imidazolone and morpholine

Multidrug resistance (MDR) is a severe problem in the treatment of cancer with overexpression of glycoprotein P (Pgp, ABCB1) as a reason for chemotherapy failure. A series of 14 novel 5-arylideneimidazolone derivatives containing the morpholine moiety, with respect to two different topologies (groups A and B), were designed and obtained in a three- or four-step synthesis, involving the Dimroth rearrangement. The new compounds were tested for their inhibition of the ABCB1 efflux pump in both sensitive (parental (PAR)) and ABCB1-overexpressing (MDR) T-lymphoma cancer cells in a rhodamine 123 accumulation assay. Their cytotoxic and antiproliferative effects were investigated by a thiazolyl blue tetrazolium bromide (MTT) assay. For active compounds, an insight into the mechanisms of action using either the luminescent Pgp-Glo™ Assay in vitro or docking studies to human Pgp was performed. The safety profile in vitro was examined. Structure-activity relationship (SAR) analysis was discussed. The most active compounds, representing both 2-substituted- (

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Cell Line, Tumor; Cell Proliferation; Cell Survival; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Imidazoles; In Vitro Techniques; Inhibitory Concentration 50; Lymphoma, T-Cell; Mice; Models, Molecular; Molecular Docking Simulation; Morpholines; Rhodamine 123; Structure-Activity Relationship; Verapamil