Conjugated chain functional benzoindole hematocyanine dye and application

A technology of benzoindole heptamethanine and benzindole heptamethanine, which can be used in tumor targeted imaging and treatment. The conjugated chain functionalized benzoindole heptamethanine dye field can Solve the problems of increased adverse conditions and side effects, probe waste, poor stability, etc., to achieve accurate and efficient photothermal and photodynamic anti-tumor, simplified synthesis steps, and mild reaction conditions.

Inactive Publication Date: 2019-02-22
XIDIAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] (1) The current clinically used heptamethanine dyes such as ICG, because they are water-soluble dyes, have fast metabolism and poor stability in the body circulation, so it is necessary to increase the amount of injection in the body to make up for the short detection life. Causes waste of probes and increases chances of adverse events and side effects
[0005] (2) The specificity of the existing heptamethine dyes to the target tumor tissue is poor, and it is easy to combine with proteins after in vivo injection, resulting in high background signal and low target tissue signal, and imaging signals with high sensit

Method used

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  • Conjugated chain functional benzoindole hematocyanine dye and application
  • Conjugated chain functional benzoindole hematocyanine dye and application
  • Conjugated chain functional benzoindole hematocyanine dye and application

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preparation example Construction

[0099] The synthesis method of the conjugated chain median functionalized benzindole heptamethine cyanine dye provided in the embodiment of the present invention comprises the following steps:

[0100] S101: In the mixed solution of DMF and CH2Cl2, add POCl3 dropwise, and then add cyclohexanone dropwise; the mixed solution is refluxed in a nitrogen atmosphere for 3 hours, and finally cooled to room temperature to obtain heptamethine with a chlorine substituent in the middle position Condensing agent A; wherein cyclohexanone: POCl 3 : The molar ratio of DMF is 1:5:15;

[0101] S102: React the benzindole quaternary ammonium salt B and the prepared heptamethine condensing agent A with chlorine substituents in glacial acetic acid and acetic anhydride for 1 to 2 hours to obtain a symmetry Heptamethine dye CyIC7; the molar ratio of indole quaternary ammonium salt B and pentamethine condensing agent A with chlorine substituents is 2:1;

[0102] S103: Combine the prepared compound C...

Embodiment 1

[0119] The preparation of Wujiachuan condensing agent compound A:

[0120]

[0121] A solution of 35 mL of dry dichloromethane and 37 mL of phosphorus oxychloride was dropped into a mixture of 80 mL of dry dichloromethane and N,N-dimethylformyl (1:1, v / v) under an ice bath. Keeping below 0°C, 10 g (0.10 mol) cyclohexanone was added dropwise to the reaction solution, and then the temperature was slowly raised to reflux for 3 h. Stop the reaction, cool in an ice-water bath, and pour the reaction solution into 200 g of crushed ice in batches. A large amount of red solid precipitated out. Filtrate under reduced pressure, wash the solid with frozen acetone in batches until yellow, and vacuum-dry to obtain a crude product, which is recrystallized with acetone to obtain 12.86 g of a yellow solid (Compound A), yield: 73%, melting point: 130-132°C.

Embodiment 2

[0123] Synthesis of dye CyBI7:

[0124]

[0125] Put 0.4g of benzindole quaternary ammonium salt B and 0.1g of heptamethine condensing agent C in 5mL of acetic anhydride, and reflux at 80°C for 1 to 2 hours. The molar ratio of feeding is strictly 2:1. When the molar ratio of feeding is less than 2:1, the by-product of pentamethine hemicyanine dye will be generated. Afterwards, the reaction solution was poured into 100 g of ice water to quench, and then 100 mL of CH was added to the ice water 2 Cl 2 , extraction, the organic layer was spin-dried under reduced pressure and separated by column chromatography (petroleum ether: dichloromethane, 1:20v / v), then the separated product solution was concentrated to 2mL, and then 20mL of diethyl ether was added to the concentrated solution to precipitate The solid was filtered to obtain 0.21 g of an earthy yellow dye with metallic luster. The NMR and mass spectrometry data of product structure identification are as follows:

[0126...

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Abstract

The invention belongs to the technical field of organic chemistry and discloses a conjugated chain functional benzoindole hematocyanine dye and an application. The stability of the novel hematocyaninedye is obviously superior to that of an existing cyanine fluorescent probe, and the novel hematocyanine dye has the multiple functional activity such as near infrared fluorescence and tumor mitochondria targeted accumulation and photo-thermal and photo-power synergic treatment of killing tumor cells. Applied as the near infrared fluorescence probe in living cell imaging research and living body infrared optical molecular imaging, a precise and efficient photo-thermal and photo-power antitumor effect is achieved synchronously. The dye can be applied to near infrared in vivo optical imaging andphoto-sound imaging of tumors, is applied to optical assisted operation navigation, and has an efficient antitumor function. The dye not only can develop a target tissue in real time, but also kill tumor cells specifically. The preparation method of the benzoindole hematocyanine dye is mild in reaction condition, simple in step and easy to operate and low in raw material cost, and is easy to purify and relatively high in yield.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a conjugated chain functionalized benzindole heptamethine cyanine dye and its application, and its application in tumor targeting imaging and treatment. Background technique [0002] At present, the existing technologies commonly used in the industry are as follows: molecular imaging technology has the advantages of high sensitivity and no radiation, and can use sensitive optical detection instruments to observe biological processes such as the occurrence, development, and transfer of diseases in vivo. Guided tumor surgical navigation has become a research hotspot in the field of optical molecular imaging in recent years. Fluorescent probes are a prerequisite for in vivo optical molecular imaging, enabling visual trace detection of target tissues. Compared with other fluorescent dyes, Qijiachuan cyanine dye has outstanding advantages in the application of l...

Claims

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Application Information

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IPC IPC(8): C09B23/08C09K11/06A61P35/00A61K41/00A61K49/00G01N21/64
Inventor 张象涵王忠良赵素梅夏玉琼宁蓬勃张瑞丽余杰
Owner XIDIAN UNIV
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