Polyboron phenylalanine compound containing nitroimidazole, as well as preparation method and application thereof

A borophenylalanine and nitroimidazole technology, which is applied in the field of polyboronphenylalanine compounds, can solve the problems of low tumor-specific accumulation ability, poor chemical stability, application limitations and the like

Inactive Publication Date: 2019-06-28
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, BSH lacks active transport ability, low tumor-specific accumulation ability and high cytotoxicity, and has a tendency to be oxidized in the air, resulting in poor chemical stability, which limits its application.

Method used

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  • Polyboron phenylalanine compound containing nitroimidazole, as well as preparation method and application thereof
  • Polyboron phenylalanine compound containing nitroimidazole, as well as preparation method and application thereof
  • Polyboron phenylalanine compound containing nitroimidazole, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] (1) Preparation of S1 compound

[0097]

[0098] Dissolve 2-nitroimidazole (500mg, 4.42mmol) in 3ml N,N-dimethylformamide, add potassium carbonate (1.22g, 8.84mmol), and add 1,3-dibromopropane ( 1.79ml, 17.69mmol), reacted overnight, TLC monitoring found that the raw material had reacted completely. Extracted three times with ethyl acetate (15ml) and water (15ml), combined the organic phases and distilled the crude product under reduced pressure through column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain a tan solid compound S1, A total of 760mg, yield 73%.

[0099] 1 H NMR (600MHz, Chloroform-d) δ7.21(s,1H),7.17(s,1H),4.63(t,J=6.1Hz,2H),3.38(t,J=5.9Hz,2H),2.45 –2.38(m,2H).

[0100] (2) Preparation of S2 compound

[0101]

[0102] Dissolve 2-nitroimidazole (500mg, 4.42mmol) in 3ml N,N-dimethylformamide, add potassium carbonate (1.22g, 8.84mmol), and add 1-bromo-4-chlorobutyl under stirring Alkanes (1.21ml, 10.44mmol) were reacted overnight...

experiment example

[0132] Experimental example: Cytotoxicity experiment

[0133] U87 cells, MCF-7 cells and L02 cells were cultured in DMEM incomplete high-glucose medium supplemented with 10% (v / v) fetal bovine serum, penicillin (80U / ml), streptomycin (0.08mg / ML) , placed at 37°C, 5% CO 2 cultured in a constant temperature incubator.

[0134] (1) U87 cells, MCF-7 cells and L02 cells in the logarithmic growth phase were treated with 0.25% trypsin digestion solution to make a concentration of 1×10 6 Add 100 μL of cell suspension to each well of a 96-well cell culture plate and incubate for 24 hours.

[0135] (2) Add concentration gradient probes after the cells adhere to the wall, design 5 replicate wells for each concentration in a 96-well plate, set a set of blank zero wells for each plate, and add cell suspension without adding drugs. Among them, the compound was prepared with medium to double the required concentration, and 100 μL was added to the corresponding wells respectively, and the ...

Embodiment

[0140] Example: Evaluation of boron uptake ability of boron-containing drugs in different cell lines

[0141] In order to investigate the enrichment ability of this type of boron drug in the hypoxic part of the tumor, each type of cell was divided into a normoxic group and a hypoxic group for the experiment. The normoxia group was placed in a cell incubator with an oxygen concentration of 20%, and the anoxic group was placed in a three-gas incubator with an oxygen concentration of 1%.

[0142] (1) Three cell lines, human normal liver cell L02, human breast cancer cell MCF-7, and human glioma cell U87, were taken out of the cryopreservation box and put into a 37°C water bath to quickly thaw. Take out the thawed liquid at 1000g, centrifuge for 5min, remove the supernatant, add 1ml of medium to the centrifuge tube and blow the cell pellet evenly, add the blown cell suspension into the cell culture dish, then add 7ml DMEM for culture base. Shake to make it evenly mixed, and then...

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Abstract

The invention discloses a polyboron phenylalanine compound containing nitroimidazole as shown in a general formula (I) in the specification or pharmaceutically acceptable salt thereof, as well as a preparation method and application thereof. The compound can be prepared through substitution, addition, nitrification and deprotection reactions, and has the advantages of low cost, easy preparation, high content boron, high affinity for tumor cells, specific response for hypoxic tumor area, good stability and low biotoxicity. The medicinal composition containing a boron compound has a relatively good application prospect in BNCT.

Description

technical field [0001] The invention belongs to the technical field of polyboron phenylalanine compounds, and in particular relates to a polyboron phenylalanine compound containing nitroimidazole and its preparation method and application. Background technique [0002] Boron Neutron Capture Therapy (BNCT) is a promising targeted chemoradiation therapy. The research and development of advanced boron drugs has always been the key to BNCT technology. The continuous development of BNCT technology puts forward the following research on boron drugs: Requirements: (1) Low biotoxicity; (2) High tumor targeting specificity; (3) Effective enrichment of boron sources. Boric acid and its derivatives, closed-type borane, as the first-generation boron drug, were quickly replaced by the second-generation boron drug in the development of BNCT technology due to low absorption efficiency or short residence time in the body. [0003] At present, the second-generation boron drugs L-boron pheny...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02C07D231/16A61P35/00A61P35/04A61K41/00
CPCY02P20/55
Inventor 陈海燕李瑞熙袁振伟何晴王菲万浩张娟娟
Owner CHINA PHARM UNIV
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