Evaluation of Novel Diaza Cage Compounds as MRP Modulators in Cancer Cells.

IF 2.6 4区医学 Q3 CHEMISTRY, MEDICINAL

Anti-cancer agents in medicinal chemistry Pub Date : 2024-08-30 DOI:10.2174/0118715206331206240828111126

Henry Döring, David Kreutzer, Jannis von Veh, Christoph R Ritter, Andreas Hilgeroth

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引用次数: 0

Abstract

Aim: Novel MRP modulators are needed to combat MRP-mediated multidrug resistance (MDR) in cancer cells.

Background: Anticancer drug resistance is the main problem in cancer therapy. Causative multidrug efflux pumps are attractive target structures for the development of inhibitors of their activity.

Objective: We synthesized novel cage dimeric 1,4-dihydropyridines to evaluate them as MRP modulators in cancer cells targeting MRP1, MRP2, and MRP4.

Method: Cage compounds were synthesized by solution dimerization of monomeric 1,4-dihydropyridines and a final functionalization reaction. The MRP modulation was determined in cellular efflux assays by the use of the flow cytometry technique as well as cellular fluorescent measurements with each fluorescent substrate of the efflux pumps.

Results: Difluoro phenyl and methoxy or dimethoxy benzyl substitutions were most favourable for the MRP1 and MRP2 inhibition, whereas monofluor phenyl and dimethoxy benzyl substitutions were most favourable for the MRP4 inhibition.

Conclusion: Effective inhibitors were identified that were demonstrated to restore the respective cancer cell line sensitivity for the anticancer drug as a proof-of-concept that encourages further preclinical studies.

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评估在癌细胞中作为 MRP 调节剂的新型 Diaza Cage 化合物。

目的：需要新型 MRP 调节剂来对抗癌细胞中 MRP 介导的多药耐药性（MDR）：背景：抗癌药物耐药性是癌症治疗中的主要问题。背景：抗癌药物耐药性是癌症治疗中的主要问题，多药外排泵是开发其活性抑制剂的诱人靶标结构：我们合成了新型笼状二聚体 1,4-二氢吡啶，以评估它们作为 MRP 调节剂在癌细胞中针对 MRP1、MRP2 和 MRP4 的作用：方法：通过单体 1,4-二氢吡啶的溶液二聚化和最后的官能化反应合成笼状化合物。在细胞外流试验中，使用流式细胞仪技术以及外流泵的每种荧光底物进行细胞荧光测量，以确定 MRP 的调节作用：结果：二氟苯基和甲氧基或二甲氧基苄基取代最有利于抑制 MRP1 和 MRP2，而单氟苯基和二甲氧基苄基取代最有利于抑制 MRP4：结论：研究发现了有效的抑制剂，这些抑制剂能恢复相应癌细胞系对抗癌药物的敏感性，从而证明了这一概念，并鼓励进一步开展临床前研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Anti-cancer agents in medicinal chemistry ONCOLOGY-CHEMISTRY, MEDICINAL

CiteScore

5.10

自引率

3.60%

发文量

323

审稿时长

4-8 weeks

期刊介绍： Formerly: Current Medicinal Chemistry - Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of anti-cancer agents. Each issue contains a series of timely in-depth reviews and guest edited issues written by leaders in the field covering a range of current topics in cancer medicinal chemistry. The journal only considers high quality research papers for publication. Anti-Cancer Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cancer drug discovery.