© 1986 Oxford University Press
research-article |
Interaction of Soman with ß-Cyclodextrin1
Centre de Recherches du Service de Santé de Santédes Armées, Division de Chimie et Pharmacologie 108, BoulevardPinel, 69275 Lyon Cedex 03, France
Interaction of Soman with ß-CycIodextrin. DESIRE, B., AND SAINT-ANDRE, S. (1986). Fun-dam. Appl. Toxicol. 7, 646-657. Of the following neurotoxic agents, pinacolyl methylphospho-nofluoridate (soman), isopropyl methylphosphonofluoridate (sarin) and ethyl N, N-dimethyl-phosphoramidocyanidate (tabun), only soman was inactivated appreciably at pH 7.40 by ß-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 (i) the irreversible inhibition of acetylcholinesterase (AChE) that is phosphonylated chiefly by P(–)-isomers of racemic soman and (ii) continuous titration of fluoride ions released by soman using a fluoride-specific electrode. Soman and ß-cyclodextrin form a 1:1 complex. At pH 7.40 and 25°C the dissociation constant Kd of this complex and the rate constant k2 of cleavage of soman by ß-cyclodextrin are (0.53 ± 0.05) mM and (5.9 ± 0.6) x 102 min1, respectively. The rate constant k2max for the cleavage of soman by monoionized ß-cyclodextrin has a value of 2.8 x 103 min1 and the second order rate constant k2max/Kd 5.3 x 106 M–1 min–1. Consequently, soman is hydrolyzed about 2500 times faster by the monoanion of ß-cyclodextrin, than by the hydroxide ion. The cleavage of P(–)-soman by ß-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(-Hsomers reacting faster than the P(+)-isomers. At pH 7.40, the inactivation rate of soman by ß-cyclodextrin was as fast in human plasma in vitro as in Tris buffer. This interaction between soman and ß-cyclodextrin, and other data from the literature, suggests that the introduction of catalytic or noncatalytic groups on ß-cyclodextrin might possibly make it a better catalyst for soman inactivation through improvement in the catalytic or in the binding process.