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Inhibition of Acetylcholinesterases by Stereoisomeric Organophosphorus Compounds Containing Both Thioester and p-Nitrophenyl Leaving Groups.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-08-24 , DOI: 10.1021/acs.chemrestox.0c00236 Todd T Talley 1 , Chih-Kai Chao 1 , Clifford E Berkman 2 , Rudy J Richardson 3, 4 , Charles M Thompson 1
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-08-24 , DOI: 10.1021/acs.chemrestox.0c00236 Todd T Talley 1 , Chih-Kai Chao 1 , Clifford E Berkman 2 , Rudy J Richardson 3, 4 , Charles M Thompson 1
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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 of O-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 MSNP RPRC isomer was the strongest inhibitor of both eeAChE and rmAChE at 8- and 24-fold greater potency, respectively, than the weakest SPSC isomer. eeAChE inhibited by the RPRC- or RPSC-MSNP isomer underwent spontaneous reactivation ∼10- to 20-fold faster than the enzyme inhibited by SPRC- and SPSC-MSNP, and only 4% spontaneous reactivation was observed from the SPRC-eeAChE adduct. Using 2-pyridine aldoxime methiodide (2-PAM) or trimedoxime (TMB-4), eeAChE inhibited by RPRC- or SPRC-MSNP reactivated up to 90% and 3- to 4-fold faster than eeAChE inhibited by the RPSC- or SPSC-MSNP isomer. Spontaneous reactivation rates for rmAChE were 1.5- to 10-fold higher following inhibition by RPSC- and SPSC-MSNPs than inhibition by either RC isomer, a trend opposite to that found for eeAChE. Oxime reactivation of rmAChE following inhibition by RPRC- and SPRC-MSNPs was 2.5- to 5-fold faster than inhibition by RPSC- or SPSC-MSNPs. Due to structural similarities, MSNPs that phosphylate AChE with the loss of the p-nitrophenoxy (PNP) group form identical, nonreactivatable adducts to those formed from SP-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.
中文翻译：
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。
对具有两个手性中心的有机磷 (OP) 化合物抑制的乙酰胆碱酯酶 (AChE) 的研究可以作为模型或替代物，用于了解具有双磷和碳手性中心的神经毒剂梭曼的速率、方向和抑制后机制。目前的方法是合成了O-甲基、[ S- (琥珀酸，二乙酯)、O- (4-硝基苯基)硫代磷酸酯(MSNPs)的立体异构体，并用电鳗研究了其抑制、再活化和老化机制。 AChE (eeAChE) 和重组小鼠脑 AChE (rmAChE)。MSNP R P R C异构体是 eeAChE 和 rmAChE 的最强抑制剂，其效力分别比最弱的S P S C异构体高8 倍和 24 倍。被R P R C - 或R P S C -MSNP 异构体抑制的eeAChE 经历的自发再激活比被S P R C - 和S P S C -MSNP抑制的酶快 10 到 20 倍，并且只有 4%从S P R C观察到自发再激活-eeAChE 加合物。使用 2-吡啶醛肟 (2-PAM) 或三甲肟 (TMB-4)，被R P R C - 或S P R C -MSNP抑制的eeAChE 重新激活高达 90%，比抑制的 eeAChE 快 3 到 4 倍由R P S C - 或S P S C -MSNP 异构体组成。R P S C - 和S P S C -MSNPs 抑制后rmAChE 的自发再激活率比任一R C抑制高 1.5 到 10 倍异构体，与 eeAChE 发现的趋势相反。R P R C - 和S P R C -MSNP抑制后 rmAChE 的肟再激活比R P S C - 或S P S C -MSNP抑制快 2.5 至 5 倍。由于结构的相似性，该MSNPs乙酰胆碱酯酶phosphylate与损失p -硝基苯（PNP）组形式相同，nonreactivatable加合物的那些从形成小号P-异麦芽酮糖; 然而，所有 MSNP 异构体都抑制 AChE 形成重新激活的加合物。因此，MSNPs 通过喷射 PNP 或硫代琥珀酰基团来灭活 AChE，形成可重新激活和不可重新激活的加合物的组合，这与异麦芽硫磷抑制 AChE 的机制不同。
更新日期：2020-09-21
中文翻译：
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。
对具有两个手性中心的有机磷 (OP) 化合物抑制的乙酰胆碱酯酶 (AChE) 的研究可以作为模型或替代物，用于了解具有双磷和碳手性中心的神经毒剂梭曼的速率、方向和抑制后机制。目前的方法是合成了O-甲基、[ S- (琥珀酸，二乙酯)、O- (4-硝基苯基)硫代磷酸酯(MSNPs)的立体异构体，并用电鳗研究了其抑制、再活化和老化机制。 AChE (eeAChE) 和重组小鼠脑 AChE (rmAChE)。MSNP R P R C异构体是 eeAChE 和 rmAChE 的最强抑制剂，其效力分别比最弱的S P S C异构体高8 倍和 24 倍。被R P R C - 或R P S C -MSNP 异构体抑制的eeAChE 经历的自发再激活比被S P R C - 和S P S C -MSNP抑制的酶快 10 到 20 倍，并且只有 4%从S P R C观察到自发再激活-eeAChE 加合物。使用 2-吡啶醛肟 (2-PAM) 或三甲肟 (TMB-4)，被R P R C - 或S P R C -MSNP抑制的eeAChE 重新激活高达 90%，比抑制的 eeAChE 快 3 到 4 倍由R P S C - 或S P S C -MSNP 异构体组成。R P S C - 和S P S C -MSNPs 抑制后rmAChE 的自发再激活率比任一R C抑制高 1.5 到 10 倍异构体，与 eeAChE 发现的趋势相反。R P R C - 和S P R C -MSNP抑制后 rmAChE 的肟再激活比R P S C - 或S P S C -MSNP抑制快 2.5 至 5 倍。由于结构的相似性，该MSNPs乙酰胆碱酯酶phosphylate与损失p -硝基苯（PNP）组形式相同，nonreactivatable加合物的那些从形成小号P-异麦芽酮糖; 然而，所有 MSNP 异构体都抑制 AChE 形成重新激活的加合物。因此，MSNPs 通过喷射 PNP 或硫代琥珀酰基团来灭活 AChE，形成可重新激活和不可重新激活的加合物的组合，这与异麦芽硫磷抑制 AChE 的机制不同。
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