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

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 (<6 h). Interestingly, unlike VRP, 4i showed no stimulation on the P-gp ATPase activity, suggesting it is not a substrate of P-gp. Given the low intrinsic cytotoxicity of 4iin vitro, it may represent a promising lead for developing therapeutics targeting P-gp-mediated MDR in combinational cancer chemotherapy.

Compound 4i more potently reversed P-gp-mediated multidrug resistance and persisted longer time than verapamil.Figure optionsDownload as PowerPoint slideHighlights
► Novel DDB derivatives were synthesized and evaluated as P-glycoprotein inhibitors.
► Compound 4i more potently reversed P-gp-mediated MDR than DDB and verapamil.
► The chemo-sensitizing effect of 4i persisted longer time than that of verapamil.
► Unlike verapamil, compound 4i was not a substrate of P-gp.