Since the September 11, 2001, terrorist attacks in the United States, the specter of a chemical threat against civilian populations has renewed research interest in chemical warfare agents, their mechanisms of action, and treatments that reverse their effects. In this Account, we focus specifically on organophosphorus nerve agents (OPNAs). Although some OPNAs are used as pest control, the most toxic chemicals in this class are used as chemical warfare agents in armed conflicts. The acute toxicity of OPNAs results from the irreversible inhibition of acetylcholinesterase (AChE, EC 3.1.1.7) via the formation of a covalent P-O bond at the serine hydroxyl group in the enzyme active site. AChE breaks down the neurotransmitter acetylcholine at neuronal synapses and neuromuscular junctions. The irreversible inhibition of AChE causes the neurotransmitter to accumulate in the synaptic cleft, leading to overstimulation of cholinergic receptors, seizures, respiratory arrest, and death. The current treatment for OPNA poisoning combines an antimuscarinic drug (e.g., atropine), an anticonvulsant drug (e.g., diazepam), and an AChE reactivator of the pyridinium aldoxime family (pralidoxime, trimedoxime, obidoxime, HI-6, HLö-7). Because of their high nucleophilicity, oximes can displace the phosphyl group from the catalytic serine, thus restoring the enzyme's catalytic activity. During 50 years of research in the reactivator field, researchers have synthesized and tested numerous structural modifications of monopyridinium oximes and bispyridinium oximes. In the past decade, medicinal chemists have focused their research on the more efficient bispyridinium reactivators, but all known reactivators have several drawbacks. First, due to their permanent positive charge, they do not cross the blood-brain barrier (BBB) efficiently and do not readily reactivate AChE in the central nervous system. Second, no single oxime is efficient against a wide variety of OPNAs. Third, oximes cannot reactivate "aged" AChE. This Account summarizes recent strategies for the development of AChE reactivators capable of crossing the BBB. The use of nanoparticulate transport and inhibition of P-glycoprotein efflux pumps improves BBB transport of these AChE reactivators. Chemical modifications that increased the lipophilicity of the pyridinium aldoximes, the addition of a fluorine atom and the replacement of a pyridyl ring with a dihydropyridyl moiety, enhances BBB permeability. The glycosylation of pyridine aldoximes facilitates increased BBB penetration via the GLUT-1 transport system. The development of novel uncharged reactivators that can move efficiently across the BBB represents one of the most promising of these new strategies.
Nerve agents are highly toxic organophosphorus compounds with strong inhibition potency against acetylcholinesterase (AChE). Herein, we describe two first extremely promising uncharged reactivators for poisoned human AChE with a superior or similar in vitro ability to reactivate the enzyme as compared to that of HI-6, obidoxime, TMB-4 and HLö-7.
Exquisite chemoselectivity for cysteine has been found for a novel class of remarkably hydrolytically stable reagents, 3-arylpropiolonitriles (APN). The efficacy of the APN-mediated tagging was benchmarked against other cysteine-selective methodologies in a model study on a series of traceable amino acid derivatives. The selectivity of the methodology was further explored on peptide mixtures obtained by trypsin digestion of lysozyme. Additionally, the superior stability of APN-cysteine conjugates in aqueous media, human plasma, and living cells makes this new thiol-click reaction a promising methodology for applications in bioconjugation.
A new series of 3-hydroxy-2-pyridine aldoxime compounds have been designed, synthesised and tested in vitro, in silico, and ex vivo as reactivators of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs), for example, VX, sarin, cyclosarin, tabun, and paraoxon. The reactivation rates of three oximes (16-18) were determined to be greater than that of 2-PAM and comparable to that of HI-6, two pyridinium aldoximes currently used by the armies of several countries. The interactions important for a productive orientation of the oxime group within the OP-inhibited enzyme have been clarified by molecular-modelling studies, and by the resolution of the crystal structure of the complex of oxime 17 with Torpedo californica AChE. Blood-brain barrier penetration was predicted for oximes 15-18 based on their physicochemical properties and an in vitro brain membrane permeation assay. Among the evaluated compounds, two morpholine-3-hydroxypyridine aldoxime conjugates proved to be promising reactivators of OP-inhibited cholinesterases. Moreover, efficient ex vivo reactivation of phosphylated native cholinesterases by selected oximes enabled significant hydrolysis of VX, sarin, paraoxon, and cyclosarin in whole human blood, which indicates that the oximes have scavenging potential.
Apicularen A (1, Scheme 1) is a polyketide natural product with a novel molecular architecture and impressive antiproliferative properties against a series of human cancer cells including a drug-resistant line. [1,2] Recently isolated from various strains of the myxobacterial genus Chondromyces (i.e., C. apiculatus, C. lanuginosus, C. pediculatus, and C. robustus), [1] apicularen A possesses a structure characterized by a salicylic acid residue, a macrolide ring bridged by an oxygen atom in such a way as to form a tetrahydropyran system, and a 10-membered ring lactone bearing a side chain with a doubly unsaturated acylenamine moiety. Interestingly, biosynthetic studies revealed the incorporation of eleven intact acetate units into the molecule of apicularen A that account for the entire natural carbon skeleton of the molecule except for C-17 (which stems from glycine), C-18, and C-25 (which is derived from methionine). [2] Here we report a total synthesis [3] of apicularen A (1) and its D 17,18 Z isomer (2) inspired by its polyacetate-based biosynthesis.Scheme 1 traces retrosynthetically the origins of apicularen A (1) (and its isomer 2) to key building blocks 3, 4 a±c, and 5, all of which are readily available. [4±6] In this analysis, we equated the introduction of an acetate unit to a two-step procedure involving allylation followed by ozonolysis. The five projected reiterations of the allylation±ozonolysis sequence are indicated on the structure of 1 and were to be performed in the designated order ( 1 to 5 ). These steps not only would ™mimic∫ nature×s polyacetate biosynthetic pathway to 1, but also would have the potential of yielding the correct stereochemistry at each chiral center of the target molecule through the judicious choice of appropriate reagents and conditions. Thus, while the first planned allylation [7] with allyltributyltin and a palladium catalyst should provide the required extension from the salicylic acid residue, the second and third allylations with Brown×s reagent (Ipc 2 Ballyl) [5] should install the C-9 and C-11 hydroxy groups in their absolute stereochemistry through the use of the appropriate enantiomer. The fourth allylation calls upon allyltrimethylsilane as a reagent to further extend the growing chain with concomitant formation of the C-13 stereocenter in a diastereocontrolled manner. The fifth allylation would require, once more, the use of Brown©s reagent (Ipc 2 Ballyl) for the construction of the final chiral center in its absolute stereochemical configuration. This strategy left the required ringforming reactions and the stereoselective installment of the acylenamine side chain to be negotiated in the synthetic direction.Scheme 2 details the construction of advanced intermediate 14 from which both 1 and 2 would be derived. Acetonide triflate 3 [4] was coupled with allyltributyltin [7] under the influence of catalytic [Pd(PPh 3 ) 4 ] to afford allyl compound 6 (99 % yield) whose rupture with ozone led, upon reduction with PPh 3 , to aldehyde 7 (92 % yield). The addition of...
Treatment of unfunctionalized acyclic ketoaldehydes with a catalytic amount of 1,5,7-triazabicyclo[4.4.0]dec-5-ene induces a direct intramolecular 5-and 6-enolexo aldolization, furnishing 2-ketocyclopentanols and 2-ketocyclohexanols in good-to-excellent yields.
Pyridinium and bis-pyridinium aldoximes are used as antidotes to reactivate acetylcholinesterase (AChE) inhibited by organophosphorus nerve agents. Herein, we described a series of nine nonquaternary phenyltetrahydroisoquinoline-pyridinaldoxime conjugates more efficient than or as efficient as pyridinium oximes to reactivate VX-, tabun- and ethyl paraoxon-inhibited human AChE. This study explores the structure-activity relationships of this new family of reactivators and shows that 1b-d are uncharged hAChE reactivators with a broad spectrum.
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