Discovery of phenylselenoether-hydantoin hybrids as ABCB1 efflux pump modulating agents with cytotoxic and antiproliferative actions in resistant T-lymphoma

Ali, Wesam; Spengler, Gabriella; Nové, Márta; Battistelli, Cecilia; Latacz, Gniewomir; Starek, Małgorzata; Dąbrowska, Monika; Honkisz-Orzechowska, Ewelina; Romanelli, Annalisa; Rasile, Manuela Monica; Szymańska, Ewa; Jacob, Claus; Zwergel, Clemens; Handzlik, Jadwiga

doi:10.1016/j.ejmech.2020.112435

Cited by 35 publications

(31 citation statements)

References 43 publications

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“…The opposite results, however, were observed for the fluorophenyl derivatives. In contrast to the previous studies concerning hydantoin derivatives, [27] the resultant lipophilicity of compounds did not affect the ABCB1 modulating potency in this series ( 7 – 23 ). As the clearest example, the most lipophilic compound 21 did not demonstrate ABCB1‐modulating action, while the most active modulator 22 showed in 1‐unit lower lipophilicity than that of 21 (2.30 vs 3.35, Figure 5).…”

Section: Resultscontrasting

confidence: 99%

“…In this context, the mechanism of ABCB1 modulation observed in the rhodamine 123 accumulation assay for compounds 12 , 20 , and 22 (Table 4) was not associated with the pump inactivation via ATPase inhibition. These results are in compilations with previous ones obtained for imidazolones and hydantoins [24,27] . It suggests a competition with the dye‐substrate towards ABCB1 binding site as the most probable mechanism of the pump modulating action for compounds 12 , 20 and 22 .…”

Section: Resultssupporting

confidence: 85%

“…Prior to estimate an impact on ABCB1 for synthesized 2‐amine‐5‐arylideneimidazolones ( 7 – 23 ), their cytotoxicity was examined using MTT assays [27] . The assays were performed in two mouse T‐lymphoma cell lines: the chemosensitive parental (PAR) and the multidrug resistant (MDR) ones.…”

Section: Resultsmentioning

confidence: 99%

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Computer‐Aided Search for 5‐Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1‐Based Multidrug Resistance

et al. 2021

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Section: Resultscontrasting

confidence: 99%

Section: Resultssupporting

confidence: 85%

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Computer‐Aided Search for 5‐Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1‐Based Multidrug Resistance

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“…For the compound RSe-2, Se-alkylation of 1-bromo-4-chlorobutane was performed under a nitrogen atmosphere and in absolute ethanol at RT. The crude product was then reacted with methyl piperazine in the presence of anhydrous K 2 CO 3 and acetone at 50 °C ( Scheme 2 ) [ 19 ]. The structure and purity of the final compounds were confirmed via spectroscopic and chromatographic methods.…”

Section: Methodsmentioning

confidence: 99%

EPR Study of KO2 as a Source of Superoxide and •BMPO-OH/OOH Radical That Cleaves Plasmid DNA and Detects Radical Interaction with H2S and Se-Derivatives

et al. 2021

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Superoxide radical anion (O2•−) and its derivatives regulate numerous physiological and pathological processes, which are extensively studied. The aim of our work was to utilize KO2 as a source of O2•− and the electron paramagnetic resonance (EPR) spin trapping 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide (BMPO) technique for the preparation of •BMPO-OOH and/or •BMPO-OH radicals in water solution without DMSO. The method distinguishes the interactions of various compounds with •BMPO-OOH and/or •BMPO-OH radicals over time. Here, we show that the addition of a buffered BMPO-HCl mixture to powdered KO2 formed relatively stable •BMPO-OOH and •BMPO-OH radicals and H2O2, where the •BMPO-OOH/OH ratio depended on the pH. At a final pH of ~6.5–8.0, the concentration of •BMPO-OOH radicals was ≥20 times higher than that of •BMPO-OH, whereas at pH 9.0–10.0, the •BMPO-OH radicals prevailed. The •BMPO-OOH/OH radicals effectively cleaved the plasmid DNA. H2S decreased the concentration of •BMPO-OOH/OH radicals, whereas the selenium derivatives 1-methyl-4-(3-(phenylselanyl) propyl) piperazine and 1-methyl-4-(4-(phenylselanyl) butyl) piperazine increased the proportion of •BMPO-OH over the •BMPO-OOH radicals. In conclusion, the presented approach of using KO2 as a source of O2•−/H2O2 and EPR spin trap BMPO for the preparation of •BMPO-OOH/OH radicals in a physiological solution could be useful to study the biological effects of radicals and their interactions with compounds.

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“…Thus, the search for new ABCB1 modulators is a still an ongoing challenge of the pharmaceutical industry. In this context, our research team has explored a new class of chemical compounds, including derivatives of various (un)substituted 5-arylhydantoins and 5-arylidenehydantoins (Spengler et al, 2010(Spengler et al, , 2011Ali et al, 2020), 5,5-dimethylhydantoins (Martins et al, 2012), arylidene-imidazolones (Handzlik et al, 2012;Kaczor et al, 2020) and spirofluorene-imidazolidinediones (Ż esławska et al, 2016, 2019, 2021). Among the 3-methyl-5spirofluorenehydantoin derivatives with arylpiperazine-alkyl groups, substitution at position 1 produced the most potent ABCB1 modulators, with the ability to inhibit the efflux pump with 5-25 times more potentcy than verapamil, a known firstgeneration ABCB1-modulator (Ż esławska et al, 2019, 2021).…”

Section: Introductionmentioning

confidence: 99%

Crystallographic studies of piperazine derivatives of 3-methyl-5-spirofluorenehydantoin in search of structural features of P-gp inhibitors

Żesławska

Szymańska

Nitek

et al. 2021

Acta Crystallogr C Struct Chem

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5-Spirofluorenehydantoin derivatives show efflux modulating, cytotoxic and antiproliferative effects in sensitive and resistant mouse T-lymphoma cells. In order to extend the knowledge available about the pharmacophoric features responsible for the glycoprotein P (P-gp) inhibitory properties of arylpiperazine derivatives of 3-methyl-5-spirofluorenehydantoin, we have performed crystal structure analyses for 1-[3-(3′-methyl-2′,4′-dioxospiro[fluorene-9,5′-imidazolidin]-1′-yl)propyl]-4-phenylpiperazine-1,4-diium dichloride monohydrate, C29H32N4O2 2+·2Cl−·H2O (1), 3′-methyl-1′-{3-[4-(4-nitrophenyl)piperazin-1-yl]propyl}spiro[fluorene-9,5′-imidazolidine]-2′,4′-dione, C29H29N5O4·H2O (2), 3′-methyl-1′-{5-[4-(4-nitrophenyl)piperazin-1-yl]pentyl}spiro[fluorene-9,5′-imidazolidine]-2′,4′-dione, C31H33N5O4 (3), and 1-benzyl-4-[5-(3′-methyl-2′,4′-dioxospiro[fluorene-9,5′-imidazolidin]-1′-yl)pentyl]piperazine-1,4-diium dichloride 0.613-hydrate, C32H38N4O2 2+·2Cl−·0.613H2O (4). Structure 3 is anhydrous but the other three structures crystallize with water present. The investigated compounds crystallize in the monoclinic crystal system, with the space group P21/n for 1 and 3, and P21/c for 2 and 4. The cations of salts 1 and 4 are doubly protonated, with the protons located on the N atoms of the piperazine rings. The packing of 1 and 4 in the crystals is dominated by intermolecular N—H...Cl and O—H...Cl hydrogen bonds. In the crystal structure of 2, the intermolecular interactions are dominated by O—H...O and O—H...N hydrogen bonds, while in 3, which is lacking in classic hydrogen-bond donors, it is C—H...O contacts that dominate. Additionally, we have performed induced-fit docking studies for the investigated compounds docked to the P-gp human homology model.

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Discovery of phenylselenoether-hydantoin hybrids as ABCB1 efflux pump modulating agents with cytotoxic and antiproliferative actions in resistant T-lymphoma

Cited by 35 publications

References 43 publications

Computer‐Aided Search for 5‐Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1‐Based Multidrug Resistance

Computer‐Aided Search for 5‐Arylideneimidazolone Anticancer Agents Able To Overcome ABCB1‐Based Multidrug Resistance

EPR Study of KO2 as a Source of Superoxide and •BMPO-OH/OOH Radical That Cleaves Plasmid DNA and Detects Radical Interaction with H2S and Se-Derivatives

Crystallographic studies of piperazine derivatives of 3-methyl-5-spirofluorenehydantoin in search of structural features of P-gp inhibitors

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