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Nitrones with the function of trapping free radicals and their preparation methods and applications

A technology of compounds and free radicals, applied in peptides, material excitation analysis, fluorescence/phosphorescence, etc., can solve the problems of small molecule free radicals chemical instability, low detection method, short lifespan, etc., and achieve high-efficiency free radical capture ability, Effects of improving analytical sensitivity and reducing quenching probability

Inactive Publication Date: 2011-12-21
INST OF CHEM CHINESE ACAD OF SCI
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  • Abstract
  • Description
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Problems solved by technology

[0003] Although oxygen free radicals play an important role in the pathological process of many major chronic diseases that endanger human life, such as cerebral apoplexy, myocardial infarction, Alzheimer's disease (AD), aging, and cancer, the small molecule free radicals themselves The chemical instability and short lifespan lead to great limitations in its detection methods (low selectivity), which affects the accurate revealing of its important physiological functions
There are currently three main analysis methods for the detection of free radicals in biological systems: the combination of ESR and spin trapping is the most classic free radical analysis method (Rosen GM et al, Free Radicals: Biology and Detection by SpinTrapping, 1999, Publisher: Oxford Univ Press, New York, N.Y., pp-496), its advantage is that this technology has strong structural characteristics for free radicals, and it is easy to analyze and identify the molecular structures of various free radicals at the same time; the research of fluorescent probe method It is characterized by high sensitivity (Gomes et al, J Biochem BiophysMethods, 2005 65:45-80), and is easy to study free radical biology in single cells, but the selectivity to free radical reactions is not high; the electrochemical sensor method is another The high-sensitivity free radical analysis method (DalbastiT and Kilinc E, Methods Enzymol, 2005 396: 584-592) is characterized in that it is suitable for dynamic tracking of free radical concentration changes, but there are still extremely limited free radical analysis in cells. big difficulty

Method used

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  • Nitrones with the function of trapping free radicals and their preparation methods and applications
  • Nitrones with the function of trapping free radicals and their preparation methods and applications
  • Nitrones with the function of trapping free radicals and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1. Preparation of glutathione-linked phosphoryl radical capture probe (compound III)

[0057] 1. Preparation of diethyl phosphite (compound 1)

[0058] A 500mL dry two-necked flask with a built-in magnetic stirrer is used as the reactor, one is connected to a constant pressure dropping funnel, and the other is connected to a thermometer. A mixture of 88 mL (1.5 mol, 70 g) of absolutely absolute ethanol (purity> 99.95%) and 50 mL of anhydrous benzene was added to the reactor. It was cooled to 10°C in an ice water bath, and a mixture consisting of 44 mL (0.5 mol, 69 g) of newly distilled phosphorus trichloride and 50 mL of anhydrous benzene was added dropwise over 1 hour under stirring. The reaction temperature is controlled between 5-10°C. After the reaction is completed, the water pump is depressurized, and nitrogen is introduced from the capillary tube to eliminate hydrogen chloride. Distill the solvent and remaining reactants (15-20°C), and then use an oil pump ...

Embodiment 2

[0086] Example 2. Preparation of phosphoryl radical trap probes linking glutathione and fluorescein isothiocyanate (IV)

[0087] Configure pH 9.5, 500mM carbonate buffer solution (add 17g Na in 1L ultrapure water 2 CO 3 And 28gNaHCO 3 ). The FITC (1mg / ml, 3.7g, 0.0095mM) carbonate buffer solution was dropped into the compound III (1mg / ml, 6.3mg, 0.0095mM) under agitation at a temperature of 4℃ under dark conditions. In the carbonate buffer solution, the reaction was carried out in a 25ml Erlenmeyer flask. After 5 minutes of feeding was completed, the stirring was continued for 12 hours. To ensure the temperature, the reactor was moved into a 4°C refrigerator.

[0088] After the reaction was completed, Sephadex G-10 was used for desalination, and the final product was directly separated by HPLC. The product structure was identified by mass spectrometry. MS(ESI, m / z): 1065.3([M+H] + , 100%), 1103.3([M+K] + , 32.1%).

[0089]

[0090] Compound (IV)

Embodiment 3

[0091] Example 3. Preparation of phosphoryl radical capture probe linking thymopentin and dansyl chloride fluorescein (VI)

[0092] See Example 1 for the synthesis steps of compound 7.

[0093] 1. Link thymopentin and phosphoryl radical capture probe (V)

[0094] Thymopentin (0.48g, 0.7mmol) was dissolved in 50mL DMSO solution containing compound 7 (0.30g, 0.6mmol); stirred at room temperature and protected from light for 12 hours; after the reaction was completed, the solution was added with frozen ether to obtain Light yellow solid, compound V (38.9% yield).

[0095] 2. Phosphoryl radical capture probe linking thymopentin and dansyl chloride fluorescein (VI)

[0096] Dissolve dansyl chloride fluorescein (0.24g) in 50ml pyridine, add dropwise the free radical trapping probe (V) pyridine solution (0.01mM, 10ml) under stirring at 4℃, then continue stirring for 8h, keep the reactor at 4℃ In the reaction.

[0097] The reaction product was crudely separated by Sephadex LH-20 to remove unre...

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Abstract

The invention discloses a nitrone compound with the function of trapping free radicals, a preparation method and application thereof. The structure of the nitrone compound is shown in formula (I). The compound in which R is PLP or PLP-LF in the formula (I) can be used as a free radical capture probe, wherein, PLP represents a polypeptide or protein containing a sulfhydryl group, and LF represents a fluorescent substance. In the present invention, phosphoryl-substituted linear nitrone, which has the function of capturing superoxide anion free radicals, is covalently combined with a tripartite of polypeptide fragments and fluorescein derivatives, and then realizes electron spin resonance of active free radicals under the recognition and guidance of polypeptide molecules ( ESR) and fluorescence detection and imaging multifunctional analysis. Experiments have shown that this series of free radical capture probes not only have efficient free radical capture capabilities (including the very important superoxide anion free radicals), but also can be used in the analysis and identification of active free radicals in intact cells or organelle systems.

Description

Technical field [0001] The invention relates to a nitrone compound with the function of capturing free radicals and a preparation method and application thereof. Background technique [0002] Free radicals, especially superoxide anion radicals (O 2 -. ), nitric oxide (NO) and hydroxyl radicals ( . OH) are unstable intermediate products induced by the body's normal physiological metabolic process and living environment. Generally speaking, when they are excessively produced and disordered, they will cause oxidative damage to cells and tissues, thereby mediating various diseases, aging, and functional degradation of various tissues and organs; on the other hand, under normal physiological conditions, reactive oxygen species also directly participate in biological The redox balance in the body has various physiological functions such as relaxing smooth muscle, inhibiting platelet adhesion, inhibiting pathogens and regulating tumor cell growth. Therefore, to a certain extent, the dy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/083C07K7/06A61K49/14G01N21/64
Inventor 刘扬纪艺琼刘阳平田秋贾宏瑛韩璐
Owner INST OF CHEM CHINESE ACAD OF SCI
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