Soman mechanism

S. H. Stem, G. Valdai, S. Lyngaas, E. Odden, D. Malthe-Sprenssen, F. Fonnum, The Mechanism of Soman Detoxification in Perfused Rat Liver , Biochem. Pharmacol. 1983, 32, 1941-1943. 

Menger et al. synthesized a Ci4H29-attached copper(II) complex 3 that possessed a remarkable catalytic activity in the hydrolysis of diphenyl 4-nitrophenyl phosphate (DNP) and the nerve gas Soman (see Scheme 2) [21], When 3 was used in great excess (ca. 1.5 mM, which is more than the critical micelle concentration of 0.18 mM), the hydrolysis of DNP (0.04 mM) was more than 200 times faster than with an equivalent concentration of the nonmicellar homo-logue, the Cu2+-tetramethylethylenediamine complex 9, at 25°C and pH 6 (Scheme 4). The DNP half-life is calculated to be 17 sec with excess 1.5 mM 3 at 25°C and pH 6. The possible reasons for the rate acceleration with 3 were the enhanced electrophilicity of the micellized copper(II) ion or the acidity of the Cu2+-bound water and an intramolecular type of reaction due to the micellar formation. On the basis of the pH(6-8.3)-insensitive rates, Cu2+-OH species 3b (generated with pK3 < 6) was postulated to be an active catalytic species. In this study, the stability constants for 3 and 9 and the thermodynamic pvalue of the Cu2+-bound water for 3a —> 3b + H+ were not measured, probably because of complexity and/or instability of the metal compounds. Therefore, the question remains as to whether or not 3b is the only active species in the reaction solution. Despite the lack of a detailed reaction mechanism, 3 seems to be the best detoxifying reagent documented in the literature. 

Figure 9.17. Organophosphate inhibitors of acetylcholinesterase. a The catalytic mechanism, shown here for diiso-propylfluorophosphate(DFP).b Stmcturesof soman and tabun. Like DFP, these were developed during world war II as nerve gases , c Stractures of the insecticides parathion and malathion, and of paraoxon, which is the achve metabolite of parathion. (Malathion likewise requires conversion to malaoxon.) The arrow above the malathione stmcture indicates the esterase cleavage sites in its leaving group esterase cleavage occurs in human plasma and renders the molecule non-toxic.

Grigoryan, H., Schopfer, L.M., Thompson, C.M., Terry, A.V., Masson, P., Lockridge, O. (2008). Mass spectrometry identifies covalent binding of soman, sarin, chlorpyrifos oxon, diisopropyl fluorophosphate, and FP-biotin to tyrosines on tubulin a potential mechanism of long term toxicity by organophos-phoms agents. Chem. Biol. Interact. April 22. (Epub ahead of print)... 

Contrary to these findings of decreased CarbE activity increasing the toxicity of many OPs, there are also data showing that increased CarbE activity can decrease toxicity of OPs. Activity of CarbE can be increased by about 80% after repeated administration of phenobarbital to rats and mice by a mechanism of enzyme induction which caused a decrease in soman and tabun toxicity by two-fold, while... 

Shih, T.M., Koviak, T.A., Capacio, B.R. (1991). Anticonvulsants for poisoning by the organophosphorus compound soman pharmacological mechanisms. Neurosci. Biobehav. Rev. 15(3) 349-62. 

Hassel, B. (2006). Nicotinic mechanisms contribute to soman-induced symptoms and lethality. Neurotoxicology 27 501-7. 

Clement, J.G. (1981). Toxicology and pharmacology of hispyr-idinium oximes - insight into the mechanism of action vs. soman poisoning in vivo. Fundam. Appl. Toxicol. 1 193-202. 

Viragh, C., Akhmetshin, R., Kovach, I. (1997). Unique push-pull mechanism of dealkylation of soman-inhibited cholinesterases. 

Of particular interest is the study of the biological mechanisms associated with enzyme stereoselectivity and enantioselectivity. For example, MD simulations have been successful in explaining the different affinities of trypsin and acetylcholinesterase to the diastereomers of soman inhibitors [154] and the ability of subtilisin Carlsberg and a-chymotrypsin to discriminate between R-and S- configurations of chiral aldehyde inhibitors [155, 156]. 

The most important inhibitors of CarbEs are organo-phosphorus insecticides (malathion, parathion, para-oxon, methyl parathion, EPN, and others), nerve agents (DFP, soman, sarin, tabun, and VX) and carbamate insecticides (carbofuran, carbaryl, aldicarb, propoxur, oxamyl, methomyl, and others). Organo-phosphorus toxicants inhibit CarbEs irreversibly by phosphorylation and carbamates inhibit CarbEs reversibly by carbamylation similar to the basic mechanism (i.e., acylation of the active site) ... 

Structures of several common substrates and an inhibitor used to study the mechanisms of OPA anhydrase activity. DFP (diisopropylfluorophosphate), mipafox (N,N -diisopropylphosphorodi-amidofluoridate), tabun (N,N-dimethylethylphosphoroamidocyanidate), soman(0-l,2,2-trimethylpropylmethylphosphonofluoridate, paraoxon (diethyl 4-nitrophenyl phosphate), and parathion. 

Shih, T. M., McDonough, J. H. (1997). Neurochemical mechanisms in soman-induced seizures. Journal of Applied Toxicology, 17, 255-264. 

---