Highly Potent and Intestine Specific P-Glycoprotein Inhibitor to Enable Oral Delivery of Taxol

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.