Molecules, Vol. 25, Pages 2258: Search for ABCB1 Modulators Among 2-Amine-5-arylideneimidazolones As a New Perspective to Overcome Cancer Multidrug Resistance

Molecules, Vol. 25, Pages 2258: Search for ABCB1 Modulators Among 2-Amine-5-arylideneimidazolones As a New Perspective to Overcome Cancer Multidrug Resistance Molecules doi: 10.3390/molecules25092258 Authors: Aneta Kaczor Márta Nové Annamária Kincses Gabriella Spengler Ewa Szymańska Gniewomir Latacz Jadwiga Handzlik 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- (11) and Dimroth-rearranged 3-substituted (18) imidazolone topologies...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research