Abstract
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.
Highlights
Multidrug resistance (MDR) is nowadays one of the most important problems in the treatment of various diseases including cancer
5-arylideneimidazolone intermediates (21–26) that were subsequently reacted with iodomethane in sodium ethanolate solution
In the case of group B (14–20), the Dimroth rearrangement was observed to proceed via a similar mechanism to that described previously [22]
Summary
Multidrug resistance (MDR) is nowadays one of the most important problems in the treatment of various diseases including cancer. One of them involves an increased drug efflux through membrane transporters, e.g., P-glycoprotein (Pgp, ABCB1) [1,2,3,4]. Pgp is an ATP-binding cassette protein, encoded by the MDR1 (ABCB1) gene, which is present in both normal and cancer cells [5,6]. The structure includes two hydrophobic transmembrane domains, which contain drug binding domain (DBD). There are two nucleotide binding domains (NBDs) in which coupling ATP hydrolysis takes place [5,7,8,9]. ABCB1 obtains energy from the ATP hydrolysis process and uses it to translocate to the cell exterior structurally unrelated compounds, e.g., Molecules 2020, 25, 2258; doi:10.3390/molecules25092258 www.mdpi.com/journal/molecules
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