Naslov
Oximes developed as antidotes for organophosphates present a scaffold for new research(es) candidates

Autori
Zandona, Antonio ; Maraković, Nikola ; Katalinić Maja

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

Izvornik
Book of abstracts of 6th Mini Symposium of Section of Medicinal and Pharmaceutical Chemistry / - Zagreb, 2022, 2-2

Skup
6th Mini Symposium of Section of Medicinal and Pharmaceutical Chemistry

Mjesto i datum
Zagreb, Hrvatska, 22.11.2022

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Domaća recenzija

Ključne riječi
quinuclidinium ; oximes ; repurposing ; cytotoxicity ; apoptotis

Sažetak
Scaffolds for development of the antidotes for organophosphates, have one or more nucleophilic oxime group(s) along with the presence of aromatic rings, alcohol groups, nitrogen and chlorine atoms. Their main purpose is to reactivate activity of acetylcholinesterase in synapses upon covalent inhibition by highly toxic organophosphorus compounds (nerve agents, pesticides). However, a lot of designed and synthetized oximes do not reach the expected efficiency level in in vitro experiments as antidotes, and they usually get discarded from further evaluations. To prevent such compounds from being forgotten and unused for other research objective, we evaluated them thorough the cell- based assays and determined their new potential targets. We focused our research on a set of quinuclidinium oximes (Qox). Our results indicate that compounds having a longer alkyl chain in the structure disrupt cell and mitochondria membrane fluidity by mimicking fatty acids. Causing changes in membranes, they activate caspase 8 mediated by the death receptor. However, due to the simultaneous influence on the integrity of the membrane, we did not observe the activation of apoptosis but only immediate necrosis. Additionally, computational pharmacophore modelling revealed pharmacological potential of Qox as inhibitors for the enzyme ALDH1. Moreover, changes in ALDH1 lead to cancer progression and therapy resistance, which makes our findings interesting and worth further investigation. This work was supported by the Croatian Science Foundation (HrZZ-UIP-2017-05-7260).

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija

POVEZANOST RADA