P-糖蛋白(ABCB1)介导的多药耐药(MDR)已成为临床治疗中癌症化疗疗效的重要障碍。这可以促进MDR逆转的有效药物的开发。在这项工作中,我们报道了新型吡唑并[1,5-a]嘧啶衍生物作为能够增强ABCB1介导的MDRMCF-7/ADR细胞对紫杉醇(PTX)敏感性的有效逆转剂的探索.其中,化合物16q显著增加MCF-7/ADR细胞对5μMPTX的敏感性(IC50=27.00nM,RF=247.40)和10μM(IC50=10.07nM,RF=663.44)。化合物16q能有效结合和稳定ABCB1,不影响ABCB1在MCF-7/ADR细胞中的表达和亚细胞定位。化合物16q抑制ABCB1的功能,从而增加PTX的积累,并中断ABCB1介导的Rh123的积累和流出,从而表现出良好的逆转作用。此外,由于化合物16q的有效逆转作用,PTX抑制微管蛋白解聚的能力,并诱导MCF-7/ADR细胞在低剂量条件下的细胞周期阻滞和凋亡得到恢复。这些结果表明,化合物16q可能是一种有前途的有效逆转剂,能够修正ABCB1介导的MDR,和吡唑并[1,5-a]嘧啶可能代表发现新的ABCB1介导的MDR逆转剂的新型支架。
The P-glycoprotein (
ABCB1)-mediated multidrug resistance (MDR) has emerged as a significant impediment to the efficacy of cancer chemotherapy in clinical therapy, which could promote the development of effective agents for MDR reversal. In this work, we reported the exploration of novel pyrazolo [1,5-a]pyrimidine derivatives as potent reversal agents capable of enhancing the sensitivity of
ABCB1-mediated MDR MCF-7/ADR cells to paclitaxel (PTX). Among them, compound 16q remarkably increased the sensitivity of MCF-7/ADR cells to PTX at 5 μM (IC50 = 27.00 nM, RF = 247.40) and 10 μM (IC50 = 10.07 nM, RF = 663.44). Compound 16q could effectively bind and stabilize ABCB1, and does not affect the expression and subcellular localization of
ABCB1 in MCF-7/ADR cells. Compound 16q inhibited the function of
ABCB1, thereby increasing PTX accumulation, and interrupting the accumulation and efflux of the
ABCB1-mediated Rh123, thus resulting in exhibiting good reversal effects. In addition, due to the potent reversal effects of compound 16q, the abilities of PTX to inhibit tubulin depolymerization, and induce cell cycle arrest and apoptosis in MCF-7/ADR cells under low-dose conditions were restored. These results indicate that compound 16q might be a promising potent reversal agent capable of revising ABCB1-mediated MDR, and pyrazolo [1,5-a]pyrimidine might represent a novel scaffold for the discovery of new ABCB1-mediated MDR reversal agents.