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Pregled bibliografske jedinice broj: 1069652

Targeting Organophosphorus Compounds Poisoning by Novel quinuclidine-3 Oximes: Development of Butyrylcholinesterase-Based Bioscavengers


Zandona, Antonio; Katalinić, Maja; Šinko, Goran; Radman Kastelic, Andreja; Primožič, Ines; Kovarik, Zrinka
Targeting Organophosphorus Compounds Poisoning by Novel quinuclidine-3 Oximes: Development of Butyrylcholinesterase-Based Bioscavengers // Archives of toxicology, 94 (2020), 9; 3157-3171 doi:10.1007/s00204-020-02811-5 (međunarodna recenzija, članak, znanstveni)


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Naslov
Targeting Organophosphorus Compounds Poisoning by Novel quinuclidine-3 Oximes: Development of Butyrylcholinesterase-Based Bioscavengers

Autori
Zandona, Antonio ; Katalinić, Maja ; Šinko, Goran ; Radman Kastelic, Andreja ; Primožič, Ines ; Kovarik, Zrinka

Izvornik
Archives of toxicology (0340-5761) 94 (2020), 9; 3157-3171

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Aldoxime ; Antidote ; Bioscavenging ; Cytotoxicity ; Nerve agents ; Reactivation

Sažetak
A library of 14 mono-oxime quinuclidinium-based compounds with alkyl or benzyl substituent were synthesized and characterized in vitro as potential antidotes for organophosphorus compounds (OP) poisoning treatment. We evaluated their potency for reversible inhibition and reactivation of OP inhibited human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and evaluated interactions by molecular docking studies. The reactivation was notable for both AChE and BChE inhibited by VX, cyclosarin, sarin and paraoxon, if quinuclidinium compounds contained the benzyl group attached to the quinuclidinium moiety. Out of all 14, oxime Q8 [4-bromobenzyl- 3-(hydroxyimino)quinuclidinium bromide] was singled out as having the highest determined overall reactivation rate of approximately 20, 000 M-1 min-1 for cyclosarin-inhibited BChE. Furthermore, this oxime in combination with BChE exhibited a capability to act as a bioscavenger of cyclosarin, degrading within 2 h up to 100-fold excess of cyclosarin concentration over the enzyme. Molecular modeling revealed that the position of the cyclohexyl moiety conjugated with the active site serine of BChE directs the favorable positioning of the quinuclidinium ring and the bromophenyl moiety of Q8, which makes phosphonylated-serine easily accessible for the nucleophilic displacement by the oxime group of Q8. This result presents a novel scaffold for the development of new BChE-based bioscavengers. Furthermore, a cytotoxic effect was not observed for Q8, which also makes it promising for further in vivo reactivation studies.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija



POVEZANOST RADA


Projekti:
HRZZ-IP-2016-06-3775 - Aktivnošću i in silico usmjeren dizajn malih bioaktivnih molekula (ADESIRE) (Hrenar, Tomica, HRZZ - 2016-06) ( POIROT)
UIP-2017-05-7260 - MOLEKULARNI MEHANIZMI TOKSIČNOSTI PROTUOTROVA I POTENCIJALNIH LIJEKOVA (CellToxTargets) (Katalinić, Maja, HRZZ - 2017-05) ( POIROT)
IP-2018-01-7683 - Analiza interakcija butirilkolinesteraze s novim inhibitorima i reaktivatorima (AnalyseBChE) (Kovarik, Zrinka, HRZZ - 2018-01) ( POIROT)

Ustanove:
Institut za medicinska istraživanja i medicinu rada, Zagreb,
Prirodoslovno-matematički fakultet, Zagreb

Citiraj ovu publikaciju

Zandona, Antonio; Katalinić, Maja; Šinko, Goran; Radman Kastelic, Andreja; Primožič, Ines; Kovarik, Zrinka
Targeting Organophosphorus Compounds Poisoning by Novel quinuclidine-3 Oximes: Development of Butyrylcholinesterase-Based Bioscavengers // Archives of toxicology, 94 (2020), 9; 3157-3171 doi:10.1007/s00204-020-02811-5 (međunarodna recenzija, članak, znanstveni)
Zandona, A., Katalinić, M., Šinko, G., Radman Kastelic, A., Primožič, I. & Kovarik, Z. (2020) Targeting Organophosphorus Compounds Poisoning by Novel quinuclidine-3 Oximes: Development of Butyrylcholinesterase-Based Bioscavengers. Archives of toxicology, 94 (9), 3157-3171 doi:10.1007/s00204-020-02811-5.
@article{article, year = {2020}, pages = {3157-3171}, DOI = {10.1007/s00204-020-02811-5}, keywords = {Aldoxime, Antidote, Bioscavenging, Cytotoxicity, Nerve agents, Reactivation}, journal = {Archives of toxicology}, doi = {10.1007/s00204-020-02811-5}, volume = {94}, number = {9}, issn = {0340-5761}, title = {Targeting Organophosphorus Compounds Poisoning by Novel quinuclidine-3 Oximes: Development of Butyrylcholinesterase-Based Bioscavengers}, keyword = {Aldoxime, Antidote, Bioscavenging, Cytotoxicity, Nerve agents, Reactivation} }
@article{article, year = {2020}, pages = {3157-3171}, DOI = {10.1007/s00204-020-02811-5}, keywords = {Aldoxime, Antidote, Bioscavenging, Cytotoxicity, Nerve agents, Reactivation}, journal = {Archives of toxicology}, doi = {10.1007/s00204-020-02811-5}, volume = {94}, number = {9}, issn = {0340-5761}, title = {Targeting Organophosphorus Compounds Poisoning by Novel quinuclidine-3 Oximes: Development of Butyrylcholinesterase-Based Bioscavengers}, keyword = {Aldoxime, Antidote, Bioscavenging, Cytotoxicity, Nerve agents, Reactivation} }

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


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