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Using sodium p-nitrophenyl methylphosphonate as a model for aged (dealkylated) phosphonylated cholinesterase, a study was made of its rate of reaction with various alkylating reagents containing nucleophilic groups.In DMF the alkylation rate ranged widely between a second-order rate constant, k2 = 190 M~l hr-1, at 25°, to no observable reaction in 96 hr at 60°c orresponding to k2 <0.02 M~l hr-1. Aqueous hydrolysis rates at pH 7.15, 25°, were determined for 20 of the mixed esters. The hydrolysis rates also varied extensively, with ii" ranging from 106 sec to less than 5 sec. The exceptionally rapid aqueous hydrolysis of several activated -bromo ketones strongly supports a mechanism involving attack by OHon the CO group. The first example of the intramolecular participation of an amide group in phosphonate hydrolysis by attack on P was observed in carbamoylmethyl p-nitrophenyl methylphosphonate. An exceptionally small rate ratio of 0.025 was found for the reaction of phenacyl methylsulfonate vs. phenacyl bromide with sodium p-nitrophenyl methylphosphonate in DMF. It is suggested that this ratio reflects steric interference in the reaction of the sulfonate and indicates that caution must be exercised in using the Hoffman method for estimating the position of the transition state on the reaction coordinate in SNs reactions. Finally, it was found that the spontaneous reactivation of phenacyl methylphosphonylated eel acetylcholinesterase occurs about 100 times more rapidly than that of the corresponding ethyl methylphosphonylated enzyme.

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A structure-activity analysis of the ability of oximes to reactivate rat plasma carboxylesterase (CaE) that was inhibited by organophosphorus (OP) compounds revealed that uncharged oximes, such as diacetylmonoxime or monoisonitrosoacetone, were better reactivators than cationic oximes.Cationic oximes that are excellent reactivators of OP-inhibited acetylcholinesterase, such as pyridinium-2-aldoxime or the bispyridinium oximes, HI-6 and TMB-4, produced poor reactivation of OP-inhibited CaE.The best uncharged reactivator was diacetylmonoxime which produced complete reactivation at 0.3 mM in 2 hr of CaE that was inhibited by organophosphinates, alkoxycontaining phosphates, and alkoxy-containing phosphonates. Complete reactivation of CaE could be achieved even after inhibition by phosphonates with highly branched alkoxy groups, such as sarin and soman, that undergo rapid aging with acetylcholinesterase.CaE that was inhibited by phosphonates or phosphates that contained aryloxy groups were reactivated to a lower extent.The cause of this decreased reactivation appears to be an oxime-induced aging reaction that competes with the reactivation reaction.This oxime-induced aging reaction is accelerated by electron-withdrawing substituents on the aryloxy groups of phosphonates and by the presence of multiple aryloxy groups on phosphates.Thus, reactivation and aging of OP-inhibited CaE differ from the same processes for OP-inhibited acetyicholinesterase in both their oxime specificity and inhibitor specificity and, presumably, in their underlying mechanisms. 94-08715 IIIIIIIIIIUE = a82CCGPONENT PART NOTICE