3-benzazecine-based cyclic allene derivatives as highly potent P-glycoprotein inhibitors overcoming doxorubicin multidrug resistance.

Enamino 3-benzazecine compounds, incorporating the C6-C8 allene system, were synthesized and evaluated as inhibitors of P-glycoprotein (P-gp) and/or multidrug resistance-associated protein 1 (MRP1), two efflux pumps mainly connected with multidrug resistance (MDR) in cancer cells. Most of the synthesized compounds were selective P-gp inhibitors in Calcein-AM uptake assay. Structure-activity relationships (SARs) pointed out that COMe derivatives are more potent than acetyl derivatives, and 10,11-dimethoxy compounds are five to tenfold more potent inhibitors than the respective unsubstituted compounds, and that the P-gp inhibition potency is mainly related to volume parameters. Nanomolar P-gp inhibitors, such as (IC = 4.2 nM), restored the antiproliferative activity of doxorubicin in multidrug-resistant cells. The observed activities showed that 3-benzazecine-based compounds may be promising MDR reversers.