Novel irreversible butyrylcholinesterase inhibitors: 2-chloro-1-(substituted-phenyl)ethylphosphonic acids.
Novel irreversible butyrylcholinesterase inhibitors: 2-chloro-1-(substituted-phenyl)ethylphosphonic acids.
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DOI：
10.1016/s0968-0896(01)00391-1
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发表时间：
2002-05
影响因子：
3.5
通讯作者：
Nanjing Zhang;J. Casida
中科院分区：
文献类型：
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作者：
Nanjing Zhang;J. Casida
2-氯乙基膦酸（乙烯利）作为二价阴离子磷酸化丁酰胆碱酯酶（BChE）的活性位点。相比之下，经典的有机磷酯酶抑制剂包括取代的苯基二烷基磷酸酯（例如，对氧磷）与吸电子芳基取代基。本研究中，将氯乙基和取代苯基部分组合为2-氯-1-（取代苯基）乙基膦酸（1），以确定乙烯利及其类似物抑制BChE的构效关系和机制。所考虑的苯基取代基是3-和4-硝基、3-和4-二甲氨基以及3-和4-三甲基铵。通过相应的O，O-二乙基膦酸酯前体，然后用三甲基溴化硅脱保护，合成膦酸1。它们在碱性条件下的分解速度比乙烯利快100倍，产生相应的苯乙烯衍生物。苯环上的吸电子取代基降低水解速率，而给电子取代基增加速率。4-三甲基铵类似物具有最高的亲和力（Ki=180 μM）和效力（IC 50 =19 μM），首先可逆结合底物位点（可能在二阴离子-单阴离子环境中稳定），然后逐渐不可逆地抑制酶活性。这些观察结果表明，解离的氯化物作为第一个和限速步骤都在水解和类比在磷酸化的BChE由1结合在活性位点。
2-Chloroethylphosphonic acid (ethephon) as the dianion phosphorylates butyrylcholinesterase (BChE) at its active site. In contrast, the classical organophosphorus esterase inhibitors include substituted-phenyl dialkylphosphates (e.g., paraoxon) with electron-withdrawing aryl substituents. The chloroethyl and substituted-phenyl moieties are combined in this study as 2-chloro-1-(substituted-phenyl)ethylphosphonic acids (1) to define the structure–activity relationships and mechanism of BChE inhibition by ethephon and its analogues. Phenyl substituents considered are 3- and 4-nitro, 3- and 4-dimethylamino, and 3- and 4-trimethylammonium. Phosphonic acids 1 were synthesized via the corresponding O,O-diethyl phosphonate precursors followed by deprotection with trimethylsilyl bromide. They decompose under basic conditions about 100-fold faster than ethephon to yield the corresponding styrene derivatives. Electron-withdrawing substituents on the phenyl ring decrease the hydrolysis rate while electron-donating substituents increase the rate. The 4-trimethylammonium analogue has the highest affinity (Ki=180 μM) and potency (IC50=19 μM) in first binding reversibly at the substrate site (possibly with stabilization in a dianion–monoanion environment) and then progressively and irreversibly inhibiting the enzyme activity. These observations suggest dissociation of chloride as the first and rate-limiting step both in the hydrolysis and by analogy in phosphorylation of BChE by 1 bound at the active site.