Multidrug resistance (MDR) mediated by P-glycoprotein is one of the best characterized transporter-mediated barriers to successful cancer chemotherapy. In an attempt to find MDR-reversing agents, a series of novel acridine derivatives were synthesized and evaluated for their in vitro antiproliferative activities against K562 and K562/ADM cells. Some of these compounds showed superior MDR-reversing activities than Amsacrine, the reference compound. Structure-activity relationships (SAR) of these compounds indicated that the N, N-diethylamine moiety had an affect on the in vitro antiproliferative activity. Interestingly, the compounds bearing N, N-diethylamine moiety showed higher growth-inhibitory activity against K562/ADM cells than K562 cells. The high duplex DNA binding affinity and inhibition of topoisomerase of these acridine compounds are maintained which were confirmed by fluorescent quenching and DNA topoisomerase II cleavage assay, respectively. Moreover, several compounds were examined for their ability to increase the accumulation of rhodamine 123 in K562 and K562/ADM cells, and the result suggested that they may be inhibitors for P-glycoprotein. Our study suggested that acridine framework is a potentially interesting scaffold for developing novel MDR-reversing agents.

译文

由P-糖蛋白介导的多药耐药性 (MDR) 是成功进行癌症化疗的最典型的转运蛋白介导的障碍之一。为了寻找MDR逆转剂,合成了一系列新型的a啶衍生物,并评估了它们对K562和K562/ADM细胞的体外抗增殖活性。这些化合物中的一些显示出比参考化合物Amsacrine更好的MDR逆转活性。这些化合物的构效关系 (SAR) 表明N,N-二乙胺部分对体外抗增殖活性有影响。有趣的是,带有N,N-二乙胺部分的化合物对K562/ADM细胞的生长抑制活性高于K562细胞。这些吖啶化合物的高双链DNA结合亲和力和拓扑异构酶的抑制作用得以维持,这分别通过荧光猝灭和DNA拓扑异构酶II裂解试验得到证实。此外,检查了几种化合物增加K562和K562/ADM细胞中罗丹明123积累的能力,结果表明它们可能是P-糖蛋白的抑制剂。我们的研究表明,a啶框架是开发新型MDR逆转剂的潜在有趣的支架。

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