title: 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 sterospecific inhibition of alpha-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 sterospecifically the P(+)-isomers. Solutions (0.2 mM) of the steroisomers in organic solvents are optically stable for at least a month at -20 degrees C. The bimolecular rate constants for inhibition of electric eel acetylcholinesterase (AChE) at pH 7.7, 25 degrees C, are at least 3.6 X 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, greater than 5000, greater than 2000, 214, 133, and 156 micrograms/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.
mesh_terms: D000818:Animals; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D002800:Cholinesterase Inhibitors; D004793:Enzyme Reactivators; D006736:Horses; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010091:Oximes / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D012756:Sheep; D012999:Soman / Q000302:isolation & purification / Q000633:toxicity*; D013237:Stereoisomerism; D013552:Swine; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors
chemical_list: D002800:Cholinesterase Inhibitors; D004793:Enzyme Reactivators; D009943:Organophosphorus Compounds; D010091:Oximes; D012999:Soman