CN115746036A - Fluorescent probe SN-BODIPY compound for targeted recognition of Abeta fibers and preparation method thereof - Google Patents
Fluorescent probe SN-BODIPY compound for targeted recognition of Abeta fibers and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an SN-BODIPY compound which is synthesized by acetalization reaction of fluorine boron dipyrrole fluorescent dye containing aldehyde group and o-amino thiophenol compound. The organic sulfide of o-aminothiophenol can be used as a precursor of benzothiazole compounds and can also be used as a dye, has a specific binding function on beta-amyloid protein (A beta) fibers, and can be introduced into BODIPY to synthesize SN-BODIPY so as to identify the A beta fibers through fluorescence signal output. In addition, the A beta in the brain is folded to form fibers, the deposition of the fibers is in positive correlation with AD, and the A beta deposition contains different main structural variants of peptides and has polymorphism, so that the probe recognizes the A beta fibers and is characterized in that the protein fibers form a groove similar to an arch shape through pi-pi action. The fluorescent probe SN-BODIPY has small molecular weight, and the molecular structure and the size thereof enable the fluorescent probe SN-BODIPY to just enter an arch and be combined with a groove through pi-pi action to show fluorescence, so that the fluorescent imaging of the A beta fiber is realized in a targeted manner, and the purpose of AD disease diagnosis is achieved.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, relates to preparation of a fluorescent probe, and particularly relates to an SN-BODIPY compound for targeted recognition of Abeta fibers and a preparation method thereof, wherein the SN-BODIPY compound has potential application value in the aspect of diagnosis of Alzheimer's disease.
Background
Alzheimer's Disease (AD), commonly known as senile dementia, is a neurodegenerative disease with clinical manifestations of memory loss, cognitive function loss and spatial recognition disorders. The 2022 national Wei Jian committing to the news agency has shown that this disease has had a tremendous impact on the health and quality of life of the elderly. According to statistics, about 1500 million of the senile people of 60 years old and older in China have dementia patients, of which 1000 million are the patients of Alzheimer disease. National Wei Jian, the health promotion action of the elderly in the healthy Chinese locomotion, is one of the indicators of "the increase and decrease in the prevalence of senile dementia in the group of 65 years and older". The research field of AD treatment shows that the treatment and research of AD are difficult due to the lack of accurate and effective diagnosis means, and the curative effect of only drugs is not ideal. Therefore, accurate and effective diagnosis of AD can be critical for the prevention, containment, and treatment of disease.
The A β sheets within the brain form fibers, the deposition of which is positively correlated with AD. Since 1959, the fluorescent dye thioflavin-T (ThT) has been the widely used "gold standard" for selectively staining and identifying a β fibers that are the result of self-assembly of proteins. However, due to the charge and emission wavelength of ThT (less than 650 nm), use in vivo is limited, affecting diagnostic accuracy.
Therefore, for the early diagnosis of AD, it is highly required to develop a new fluorescent probe for recognizing a β fiber to improve the sensitivity and accuracy of diagnosis.
Disclosure of Invention
In view of the disadvantages of the prior art, the main object of the present invention is to provide a long-wavelength, highly sensitive, and highly selective fluorescent probe for AD diagnosis, and a method for preparing the same.
The invention is realized by the following technical scheme:
a fluorescent probe SN-BODIPY compound for targeted recognition of Abeta fibers has a molecular structural formula shown as follows:
in the formula, 8-position of the BODIPY compound has a benzothiazole substituent, and 1,3,5,7-position has four methyl.
The invention further improves the scheme as follows:
a preparation method of a fluorescent probe SN-BODIPY compound for targeted recognition of A beta fibers comprises the following steps:
(1) Using glyoxal and glycol as raw material, benzene as solvent, in the presence of catalyst 732 # Under the action of strong acid cation exchange resin, 1,3-dioxolane-2-acetaldehyde is prepared by reaction;
(2) Using 1,3-dioxolane-2-acetaldehyde and 2,4-dimethylpyrrole obtained in the step (1) as raw materials, using dichloromethane as a solvent, 2,3-dimethyl-5,6-dicyanobenzoquinone as a catalyst, using boron trifluoride diethyl ether as a complexing agent, firstly obtaining a light yellow solid product SN1, and then preparing a boron fluoride dipyrromethene compound SN2 containing aldehyde groups from the SN1;
(3) Preparing a fluorescent probe SN-BODIPY compound by using the SN2 obtained in the step (2) and o-aminothiophenol as raw materials, absolute ethyl alcohol as a solvent and concentrated hydrochloric acid and hydrogen peroxide as catalysts;
the reaction route is shown as the following formula:
further, the specific process of the step (1) is as follows: mixing and dissolving glyoxal and ethylene glycol into a triangular flask, adding a catalyst 732 # Slowly heating strong acid cation exchange resin and solvent benzene to 65-115 ℃, simultaneously starting a stirrer to stir for 1.5-3 h, carrying water generated in the reaction to a water separator when benzene is azeotroped, filtering a reaction product after about 1.5-3 h, and removing the catalyst in a pressure reduction and filtration manner to obtain 1,3-dioxolane-2-acetaldehyde.
Further, the glyoxal, the glycol, 732 # The molar ratio of the strong acid cation exchange resin is (1-1.5) to (1-1.75) to (0.1-0.5).
In the step (1), one of two aldehyde groups of the dicarbaldehyde is subjected to acetalization reaction by using a molecule of glycol to protect the aldehyde group, so that 1,3-dioxolane-2-acetaldehyde is obtained, and in the preparation process, benzene is used as a water-carrying agent to carry away water generated by the reaction.
Further, the specific process of the step (2) is that 1,3-dioxolane-2-acetaldehyde and 2,4-dimethylpyrrole are mixed and dissolved in dichloromethane, triethylamine is added, stirring is carried out for 0.5h to 6h at room temperature, boron trifluoride diethyl etherate is slowly added in ice bath, stirring is carried out for 0.5h to 6h, 2,3-dimethyl-5,6-dicyanobenzoquinone is added, extraction is carried out by adopting dichloromethane, anhydrous sodium sulfate is dried, the solvent is removed by vacuum rotary evaporation, and the chromatographic column is separated and purified to obtain a light yellow solid product SN1; and placing the product SN1 in a hydrogen chloride aqueous solution, stirring for 1-1.5 h, performing aldehyde group deprotection, distilling to remove water, drying and purifying to obtain the boron-fluorine dipyrromethene compound SN2 containing aldehyde groups.
Furthermore, the molar ratio of 1,3-dioxolane-2-acetaldehyde, 2,4-dimethylpyrrole, triethylamine, boron trifluoride diethyl etherate and 2,3-dimethyl-5,6-dicyanobenzoquinone is (1-3.3): (0.3-2.3): (0.3-4.3): (0.3-3): 0.01-0.43.
Further, the specific process of the step (3) is as follows: adding the obtained SN2 and o-aminothiophenol into a flask, adding absolute ethyl alcohol to dissolve solids, violently stirring, sequentially adding hydrogen peroxide and hydrochloric acid, fully mixing and stirring for 12-14 hours, tracking by Thin Layer Chromatography (TLC) to show that the materials disappear until the reaction is complete, distilling and filtering at normal pressure to obtain a black solid product, washing the filtrate for three times by using the absolute ethyl alcohol and drying, and purifying and crystallizing by silica gel column chromatography to obtain the final black product SN-BODIPY.
Furthermore, the molar ratio of the SN2 to the o-amino thiophenol, the concentrated hydrochloric acid and the hydrogen peroxide is (1-3.5) to (1-3.56) to (2.2-2.8) to (3.2-3.8).
Compared with the prior art, the invention has the beneficial effects of
The A beta in the brain is folded to form fibers, the deposition of the fibers is in positive correlation with AD, and the A beta deposition contains different main structural variants of peptides and has polymorphism, so that the A beta fibers identified by the probe are characterized in that protein fibers form a groove similar to an arch shape through pi-pi action. The invention adopts the organic sulfide of o-aminothiophenol which can be used as a precursor of benzothiazole compounds and can also be used as a dye, has a specific binding function on the A beta fiber, is introduced into the BODIPY to synthesize SN-BODIPY and can identify the A beta fiber through fluorescence signal output. The fluorescent probe SN-BODIPY has small molecular weight, and the molecular structure and the size of the fluorescent probe SN-BODIPY ensure that the fluorescent probe SN-BODIPY can just enter the groove and is combined with the groove through pi-pi action to show fluorescence, so that the fluorescent imaging of the A beta fiber is realized in a targeted manner, and the purpose of diagnosing AD diseases is achieved.
The fluorescent probe SN-BODIPY has high sensitivity and selectivity, the preparation method is simple and easy to operate, and the fluorescent probe SN-BODIPY has great application value in the field of AD diagnosis and treatment.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of SN-BODIPY compound obtained in example 1 of the present invention;
FIG. 2 shows the fluorescent staining of brain tissue sections of AD mice with SN-BODIPY compounds obtained in example 1 of the present invention.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further explained by combining the specific embodiments.
The preparation method of the boron-dipyrromethene compound SN2 containing aldehyde group used in the following examples is as follows:
(1) 232mg (4.0 mmol) of glyoxal and 248mg (4.0 mmol) of ethylene glycol are placed in a flask, and 50mg of 732 are added # Heating strong acid cation exchange resin and 40ml benzene as water carrying agent, starting stirrer, heating at 85 deg.C, performing acetalation reaction, condensing and refluxing, carrying water generated by reaction to water separator when water carrying agent azeotropes, and reacting for 90 min. Slightly cooling, filtering the reaction product (removing the catalyst by reduced pressure filtration), distilling the filtrate at normal pressure to remove low boiling point substances, then distilling under reduced pressure, and collecting the fraction to obtain 1,3-dioxolane-2-acetaldehyde.
(2) 204mg (2.0 mmol) 1,3-dioxolane-2-acetaldehyde are weighed out and dissolved in 200mL freshly distilled dichloromethane, 412mg (4.4 mmol) of colourless 2,4-dimethylpyrrole liquid and 3mL triethylamine are injected, stirring is carried out rapidly by magnetic force, 3mL boron trifluoride etherate is slowly added dropwise in an ice bath, stirring is carried out for 30 minutes, 2,3-dimethyl-5,6-dicyanobenzoquinone 45.4mg (0.2 mmol) are added. TLC tracking till the raw material reaction is completed, extracting with dichloromethane, and extracting with anhydrous Na 2 SO 4 Drying, removing the solvent in vacuum at 50 ℃, and separating and purifying by adopting a chromatographic column to obtain a light yellow solid product SN1; and (3) placing the SN1 in a hydrochloric acid solution (3 ml, 6 equivalents) and stirring for 5h, carrying out deprotection reaction on aldehyde groups, and drying and purifying to obtain the BODIPY fluorescent dye SN2.
Example 1
483mg (1.75 mmol) of SN2 and 218.75mg (1.75 mmol) of o-aminothiophenol were added to the dried flask, 100 ml of absolute ethanol was added to dissolve the solid, and the flask was cooled with an ice bath. While stirring vigorously, concentrated hydrochloric acid (0.14 ml, 2.6 equivalents) and hydrogen peroxide (0.24 ml, 4.5 equivalents) were added sequentially to the solution. After stirring for 12h, tracking by TLC until the reaction material disappears and the reaction is complete, distilling and filtering the reaction product under normal pressure, washing and drying by absolute ethyl alcohol, purifying and crystallizing to obtain a black solid product SN-BODIPY which is 200.025mg (0.525 mmol) in total, wherein the yield is 30%. The compound is identified as the target product by a nuclear magnetic 1H NMR spectrum.
Example 2
To the dried flask were added 510.6mg (1.85 mmol) of SN2 and 237.5mg (1.9 mmol) of o-aminothiophenol, followed by addition of 125 ml of anhydrous ethanol to dissolve the solid. The flask was cooled with an ice bath. With vigorous stirring, concentrated hydrochloric acid (0.18 ml, 2.6 equivalents) and hydrogen peroxide (0.26 ml, 4.5 equivalents) were added sequentially to the solution. After stirring for 12h, TLC was used to trace until the reaction material disappeared completely, the reaction product was distilled and filtered under normal pressure, washed with absolute ethanol and dried, and then purified and crystallized to obtain a black solid product SN-BODIPY of 213.36mg (0.56 mmol) in total, with a yield of 30.3%. The compound is identified as the target product by a nuclear magnetic 1H NMR spectrum.
Example 3
To the dried flask were added 552mg (2.0 mmol) SN2 and 267.5mg (2.14 mmol) o-aminothiophenol, and then 150 ml absolute ethanol was added to dissolve the solid. The flask was cooled with an ice bath. With vigorous stirring, concentrated hydrochloric acid (0.22 ml, 2.6 equivalents) and hydrogen peroxide (0.30 ml, 4.5 equivalents) were added sequentially to the solution. After stirring for 12h, tracking by TLC until the reaction material disappears and the reaction is complete, distilling and filtering the reaction product under normal pressure, washing and drying by absolute ethyl alcohol, purifying and crystallizing to obtain a black solid product SN-BODIPY which is 232.41mg (0.61 mmol) altogether, wherein the yield is 30.5%. The target product of the compound is determined by a nuclear magnetism 1HNMR spectrogram.
Example 1 application of the prepared Material
Fluorescent staining of AD brain tissue sections by SN-BODIPY presented a recognition analysis:
histological analysis was performed using adult Alzheimer's disease model mouse APPswe/PS1dE9 brain tissue. The method is characterized in that part of tissue of a hippocampus is embedded by paraffin, the section is 12 mu m thick, the tissue is stained for 2 hours by 40% ethanol SN-BODIPY compound solution (120 uM), the tissue is washed for 30 minutes by 40% ethanol, all the sections are washed and covered by a fluorescence preservation reagent under a confocal laser microscope (Nikon A1R) with the wavelength of 640nm, and the SN-BODIPY compound is found to enable A beta fibers to show green fluorescence, which shows that the SN-BODIPY compound has potential application value for accurate diagnosis of AD.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (8)
1. A fluorescent probe SN-BODIPY compound for targeted recognition of A beta fibers is characterized by having a molecular structural formula as shown in the following:
2. the method for preparing the fluorescent probe SN-BODIPY compound for targeted recognition of the A beta fiber as claimed in claim 1, which comprises the following steps:
(1) Using glyoxal and glycol as raw material, benzene as solvent, in the presence of catalyst 732 # Under the action of strong acid cation exchange resin, 1,3-dioxolane-2-acetaldehyde is prepared by reaction;
(2) Using 1,3-dioxolane-2-acetaldehyde and 2,4-dimethylpyrrole obtained in the step (1) as raw materials, using dichloromethane as a solvent, 2,3-dimethyl-5,6-dicyanobenzoquinone as a catalyst, using boron trifluoride diethyl ether as a complexing agent, firstly obtaining a light yellow solid product SN1, and then preparing a boron fluoride dipyrromethene compound SN2 containing aldehyde groups from the SN1;
(3) Preparing a fluorescent probe SN-BODIPY compound by taking the SN2 obtained in the step (2) and o-aminothiophenol as raw materials, absolute ethyl alcohol as a solvent and hydrogen peroxide and hydrochloric acid as catalysts;
the reaction route is shown as the following formula:
3. the preparation method of the fluorescent probe SN-BODIPY compound for targeted recognition of the A beta fiber, according to claim 2, characterized in that: the specific process of the step (1) is as follows: mixing glyoxal and ethylene glycol, dissolving into a triangular flask, adding catalyst 732 # Slowly heating strong acid cation exchange resin and solvent benzene to 65-115 ℃, simultaneously starting a stirrer to stir for 1.5-3 h, carrying water generated in the reaction to a water separator when the benzene is azeotroped, filtering a reaction product after about 1.5-3 h, and removing the catalyst in a pressure reduction and filtration manner to obtain 1,3-dioxolane-2-acetaldehyde.
4. The preparation method of the SN-BODIPY compound for the targeted recognition of the fluorescent probe of the A beta fiber according to claim 3, characterized in that: the glyoxal, the glycol, 732 # The molar ratio of the strong acid cation exchange resin is (1-1.5) to (1-1.75) to (0.1-0.5).
5. The preparation method of the fluorescent probe SN-BODIPY compound for targeted recognition of the A beta fiber, according to claim 2, characterized in that: the specific process of the step (2) is as follows: mixing 1,3-dioxolane-2-acetaldehyde and 2,4-dimethylpyrrole, dissolving in dichloromethane, adding triethylamine, stirring for 0.5-6 h at room temperature, slowly adding boron trifluoride diethyl etherate in an ice bath, stirring for 0.5-6 h, adding 2,3-dimethyl-5,6-dicyanobenzoquinone, extracting with dichloromethane, drying with anhydrous sodium sulfate, removing the solvent by vacuum rotary evaporation, and separating and purifying with a chromatographic column to obtain a light yellow solid product SN1; and (3) placing the product SN1 into a hydrogen chloride aqueous solution, stirring for 1-1.5 h, distilling to remove water, drying and purifying to obtain the aldehyde group-containing BODIPY compound SN2.
6. The method for preparing the fluorescent probe SN-BODIPY compound for targeted recognition of the A beta fiber according to claim 5, wherein the method comprises the following steps: the molar ratio of 1,3-dioxolane-2-acetaldehyde, 2,4-dimethylpyrrole, triethylamine, boron trifluoride diethyl etherate and 2,3-dimethyl-5,6-dicyanobenzoquinone is (1-3.3): (0.3-2.3): (0.3-4.3): (0.3-3): 0.01-0.43).
7. The preparation method of the fluorescent probe SN-BODIPY compound for targeted recognition of the A beta fiber, according to claim 2, characterized in that: the specific process of the step (3) is as follows: adding the obtained SN2 and o-aminothiophenol into a flask, adding absolute ethyl alcohol to dissolve solids, violently stirring, sequentially adding hydrogen peroxide and concentrated hydrochloric acid, fully mixing and stirring for 12-14 hours, tracking by Thin Layer Chromatography (TLC) to show that materials disappear until the reaction is complete, distilling and filtering at normal pressure to obtain a black solid product, washing the filtrate for three times by using the absolute ethyl alcohol and drying, and purifying and crystallizing by using a silica gel column chromatography to obtain the final black product SN-BODIPY.
8. The method for preparing the fluorescent probe SN-BODIPY compound for targeted recognition of the A beta fiber according to claim 7, wherein the method comprises the following steps: the mol ratio of SN2 to o-amino thiophenol, concentrated hydrochloric acid and hydrogen peroxide is (1-3.5) to (1-3.56) to (2.2-2.8) to (3.2-3.8).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116003448A (en) * | 2022-11-07 | 2023-04-25 | 淮阴工学院 | BODIPY near infrared fluorescent probe containing indoline polyethylenically recognized Abeta fiber and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2022794A1 (en) * | 2006-04-28 | 2009-02-11 | Keio University | Fluorescent compound and labeling agent comprising the same |
| US20110208064A1 (en) * | 2008-07-31 | 2011-08-25 | Ran Chongzhao | Curcumin Derivatives for Amyloid-Beta Plaque Imaging |
| CN106349261A (en) * | 2015-07-16 | 2017-01-25 | 中国科学院上海药物研究所 | Fluorescent switch type BODIPY (Boron-dipyrromethene) compound as well as preparation method and application thereof |
| KR20200142215A (en) * | 2019-06-12 | 2020-12-22 | 한국과학기술연구원 | Novel compounds useful as fluorescent probes selectively binding to tau aggregates and preparation method thereof |
| CN116375751A (en) * | 2023-03-24 | 2023-07-04 | 淮阴工学院 | Benzothiazole-containing BODIPY dimer fluorescent probe DSN-BODIPY and preparation method and application thereof |
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2022794A1 (en) * | 2006-04-28 | 2009-02-11 | Keio University | Fluorescent compound and labeling agent comprising the same |
| US20110208064A1 (en) * | 2008-07-31 | 2011-08-25 | Ran Chongzhao | Curcumin Derivatives for Amyloid-Beta Plaque Imaging |
| CN106349261A (en) * | 2015-07-16 | 2017-01-25 | 中国科学院上海药物研究所 | Fluorescent switch type BODIPY (Boron-dipyrromethene) compound as well as preparation method and application thereof |
| KR20200142215A (en) * | 2019-06-12 | 2020-12-22 | 한국과학기술연구원 | Novel compounds useful as fluorescent probes selectively binding to tau aggregates and preparation method thereof |
| CN116375751A (en) * | 2023-03-24 | 2023-07-04 | 淮阴工学院 | Benzothiazole-containing BODIPY dimer fluorescent probe DSN-BODIPY and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 杜蕾;冯海威;李玉艳;: "阿尔茨海默病β-淀粉样蛋白的近红外荧光探针研究进展", 药学学报, no. 05, 12 May 2015 (2015-05-12), pages 528 - 534 * |
| 王宇轩: "基于BODIPY骨架的荧光探针的构建及其在Aβ蛋白和黏度成像中的应用", 《万方数据知识服务平台》, 15 July 2023 (2023-07-15), pages 1 - 139 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116003448A (en) * | 2022-11-07 | 2023-04-25 | 淮阴工学院 | BODIPY near infrared fluorescent probe containing indoline polyethylenically recognized Abeta fiber and preparation method thereof |
| CN116003448B (en) * | 2022-11-07 | 2024-06-11 | 淮阴工学院 | BODIPY near infrared fluorescent probe containing indoline polyethylenically recognized Abeta fiber and preparation method thereof |
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