S. K. Raza

Prophylactic efficacy of amifostine and its analogues against sulphur mustard toxicity.

The successful implication of the chemical weapons convention stimulated research with a new vigour on the destruction of the stockpiled sulphur mustard (SM). A prophylactic agent for SM will be very useful for personnel engaged in the destruction of SM and during inspections by the Organisation for the Prohibition of Chemical Weapons. Due to simple method of preparation, SM can be used clandestinely during war or by terrorist groups. Inspite of research over several decades no satisfactory prophylactic or treatment regimen has evolved for SM. Amifostine an organophosphorothioate, originally developed as a radioprotector, and its analogues were evaluated as a prophylactic agent for SM. Three analogues by varying the chain length and substitution at the sulphur atom were synthesised and coded as DRDE-06, DRDE-07 and DRDE-08. LD(50) of amifostine and its analogues were estimated through intraperitoneal (i.p.) route. For the protection studies, amifostine and its analogues were administered i.p. in mice, 30 min before dermal (percutaneous) application of SM. The dose of the prophylactic agent was 0.2 LD(50) (i.p.) and that of SM was 152 mg/kg (undiluted) equal to 19-fold LD(50) of SM. Amifostine and one of its analogues, DRDE-07 gave significant protection. Further studies were carried out using amifostine and DRDE-07, and both of them significantly protected mice against SM (155 mg/kg, in PEG 300, equal to 19 LD(50)) when they were administered i.p. either 30 min before or simultaneously. LD(50) of amifostine and DRDE-07 were also estimated through the oral route (1049 or 1248 mg/kg, respectively). Prophylactically administered amifostine and DRDE-07 (0.2 LD(50), p.o.) significantly protected the mice against dermally applied SM (155 mg/kg, in PEG 300, equal to 19 LD(50)). The protection offered by DRDE-07 was better than that of amifostine by the oral route. DRDE-07 (0.2 LD(50), p.o.) also protected significantly with respect to the decrease in body weight and the depletion of GSH induced by SM. DNA damage induced by SM was also significantly reduced by amifostine and DRDE-07 (0.2 LD(50), p.o.). Further studies are in progress on the various pharmacological and toxicological properties of DRDE-07.

Fluorinated phosphonium ylides: versatile in situ Wittig intermediates in the synthesis of hydrofluorocarbons

Abstract A simple and convenient technique has been developed for the synthesis, characterisation and isolation of hydrofluoro/hydrohalofluorocarbons such as chlorodifluoromethane (CF2ClH), difluoromethane (CF2H2), bromodifluoromethane (CF2BrH) and dibromofluoromethane (CFBr2H) as possible chlorofluorocarbon (CFC) alternatives. The Wittig reaction of carbonyl compounds with in situ generated triphenylphosphonium ylides in DMF forms terminal fluoroolefins. However, in the absence of the carbonyl moiety these ylides undergo decomposition. The high reactivity of fluoromethylene triphenylphosphonium ylides in DMF in the absence of the carbonyl moiety has been exploited for the first time to design the synthesis of hydrofluorocarbons.

A semi-molten mixture of hexadecyltributylphosphonium bromide and potassium fluoride in the synthesis of organofluorine compounds

Abstract A facile and effective reagent system comprising of a semi-molten mixture of hexadecyltributylphosphonium bromide and potassium fluoride has been developed and its scope has been investigated in nucleophilic fluoride exchange with various organohalides. This simple and convenient reagent system provides organofluorine compounds in high yields even with haloesters in which fluoride catalysed elimination is also feasible.

Synthesis, characterisation and mass spectrometric fragmentation of O-(chlorodifluoroacylated) alcohols

Abstract An indirect and uncatalysed esterification of chlorodifluoroacetic acid with polyfluoro and hydrocarbon alcohols has been developed. The method which involves the reaction between sodium chlorodifluoroacetate and alcohols in dimethylformamide (DMF) is particularly facile with polyfluorinated alcohols resulting in esters in 71–85% yield. The esters have been characterised on the basis of 1 H and 19 F NMR and mass spectral data. The electron impact (EI) mass spectrometric fragmentation of these polyfluorinated esters have shown some interesting features which have been substantiated by using tandem mass spectrometry.

Analysis of Chemical Neutralization Products of Phosphonothiolates by Gas Chromatography Mass Spectrometry

A series of phosphonothiolates, including the highly toxic O-Ethyl-S-(2-diisopropylamino) ethyl methylphosphonothioate (VX), have been subjected to chemical neutralization reaction with metallic sodium. The phosphonothiolates decompose to their respective phosphonic and phosphonothioic acids and this results in the detoxification of VX. GC/MS technique in both EI and CI mode has been applied for reaction monitoring and final identification of the neutralization products formed in this reaction.

Mass spectral studies on synthetic analogs of organophosphorus toxin occurring in dinoflagellate algae

A series of organophosphorus compounds related to PB-1 toxin [O,O-diphenyl N-cyclooctylphosphoramidate] occurring in dinoflagellate algae as fish toxin have been synthesized and subjected to mass spectral studies under electron ionization. The fragmentation pattern obtained for the compounds has been substantiated by performing tandem mass spectrometry experiments in product ion scan mode.

MASS SPECTRAL STUDIES ON SYNTHETIC ANALOGUES OF ORGANOPHOSPHORUS TOXIN ISOLATED FROM PTYCHODISCUS BREVIS

Abstract A series of structurally related organophosphorus oximes analogous to O,O-dipropyl-(E)-2-(1-methyl-2-oxopropylidene)phosphorahydrazidothioate-(E)-oxime, isolated from Ptychodiscus brevis, have been synthesised and subjected to electron impact (EI) mass spectral studies. These studies, though aimed at total identification of these compounds, resulted in certain interesting observations and hence are being reported. In order to confirm the observations under electron impact and to support the mechanism of fragmentation we have also performed tandem mass spectrometry experiments in some cases.

Direct detection of alkylphosphonic acids in environmental matrices by proton coupled phosphorus NMR.

A simple, convenient, and direct one‐dimensional (1D) 31P NMR technique is demonstrated for the detection of alkylphosphonic acids (marker of nerve agents). The results of detection were validated after conducting various in‐house exercises. The confidence generated by this study was found very useful in detection of different alkylphosphonic acids spiked in various official interlaboratory proficiency tests conducted by Organisation for the Prohibition of Chemical Weapons (OPCW). Copyright

MASS SPECTROMETRIC FRAGMENTATION OF UNSYMMETRICALLY SUBSTITUTED METHYLPHOSPHONATE DIESTERS

Abstract A series of structurally related unsymmetrically substituted methylphosphonate diesters have been synthesised and subjected to electron impact (El) mass spectral studies. These studies though aimed at total identification of the compounds, resulted in certain interesting observations and hence are being reported. In order to confirm the observations under electron impact and to support the mechanism of fragmentation we have also performed MSNS experiments in both daughter ion and parent ion modes.

Configurational assignment of long-chain alkylated pyridinium aldoxime bromides by Noesy experiments

A configurational study of long-chain N-alkylated pyridinium aldoxime derivatives and their positional isomers has been carried out by two-dimensional 1H-1H NOESY (nuclear Overhauser effect spectroscopy). Cross peak intensities were observed to be enhanced with increasing mixing time. Mixing times longer than 250 ms result in increasing contribution of spin diffusion that produces unrealistic hydrogen-hydrogen distances. The results of NOE measurements showed significant enhancement in the intensity of iminyl proton resonances on irradiation of hydroxyl proton resonances and vice versa. The chemical shift difference between hydroxyl proton resonances and iminyl proton resonances was found to be ~4 ppm for syn and ~5 ppm for anti configurations. The study reveals that these compounds exist in the E configuration i.e. the syn form in solution. The syn isomer predominates; the anti isomer amounts are 3% (2-oxime), 4% (3-oxime) and 6% (4-oxime).