Computer‐Aided Search for 5‐Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1‐Based Multidrug Resistance. (7th June 2021)

• Record Type: Journal Article
• Authors: Kaczor, Aneta; Szemerédi, Nikoletta; Kucwaj‐Brysz, Katarzyna; Dąbrowska, Monika; Starek, Małgorzata; Latacz, Gniewomir; Spengler, Gabriella; Handzlik, Jadwiga
• Is Part Of: ChemMedChem. Volume 16:Number 15(2021)
• Page Start: 2386
• Page End: 2401
• Publication Date: 2021-06-07
• Subjects: cancer -- structure-activity relationships -- lipophilicity -- imidazolones -- ABCB1; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100252
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: ABCB1 modulation is an interesting strategy in the search for new anticancer agents that can overcome multidrug resistance (MDR). Hence, 17 new 5‐arylideneimidazolones containing an amine moiety, as potential ABCB1 inhibitors, were designed, synthesized, and investigated. The series was tested in both parental (PAR) and multidrug‐resistant (MDR) ABCB1‐overexpressing T‐lymphoma cancer cells using cytotoxicity assays. The ABCB1‐modulating activity was examined in rhodamine 123 accumulation tests, followed by Pgp‐Glo™ Assay to determine the influence of the most active compounds on ATPase activity. Lipophilic properties were assessed both, in silico and experimentally (RP‐TLC). Pharmacophore‐based molecular modelling toward ABCB1 modulation was performed. The studies allowed the identification of anticancer agents ( p ‐fluorobenzylidene derivatives) more potent than doxorubicin, with highly selective action on MDR T‐lymphoma cells (selectivity index >40). Most of the investigated compounds showed ABCB1‐modulating action; in particular, two 5‐benzyloxybenzylidene derivatives displayed activity nearly as strong as that of tariquidar. Abstract : Easy as ABCB1 : New 2‐amine‐5‐arylideneimidazolones have a promising chemical scaffold for further development, with demonstrated ABCB1‐modulatory properties and selective cytotoxicity toward multidrug‐resistant cancer cells. The results from biological assays along with ABCB1 pharmacophore modeling are discussed, pointing out the lead structure for further development.