New structural scaffolds for centrally acting oxime reactivators of phosphylated cholinesterases

Rakesh K. Sit, Zoran Radić, Valeria Gerardi, Limin Zhang, Edzna Garcia, Maja Katalinić, Gabriel Amitai, Zrinka Kovarik, Valery V. Fokin, K. Barry Sharpless, Palmer Taylor

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

We describe here the synthesis and activity of a new series of oxime reactivators of cholinesterases (ChEs) that contain tertiary amine or imidazole protonatable functional groups. Equilibration between the neutral and protonated species at physiological pH enables the reactivators to cross the blood-brain barrier and distribute in the CNS aqueous space as dictated by interstitial and cellular pH values. Our structure-activity analysis of 134 novel compounds considers primarily imidazole aldoximes and N-substituted 2- hydroxyiminoacetamides. Reactivation capacities of novel oximes are rank ordered by their relative reactivation rate constants at 0.67 mM compared with 2-pyridinealdoxime methiodide for reactivation of four organophosphate (sarin, cyclosarin, VX, and paraoxon) conjugates of3 human acetylcholinesterase (hAChE). Rank order of the rates differs for reactivation of human butyrylcholinesterase (hBChE) conjugates. The 10 best reactivating oximes, predominantly hydroxyimino acetamide derivatives (for hAChE) and imidazole-containing aldoximes (for hBChE) also exhibited reasonable activity in the reactivation of tabun conjugates. Reactivation kinetics of the lead hydroxyimino acetamide reactivator of hAChE, when analyzed in terms of apparent affinity (1/Kox) and maximum reactivation rate (k2), is superior to the reference uncharged reactivators monoisonitrosoacetone and 2,3-butanedione monoxime and shows potential for further refinement. The disparate pH dependences for reactivation of ChE and the general base-catalyzed oximolysis of acetylthiocholine reveal that distinct reactivator ionization states are involved in the reactivation of ChE conjugates and in conferring nucleophilic reactivity of the oxime group.

Original languageEnglish
Pages (from-to)19422-19430
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number22
DOIs
Publication statusPublished - 3 Jun 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Sit, R. K., Radić, Z., Gerardi, V., Zhang, L., Garcia, E., Katalinić, M., Amitai, G., Kovarik, Z., Fokin, V. V., Sharpless, K. B., & Taylor, P. (2011). New structural scaffolds for centrally acting oxime reactivators of phosphylated cholinesterases. Journal of Biological Chemistry, 286(22), 19422-19430. https://doi.org/10.1074/jbc.M111.230656