Naslov
Activation of (un)regulated cell death as a new perspective for oxime activity research

Autori
Zandona, Antonio ; Maraković, Nikola ; Miš, Katarina ; Dolinar, Klemen ; Pirkmajer, Sergej ; Katalinić, Maja

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Virtual 45th FEBS Congress, Molecules of Life: Towards New Horizons, Ljubljana, Slovenia, July 3–8, 2021 / - : Federation of European Biochemical Societies (FEBS), 2021, 364-364

Skup
45th FEBS Congress: Molecules of Life: Towards New Horizons (FEBS 2021)

Mjesto i datum
Ljubljana, Slovenija, 03.07.2021. - 08.07.2021

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
cytotoxicity ; apoptotis ; necrosis ; caspase ; pharmacophore

Sažetak
Compounds known as oximes are tested as antidotes against the toxic effects of organophosphates (OP). Oximes have diverse scaffolds, created with the purpose to fit the active site of the acetylcholinesterase-OP conjugate as their main target in the organism. After primary screening, candidates which meet the in vitro kinetic parameters of action as antidotes are promoted to further evaluation, while others are discarded. Our previous research showed that some of the oximes display toxic effects on cell level which could be explored beyond their main mechanism of action. To investigate this further, we performed an in vitro cell-based evaluation of four structurally diverse groups of oximes at concentrations of up to 0.8 mM, identifying specific biomarkers. We tested the effect of oximes on several in vitro cell models: skeletal muscles, kidneys, liver, and neurons. As our results indicate, the effect of oximes was consistent in all cells tested. Compounds with quinuclidine and imidazolium core induced unregulated cell death caused by cell burst, with increased levels of reactive oxygen species formation, but without antioxidant scavenging activation. On the other hand, oximes with a pyridine or pyridinium core activated apoptosis and specific caspases-3, -8, and/or -9. Interestingly, some of the compounds even had a synergistic effect. We generated a pharmacophore model for each series and identified ligands from public databases that map to generated pharmacophores. Several interesting hits were obtained including well known chemotherapy agents, gene expression modulators, antibiotics, cytochrome P450 modulators, etc. Even though the exact mechanism by which oximes act to trigger observed cell effects needs to be explained, our findings should open up a whole new perspective for oxime research. Acknowledgement: This work was supported by the Croatian Science Foundation under the project UIP-2017-05-7260 and by Croatian-Slovenian bilateral grant 2020-2021

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija

POVEZANOST RADA