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

• Published in: Angewandte Chemie International Edition 2024-11, Vol.63 (45), p.e202412649-n/a
• Main Authors: Zhou, Xianjing, Zhang, Ping, Yang, Yuyan, Shi, Wei, Liu, Lei, Lai, Zhencheng, Zhang, Xing, Pan, Peichen, Li, Lan, Du, Juan, Qian, Hai, Cui, Sunliang
• Format: Article
• Language: English
• Subjects: Absorption; Administration, Oral; Animals; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Benzofuran; Biological activity; Cell Line, Tumor; Chemotherapy; drug delivery; Efflux; Glycoproteins; Humans; Inhibitors; Intestine; Mice; Molecular Structure; multicomponent reaction; Oral administration; P-glycoprotein; Paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - chemistry; Paclitaxel - pharmacokinetics; Paclitaxel - pharmacology; Piperidine; Structure-Activity Relationship; Taxol; Toxicity; Xenotransplantation
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202412649

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 16 c with potent P‐gp inhibitory activity. Notably, 16 c 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 16 c showed high therapeutic efficiency and low toxicity, thus providing a valuable chemotherapy strategy. Taxol is widely used in chemotherapy but couldn't be orally administrated. In this protocol, a series of benzofuran‐fused‐piperidine derivatives were achieved and compound 16 c was identified as potent and intestine specific P‐gp inhibitor, which could enable oral delivery of Taxol in high efficiency and offers high therapeutic effects in breast cancer xenograft model along with almost none oral absorption itself. Therefore, this work provides a valuable strategy of Taxol's oral delivery and chemotherapy.