Naslov
Application of "click chemistry" in the synthesis of new reactivators of inhibited acetylcholinesterase (AChE)

Autori
Kalisiak, Jaroslaw ; Radić, Zoran ; Zhang, Limin ; Kovarik, Zrinka ; Čalić, Maja ; Taylor, Palmer ; Fokin, Valery V. ; Sharpless, Barry K.

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

Izvornik
The 41st Western Regional Meeting American Chemical Society: "Frontiers in Chemistry, Biopharmaceuticals & Biotechnology", San Diego, SAD, Book of Abstracts / - , 2007, 229-229

Skup
The 41st Western Regional Meeting American Chemical Society: "Frontiers in Chemistry, Biopharmaceuticals & Biotechnology"

Mjesto i datum
San Diego (CA), Sjedinjene Američke Države, 09.10.2007. - 13.10.2007

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
click-chemistry; 2-PAM; HI-6; reactivation; tabun sarin; VX; parathion; chlorpyrifos

Sažetak
Organophosphorus pesticides (e.g. Parathion, Chlorpyrifos) and chemical warfare nerve agents (e.g. Sarin, Tabun, VX) are potent irreversible inhibitors of synaptic AChE, causing cholinergic overstimulation and death due to respiratory system failure. The current standard treatment consists of the combination of atropine and an AChE reactivator. Two currently approved drugs are HI-6 and 2-PAM (Scheme 1). Unfortunately, their potency is strongly dependant upon the type of toxic agent and none of them possess sufficient activity toward reactivation of inhibited AChE by wide range of organophosphorus. Application of the [3+2] cycloaddition reaction between alkynes and azides (“ Click reaction” ) as a combinatorial approach allows for the fast and reliable synthesis of libraries of new reactivators. Initial screening toward reactivation of Paraoxon- or Tabun- inhibited AChE revealed high activity, comparable to that of HI-6 and 2-PAM, for compounds possessing oxime group in ortho position of a pyridine– based scaffold. Subsequent SAR studies led to the observation that bi-functional oximes exhibit even higher activity than their mono-functional counterparts. A library of bisoximes was prepared possessing linkers of various lengths designed to control the distance between the two pyridinium quaternary centers. Reactivation studies showed that a distance of 8 atoms between both quaternary nitrogens yields the most optimal compound for the reactivation of Paraoxon-inhibited AChE as well as of tabun-inhibited AChE.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti

POVEZANOST RADA