31767-14-3Relevant articles and documents
Dual acting oximes designed for therapeutic decontamination of reactive organophosphatesviacatalytic inactivation and acetylcholinesterase reactivation
Cannon, Jayme,Choi, Seok Ki,Harrison, Racquel,Tang, Shengzhuang,Yang, Kelly
, p. 1592 - 1603 (2021)
A conventional approach in the therapeutic decontamination of reactive organophosphate (OP) relies on chemical OP degradation by oxime compounds. However, their efficacy is limited due to their lack of activity in the reactivation of acetylcholinesterase (AChE), the primary target of OP. Here, we describe a set of α-nucleophile oxime derivatives which are newly identified for such dual modes of action. Thus, we prepared a 9-member oxime library, each composed of an OP-reactive oxime core linked to an amine-terminated scaffold, which varied through anN-alkyl functionalization. This library was screened by enzyme assays performed with human and electric eel subtypes of OP-inactivated AChE, which led to identifying three oxime leads that displayed significant enhancements in reactivation activity comparable to 2-PAM. They were able to reactivate both enzymes inactivated by three OP types including paraoxon, chlorpyrifos and malaoxon, suggesting their broad spectrum of OP susceptibility. All compounds in the library were able to retain catalytic reactivity in paraoxon inactivation by rates increased up to 5 or 8-fold relative to diacetylmonoxime (DAM) under controlled conditions at pH (8.0, 10.5) and temperature (17, 37 °C). Finally, selected lead compounds displayed superb efficacy in paraoxon decontamination on porcine skinin vitro. In summary, we addressed an unmet need in therapeutic OP decontamination by designing and validating a series of congeneric oximes that display dual modes of action.
Mechanistic rationalization of unusual sigmoidal kinetic profiles in the machetti-de sarlo cycloaddition reaction
Mower, Matthew P.,Blackmond, Donna G.
, p. 2386 - 2391 (2015)
Unusual sigmoidal kinetic profiles in the Machetti-De Sarlo base-catalyzed 1,3-dipolar cycloaddition of acrylamide to N-methylnitroacetamide are rationalized by detailed in situ kinetic analysis. A dual role is uncovered in which a substrate acts as a precursor to catalyze its own reaction. Such kinetic studies provide a general protocol for distinguishing among different mechanistic origins of induction periods in complex organic reactions.
Structure-property relationship study of n-(hydroxy)peptides for the design of self-assembled parallel β-sheets
Roche, Stéphane P.,Richaud, Alexis D.
, p. 12329 - 12342 (2020/11/10)
The design of novel and functional biomimetic foldamers remains a major challenge in creating mimics of native protein structures. Herein, we report the stabilization of a remarkably short β-sheet by incorporating N-(hydroxy)glycine (Hyg) residues into the backbone of peptides. These peptide- peptoid hybrids form unique parallel β-sheet structures by selfassembly upon hydrogenation. Our spectroscopic and crystallographic data suggest that the local conformational perturbations induced by N-(hydroxy)amides are outweighed by a network of strong interstrand hydrogen bonds.
In vitro and in silico evaluation of non-quaternary reactivators of AChE as antidotes of organophosphorus poisoning - A new hope or a blind alley?
Soukup, Ondrej,Korabecny, Jan,Malinak, David,Nepovimova, Eugenie,Pham, Ngoc L.,Musílek, Kamil,Hrabinova, Martina,Hepnarova, Vendula,Dolezal, Rafael,Pavek, Petr,Jost, Petr,Kobrlova, Tereza,Jankockova, Jana,Gorecki, Lukas,Psotka, Miroslav,Nguyen, Thuy D.,Box, Karl,Outhwaite, Breeze,Ceckova, Martina,Sorf, Ales,Jun, Daniel,Kuca, Kamil
, p. 281 - 292 (2018/05/17)
Background: In the last decade, the concept of uncharged reactivators potentially able to penetrate the CNS has been introduced as an alternative to the classic charged oxime reactivators. However, this concept brings with it several associated drawbacks
