Abstract：
Multi-drug resistance (MDR) is a serious challenge in contemporary clinical practice and is mostly responsible for the failure of cancer medication therapies. Several experimental evidence links MDR to the overexpression of the drug efflux transporter P-gp, therefore, the discovery of novel P-glycoprotein inhibitors is required to treat or prevent MDR and to improve the absorption of chemotherapy drugs via the gastrointestinal system. In this work, we explored a series of novel pyridoquinoxaline-based derivatives designed from parental compounds, previously proved active in enhancing anticancer drugs in MDR nasopharyngeal carcinoma (KB). Among them, derivative 10d showed the most potent and selective inhibition of fluorescent dye efflux, if compared to reference compounds (MK-571, Novobiocin, Verapamil), and the highest MDR reversal activity when co-administered with the chemotherapeutic agents Vincristine and Etoposide, at non-cytotoxic concentrations. Molecular modelling predicted the two compound 10d binding mode in a ratio of 2:1 with the target protein. No cytotoxicity was observed in healthy microglia cells and off-target investigations showed the absence of CaV1.2 channel blockade. In summary, our findings indicated that 10d could potentially be a novel therapeutic coadjutant by inhibiting P-gp transport function in vitro, thereby reversing cancer multidrug resistance.
摘要：
多重耐药性（MDR）是当代临床实践中的严峻挑战，是癌症药物治疗失败的主要原因。一些实验证据将MDR与药物外排转运蛋白P-gp的过表达联系起来，因此,需要发现新的P-糖蛋白抑制剂来治疗或预防MDR并改善化疗药物通过胃肠道系统的吸收。在这项工作中,我们探索了一系列由母体化合物设计的新型吡啶并喹喔啉衍生物，先前证明在增强MDR鼻咽癌（KB）的抗癌药物中具有活性。其中,衍生物10d显示出最有效和选择性的抑制荧光染料流出，如果与参考化合物(MK-571，Novobiocin，维拉帕米)，与化学治疗剂长春新碱和依托泊苷共同给药时，MDR逆转活性最高，在非细胞毒性浓度。分子建模预测了两种化合物10d与靶蛋白的比例为2:1的结合模式。在健康的小胶质细胞中未观察到细胞毒性，脱靶研究显示不存在CaV1.2通道阻断。总之,我们的发现表明，10d可能是一种新的治疗辅助药，通过抑制P-gp的体外转运功能，从而逆转癌症多药耐药性。
