WO2018052243A1 - Sonde fluorescente destinée à la détection de sulfure d'hydrogène et procédé de préparation de ladite sonde fluorescente - Google Patents

Sonde fluorescente destinée à la détection de sulfure d'hydrogène et procédé de préparation de ladite sonde fluorescente Download PDF

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WO2018052243A1
WO2018052243A1 PCT/KR2017/010046 KR2017010046W WO2018052243A1 WO 2018052243 A1 WO2018052243 A1 WO 2018052243A1 KR 2017010046 W KR2017010046 W KR 2017010046W WO 2018052243 A1 WO2018052243 A1 WO 2018052243A1
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hydrogen sulfide
formula
compound represented
fluorescent probe
fluorescence
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PCT/KR2017/010046
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English (en)
Korean (ko)
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이창수
권오석
박철순
하태환
최선애
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한국생명공학연구원
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/4738—Diffuse reflection, e.g. also for testing fluids, fibrous materials
    • G01N21/474—Details of optical heads therefor, e.g. using optical fibres
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6402—Atomic fluorescence; Laser induced fluorescence
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/0004—Gaseous mixtures, e.g. polluted air
    • G01N33/0009—General constructional details of gas analysers, e.g. portable test equipment
    • G01N33/0027—General constructional details of gas analysers, e.g. portable test equipment concerning the detector
    • G01N33/0036—General constructional details of gas analysers, e.g. portable test equipment concerning the detector specially adapted to detect a particular component
    • G01N33/0044—Sulphides, e.g. H2S
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47—Scattering, i.e. diffuse reflection
    • G01N21/4738—Diffuse reflection, e.g. also for testing fluids, fibrous materials
    • G01N2021/4764—Special kinds of physical applications
    • G01N2021/4766—Sample containing fluorescent brighteners

Definitions

  • the present invention relates to a fluorescent probe for detecting hydrogen sulfide represented by the following formula (1) and a preparation method thereof.
  • Hydrogen sulfide is a newly recognized messenger, such as cystathinone- ⁇ -lyase (CSE) and cystathionine- ⁇ -synthase (CBS). It is synthesized in mammalian tissue from cysteine and homocysteine through the activity of enzymes.
  • CSE cystathinone- ⁇ -lyase
  • CBS cystathionine- ⁇ -synthase
  • Korean Patent No. 1,404,369 discloses a real-time biosignal measuring apparatus for cardiac ischemia and reperfusion having a hydrogen sulfide sensor for detecting hydrogen sulfide concentration in real time.
  • the concentration of hydrogen sulfide in plasma of human blood is known to be 50-100 ⁇ m, so if the concentration level of hydrogen sulfide can be detected quantitatively, Down syndrome, Alzheimer's disease, diabetes and It is possible to diagnose diseases such as cirrhosis.
  • H 2 S hydrogen sulfide
  • an object of the present invention is to provide a fluorescent probe that can detect hydrogen sulfide (H 2 S) using a non-invasive image in vivo and its manufacturing method.
  • the hydrogen sulfide detection fluorescent probe is characterized by the following formula (1).
  • the hydrogen sulfide detection fluorescent probe is characterized in that it reacts with hydrogen sulfide in the living body to vary in fluorescence at 550 to 680 nm and 695 to 770 nm.
  • a method for producing a fluorescent sulfide probe for detecting hydrogen sulfide includes the steps of preparing a compound represented by Chemical Formula 3 by reacting the compound represented by Chemical Formula 2 with 4-chlororesinol; And reacting the compound represented by Chemical Formula 3 prepared above with the compound represented by Chemical Formula 4 to prepare a compound represented by Chemical Formula 1.
  • a method of detecting hydrogen sulfide comprises the steps of: injecting a fluorescent probe for detecting hydrogen sulfide into a living body; The fluorescent probe for detecting hydrogen sulfide reacts with hydrogen sulfide in vivo to fluoresce; And confirming the fluorescence.
  • the fluorescent probe capable of detecting hydrogen sulfide according to the present invention has the effect of selectively detecting hydrogen sulfide quickly and accurately.
  • 1 shows absorbance of a fluorescent probe for detecting hydrogen sulfide.
  • Figure 2 shows the results of the pH dependence of the fluorescent probe for detecting hydrogen sulfide prepared according to the present invention.
  • Figure 3 shows the fluorescence detection results according to the absorbance of the compound represented by the formula (1) and the concentration of hydrogen sulfide.
  • Figure 5 shows the results of confirming the fluorescence response of the fluorescent probe for detecting hydrogen sulfide of the present invention in the macrophages of mice.
  • Figure 6 shows the results confirming the cytotoxicity of the fluorescent probe for detecting hydrogen sulfide of the present invention in HeLa cells.
  • Figure 7 shows the results of confirming the fluorescence response according to the concentration of the fluorescent probe for detecting hydrogen sulfide of the present invention in mice.
  • Figure 8 shows the results of confirming the fluorescence response over time in the rat.
  • the term 'probe' is also referred to as 'sensor' and is defined as being capable of detecting or imaging an in vivo / external target. In general, it is used interchangeably with terms such as imaging agent, contrast agent, radiopharmaceutical.
  • the fluorescent probe for detecting hydrogen sulfide of the present invention is a compound represented by the following Chemical Formula 1.
  • the compound represented by Chemical Formula 1 may include an azide group to improve accessibility toward hydrogen sulfide.
  • the hydrogen sulfide detection probe is a near-infrared fluorescence (NIRF), and may be selectively located in the mitochondria or cytoplasm when injected in vivo.
  • NIRF near-infrared fluorescence
  • the intensity of fluorescence is changed at 550 to 680 nm and 695 to 770 nm, and hydrogen sulfide can be detected by measuring the same. (See FIG. 1).
  • the fluorescent probe for detecting hydrogen sulfide can preferably detect hydrogen sulfide at a penetration depth of 100 to 200 ⁇ m in vivo such as cells or tissues, and can also image in real time. Therefore, it can greatly contribute to the life science research related to hydrogen sulfide and the early diagnosis of diseases, the development of diagnostic reagents and therapeutics.
  • Scheme 1 is prepared by reacting a compound represented by Formula 2 with 4-chlororesinol to a compound represented by Formula 3; And reacting the compound represented by Chemical Formula 3 prepared above with a compound represented by Chemical Formula 4 to prepare a compound represented by Chemical Formula 1.
  • the compound represented by Chemical Formula 2 is a near-infrared (NIR) fluorescent dye having a higher and more stable fluorescence intensity than the clinical application dye Indocyanine green (ICG), and is a chloro-substituted cyanine dye.
  • NIR near-infrared
  • ICG Indocyanine green
  • the compound of Formula 2 is 2- [2- [2-chloro-3- [1,3-dihydro-3,3-dimethyl-1-propyl-2H-indol-2-ylidene) ethylidene] -1 -Cyclohexane-1-yl] ethyl] 3,3-dimethyl-1-propylindolium iodine (2- [2- [2-Chloro-3-[(1,3-dihydro-3,3-dimethyl- 1-propyl-2H-indol-2-ylidene) ethylidene] -1-cyclohexen-1-yl] ethenyl] -3,3-dimethyl-1-propylindolium iodide), near-infrared (NIR) IR-780 iodide ( Commercially available from Aldrich ® Chemistry).
  • NIR near-infrared
  • an organic solvent may be added together when the 4-chlororesinol is added.
  • the organic solvent is dimethylformamide (DMF), triethylamine (TEA), ethanol, diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran (THF), dimethylacetamide (DMA), dimailsulfoxide (DMSO), methylene chloride (MC), acetonitrile (ACN), chlorobenzene, toluene and benzene, and preferably in dimethylformamide (DMF) and triethylamine (TEA) At least one or more may be used.
  • the compound represented by Chemical Formula 1 is prepared by reacting the compound and the compound represented by Chemical Formula 4.
  • the reaction may be preferably performed at 30 to 70 ° C.
  • an organic solvent may be included when the compound of Chemical Formula 4 is added.
  • the organic solvent is dimethylformamide (DMF), triethylamine (TEA), ethanol, diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran (THF), dimethylacetamide (DMA), dimail
  • the organic solvent is dimethylformamide (DMF), triethylamine (TEA), ethanol, diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran (THF), dimethylacetamide (DMA), dimail
  • DMSO dimethylformamide
  • MC methylene chloride
  • ACN acetonitrile
  • chlorobenzene toluene and benzene
  • THF dimethylacetamide
  • THF dimethylacetamide
  • dimail may include at least one or more of sulfoxide (DMSO), methylene chloride (MC), ace
  • the organic solvent may further include potassium carbonate (K 2 CO 3 ).
  • the organic solvent may further include a buffer.
  • the buffer is preferably phosphate-buffered saline (“PBS"), sodium acetate, ammonium acetate, acetic acid, citric acid, sodium citrate, tris (hydroxymethyl) aminoethane ("tris"), N-2-hydroxy Ethylpiperazin-N'-2-ethanesulfonic acid (“HEPES”), 3- (N-morpholino) propanesulfonic acid (“MOPS”), 2- (N-morpholino) ethanesulfonic acid (“MES”) , N- (2-acetamido) iminodiacetic acid (“ADA”), piperazine-N, N'-bis (2-ethanesulfonic acid) (“PIPES”), and N- (2-acetamido) At least one of 2-aminoethanesulfonic acid (“ACES”), most preferably PBS.
  • the PBS preferably has a pH of 7.4.
  • (a) is 4-aminobenzyl alcohol, sodium nitrite (NaNO 2 ), sodium azide (NaN 3 ), HCl, water, (b) sulfulyl chloride (SO 2 Cl 2 ), dichloromethane (DCM).
  • Hydrogen sulfide detection method of the present invention comprising the steps of injecting a fluorescent probe for detecting hydrogen sulfide prepared above in vivo;
  • the fluorescent probe for detecting hydrogen sulfide reacts with hydrogen sulfide in vivo to fluoresce; And identifying the fluorescence.
  • the hydrogen sulfide detection fluorescent probe represented by the following Chemical Formula 1 is characterized by fluorescence when it reacts with hydrogen sulfide to be converted into the compound represented by the following Chemical Formula 3.
  • the fluorescence intensity is variable at the same time at 550 to 680nm and 695 to 770nm.
  • MS Mass spectrometry
  • ESI Electrospray Ionizer
  • reaction was examined by thin layer chromatography (TLC) and the reaction was stopped after two hours. After extraction three times with ether, the organic phase was washed sequentially with saturated aqueous NaHCO 3 , water and brine.
  • TLC thin layer chromatography
  • the product was purified by silica column chromatography using ethyl acetate / n-hexane as eluent to afford the compound represented by the formula (2) as a yellow oil (1.33 g, yield 89%).
  • reaction was then examined by TLC, and the reaction mixture was diluted in EtOAc and washed sequentially with saturated aqueous NaHCO 3 , water and brine.
  • the organic phase was dried over MgSO 4 .
  • the compound represented by Formula 1 prepared in Synthesis Example 4 was prepared using PBS buffer (10 ⁇ M, pH 7.4).
  • the fluorescence spectra were examined by reacting NaHS (hydrogen sulfide source) at 37 ° C. for 30 minutes. The results are shown in Figure a).
  • the compound represented by Formula 1 prepared in Synthesis Example 4 was prepared using PBS buffer (10 ⁇ M, pH 7.4). The compound was reacted with NaHS (hydrogen sulfide source) at 37 ° C. Herein, the compound represented by Chemical Formula 1 was measured for fluorescence at 720 nm. The concentration of NaHS (hydrogen sulfide source) was changed from 0 to 50 ⁇ m, and the fluorescence reaction according to the concentration was investigated. Indicated.
  • the fluorescence intensity increases linearly with hydrogen sulfide from 0 to 50 ⁇ m, indicating that quantitative measurement of hydrogen sulfide concentration is possible only by measuring the fluorescence intensity.
  • Analytes are shown in Table 1.
  • the analyte 1 shows only the compound represented by the formula (1)
  • Analyte 2 to 17 represents a mixture with the compound represented by the formula (1).
  • Rat macrophages were placed in Dulbecco's modified Eagle's medium (DMEM) at 37 ° C., and cultured with 10% FBS (fetal bovine serum) in an atmosphere of 5% CO 2 and 95% air.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • the compound represented by the formula (1) of 5 ⁇ m was added to the cell sample and incubated for 30 minutes.
  • NaHS was added at 0, 20, 40, and 80 ⁇ m to determine the fluorescence intensity.
  • CCK-8 solution (Dojindo, Japan) was added to each plate, and the cells were incubated for an additional 30 minutes.
  • Balb C nude mice (15-22 g) were anesthetized by intraperitoneal injection of xylazine (10 mg / kg) and ketamine (80 mg / kg).
  • rats were injected with the compound represented by the formula (1) (50 ⁇ m, 20 ⁇ L DMSO) into the abdominal cavity, and NaHS (0, 50, 100, 200 ⁇ m, 100 ⁇ L PBS) was injected into the abdominal cavity.
  • mice were detected for fluorescence using IVIS Lumina II in an in vivo imaging system with a 675 nm excitation filter and a 695-770 nm luminescence filter. The result is shown in FIG.
  • Balb C nude mice (15-22 g) were anesthetized by intraperitoneal injection of xylazine (10 mg / kg) and ketamine (80 mg / kg).
  • rats were injected with the compound represented by the formula (50 ⁇ m, 20 ⁇ L DMSO) into the abdominal cavity, and NaHS (100 ⁇ m, 100 ⁇ L of PBS) was injected into the abdominal cavity.
  • Rats were fluorescent using IVIS Lumina II in an in vivo imaging system at different times (0, 0.5, 1, 2, 3 hours) using a 675 nm excitation filter, a 695-770 nm luminescence filter and a 695-770 nm luminescence filter. Detected. The result is shown in FIG.

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Abstract

La présente invention concerne une sonde fluorescente destinée à la détection de sulfure d'hydrogène et un procédé de préparation de ladite sonde fluorescente. Selon la présente invention, un capteur fluorescent apte à détecter le sulfure d'hydrogène peut détecter de manière sélective uniquement le sulfure d'hydrogène, rapidement et avec précision. De plus, la présente invention peut reconnaître, en temps réel, des phénomènes biologiques se produisant profondément dans les cellules et les tissus à l'aide d'images in vivo non invasives.
PCT/KR2017/010046 2016-09-19 2017-09-13 Sonde fluorescente destinée à la détection de sulfure d'hydrogène et procédé de préparation de ladite sonde fluorescente WO2018052243A1 (fr)

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CN108456197A (zh) * 2018-03-23 2018-08-28 华南师范大学 用于活体检测硫化氢的光声比率纳米探针及其制备方法与应用
CN113092309A (zh) * 2021-04-13 2021-07-09 福州大学 一种毛细管高度指示剂装置及其检测硫化氢的应用

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KR102051757B1 (ko) 2018-08-16 2019-12-03 숙명여자대학교산학협력단 황화수소 검출용 신규 화합물 및 이를 이용한 황화수소 검출용 센서 키트
CN109856104A (zh) * 2019-04-15 2019-06-07 齐齐哈尔大学 一种苯并吲哚半菁衍生物pH荧光探针及其制备方法
CN110669026B (zh) * 2019-10-22 2022-04-01 中国科学院新疆理化技术研究所 一种用于检测亚硝酸盐的荧光探针分子及其制备方法
KR102336338B1 (ko) * 2020-07-01 2021-12-09 대한민국 황화수소 검출 키트
KR102314070B1 (ko) * 2020-04-28 2021-10-19 대한민국 황화 이온 선택성 화학센서 및 그 제조방법

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
CN108456197A (zh) * 2018-03-23 2018-08-28 华南师范大学 用于活体检测硫化氢的光声比率纳米探针及其制备方法与应用
CN108456197B (zh) * 2018-03-23 2019-10-22 华南师范大学 用于活体检测硫化氢的光声比率纳米探针及其制备方法与应用
CN113092309A (zh) * 2021-04-13 2021-07-09 福州大学 一种毛细管高度指示剂装置及其检测硫化氢的应用
CN113092309B (zh) * 2021-04-13 2022-01-28 福州大学 一种毛细管高度指示剂装置及其检测硫化氢的应用

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