Abstract：
Taxol is widely used in cancer chemotherapy; however, the oral absorption of Taxol remains a formidable challenge. Since the intestinal p-glycoprotein (P-gp) mediated drug efflux is one of the primary causes, the development of P-gp inhibitor is emerging as a promising strategy to realize Taxol\'s oral delivery. Because P-gp exists in many tissues, the non-selective P-gp inhibitors would lead to toxicity. Correspondingly, a potent and intestine specific P-gp inhibitor would be an ideal solution to boost the oral absorption of Taxol and avoid exogenous toxicity. Herein, we would like to report a highly potent and intestine specific P-gp inhibitor to enable oral delivery of Taxol in high efficiency. Through a multicomponent reaction and post-modification, various benzofuran-fused-piperidine derivatives were achieved and the biological evaluation identified 16c with potent P-gp inhibitory activity. Notably, 16c was intestine specific and showed almost none absorption (F = 0.82%), but possessing higher efficacy than Encequidar to improve the oral absorption of Taxol. In MDA-MB-231 xenograft model, the oral administration of Taxol and 16c showed high therapeutic efficiency and low toxicity, thus providing a valuable chemotherapy strategy.
摘要：
紫杉醇广泛用于癌症化疗；然而，紫杉醇的口服吸收仍然是一个巨大的挑战.由于肠道P-糖蛋白(P-gp)介导的药物外排是其主要原因之一,P-gp抑制剂的开发正在成为实现紫杉醇口服给药的一种有前途的策略。因为P-gp存在于许多组织中,非选择性P-gp抑制剂会导致毒性。相应地,一种有效的肠道特异性P-gp抑制剂将是促进紫杉醇口服吸收和避免外源性毒性的理想解决方案.在这里，我们想报告一种高效的肠道特异性P-gp抑制剂，以高效口服紫杉醇。通过多组分反应和后改性，获得了各种苯并呋喃-融合哌啶衍生物，生物学评估确定16c具有有效的P-gp抑制活性。值得注意的是,16c是肠道特异性的，几乎没有吸收（F=0.82%），但具有比Encequidar更高的疗效，以提高紫杉醇的口服吸收。在MDA-MB-231异种移植模型中，Taxol和16c的口服给药显示出高治疗效率和低毒性，从而提供了一种有价值的化疗策略。
