Butyrylcholinesterase inhibited by nerve agents is efficiently reactivated with chlorinated pyridinium oximes. (1st July 2019)

• Record Type: Journal Article
• Authors: Zorbaz, Tamara; Malinak, David; Kuca, Kamil; Musilek, Kamil; Kovarik, Zrinka
• Is Part Of: Chemico-biological interactions. Volume 307(2019)
• Page Start: 16
• Page End: 20
• Publication Date: 2019-07-01
• Subjects: Organophosphorus compounds -- Quaternary oxime -- Reactivators -- Cholinesterase -- Pseudo-catalytic scavenger; AChE acetylcholinesterase -- ATCh acetylthiocholine iodide -- BBB blood−brain barrier -- BChE butyrylcholinesterase -- BSA bovine serum albumin -- cyclosarin cyclohexyl methylphosphonofluoridate -- DTNB 5, 5′-dithiobis(2-nitrobenzoic acid) -- HI-6 asoxime [1-(((4-(aminocarbonyl)pyridino)methoxy)methyl)-2-((hydroxyimino)methyl)pyridinium dichloride] -- K027 4-carbamoyl-1-(3-(4-((hydroxyimino)methyl)pyridinium-1-yl)propyl)pyridinium dibromide -- K048 4-carbamoyl-1-(3-(4-((hydroxyimino)methyl)pyridinium-1-yl)butyl)pyridinium dibromide -- K203 4-carbamoyl-1-(3-(4-((hydroxyimino)methyl)pyridinium-1-yl)but-2-en-1-yl)pyridinium dibromide -- K865 4-carbamoyl-1-(3-{3-chloro-4-[(hydroxyimino)methyl]pyridinium-1-yl}propyl)pyridinium dibromide -- K866 4-carbamoyl-1-(4-{3-chloro-4-[(hydroxyimino)methyl]pyridinium-1-yl}butyl)pyridinium dibromide -- K867 4-carbamoyl-1-[(2E)-4-{3-chloro-4-[(hydroxyimino)methyl]pyridinium-1-yl}but-2-en-1-yl]pyridinium dibromide -- K868 4-carbamoyl-1-(4-{3, 5-dichloro-4-[(hydroxyimino)methyl]pyridinium-1-yl}propyl)pyridinium dibromide -- K869 4-carbamoyl-1-(4-{3, 5-dichloro-4-[(hydroxyimino)methyl]pyridinium-1-yl}butyl)pyridinium dibromide -- K870 4-carbamoyl-1-[(2E)-4-{3, 5-dichloro-4-[(hydroxyimino)methyl]pyridinium-1-yl}but-2-en-1-yl]pyridinium dibromide -- OP organophosphorus compound -- sarin isopropyl methylphosphonofluoridate -- 2-PAM pralidoxime [2-pyridinealdoxime methiodide] -- tabun N, N-dimethylamido-O-ethyl cyanophosphate -- TMB-4 trimedoxime [1, 3-bis(4-hydroxyiminomethylpyridinium)propane dichloride] -- VX O-ethyl S-[2-(disopropylamino)ethyl]methylphosphonothioate; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2019.04.020
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Bispyridinium oximes with one (K865, K866, K867) or two (K868, K869, K870) ortho -positioned chlorine moiety, analogous to previously known K027, K048 and K203 oximes, and potent reactivators of human acetylcholinesterase (AChE) inhibited by nerve agents, were tested in the reactivation of human butyrylcholinesterase (BChE) inhibited by sarin, cyclosarin, VX, and tabun. A previously highlighted AChE reactivator, dichlorinated bispyridinium oxime with propyl linker (K868), was tested in more detail for reactivation of four nerve agent-BChE conjugates. Its BChE reactivation potency was showed to be promising when compared to the standard oximes used in medical practice, asoxime (HI-6) and pralidoxime (2-PAM), especially in case of sarin and tabun. This finding could be used in the pseudo-catalytic scavenging of the most nerve agents due to its cumulative capacity to reactivate both AChE and BChE. Graphical abstract: Image 1 Highlights: Ortho -positioned chlorine moiety of pyridinium oximes improves reactivation. Dichlorinated oxime K868 is the lead reactivator of BChE inhibited by nerve agents. K868 is superior reactivator than HI-6 and 2-PAM for sarin- and tabun-BChE. K868 could serve as post-exposure therapy for sarin, cyclosarin, and VX.