Application for taking NO donor-type compounds as P-glycoprotein inhibitors and tumor multi-drug resistance reversal agents

A multi-drug resistance and multi-drug resistance technology, which is applied in the direction of antineoplastic drugs, pharmaceutical formulations, drug combinations, etc., to achieve the effects of reducing survival rate, increasing cell uptake, and obvious synergy

Inactive Publication Date: 2009-09-16
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There are no research reports and related patent publications on NO-donating alkoxybiphenyl carboxylic acid compounds as P-gp inhibitors and tumor multidrug resistance reversal agents at home and abroad

Method used

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  • Application for taking NO donor-type compounds as P-glycoprotein inhibitors and tumor multi-drug resistance reversal agents
  • Application for taking NO donor-type compounds as P-glycoprotein inhibitors and tumor multi-drug resistance reversal agents
  • Application for taking NO donor-type compounds as P-glycoprotein inhibitors and tumor multi-drug resistance reversal agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] NO-donating alkoxybiphenylcarboxylic acid compounds reduce the efflux ratio of the P-gp substrate digoxin. Taking the two compounds 14c and 14j as examples, the specific structures are as follows:

[0024]

[0025] experimental method:

[0026] Caco-2 cells by 1×10 5 Cells / ml were inoculated in Millicell small baskets (12mm, 0.4μm, Millicell-PCF, Millipore, USA), and the medium was replaced every other day. When the cells were cultured for 19-25 days, the cells fused to form a dense monolayer, and the EVOMTM epithelial voltage ohmmeter was used to (World Precision Instrument, Sarasota, FL) and only cell monolayers with a TEER greater than 4000 x cm2 were used for transport experiments. At the beginning of the test, the medium in each well was blotted dry, carefully washed twice with 37°C Hank’s solution, 0.4ml was added to the small basket, and 0.6ml blank Hank’s solution was added, and pre-equilibrated at 37°C for 30 minutes. Both the inner and outer solutions of ...

Embodiment 2

[0039] NO-donating alkoxybiphenylcarboxylic acid compounds enhance the uptake of P-gp substrate digoxin, exemplified by 14c and 14j.

[0040] experimental method:

[0041] Caco-2 cells were seeded on 24-well culture plates, and the culture medium was changed every 3 days or so. When the cell monolayer was completely confluent, the uptake test could be carried out. Before the uptake experiment, first suck out the medium in the 24-well plate, add 37 ℃ blank Hank's solution to the wall to wash the cells for 3 times, gently blot the liquid in the well, add 1ml of the drug solution diluted with Hank's solution, and each drug The final concentrations were 5 μM, 10 μM, and 25 μM, respectively. Place the cell plate in a 37°C incubator and record the time. After 90 minutes, the cell plate was taken out, the solution in the well was sucked out immediately, and 1 ml of digoxin solution diluted with the above-mentioned drug-containing solution was added correspondingly, so that the fina...

Embodiment 3

[0044] NO-donating alkoxybiphenylcarboxylic acid compounds enhance the uptake of P-gp substrate doxorubicin by tumor drug-resistant cells, taking 14c and 14j as examples.

[0045] experimental method:

[0046] MCF-7 and MCF-7 / Adr cells were seeded on 24-well culture plates, and the medium was replaced every other day. When the cell monolayer was completely confluent, the uptake test could be performed. Before the uptake experiment, first suck out the medium in the 24-well plate, add 37 ℃ blank Hank's solution to the wall to wash the cells for 3 times, gently blot the liquid in the well, add 1ml of the drug solution diluted with Hank's solution, and each drug The final concentration was 25 μM. Place the cell plate in a 37°C incubator and record the time. Take out the cell plate after 90 minutes, suck out the solution in the well immediately, and add 1 ml of doxorubicin solution diluted with the above-mentioned drug-containing solution correspondingly, so that the final concen...

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Abstract

The invention relates to the medical field of sensitizing antitumor medicaments and reversing tumor multi-drug resistance, in particular to inhibiting effect of nitric oxide (NO) donor-type alkoxy biphenyl carboxylic acid compounds on P-glycoprotein, and application thereof in reversing tumor multi-drug resistance. The characteristics of the invention are summarized as follows: NO donor-type alkoxy biphenyl compounds are characterized in that the compounds have alkoxy biphenyl carboxylic acid parent framework and furazan nitrogen oxide type NO donor radicals, are formed by connected amino acids unequal in length with radicals, can be taken as P-gp inhibitors and tumor multi-drug resistance reversal agents, can remarkably increase the cell uptake amount of P-gp substrates, reduce substrate efflux, regulate the expression of P-gp down, can be used in combination with the antitumor medicaments to increase the concentration of the compounds in multi-drug resistance tumor cells, have a drug-resistance reversal multiple up to hundreds of times, enable multi-drug resistance cell strains to recover sensibility to chemotherapeutic medicaments, and have extensive application prospects.

Description

technical field [0001] The invention relates to the medical field of sensitizing antitumor drugs and reversing tumor multidrug resistance, in particular to the inhibitory effect of NO donor alkoxy biphenyl carboxylic acid compounds on the function of P-glycoprotein and its role in reversing tumor multidrug resistance application in medicine. Background technique [0002] Multidrug resistance (Muti-drug resistance, MDR) is one of the main reasons for the failure of current clinical chemotherapy for cancer. In clinical treatment, due to the existence of the MDR phenomenon, tumor cells are generally resistant to chemotherapeutic drugs that are irrelevant in function and structure, which will not only lead to a decline in the treatment effect, but also increase the tumor recurrence rate. One of the important reasons for tumor MDR is that resistant tumor cells overexpress ATP-binding cassette family transporters (ABC transporters), including P-glycoprotein (P-gp), breast cancer ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4245A61P43/00A61P35/00
Inventor 王广基张奕华艾华吴晓兰周芳孙建国张经纬孔祥文
Owner CHINA PHARM UNIV
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