Naslov
Oxime-assisted reactivation of tabun-phosphorylated acetylcholinesterase

Autori
Kovarik, Zrinka ; Čalić, Maja ; Bosak, Anita ; Šinko, Goran

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

Izvornik
Congress of the Croatian Society of Biochemistry and Molecular Biology on the occasion of the 30th Anniversary with international participation, Book of Abstracts / - Zagreb : Hrvatsko društvo za biokemiju i molekularnu biologiju (HDBMB), 2006

Skup
Congress of the Croatian Society of Biochemistry and Molecular Biology on the occasion of the 30th Anniversary with international participation

Mjesto i datum
Vodice, Hrvatska, 03.10.2006. - 07.10.2006

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
oxime; tabun; reactivation; acetylcholinesterase

Sažetak
The threat of misuse of highly toxic organophosphorus nerve agent, such as tabun, calls for urgent development of an effective treatment. The basic mechanism of tabun action is the obstruction of cholinergic nerve transmission by inhibiting acetylcholinesterase (AChE ; EC 3.1.1.7) and it can lead to death in just a few minutes. One of the therapeutic approaches to tabun poisoning is to reactivate AChE with a site-directed nucleophile such as an oxime. We evaluated the ability of eleven bisquaternary oximes to reactivate tabun-inhibited human erythrocyte AChE in order to find a more potent reactivator than currently used in the treatment of tabun poisoning. Oxime structures varied in characteristics that are shown to be important for reactivation: type of the ring (pyridinium and/or imidazolium), length and type of the linker between rings, the ortho or para position of the oxime group on the ring(s) and the overall flexibility of the oxime molecule. Since oximes are reversible inhibitors of AChE, meaning that by binding to native AChE they can protect it from tabun inhibition, we calculated their protective index. Tabun-inhibited AChE was completely reactivated by three flexible bispyridinium oximes with oxime group in para position and with three or four methylene groups as linker. Their overall reactivation rate constants varied between 300 min-1M-1 and 670 min-1M-1. The highest reactivation rate was observed for para-oxime K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoyl-pyridinium) butane dibromide] and therefore it emerged as a new potent drug deserving further investigation. Although oximes with the oxime group in ortho position or with imidazolium ring had similar electron density on the oxygen of the oxime group as para bispyridinium oximes, which is important for the nucleophilic attack, they did not show significant reactivation potency. Their maximum was only 60%, with the highest rate constant 10 min-1M-1. However, these oximes might be of interest as pretreatment drugs due to their high affinity for native AChE.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA