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Carborane celecoxib, preparation thereof and application thereof in head and neck cancer boron neutron capture therapy drugs

A carboryl plug and coxib technology, which is applied in the fields of medicinal chemistry and radiation medicine, can solve the problems of tumor targeting and low boron content, achieve good inhibitory effect, strong selective uptake, and reduce side effects

Active Publication Date: 2021-02-12
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, BSH and BPA both showed limited tumor targeting and low boron content in BNCT clinical research.

Method used

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  • Carborane celecoxib, preparation thereof and application thereof in head and neck cancer boron neutron capture therapy drugs
  • Carborane celecoxib, preparation thereof and application thereof in head and neck cancer boron neutron capture therapy drugs
  • Carborane celecoxib, preparation thereof and application thereof in head and neck cancer boron neutron capture therapy drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: the synthesis of intermediate product formula II

[0028]

[0029] Use celecoxib as the reactant and 3-bromopropyne for substitution reaction in an acetone solution dissolved in potassium carbonate, wherein the molar ratio of celecoxib, potassium carbonate and 3-bromopropyne is 1:2.5:2.3 , the organic solvent consumption is 200 times of the molar number of celecoxib. After the substitution reaction, the filtrate was collected by filtration, and the solvent was removed under reduced pressure to obtain the crude product of celecoxib derivative, and then the crude product of celecoxib derivative was passed through petroleum ether and ethyl acetate in a volume ratio of 10:1 to 7:1. The high-purity intermediate product can be obtained by silica gel column chromatography separation with ester eluent.

[0030] The detection data of the product are as follows: white solid, yield 86.0%. 1 H NMR (400MHz, Chloroform-d, ppm): δ7.74(d, J=8.7Hz, 2H), 7.39(d, J=8.6H...

Embodiment 2

[0031] Embodiment 2: Synthesis of carboryl celecoxib formula I

[0032]

[0033] Decaborane and acetonitrile react in toluene solution at 110°C to form decaborane acetonitrile complex, and then decaborane acetonitrile complex is heated with N,N-bis(propynyl)-celecoxib in toluene solution Addition reaction occurs at 110°C, wherein the molar ratio of decaborane to N,N-bis(propynyl)-celecoxib is 3:1, and the amount of organic solvent acetonitrile and toluene is the number of moles of decaborane 100 times and 400 times. After the addition reaction, remove the solvent under reduced pressure to obtain the crude product of celecoxibated carborane, and then pass the crude product of celecoxibated carborane through n-hexane and acetic acid with a volume ratio of 15:1 to 10:1 Carboryl celecoxib with high purity can be obtained by silica gel column chromatography separation with ethyl ester eluent.

[0034] The detection data of the product are as follows: white solid, yield 75.0%. ...

Embodiment 3

[0035] Example 3: Uptake detection of carboryl celecoxib in CAL27 cells

[0036] CAL27 cells in the logarithmic growth phase with a cell content of 80-85% were seeded into 6-well plates (1×10 per well 6cells). After the cells adhered to the wall, the control group (BSH or celecoxib) or carboryl celecoxib with a concentration of 20, 50 or 100 μM was used to act on the cells for 24 hours respectively (4 parallel experiments were set up for each group, and Set up a blank control group). After the effect, the culture medium was discarded, and the cells were washed 3 times with PBS; then 1 mL of pronase solution with a concentration of 2 mg / mL was added to each well and incubated at 4 °C for 4 h to remove the compound bound to the cell surface. The pronase-containing solution was discarded, the cells were washed 3 times with PBS, the cells were lysed with RIPA lysate, the cell lysate was collected, and the supernatant was collected by centrifugation at 10,000 rpm. The supernatan...

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Abstract

The invention discloses preparation of carborane celecoxib and application of carborane celecoxib in head and neck cancer boron neutron capture therapy drugs, and relates to the field of medicinal chemistry and radiological medicine. The compound can be prepared from celecoxib, 3-propargyl bromide and decaborane in a toluene solution through substitution and addition reactions step by step. The preparation process is simple and easy to operate, and the product is high in yield and purity. Head and neck cancer cell experiment results prove that the compound has high selectivity on head and neckcancer cells and has an obvious apoptosis induction effect on the head and neck cancer cells in boron neutron capture therapy. Compared with an existing clinical medicine applied to boron neutron capture therapy, the compound is high in boron loading capacity and high in tumor selectivity, the anti-inflammatory effect can be achieved while the radiotherapy effect is achieved, and the toxic and side effects of therapy are reduced.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and radiation medicine, in particular to a carboryl celecoxib, the preparation of the compound and its application in boron neutron capture therapy drugs for head and neck cancer. Background technique [0002] As one of the major diseases that endanger human life and health, head and neck cancer is difficult to cure, and cancer cells are very easy to spread and metastasize. At the same time, because of the special location, surgical treatment often cannot completely eradicate cancer cells. Globally, patients with head and neck cancer account for about 10% of all cancers, the incidence rate ranks sixth among all tumors, and the mortality rate ranks eighth. Despite recent advances in diagnostic techniques and the development of novel anticancer drugs, mortality among head and neck cancer patients remains high. Boron neutron capture therapy (BNCT) is a novel radiotherapy modality targeting tumor ...

Claims

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Application Information

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IPC IPC(8): C07F5/02A61K41/00A61P35/00
CPCC07F5/027A61K41/0095A61P35/00
Inventor 张涛锋刘斌余晗玥艾克清颜郭艳珠伊洋蔓马千龙
Owner LANZHOU UNIVERSITY
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