title: Chemical synthesis of two series of nerve agent model compounds and their stereoselective interaction with human acetylcholinesterase and human butyrylcholinesterase.
abstract: 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 (CH(3)-S-) and thiocholine [(CH(3))(3)NCH(2)CH(2)-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.
authors.affiliation: Human BioMolecular Research Institute, San Diego, California 92121, USA.
authors.forename: Nora H
authors.initials: NH
authors.lastname: Barakat
authors.forename: Xueying
authors.initials: X
authors.lastname: Zheng
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Gilley
authors.forename: Mary
authors.initials: M
authors.lastname: MacDonald
authors.forename: Karl
authors.initials: K
authors.lastname: Okolotowicz
authors.forename: John R
authors.initials: JR
authors.lastname: Cashman
authors.forename: Shubham
authors.initials: S
authors.lastname: Vyas
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Beck
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hadad
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D003198:Computer Simulation; D006801:Humans; D007700:Kinetics; D010755:Organophosphates / Q000737:chemistry / Q000633:toxicity; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000633:toxicity; D009946:Organothiophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011485:Protein Binding; D012524:Sarin / Q000737:chemistry / Q000633:toxicity; D012999:Soman / Q000737:chemistry / Q000633:toxicity; D013237:Stereoisomerism
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D009943:Organophosphorus Compounds; D009946:Organothiophosphorus Compounds; C051451:methylphosphonothiolate; D012999:Soman; D012524:Sarin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C009374:tabun; C053914:cyclohexyl methylphosphonofluoridate