Synthesis and biological evaluation of novel bifendate derivatives bearing 6,7-dihydro-dibenzo[c,e]azepine scaffold as potent P-glycoprotein inhibitors

• Published in: European journal of medicinal chemistry 2012-05, Vol.51, p.137-144
• Main Authors: Gu, Xiaoke, Ren, Zhiguang, Tang, Xiaobo, Peng, Hui, Zhao, Qing, Lai, Yisheng, Peng, Sixun, Zhang, Yihua
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - metabolism; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Azepines - chemistry; Bifendate; Biological and medical sciences; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Chemistry Techniques, Synthetic; dibenzo[c,e]azepine; Doxorubicin - metabolism; Gene Expression Regulation - drug effects; Humans; K562 Cells; Medical sciences; Miscellaneous; Multidrug resistance; P-gp inhibitor; Pharmacology. Drug treatments; Rhodamine 123 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.02.034

Overexpression of P-glycoprotein (P-gp) is one of the major problems in successful treatment of cancers. To find new P-gp inhibitors, a series of bifendate (DDB) derivatives bearing dibenzo[c,e]azepine scaffold were synthesized and evaluated. Compound 4i more potently reversed P-gp-mediated multidrug resistance (MDR) than DDB and verapamil (VRP) by blocking P-gp mediated drug efflux function and increasing drug accumulation in K562/A02 MDR cells, and persisted longer chemo-sensitizing effect (>24 h) than VRP (