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Carboryl celecoxib and its preparation and application in boron neutron capture therapy for head and neck cancer

A carboryl-based plug and celecoxib 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 Effect

Active Publication Date: 2022-04-15
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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  • Carboryl celecoxib and its preparation and application in boron neutron capture therapy for head and neck cancer
  • Carboryl celecoxib and its preparation and application in boron neutron capture therapy for head and neck cancer
  • Carboryl celecoxib and its preparation and application in boron neutron capture therapy for head and neck cancer

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, 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 is completed, the solvent is removed under reduced pressure to obtain the crude product of celecoxibated carborane, and then the crude product of celecoxibated carborane is passed 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 s...

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 a preparation of carboryl celecoxib and its application in boron neutron capture therapy drugs for head and neck cancer, and relates to the fields of medicinal chemistry and radiation medicine. The compound can be prepared by stepwise substitution and addition reaction of celecoxib with 3-bromopropyne and decaborane in toluene solution. The invention has simple preparation process, easy operation, high product yield and high purity. The compound of the present invention has been proved by head and neck cancer cell experiment results that the compound has high selectivity to head and neck cancer cells, and has obvious apoptosis-inducing effect on head and neck cancer cells in boron neutron capture therapy. Compared with the existing clinical drugs used in boron neutron capture therapy, the compound not only has high boron loading capacity and strong tumor selectivity, but also can exert anti-inflammatory effect while exerting the curative effect of radiotherapy, and reduce the toxic and side effects of treatment.

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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Patent Type & Authority Patents(China)
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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