Isolation, in vitro activity, and acute toxicity in mice of the four stereoisomers of soman

Abstract

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 m m) 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 × 10 4 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 neuromuscular 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.