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Integrin alpha v beta 3-targeting AIE fluorescent compound and preparation and application thereof

A fluorescent compound and compound technology, applied in the preparation method of peptides, fluorescence/phosphorescence, luminescent materials, etc., can solve the problems of high background, fluorescence quenching, discrimination, etc., and achieve the effect of low background, high luminous intensity, and high sensitivity

Active Publication Date: 2020-02-18
杭州思诺达医药科技有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, these probes all have the problem of high background caused by fluorescent dyes in biological solutions. It is difficult to distinguish the non-specific fluorescence emission of the probe from the fluorescence emission of the target region, which brings great problems to the accuracy of the probe. positive effect
In addition, traditional fluorescent molecules will produce fluorescence quenching (ACQ) in the process of biological targeting aggregation, which will reduce the sensitivity of the probe.

Method used

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  • Integrin alpha v beta 3-targeting AIE fluorescent compound and preparation and application thereof
  • Integrin alpha v beta 3-targeting AIE fluorescent compound and preparation and application thereof
  • Integrin alpha v beta 3-targeting AIE fluorescent compound and preparation and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: the synthesis of compound (VIII)

[0049] (1) Dissolve 2.0g (5.12mmol) of compound II in 3mL of anhydrous DMF, add 1.9g (7.67mmol) of biboronic acid pinacol ester, PdCl 2(dppf) 224.3mg (0.306mmol), potassium acetate 1.4g (14.3mmol), under the protection of nitrogen, react at 80°C for 12 hours. TLC spot plate reaction is complete (Ninhydrin color development after TFA fumigation), respectively add 50mL of dichloromethane and water, extract 2 times to collect the organic phase. After washing with saturated sodium chloride solution and drying over anhydrous sodium sulfate, the solvent was removed by rotary evaporation under reduced pressure, and the concentrate was subjected to silica gel column separation (dichloromethane:methanol=30:1, v / v) to obtain a colorless oil compound III 1.82g, yield 91%. The H NMR spectrum of compound III is shown in figure 1 , (1H NMR (500MHz, CDCl3) δ7.77(d, J=7.8Hz, 2H), 7.21(d, J=7.5Hz, 2H), 4.94(d, J=7.0Hz, 1H), 4.61(d ,J=...

Embodiment 2

[0056] Embodiment 2: Fluorescence performance detection of compound (VIII)

[0057] (1) Detection of fluorescence properties in different solvents:

[0058] 10 μL of compound (VIII) DMSO stock solution (4 mM) was pipetted into 990 μL of PBS solution (pH 7.2, 50 mmol / L) and 990 μL of DMSO solution respectively, and the probe concentration was 40 μM. Using a microplate reader, the fluorescence values ​​were measured at 37°C, the excitation wavelength was 340nm, and the emission wavelength was 460nm. The fluorescence spectrum is shown in Figure 9 .

[0059] Experiments have proved that the fluorescence intensity of compound (VIII) (40 μM) in DMSO solution with good solubility is much lower than that in PBS solution with poor solubility, and the AIE fluorescence characteristic caused by solubility is obvious.

[0060] (2) Detection of fluorescence properties at different concentrations:

[0061] Pipette gun to draw 10 μL compound (VIII) DMSO solution (8 mM) into 990 μL PBS sol...

Embodiment 3

[0063] Embodiment 3: The target function research of compound (VIII)

[0064] A549 and HEK293 cells at approximately 3×10 5 Cells were inoculated and cultured in two confocal dishes respectively, and cultured in DMEM medium at 37°C, 5% CO 2 Under the conditions of constant temperature culture, after 24 hours of culture, the DMEM medium was removed, and PBS 7.2 buffer was washed 3 times. Add DMEM medium (1% DMSO) prepared with 5 μM compound (VIII) respectively, and incubate at 37° C. for 30 minutes. Remove the DMEM culture solution, wash with PBS 7.2 buffer twice, and perform fluorescence imaging with a fluorescent confocal microscope with an emission wavelength of 460 nm. Figure 11 It is the fluorescence imaging map of A549 cells, Figure 12 Fluorescence imaging of HEK-293 cells.

[0065] Experiments have shown that in A549 cells with a relatively high expression of integrin αvβ3, the cell membrane is successfully labeled and there is obvious fluorescence, while there is ...

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Abstract

The present invention provides an AIE fluorescent cyclic peptide c (RGDf-TPEK) as shown in a formula (VIII) and a preparation method and an application thereof. On the premise of not destroying targeting structures and functions, construction of an AIE fluorescent probe of integrin alpha v beta 3 is realized. Compared with an existing strategy of connecting existing fluorescent molecules and targeting peptides, AIE molecules are embedded into the structure of integrin alpha v beta 3-targeting peptide c (RGDfK), aggregation can occur on surfaces of tumor cells with high expression of the integrin alpha v beta 3, and AIE luminescence generated by restriction of intramolecular rotations (RIR) has characteristics of high luminescence intensity, low background and high sensitivity.

Description

[0001] (1) Technical field [0002] The invention relates to an AIE fluorescent compound targeting integrin αvβ3, its preparation method and application. [0003] (2) Background technology [0004] The labeling and imaging of tumor cells has been applied in the diagnosis and clinical treatment of cancer, which promotes the development of cancer cell labeling probes. The effect of labeling depends on the affinity of the targeting molecule for markers expressed by cancer cells, as well as the biocompatibility and fluorescent properties of the fluorescent molecule. [0005] Integrin αvβ3, as a transmembrane receptor mediating the extracellular and extracellular environment, is a unique molecular target for early detection and treatment of rapidly growing solid tumors. The RGD (arginine-glycine-aspartic acid) tripeptide sequence can imitate cell adhesion proteins and bind to integrins, and its series Cyclo (RGDfK) is currently an effective and selective inhibitor of αvβ3 integrins...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64C07K1/06C07K1/04C09K11/06G01N21/64
CPCC07K7/64C09K11/06C09K2211/1007C09K2211/1074G01N21/6486Y02P20/55
Inventor 朱勍蒋建泽刘江
Owner 杭州思诺达医药科技有限责任公司
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