Interaction of soman with beta-cyclodextrin.
Of the following neurotoxic agents, pinacolyl methylphosphonofluoridate (soman), isopropyl methylphosphonofluoridate (sarin) and ethyl N,N-dimethylphosphoramidocyanidate (tabun), only soman was inactivated appreciably at pH 7.40 by beta-cyclodextrin. The interaction of soman, a mixture of four stereoisomers designated as C(+)P(-), C(-)P(-), C(+)P(+), and C(-)P(+), with cyclodextrins was revealed by methods based on the irreversible inhibition of acetylcholinesterase (AChE) that is phosphonylated chiefly by P(-)-isomers of racemic soman and continuous titration of fluoride ions released by soman using a fluoride-specific electrode. Soman and beta-cyclodextrin form a 1:1 complex. At pH 7.40 and 25 degrees C the dissociation constant Kd of this complex and the rate constant k2 of cleavage of soman by beta-cyclodextrin are (0.53 +/- 0.05) mM and (5.9 +/- 0.6) X 10(-2) min-1, respectively. The rate constant k2 max for the cleavage of soman by monoionized beta-cyclodextrin has a value of 2.8 X 10(3) min-1 and the second order rate constant k2 max/kd is 5.3 X 10(6) M-1 min-1. Consequently, soman is hydrolyzed about 2500 times faster by the monoanion of beta-cyclodextrin, than by the hydroxide ion. The cleavage of P(-)-soman by beta-cyclodextrin as estimated by AChE inhibition proceeds apparently at the same rate for the C(-)P(-)-and C(+)P(-)-isomers. However, the release of fluoride ions indicated a stereospecific rate of reaction, the P(-)-isomers reacting faster than the P(+)-isomers. At pH 7.40, the inactivation rate of soman by beta-cyclodextrin was as fast in human plasma in vitro as in Tris buffer. This interaction between soman and beta-cyclodextrin, and other data from the literature, suggests that the introduction of catalytic or noncatalytic groups on beta-cyclodextrin might possibly make it a better catalyst for soman inactivation through improvement in the catalytic or in the binding process.
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003505:Cyclodextrins / Q000097:blood / Q000494:pharmacology*; D003912:Dextrins / Q000494:pharmacology*; D004347:Drug Interactions; D004593:Electrophorus; D006801:Humans; D007700:Kinetics; D010755:Organophosphates / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D012524:Sarin / Q000494:pharmacology*; D012999:Soman / Q000097:blood / Q000494:pharmacology*; D013213:Starch / Q000494:pharmacology*; D047392:beta-Cyclodextrins
D002800:Cholinesterase Inhibitors; D003505:Cyclodextrins; D003912:Dextrins; D010755:Organophosphates; D009943:Organophosphorus Compounds; D047392:beta-Cyclodextrins; D013213:Starch; D012999:Soman; D012524:Sarin; D000110:Acetylcholinesterase; C031215:betadex; C009374:tabun