentration to obtain a crude product, which is rapidly filtered through a filter pad filled with silica gel to obtain a crude organoboron photosensitizer, which is then recrystallized from dichloromethane-ethanol, and filtered to obtain a high-purity organoboron photosensitizer.
The organic boron photosensitizer aggregation promoting active oxygen cluster generation system is easy to synthesize and is applied to the photodynamic treatment technology of multiple drug-resistant bacterial infection.
The organic boron photosensitizer can be used for preparing lipid drop labeling imaging probes, light-emitting diodes, photoelectric amplifiers, optical information memories, liquid crystal displays, optical waveguide materials, biosensors, logic gates and biological probes for nondestructive reading of tumor cells, normal cells, freshwater algae and saline algae.
The invention also provides a photodynamic therapy method for detecting and killing multiple drug-resistant bacteria (such as drug-resistant escherichia coli and methicillin-resistant staphylococcus aureus) in vivo and in vitro, which comprises the following steps:
A. treating multiple drug-resistant bacteria with the organic boron photosensitizer;
B. performing photodynamic therapy on the multiple drug-resistant bacteria in vitro through white light irradiation, and detecting the killing effect of the multiple drug-resistant bacteria by using a confocal laser scanning microscope and a scanning electron microscope;
C. an animal model of in-vivo three-degree scald and multiple drug-resistant bacteria infection is established, photodynamic therapy is carried out through white light irradiation, the healing degree of a wound to be treated is observed along with time, and the treatment effect is evaluated.
Terms and definitions
The term "halogen" represents fluorine, chlorine, bromine and iodine, in particular fluorine or chlorine, preferably fluorine.
The term "alkyl" represents a class of straight or branched alkyl groups containing only two atoms of carbon and hydrogen, for example C1-10 alkyl refers to straight or branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, 2-ethylbutyl, 2-ethylhexyl, 2-butyloctyl. Preferably, the alkyl group contains 1, 2, 3 or 4 carbon atoms (C1-4 alkyl), such as methyl, ethyl, n-propyl or n-butyl. "
The term "alkenyl" generally means straight or branched chain, containing from 2 to 20 carbon atoms and containing 1 or more double bonds, such as vinyl, propenyl, (E) -2-methylvinyl or (Z) -2-methylvinyl.
The term "alkynyl" generally means straight or branched chain, containing 2 to 12 carbon atoms and containing 2 or more double bonds, such as ethynyl, propynyl, 2-butynyl or 2-pentynyl.
The term "alkoxy" generally means a straight-chain or branched alkyl group bonded through an oxygen atom, wherein the term "alkyl" has the above definition, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, pentoxy or isomers thereof. Preferably, the alkoxy group contains 1 or 2 carbon atoms (C1-2 alkoxy), such as methoxy or ethoxy.
The term "alkylthio" generally means a straight or branched chain alkyl group bonded through a sulfur atom, wherein the term "alkyl" has the meaning as set forth above.
The term "cycloalkyl" generally means a straight or branched chain, saturated monocyclic hydrocarbon ring containing 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Preferred cycloalkyl groups contain 5, 6 or 7 carbon atoms (C5-7 cycloalkyl), for example cyclopentyl, cyclohexyl or cycloheptyl.
The term "cycloalkyloxy" generally means a straight or branched chain cycloalkyl group bonded through an oxygen atom, where the term "cycloalkyl" has the definition as set forth above.
The term "cycloalkylthio" generally means a straight or branched chain cycloalkyl group bonded through a sulfur atom, where the term "cycloalkyl" has the definition as set forth above.
The term "aryl" generally means an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring containing 6 to 14 carbon atoms, in particular a ring having 6 carbon atoms (e.g. phenylcyclyl or biphenylcyclyl), a ring having 9 carbon atoms (e.g. indenyl), a ring having 10 carbon atoms (e.g. dinaphthyl or naphthyl), a ring having 13 carbon atoms (e.g. fluorenyl) or a ring having 14 carbon atoms (e.g. onilyl). Preferably, aryl is a phenyl ring substituted with an "alkoxy" group containing 1 to 4 carbon atoms.
The term "heterocyclyl" generally means a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring containing 5 to 8 carbon atoms and containing 1 to 3 heteroatom-containing groups selected from oxygen, sulfur or nitrogen. Such as furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or pyranyl. Preferably, the heterocyclyl is thienyl, pyridyl or a heterocyclyl substituted therewith having 1 to 4 carbon atoms (C1-4 alkyl).
The term "heteroaryl" generally means a group of compounds in which a benzene ring is fused with a heterocyclic ring, such as quinolinyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, indolyl or purinyl.
The term "heterocycloalkyl" generally means a heterocyclic group containing from 3 to 7 carbon atoms and from 1 to 3 oxygen, sulfur or nitrogen heteroatoms, such as piperidinyl, hydroxypiperidinyl, phenanthrolinyl, piperazinyl, N-methylpiperazinyl, tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothienyl, morpholino or thiazinyl. Preferred heterocycloalkyl groups are piperidinyl, N-methylpiperazinyl or morpholino.
The term "monoalkylamino" generally means an amino group (NH)2) Wherein the term "alkyl" has the meaning as described above, is substituted for 1 hydrogen of (a). Such as methylamino, ethylamino, propylamino, butylamino or isomers thereof.
The term "dialkylamino" generally means an amine group (NH)2) Wherein the term "alkyl" has the meaning as described above. Such as dimethylamino, diethylamino, dipropylamino, dibutylamino or isomers thereof. Preferably, the dialkylamino group is a dimethylamino group or a diethylamino group.
The term "heteroatom" is generally meant to contain 1 or more oxygen, sulfur or nitrogen atoms.
The term "optionally substituted" generally means that a hydrogen in the structure is replaced by the substituent. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, or more than one position in the structure may be substituted.
As used herein, the numerical range "C1-10" and its included sub-ranges generally means having a defined number of 1-10 atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 atoms; "C1-10" and the sub-ranges contained therein, inclusive, of the number of carbon atoms, generally means a group having a defined number of 1-10 carbon atoms, i.e., a group containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
Suitable substituents are typically selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, nitro, cyano, hydroxy, C1-6 dialkylamino, piperidinyl, N-methylpiperazinyl or morpholino.
The organic boron photosensitizer based on aggregation-induced emission characteristics and the preparation method and application thereof have the following beneficial effects: the series of organic boron photosensitizers synthesized by the invention are easy to synthesize, show good AIE and active oxygen cluster generation characteristics, and have important significance and value in the technical field of biological medicine as the photosensitizers for photodynamic treatment of multiple drug-resistant bacteria infection.
Drawings
FIG. 1 is a schematic representation of the treatment of DMA-AB-F photosensitizers as multiple drug resistant bacterial infections;
FIG. 2 is a normalized ultraviolet-visible absorption spectrum and Photoluminescence (PL) spectrum of DMA-AB-F in a THF solution (concentration: 10. mu.M, excitation wavelength: 415 nm);
FIG. 3 is a normalized ultraviolet-visible absorption spectrum and Photoluminescence (PL) spectrum of F-AB-DMA in THF solution (concentration: 10. mu.M, excitation wavelength: 415 nm);
FIG. 4 shows DMA-AB-F at different water cut (F)wVol%, vol%) of the PL spectrum in a THF/water mixture (concentration: 10 μ M, excitation wavelength: 415 nm);
FIG. 5 is PL Peak intensity (I/I) of DMA-AB-F0) Water content (f) of the aqueous mixturewVolume%) (concentration: 10 μ M, excitation wavelength: 415 nm);
FIG. 6 shows F-AB-DMA at different water cut (F)wVol%, vol%) of the PL spectrum in a THF/water mixture (concentration: 10 μ M, excitation wavelength: 415 nm);
FIG. 7 is PL peak intensity (I/I) of F-AB-DMA0) Water content (f) of the aqueous mixturewVol%, vol%) in the graph (concentration: 10 μ M, excitation wavelength: 415 nm);
FIG. 8 is a diagram of a crystal pack structure of a crystal in analysis of DMA-AB-F crystals;
FIG. 9 is an intermolecular force diagram in the analysis of DMA-AB-F crystals;
FIG. 10 is a crystal bundle structure diagram of a crystal in the analysis of F-AB-DMA crystals;
FIG. 11 is an intermolecular force diagram in the analysis of F-AB-DMA crystals;
FIG. 12 is a PL profile of DMA-AB-F in PBS with DCF signal generated by different time illumination; concentration: 1 μ M (DCFH), 10 μ M (DMA-AB-F), excitation wavelength: 480 nm;
FIG. 13 is a PL profile of DCF signal generated by F-AB-DMA in PBS with varying time illumination; concentration: 1 μ M (DCFH), 10 μ M (F-AB-DMA), excitation wavelength: 480 nm;
FIG. 14 is a relative fluorescence intensity spectrum of DCFH, DCFH + DMA-AB-F, DCFH + F-AB-DMA in PBS solution with different illumination times to generate DCF signals;
FIG. 15 is a light field, dark field and merged image of MASA stained with DMA-AB-F photosensitizer detected by confocal laser scanning microscope; excitation wavelength: 405 nm; an emission filter: 448 and 548 nm; the scale used for the images was 2 μm;
FIG. 16 is a light field, dark field and merged image of confocal laser scanning microscopy of MDR E.coli stained with DMA-AB-F photosensitizer; excitation wavelength: 405 nm; an emission filter: 448 and 548 nm; the scale used for the images was 2 μm;
FIG. 17 is a scanning electron microscope examination of MASA bacterial conformation under different treatment conditions after 30 minutes of light exposure; PS refers to DMA-AB-F photosensitizer; the scale used for the images was 1 μm;
FIG. 18 is a scanning electron microscope examination of MDR E.coli configuration under different treatment conditions after 30 minutes of light exposure; PS refers to DMA-AB-F photosensitizer; the scale used for the images was 1 μm;
FIG. 19 is a block diagram of the bacterial activity of MDR E.coli incubated with different concentrations (0-40. mu.M) of DMA-AB-F photosensitizer and after different irradiation times (0, 5 and 15 minutes);
FIG. 20 is a block diagram of the bacterial activity of MASA incubated with different concentrations (0-40 μ M) of DMA-AB-F photosensitizer and after different irradiation times (0, 15 and 30 minutes);
FIG. 21 is a graph of relative wound area over time for multiple drug resistant E.coli infected wounds following treatment; PS refers to DMA-AB-F photosensitizer;
FIG. 22 is a hematoxylin-eosin stain analysis performed on different treatment methods 5 days after treatment of multiple drug resistant E.coli infected wounds; PS refers to DMA-AB-F photosensitizer;
FIG. 23 is a hematoxylin-eosin stain analysis performed on different treatment methods 10 days after treatment of multiple drug resistant E.coli infected wounds; PS refers to DMA-AB-F photosensitizer;
FIG. 24 is a Masson strain analysis performed on different treatment methods 5 days after treatment of multiple drug resistant E.coli infected wounds; PS refers to DMA-AB-F photosensitizer;
FIG. 25 is a Masson strain analysis performed on different treatment methods 10 days after treatment of a multi-drug resistant E.coli infected wound; PS refers to DMA-AB-F photosensitizer.
Detailed Description
The following description of the organoboron photosensitizer based on aggregation induced emission characteristics, its preparation method and application are provided in conjunction with the accompanying drawings and examples:
the invention adopts an acylhydrazone structure as a ligand of the organic boron photosensitizer, develops an organic boron photosensitizer system which is easy to synthesize and has aggregation-induced emission characteristics, and as shown in figure 1, the organic boron photosensitizer provided by the invention can be used for carrying out photodynamic therapy on multiple drug-resistant bacteria, provides a photosensitizer with good light stability and good biocompatibility for the biological medicine technology in the current market, and has important significance and value in the fields of biological fluorescence medicine technology and the like.
The following is a detailed description of specific examples.
Example 1: preparation of the product
(1) Synthesis of DMA-AB
In a 100mL single-neck round-bottom flask equipped with a condenser tube, 4-dimethylaminobenzaldehyde (DMA-P-CHO; 1.5g, 10mmol), benzoylhydrazine (BHA; 1.36g, 10mmol) and ethanol (EtOH; 20mL) solvent were added and heated under reflux for 24 hours. After cooling the reaction mixture back to room temperature, it was filtered and washed 3 times with cold ethanol solvent to give the white DMA-AH intermediate solid which was directly used for the next reaction without further purification after drying in vacuo. DMA-AH allyltrimethylsilane (ATMS; 2.05mL, 12.9mmol) and boron trifluoride diethyl etherate (BF) were charged into a 100mL double-necked round-bottomed flask equipped with a condenser tube3OEt2(ii) a 1.87mL, 14.87mmol) and dry dichloroethane (DCE; 50mL) of solvent, heating and refluxing for more than two hours, and monitoring the reaction by using a silica gel plate (TLC) sheet; after completion of the reaction was confirmed, the solvent was drained off, and purification was performed by column chromatography to give a yellow DMA-AB product (2.4g) in 77% yield.1H NMR(400MHz,THF-d8),δ(ppm):8.45-8.43(m, 2H),8.16(d,2H,J＝7.2Hz),7.86(s,1H),7.59-7.55(m,1H),7.51-7.49(m, 2H),6.89-6.87(m,2H),3.16(s,6H).13C NMR(100MHz,THF-d8),δ(ppm): 170.65,155.63,151.25,138.14,133.58,129.66,129.41,129.27,128.47,117.98, 112.88,112.53,40.54,40.22.MS(MALDI-TOF):calculated for C16H16BF2N3O [M+H]+316.1354；found 316.1354.
(2) Synthesis of DMA-AB-F
In a 100mL single-neck round-bottom flask equipped with a condenser tube, 4-dimethylaminobenzaldehyde (DMA-P-CHO; 1.5g, 10mmol), 4-fluorobenzoylhydrazine (4-fluorobenozohydrazide, F-BHA; 1.54g, 10mmol) and ethanol (EtOH; 20mL) were added as a solvent, and heated under reflux for 24 hours. After cooling the reaction mixture back to room temperature, it was filtered and washed 3 times with cold ethanol solvent to give a white DMA-AH-F intermediate solid which was dried under vacuum and directly used for the next reaction without further purification. DMA-AH-F allyltrimethylsilane (ATMS; 2.05mL, 12.9mmol) and boron trifluoride diethyl etherate (BF) were charged into a 100mL double-necked round-bottomed flask equipped with a condenser tube3OEt2(ii) a 1.87mL, 14.87mmol) and dry dichloroethane (DCE; 50mL) of solvent, heating and refluxing for more than two hours, and monitoring the reaction by TLC (thin layer chromatography) plates; after completion of the reaction was confirmed, the solvent was drained off, and the product was purified by column chromatography to give yellow DMA-AB-F (3.4g) in 92% yield.1H NMR(400MHz,CDCl3),δ(ppm): 8.31(d,2H,J＝7.2Hz),8.18(m,2H),7.64(s,1H),7.16(t,2H,J＝8.6Hz), 7.79(d,2H,J＝8.4Hz),3.17(s,6H).13C NMR(125MHz,CDCl3),δ(ppm): 168.85,166.53,164.51,157.25,154.56,154.14,149.73,136.99,135.14,130.85, 130.78,130.24,130.16,123.99,116.35,115.86,115.81,115.68,115.63,114.27, 111.90,111.49,40.09.MS(MALDI-TOF):calculated for C16H15BF3N3O[M]+ 333.1260；found 333.1257.
(3) Synthesis of DMA-AB-CF3
In a 100mL single-neck round-bottom flask equipped with a condenser tube, 4-dimethylaminobenzaldehyde (DMA-P-CHO; 1.5g, 10mmol), 4- (trifluoromethyl) phenylhydrazine (4- (trifluoromethyl) phenylhydrazine, CF3-BHA; 2.04g, 10mmol) and ethanol (EtOH; 20mL) of solvent, heated at reflux for 24 hours. After the reaction mixture was cooled to room temperature, it was filtered and washed with cold ethanol solvent 3 times to obtain white DMA-AH-CF3The intermediate solid product, after drying in vacuo, was carried on to the next reaction without further purification. DMA-AH-CF was added to a 100mL double-necked round-bottomed flask equipped with a condenser3Allyltrimethylsilane (ATMS; 2.05mL, 12.9mmol), boron trifluoride etherate (BF)3OEt2(ii) a 1.87mL, 14.87mmol) and dry dichloroethane (DCE; 50mL) of solvent, heating and refluxing for more than two hours, and monitoring the reaction by TLC (thin layer chromatography) plates; after confirming the reaction was complete, the solvent was drained and purified by column chromatography to give yellow DMA-AB-CF3Product (3.6g) in 95% yield.1H NMR (400MHz,CDCl3),δ(ppm):8.38-8.23(m,4H),7.74-7.68(m,3H),6.80-6.76 (m,2H),3.17(s,6H).13C NMR(125MHz,DMSO-d6),δ(ppm):166.95,155.12, 152.25,138.12,132.89,132.63,132.38,131.25,128.98,128.98,128.35,126.48, 126.45,126.42,125.33,123.17,115.72,112.62,112.35,40.18.MS (MALDI-TOF):calculated for C17H15BF5N3O[M]+383.1228；found 383.1246.
(4) Synthesis of AB-DMA
Adding benzaldehyde (P-CHO; 1.03mL, 10mmol) into a 100mL single-mouth round-bottom bottle with a condenser tube,4-Dimethylaminobenzoyl hydrazine (4-dimethylamino-benzohydrazide, BHA-DMA; 1.80g, 10mmol) and ethanol (EtOH; 20mL) were heated under reflux for 24 hours. After cooling the reaction mixture back to room temperature, it was filtered and washed 3 times with cold ethanol solvent to give a white AH-DMA intermediate solid which was directly used for the next reaction without further purification after drying in vacuo. A100 mL double-necked round-bottomed flask equipped with a condenser was charged with AH-DMA allyltrimethylsilane (ATMS; 2.05mL, 12.9mmol), boron trifluoride diethyl etherate (BF)3OEt2(ii) a 1.87mL, 14.87mmol) and dry dichloroethane (DCE; 50mL) of solvent, heating and refluxing for more than two hours, and monitoring the reaction by TLC (thin layer chromatography) plates; after completion of the reaction was confirmed, the solvent was drained off, and the product AB-DMA (1.9g) was purified by column chromatography to give a yellow color in 62% yield.1H NMR(400MHz,THF-d8),δ(ppm):8.06(d,2H,J＝7.6Hz), 8.05-8.02(m,3H),7.64-7.58(m,3H),6.80-6.78(m,2H),3.09(s,6H).13C NMR(100MHz,THF-d8),δ(ppm):174.34,155.35,148.68,135.04,134.68, 131.76,131.43,130.05,114.29,112.20,40.27.MS(MALDI-TOF):calculated for C16H16BF2N3O[M]+315.1354；found 315.1364.
(4) Synthesis of F-AB-DMA
In a 100mL single-neck round-bottom flask equipped with a condenser tube, P-fluorobenzaldehyde (4-fluorobenzaldehyde, F-P-CHO; 1.23g, 10mmol), 4-dimethylaminobenzohydrazide (4-dimethylaminobenzohydrazide, BHA-DMA; 1.80g, 10mmol) and ethanol (EtOH; 20mL) were added as a solvent, and the mixture was refluxed for 24 hours. After cooling the reaction mixture back to room temperature, it was filtered and washed 3 times with cold ethanol solvent to give the intermediate solid product of F-AH-DMA which was white and was directly used for the next reaction without further purification after drying in vacuo. Into a 100mL double-necked round-bottomed flask equipped with a condenser were charged F-AH-DMA allyltrimethylsilane (ATMS; 2.05mL, 12.9mmol), boron trifluoride diethyl ether (BF)3OEt2(ii) a 1.87mL, 14.87mmol) and dry dichloroethane (DCE; 50mL) of solvent, heating and refluxing for more than two hours, and monitoring the reaction by TLC (thin layer chromatography) plates; after completion of the reaction was confirmed, the solvent was drained off, and the product was purified by column chromatography to give yellow F-AB-DMA (3.3g) in 85% yield.1H NMR(400MHz,THF-d8), δ(ppm):8.55(s,1H),8.11-8.07(m,2H),7.97(d,2H,J＝8.8Hz),7.23-7.21(m, 2H),6.75(d,2H,J＝8.8Hz),3.09(s,6H).13C NMR(125MHz,CDCl3),δ (ppm):170.96,167.06,165.00,153.65,153.63,152.74,134.37,134.33,134.29, 134.25,134.22,130.32,130.17,129.32,124.54,117.08,116.91,115.91,115.73, 112.66,111.09,77.29,77.04,76.78,40.16,40.08.MS(MALDI-TOF): calculated for C16H15BF3N3O[M]+333.1260；found 333.1273.
(6) Synthesis of CF3-AB-DMA
To a 100mL single-neck round-bottom flask equipped with a condenser tube was added p-trifluoromethylbenzaldehyde (4- (trifluoromethyl) benzadhehyde, CF)3-P-CHO; 1.74g, 10mmol), 4-dimethylaminobenzoylhydrazine (4-dimethylamino benzohydrazide, BHA-DMA; 1.80g, 10mmol) and ethanol (EtOH; 20mL) of solvent, heated at reflux for 24 hours. After cooling the reaction mixture back to room temperature, it was filtered and washed 3 times with cold ethanol solvent to give white CF3The intermediate solid-state product of-AH-DMA, after drying in vacuo, was carried on to the next reaction without further purification. CF was added to a 100mL double-necked round-bottomed flask equipped with a condenser tube3-AH-DMA allyltrimethylsilane (ATMS; 2.05mL, 12.9mmol), boron trifluoride etherate (BF)3OEt2(ii) a 1.87mL, 14.87mmol) and dry dichloroethane (DCE; 50mL) of solvent, heating and refluxing for more than two hours, and monitoring the reaction by TLC (thin layer chromatography) plates; after confirming the reaction is complete, the solvent is drained and purified by column chromatography to obtain orange CF3Product of-AB-DMA (2.7g) with a yield of 72%.1H NMR (400MHz,THF-d8),δ(ppm):8.58(d,2H,J＝8.4Hz),8.08(d,2H,J＝9.2Hz), 7.84(d,2H,J＝8.0Hz),7.78(s,1H),6.74(d,2H,J＝9.2Hz),3.11(s,6H).13C NMR(125MHz,CDCl3),δ(ppm):174.20,154.20,144.41,137.36,134.37, 134.11,133.60,132.43,131.36,127.58,125.97,125.94,125.91,125.88,125.55, 124.47,122.30,112.37,111.11,40.38,40.09.MS(MALDI-TOF):calculated for C17H15BF5N3O[M]+383.1228；found 383.1233.
Example 2: research on optical, aggregation-induced emission and active oxygen generation characteristics of product
2 organoboron fluorescent products (DMA-AB-F and F-AB-DMA) were used as examples to examine their optical properties, aggregation-induced emission, and active oxygen-generating properties. Other products are similar in structure and will not be described in detail.
(1) Investigation of optical Properties
The ultraviolet-visible (UV-vis) absorption spectrum and Photoluminescence (PL) spectrum of DMA-AB-F and F-AB-DMA in Tetrahydrofuran (THF) solution are shown in FIGS. 2 and 3, respectively. The absorption maxima of both products in THF solution are at 415nm, but the emission wavelengths are at 473 and 555nm, respectively, and the Stokes shifts are 58 and 140nm, respectively, mainly due to the large difference in dipole moment (dipole moment) between the ground and excited states of F-AB-DMA, and the better Intramolecular Charge Transfer (ICT) effect. The absorption bands of the two products are matched with a 405nm excitation light source commonly used for biological imaging, and the two products are quite favorable for being used as photosensitizers required by biological medicine technology.
(2) Study of aggregation-induced emission characteristics
Two products were studied for their aggregation-induced emission (AIE) properties using different volume ratios of water to THF solution environment, as shown in FIGS. 4-7, the DMA-AB-F molecules emitted less light in pure THF solution, as a function of the water ratio (F)w) Up to 95% by volume, the molecules have a greatly increased fluorescence intensity due to aggregation, whichThe fluorescence intensity was enhanced nearly 28-fold compared to the pure THF solution. In contrast, F-AB-DMA molecules fluoresce yellow in pure THF solution, as a function of the water ratio (F)w) The fluorescence intensity is increased and is firstly weakened at first, mainly due to the strong ICT effect; but when fwAbove 80% by volume, the fluorescence intensity increases due to the AIE effect. The results of the study show that both products exhibit good AIE properties and exhibit good fluorescence effects for aqueous environments for biological applications.
(3) Study of solid-state luminescence
The two products were subjected to crystal growth by THF and n-hexane, and the crystal structures are shown in FIGS. 8-11 and Table 1, from which it was observed that (a) the DMA-AB-F and F-AB-DMA product structures were constituted by Z and E, respectively, and the molecular configurations were extremely coplanar; (b) the N → B bond length of the central boron five-membered ring is 1.570 and
the coordination bond belongs to a special covalent bond form, a boron atom provides an empty orbit, a nitrogen atom provides a covalent bond formed by two electrons, and the bond length is longer than that of a common covalent bond; (c) the O-B bond length in the five-membered ring is 1.469 and
is of generally normal covalent bond length; (d) the crystal units are respectively composed of a triclinic system (triclinic) and a monoclinic system (monoclinic); (e) the molecule is mainly limited by hydrogen bonds of pi.H or F.H between molecules to move, so that the non-radiative energy loss of excited state molecules is weakened, and the solid or aggregation state luminescence property is enhanced; (f) there is no significant pi-pi stacking between molecules, so that excited molecules are not susceptible to fluorescence quenching (ACQ) due to aggregation. This data demonstrates that the two organoboron products, although very planar in configuration, exhibit unique luminescent properties in solid or aggregated form, and that this study further confirms that such products are suitable for biological applications.
Table 1: crystal data summarization of DMA-AB-F and F-AB-DMA
(4) Investigation of reactive oxygen species Generation
Reactive Oxygen Species (ROS) include superoxide radicals, hydrogen peroxide, and their downstream products, peroxides and hydroxylates, among others, and are involved in cell growth, proliferation, developmental differentiation, senescence and apoptosis, as well as many physiological and pathological processes. To evaluate the ability of DMA-AB-F and F-AB-DMA to generate ROS under light, first, ROS detection was performed using a commercial fluorescent probe, 2',7' -Dichlordihydrofluorescein (DCFH). As shown in FIGS. 12 and 13, with different white light irradiation times, ROS were generated from the photosensitizers of both DMA-AB-F and F-AB-DMA with oxygen-containing substances in the water environment, and it was observed that DCFH was oxidized to generate DCF fluorescent substance. The faster the rate of increase in DCF fluorescence intensity, the faster the rate of ROS generation by the photosensitizer can be demonstrated. As shown in FIG. 14, it is evident from the relative DCF fluorescence intensity plot that the DMA-AB-F photosensitizer generates ROS at a much higher rate than F-AB-DMA in as little as 18 times as much as one minute, which means that DMA-AB-F will have some therapeutic advantage as a photosensitizer in the context of photodynamic therapy techniques. The system product is a special AIE organic boron photosensitizer molecule.
Example 3: treatment of multiple drug resistant bacterial infections with products
(1) Bacterial culture, staining and imaging
Multiple drug-resistant E.coli (MDR E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) were cultured in LB medium at 37 ℃ and 220 rpm. The bacteria were harvested by centrifugation at 3500rpm for 10 minutes and washed twice. Will contain 1X 109Bacterial colony Forming Unit (CFU mL)-1) The DMA-AB-F photosensitizer in Phosphate Buffered Saline (PBS) solution (10. mu.M, 100. mu.L) was transferred to a 1.5 ml microcentrifuge tube. After vortex dispersion, the bacteria were incubated at 37 ℃ for 1 hour with an oscillation speed of 220 rpm. To take the fluorescence image, 10 μ L of the stained bacteria solution was transferred to a slide glass, which was then covered with a cover slip. As shown in fig. 15 and 16, a confocal laser scanning microscope (S) was usedP8, Leica, Germany) that the DMA-AB-F photosensitizer successfully stains multiple drug-resistant bacteria. In addition, as shown in fig. 17 and 18, it can be observed in a Scanning Electron Microscope (SEM) that the membranes of the two multi-drug resistant bacteria are seriously damaged after photodynamic therapy, and the DMA-AB-F photosensitizer is verified to have the ability to kill the multi-drug resistant bacteria.
(2) In vitro antibacterial Effect test
For in vitro photodynamic sterilisation experiments, different concentrations of DMA-AB-F photosensitizer in PBS solutions (0, 5, 10, 20 and 40. mu.M) were incubated with the bacteria in the dark at 37 ℃ for 15 minutes. Exposure to white light (8mW cm)-2) After different times (0, 5, 15 and 30 minutes), plates were plated on LB agar and counted. The control group was placed in the dark and then incubated at 37 ℃ for 24 hours prior to quantification or imaging. Coli was killed by 10 μ M concentration of DMA-AB-F photosensitizer at 15 min of irradiation, as shown in fig. 19 and 20. Similarly, at a concentration of 20 μ M of DMA-AB-F photosensitizer at 30 minutes of irradiation, almost all MRSA was killed. These results show that the DMA-AB-F photosensitizer has a potent killing effect on bacteria.
(3) In vivo antibacterial experiments
Normal 6-8 week BALB/c mice (the animal center for medical laboratory in Guangdong province, China) with an average body weight of 20g were used for in vivo experiments. All in vivo procedures have been approved by the southern university of science and technology laboratory animal research center animal ethics committee. Mice were randomly divided into three groups according to skin burn wounds infected with bacteria. By intraperitoneal injection of 3.5% Avertin (20mL kg)-1) Mice were anesthetized. Several common iron bars were cleaned and sterilized. The clean iron rod was placed on an alcohol burner. Immediately after the iron rod had burned red, it was gently placed on the skin of the back of the mouse for 10 seconds, and two third-degree burn wounds 7mm in diameter were formed. Bacterial suspension (20. mu.L, 1X 10)9CFU ml-1) Drip onto the wound surface to keep the bacterial suspension in the wound for 30 minutes. After 30 minutes of treatment of the wounds with the bacterial suspension, DMA-AB-F in PBS solution (10. mu.M, 10. mu.L) was added as a photosensitizer to the bacterially infected wounds (3 times every 15 minutes) and white light irradiation (8mW c on top of the wounds) was performedm-230 minutes (with/without DMA-AB-F photosensitizer). Mice were individually fed in different cages in a sterile environment to promote healing of the wound after surgery. The wound size was imaged by a camera and calculated at specified time intervals. As shown in fig. 21, on day 8, the DMA-AB-F illuminated group had significantly smaller wound sizes than the other three groups. On day 10 after injury, the DMA-AB-F irradiated group had fully recovered, whereas the DMA-AB-F unirradiated group, PBS unirradiated group, and PBS irradiated group had larger wounds, and still had more pus on the wounds after the hard scab was uncovered.
(4) Histological analysis study
Histological analysis of the wounds was performed on day 5 and day 10 post-surgery. Tissues from the injured site were collected and fixed in 4% formaldehyde solution for 30 minutes. Pathological sections of wound tissue were analyzed by hematoxylin-eosin (H & E) staining and Masson strain. As shown in fig. 22-25, intact epidermis, hair follicles, blood vessels, etc. were clearly observed in the newly formed skin, which means that the recovery from the DMA-AB-F photosensitizer when irradiated with light was better. Therefore, it can be concluded that the DMA-AB-F light group exhibited the best antibacterial effect and wound healing effect. In addition, the invention has the advantage of simple material preparation, and can highlight that the organic boron photosensitizer has considerable competitiveness.
While the invention has been described with reference to multiple drug resistant forms of escherichia coli (MDR e. coli) and Methicillin Resistant Staphylococcus Aureus (MRSA), it will be apparent to those skilled in the art that modifications and variations can be made in light of the above teachings and all such modifications and variations are intended to be within the scope of the invention as defined in the appended claims. The organic boron photosensitizer is used for treating infection of other multi-drug resistant bacteria (VRE, CRE, MDR-TB and CD), photodynamic treatment of tumor cells (such as MCF-7, HeLa and MDA-MB-231 cells), or biological imaging and application of the organic boron photosensitizer coated nanoprobe. In addition, the compound can be used as a light-emitting layer and is expected to be used for an organic light-emitting diode device in consideration of good solid-state light-emitting properties of the compound.
It will be apparent to those skilled in the art to which the invention relates that the invention may be varied from the precise details described without departing from the spirit and scope of the claims set out below. The present invention is not to be considered as limited in scope by the procedures, properties or compositions defined, since the preferred embodiments and other descriptions are intended only to illustrate specific aspects of the invention presently provided. Various modifications of the described modes for carrying out the invention which are obvious to those skilled in chemistry, biochemistry or related fields are intended to be within the scope of the following claims.
It will be understood that modifications and variations can be made by persons skilled in the art in light of the above teachings, and all such modifications and variations are intended to be included within the scope of the invention as defined in the appended claims.
Claims (9)
1. An organic boron photosensitizer based on aggregation-induced emission, which is characterized in that the structural formula of the organic boron photosensitizer is shown as formula I:
wherein Ar is1And Ar2Each independently selected from the group of any of the following structural formulae:
wherein R is1The number of substitutions may be from 1 to 5 and is independently selected from H, CF3Cyano (CN), Nitro (NO)2) One of halogen, hydroxyl, amine, optionally substituted alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkylthio, acyl, aryl, heterocyclyl, heteroaryl, heterocycloalkyl, monoalkylamine, or dialkylamino; r2Independently selected from H, alkyl, optionally substituted alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, cycloalkyloxy, cycloalkaneOne of an alkylthio, aryl, heterocyclyl, heteroaryl, heterocycloalkyl, monoalkylamino, or dialkylamino group; x is independently selected from one of halide, acetate, dihydrogen phosphate, hydrogen sulfate, tetrafluoroborate, hexafluorophosphate and sulfoacid.
2. An organoboron photosensitizer as claimed in claim 1, characterised in that Ar is a metal halide1And Ar2Each independently selected from the group of any of the following structural formulae:
3. an organoboron photosensitizer as claimed in claim 2, characterised in that Ar is a metal halide1And Ar2Each independently selected from:
4. the organoboron photosensitizer of claim 1, wherein the organoboron photosensitizer is of the formula:
5. the organoboron photosensitizer of claim 4, wherein the organoboron photosensitizer is selected from one of the following structural formulas:
6. a process for the preparation of an organoboron photosensitiser as claimed in any one of claims 1 to 5, comprising the steps of:
s1, Condensation reaction (Condensation reaction) of acylhydrazone ligand: placing a compound with a structural formula shown in a formula I-1 and a hydrazide compound shown in a formula II-1 in an ethanol solvent, and heating and refluxing to obtain an intermediate product with a structural formula shown in a formula I-2;
s2, boronization reaction: the intermediate, Allyltrimethylsilane (ATMS), and Boron trifluoride etherate (BF) were combined3OEt2) Placing the organic boron photosensitizer in a dry Dichloroethane (DCE) solvent and a nitrogen environment, and refluxing to obtain the organic boron photosensitizer with the structural formula shown in the formula I in claim 1.
7. Use of an organoboron photosensitiser as claimed in any one of claims 1 to 5 in the photodynamic treatment of multiple drug resistant bacterial infections.
8. Use according to claim 7, characterized in that said photodynamic therapy comprises:
treating the multidrug-resistant bacteria with the organoboron photosensitizer;
performing photodynamic therapy on the multiple drug-resistant bacteria in vitro through white light irradiation, and detecting the killing effect of the multiple drug-resistant bacteria by using a confocal laser scanning microscope and a scanning electron microscope;
an animal model of in-vivo three-degree scald and multiple drug-resistant bacteria infection is established, photodynamic therapy is carried out through white light irradiation, the healing degree of a wound to be treated is observed along with time, and the treatment effect is evaluated.
9. Use of an organoboron photosensitizer as defined in any one of claims 1 to 5 in the preparation of a lipid droplet labelled imaging probe, light emitting diode, photoelectric amplifier, optical information storage, liquid crystal display, optical waveguide material, biosensor and logic gate, non-destructive readout bioprobe for tumor cells, normal cells, freshwater algae and saltwater algae.
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| CN114605456A (en) * | 2022-03-29 | 2022-06-10 | 山东大学深圳研究院 | Donor-acceptor type naphthalin salicylaldehyde imine boron difluoride compound and application thereof in lipid drop super-resolution imaging |
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| CN107001927A (en) * | 2014-11-21 | 2017-08-01 | 香港科技大学 | AIE illuminophores and its production method for bacterium imaging, killing, photodynamic therapy and antibiotic-screening |
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Cited By (2)
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| CN114605456A (en) * | 2022-03-29 | 2022-06-10 | 山东大学深圳研究院 | Donor-acceptor type naphthalin salicylaldehyde imine boron difluoride compound and application thereof in lipid drop super-resolution imaging |
| CN114605456B (en) * | 2022-03-29 | 2023-06-02 | 山东大学深圳研究院 | Donor-acceptor naphthalene salicylaldehyde imine boron difluoride compound and application thereof in lipid drop super-resolution imaging |
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