Chemical Synthesis of Two Series of Nerve Agent Model Compounds and Their Stereoselective Interaction with Human Acetylcholinesterase and Human Butyrylcholinesterase

详细信息    查看全文

• 作者：Nora H. Barakat ; Xueying Zheng ; Cynthia B. Gilley ; Mary MacDonald ; Karl Okolotowicz ; John R. Cashman ; Shubham Vyas ; Jeremy M. Beck ; Christopher M. Hadad ; Jun Zhang
• 刊名：Chemical Research in Toxicology
• 出版年：2009
• 出版时间：October 19, 2009
• 年：2009
• 卷：22
• 期：10
• 页码：1669-1679
• 全文大小：342K
• 年卷期：v.22,no.10(October 19, 2009)
• ISSN：1520-5010

文摘

Both G and V type nerve agents possess a center of chirality about phosphorus. The S_p enantiomers are generally more potent inhibitors than their R_p counterparts toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). To develop model compounds with defined centers of chirality that mimic the target nerve agent structures, we synthesized both the S_p and the R_p stereoisomers of two series of G type nerve agent model compounds in enantiomerically enriched form. The two series of model compounds contained identical substituents on the phosphorus as the G type agents, except that thiomethyl (CH₃−S−) and thiocholine [(CH₃)₃NCH₂CH₂−S−] groups were used to replace the traditional nerve agent leaving groups (i.e., fluoro for GB, GF, and GD and cyano for GA). Inhibition kinetic studies of the thiomethyl- and thiocholine-substituted series of nerve agent model compounds revealed that the S_p enantiomers of both series of compounds showed greater inhibition potency toward AChE and BChE. The level of stereoselectivity, as indicated by the ratio of the bimolecular inhibition rate constants between S_p and R_p enantiomers, was greatest for the GF model compounds in both series. The thiocholine analogues were much more potent than the corresponding thiomethyl analogues. With the exception of the GA model compounds, both series showed greater potency against AChE than BChE. The stereoselectivity (i.e., S_p > R_p), enzyme selectivity, and dynamic range of inhibition potency contributed from these two series of compounds suggest that the combined application of these model compounds will provide useful research tools for understanding interactions of nerve agents with cholinesterase and other enzymes involved in nerve agent and organophosphate pharmacology. The potential of and limitations for using these model compounds in the development of biological therapeutics against nerve agent toxicity are also discussed.