Inhibition of Acetylcholinesterases by Stereoisomeric Organophosphorus Compounds Containing Both Thioester and p-Nitrophenyl Leaving Groups.
Inhibition of Acetylcholinesterases by Stereoisomeric Organophosphorus Compounds Containing Both Thioester and p-Nitrophenyl Leaving Groups.
复制标题
含有硫酯和对硝基苯基离去基团的立体异构有机磷化合物对乙酰胆碱酯酶的抑制。
DOI：
10.1021/acs.chemrestox.0c00236
复制
发表时间：
2020
影响因子：
4.1
通讯作者：
Thompson,CharlesM
中科院分区：
文献类型：
--
作者：
Talley,ToddT;Chao,Chih-Kai;Berkman,CliffordE;Richardson,RudyJ;Thompson,CharlesM
Studies with acetylcholinesterase (AChE) inhibited by organophosphorus (OP) compounds with two chiral centers can serve as models or surrogates for understanding the rate, orientation, and postinhibitory mechanisms by the nerve agent soman that possesses dual phosphorus and carbon chiral centers. In the current approach, stereoisomers ofO-methyl, [S-(succinic acid, diethyl ester),O-(4-nitrophenyl) phosphorothiolate (MSNPs) were synthesized, and the inhibition, reactivation, and aging mechanisms were studied with electric eel AChE (eeAChE) and recombinant mouse brain AChE (rmAChE). The MSNPRPRCisomer was the strongest inhibitor of both eeAChE and rmAChE at 8- and 24-fold greater potency, respectively, than the weakestSPSCisomer. eeAChE inhibited by theRPRC- orRPSC-MSNP isomer underwent spontaneous reactivation ∼10- to 20-fold faster than the enzyme inhibited bySPRC- andSPSC-MSNP, and only 4% spontaneous reactivation was observed from theSPRC-eeAChE adduct. Using 2-pyridine aldoxime methiodide (2-PAM) or trimedoxime (TMB-4), eeAChE inhibited byRPRC- orSPRC-MSNP reactivated up to 90% and 3- to 4-fold faster than eeAChE inhibited by theRPSC- orSPSC-MSNP isomer. Spontaneous reactivation rates for rmAChE were 1.5- to 10-fold higher following inhibition byRPSC- andSPSC-MSNPs than inhibition by eitherRCisomer, a trend opposite to that found for eeAChE. Oxime reactivation of rmAChE following inhibition byRPRC- andSPRC-MSNPs was 2.5- to 5-fold faster than inhibition byRPSC- orSPSC-MSNPs. Due to structural similarities, MSNPs that phosphylate AChE with the loss of thep-nitrophenoxy (PNP) group form identical, nonreactivatable adducts to those formed fromSP-isomalathion; however, all the MSNP isomers inhibited AChE to form adducts that reactivated. Thus, MSNPs inactivate AChE via the ejection of either PNP or thiosuccinyl groups to form a combination of reactivatable and nonreactivatable adducts, and this differs from the mechanism of AChE inhibition by isomalathion.
