Isolation, in Vitro Activity, and Acute Toxicity in Mice of the Four Stereoisomers of Soman

Abstract

Isolation, in Vitro Activity, and Acute Toxicity in Mice of the Four Stereoisomers of Soman. BENSCHOP, H. P., KONINGS, C. A. G., VAN GENDEREN, J., AND DE JONG, L. P. A. (1984). Fundam. Appl. Toxicol. 4, S84–S95. We report the isolation, on a 0.1-to 2-mg scale, of the four stereoisomers of the nerve agent pinacolyl methylphosphonofluoridate (soman), assigned as C(+)P(+), C(+)P(−), C(−)P(+), and C(−)P(−), with more than 99% optical purity. This result was realized by means of (i) complete optical resolution of pinacolyl alcohol, (ii) synthesis of C(+)- and C(−)-soman from the (+)- and (−)-enantiomers of the alcohol, (iii) optimalization of conditions for stereospecific inhibition of α-chymotrypsin with the P(−)-isomers of C(+)- and C(−)-soman, followed by isolation of the C(+)P(+)- and C(−)P(+)-isomers, (iv) isolation of the C(+)P(−)- and C(−)P(−)-isomers after incubation in rabbit plasma of C(+)- and C(−)-soman, respectively, which hydrolyzes stereospecifically the P(+)-isomers. Solutions (0.2 mM) of the steroisomers in organic solvents are optically stable for at least a month at −20°C. The bimolecular rate constants for inhibition of electric eel acetylcholinesterase (AChE) at pH 7.7, 25°C, are at least 3.6 × 104 larger for the P(−)- than for the P(+)-isomers. AChE from electric eel as well as from mouse erythrocytes inhibited with C(+)P(−)-soman is much more effectively reactivated with the oximes HI-6, HGG-42, and obidoxime than these enzymes inhibited with C(−)P(−)-soman. Similarly, the neuro-muscular transmission (NMT) in mouse diaphragm strips poisoned with C(+)-soman is more easily restored with HI-6 than NMT of such muscle preparations poisoned with C(−)-soman. The LD50 values (mice, sc) are in accordance with the P(−)/P(+)-ratio of inhibition rates of AChE, i.e. 99, 38, >5000, >2000, 214, 133, and 156 μg/kg for C(+)P(−)-, C(−)P(−)-, C(+)P(+)-, C(−)P(+), C(+)-, C(−)-soman, and “soman,” respectively. We suggest that mice challenged with a lethal dose of soman (sc) are killed primarily by the C(−)P(−)-isomer.