Benzopyrone skeleton derivative, preparation method and uses thereof

Abstract

The invention belongs to the field of chemical pharmacy, and relates to a benzopyrone skeleton derivative, a preparation method and uses thereof, particularly to a derivative with a 2-ethyl benzopyrone bicyclic mother nucleus containing 7-alkoxy and 8-aromatic acid or an aromatic hydrocarbon acid methanol ester substituted derivative. According to the present invention, the experiment results showthat the derivative is almost non-toxic to normal cells and drug-resistant tumor cells, can significantly reverse the drug-resistant activity of P-gp overexpressing A2780 / T and KB-V to drugs by combining with paclitaxel and vincristine, does not improve the drug sensitivity of P-gp-dependent drug-resistant tumor cells, and can establish the foundation in the obtaining of the sensitizer capable ofrestoring the drug sensitivity of MDR tumors caused by P-gp overexpression and the overcoming of tumor MDR caused by P-gp overexpression.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and relates to benzopyrone skeleton derivatives and their preparation methods and applications, in particular to benzopyrone skeleton containing 2-ethyl, 7-alkoxy and 8-aromatic acid or aromatic hydrocarbons Acid methyl ester substituted derivatives, a preparation method thereof and an application in preparation of a tumor MDR reversing preparation; the reversing tumor MDR preparation can lead to the activity of tumor multidrug resistance (MDR) by reversing the overexpression of P-gp. Background technique [0002] The prior art discloses that tumor cell drug resistance, especially multidrug resistance (MDR) is a major obstacle to cure cancer. According to statistics, 90% of failures in metastatic cancer chemotherapy are caused by multidrug resistance [Pathol. -glycoprotein, P-gp) mediates drug efflux [Biochemical Journal 1990,272,281-295]; II. The expression level of DNA topoisomerase (Topo II) ...

AI Technical Summary

Problems solved by technology

[0004] According to the specificity, affinity and toxicity of P-gp inhibitors, they are divided into three generations: first-generation inhibitors are represented by verapamil and cyclosporin A, calcium ion antagonists and immunosuppressants and other drugs, due to their There is obvious toxicity within the effective dose for reversing drug resistance, which limits its clinical application; the second-generation inhibitors are mainly analogues of the first generation and some compounds with new structures, such as the oxidation product of cyclosporine A, valsip Although valspodar exhibits good pharmacokinetic properties, due to problems such as inhibition of CYP3A4, reduction of bile excretion, and poor selectivity, the pharmacokinetic changes between the inhibitor and chemotherapy drugs are unpredictable, and cannot be given. Safe and reliable clinical dosage; the third-generation inhibitors are non-competitive inhibitors, represented by compounds such as tariquidar and zosuquidar, which are superior in activity and selectivity to the second-generation, and can bind with P-gp to make it lose its efflux capacity ;Because it is not a substrate of CYP3A4, it will not change the pharmacokinetic properties of anticancer drugs combined with it, nor will it affect the functions of other proteins in the ABC family

However, due to unsatisfactory clinical trial results, the most promising third-generation inhibitors such as tariquidar have not been successfully marketed

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