Molecules (2020)
Update date:2022-08-11
Topics:
Handzlik, Jadwiga
Kaczor, Aneta
Kincses, Annamária
Latacz, Gniewomir
Nové, Márta
Spengler, Gabriella
Szymánska, Ewa
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, displayed 1.38-1.46 fold stronger efflux pump inhibiting effects than reference verapamil and were significantly safer than doxorubicin in cell-based toxicity assays in the HEK-293 cell line. Results of mechanistic studies indicate that active imidazolones are substrates with increasing Pgp ATPase activity, and their dye-efflux inhibition via competitive action on the Pgp verapamil binding site was predicted in silico.
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Doi:10.1021/jo01257a082
(1969)Doi:10.14233/ajchem.2016.19532
(2016)Doi:10.1134/S002315841001012X
(2010)Doi:10.1021/acs.inorgchem.7b01037
(2017)Doi:10.1107/S0108270111019196
(2011)Doi:10.1016/j.bmcl.2004.04.006
(2004)