Diisopropyl phosphorofluoridate

Phosphorofluoridate, diisopropyl, reaction with cyclohexaamylose, 23 237 Phosphorus in fuel, 27 316... 

The esters of monofluorophosphoric acid are of great interest because of their cholinesterase inhibiting activity which causes them to be highly toxic nerve gases and also gives them medical activity (see Enzyme inhibitors). The most studied is the bis(l-methylethyl)ester of phosphorofluoridic acid also known as diisopropyl phosphorofluoridate [155-91 DFP (5), and as the ophthalmic ointment or solution Isoflurophate USP. It is used as a... 

Hydrolysis by n/2 sodium hydroxide at room temperature, (a) Diisopropyl phosphorofluoridate (2-0532g.) was shaken with 100 ml. of 0-49 n sodium hydroxide at 17°. The oily drops disappeared after about 5 min. The shaking was continued for a total of 30 min., and then 25 ml. were withdrawn and required 13-35 ml. of 0-5n sulphuric acid for neutralization (phenolphthalein). Therefore 1 mol. of the phosphorofluoridate had reacted with 1-994 mol. of alkali. 

It was suggested,1 on the basis of kinetic measurements, that the phosphorofluoridates inhibit esterases by virtue of a highly specific affinity for the active centres of this group of enzymes. Preliminary experiments by Boursnell and Webb2 with diisopropyl phosphorofluoridate containing 32P gave results which were in accordance with this view. 

The mechanism by which A-esterases hydrolyze organophosphates is not completely understood. Involvement of a phosphorylated active-site cysteine and displacement of an activated H20 molecule are two possible hypotheses (see Sect. 3.7.1) [56], A-Esterases comprise enzymes that hydrolyze aryl esters, paraoxon (2.2) and related organophosphate pesticides, and diisopropyl-fluorophosphate (DFP, diisopropyl phosphorofluoridate, 2.3) and related compounds, including nerve gases. These enzymes are found in the current nomenclature listed under arylesterases, aryldialkylphosphatase, and diisop-ropyl-fluorophosphatase. 

Other serine hydrolases such as cholinesterases, carboxylesterases, lipases, and fl-lactamases of classes A, C, and D have a hydrolytic mechanism similar to that of serine peptidases [25-27], The catalytic mechanism also involves an acylation and a deacylation step at a serine residue in the active center (see Fig. 3.3). All serine hydrolases have in common that they are inhibited by covalent attachment of diisopropyl phosphorofluoridate (3.2) to the catalytic serine residue. The catalytic site of esterases and lipases has been less extensively investigated than that of serine peptidases, but much evidence has accumulated that they also contain a catalytic triad composed of serine, histidine, and aspartate or glutamate (Table 3.1). 

FIGURE 42.6. Levels of high-energy phosphates, ATP (A) and PCr (B) in amygdala and hippocampus of rats intoxicated with an acute dose of carhofuran (CF, 1.25mg/kg, s.c.) or diisopropyl phosphorofluoridate (DFP, 1.25mg/kg, s.c.). Rats were sacrificed 1 hour (1 h) or 3 days (3 d) after CF or DFP injection. Values of ATP and PCr are presented as means SEM (n = 4-6). Significant difference between values from control rats and DFP- or CF-treated rats (p < 0.05). 

Damodaran, T.V., Abou-Donia, M.B. (2000). Alterations in levels of mRNAs coding for glial fibrillary acidic protein (GFAP) and vimentin genes in the central nervous system of hens treated with diisopropyl phosphorofluoridate (DFP). Neurochem. Res. 25 809-16. 

Gupta, R.P., Ahou-Donia, M.B. (1999). Tau phosphorylation by diisopropyl-phosphorofluoridate (DFP)-treated hen brain supernatant inhibits its binding with microtubules role of Ca Vcalmodulin-dependent protein kinase II in tau phosphorylation. Arch. Biochem. Biophys. 365 268-78. 

Gupta, R.P., Lin, W.W., Abou-Donia, M.B. (1999). Enhanced mRNA expression of neurofilament subunits in the brain and spinal cord of diisopropyl phosphorofluoridate-treated hens. Biochem. Pharmacol. 57 1245-51. 

Gupta, R.P., Abdel-Rahman, A., Jensen, K.F., Ahou-Donia, M.B. (2000b). Altered expression of neurofilament subunits in diisopropyl phosphorofluoridate-treated hen spinal cord and their presence in axonal aggregations. Brain Res. 878 32-47. 

Billecke, S.S., Primo-Parmo, S.L., Dunlop, C.S., Doom, J.A., La Du, B.N., Broomfield, C.A. (1999). Characterization of a soluble mouse liver enzyme capable of hydrolyzing diisopropyl phosphorofluoridate. Chem. Biol. Interact. 119-20 251-6. 

Kondo, Y., Ishigami, A., Kuho, S., Handa, S., Gomi, K., Hirokawa, K., Kajiyama, N., Chiba, T., Shimokado, K., Maruyama, N. (2004). Senescence marker protein-30 is a unique enzyme that hydrolyzes diisopropyl phosphorofluoridate in the liver. FEBS Lett. 570 57-62. 

Little, J.S., Broomfield, C.A., Fox-Talbot, M.K., Boucher, L.J., Maclver, B., Lenz, D.E. (1989). Partial characterization of an enzyme that hydrolyzes sarin, soman, tabun, and diisopropyl phosphorofluoridate (DFP). Biochem. Pharmacol. 38 23-9. 

SYNS DFP DIFLUPYL DIFLUROPHATE DIISOPROPOXYPHOSPHORYL FLUORIDE DIISOPROPYL FLUOROPHOSPHATE 0,0-DIISOPROPYL FLUOROPHOSPHATE DIISOPROPYL FLUOROPHOSPHONATE DIISOPROP i LFLUORO-PHOSPHORIC ACID ESTER DIISOPROPYLFLUOR-PHOSPHORSAEUREESTER (GER.VIAN) DIISOPROPYL PHOSPHOFLUORIDATE DIISOPROPYL PHOSPHOROFLUORIDATE 0,0 -DIIS0PR0PYL PHOSP-HORYL FLUORIDE DYFLOS FLOROPRYL FLUOPHOSPHORIC ACID, DIISOPROPYL ESTER FLUORODIISOPROPYL PHOSPHATE FLUOROPRYL... 

PHOSPHOROFLUORIDIC ACID see PHJ250 PHOSPHOROFLUORIDIC ACID, DIISOPROPYL ESTER see IRFOOO... 

Walls, L.H. 1987. Isolation and purification of a diisopropyl phosphorofluoridate hydrolase from thermophilic bacteria. CRDEC-CR-87072. 

Peraica M, Moretto A, and Lotti M. Selective promotion by pheny lmethanesul-fony 1 fluoride of peripheral and spinal cord neuropathies initiated by diisopropyl phosphorofluoridate in the hen. Toxicol. Lett., 80(1-3), 115-121,1995. 

Murachi T (1963). A general reaction of diisopropyl phosphorofluoridate with proteins without direct effect on enzymic activities. Biochim BiophysActa, 71, 239-241. 

Churchill L, Padzernik TL, Cross RS et al. (1987). Cholinergic systems influence local cerebral glucose use in specific anatomical areas diisopropyl phosphorofluoridate versus soman. Neuroscience, 20, 329-340. 

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