Devendra K. Jaiswal

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.

In vivo binding of [1-14C]methylisocyanate to various tissue proteins

Liaison covalente de methyl-isocyanate MIC a differentes proteines tissulaires apres administration intraperitoneale et par inhalation. Les proteines sanguines et la globine subissent une carbamoylation apres injection IP. Ces resultats suggerent que le passage de la barriere «sang-tissu» se fait sous la forme active de MIC

A facile synthesis of organofluorine compounds using a semi-molten mixture of tetrabutylammonium bromide and an alkali metal fluoride

Abstract A semi-molten mixture of tetrabutylammonium bromide and an alkali metal fluoride (KF or CsF) has been found to be an efficient reagent system for the preparation of organofluorine compounds, e.g., CH 3 (CH 2 ) 7 F, CH 2 =CH-CH 2 F, FCH 2 CO 2 C 2 H 5 , C 6 H 5 COF, and related compounds through facile fluoride-ion exchange with organohalides. The system provides a simple and convenient alternative to ‘anhydrous’ tetrabutylammonium fluoride for the synthesis of oragnofluorine compounds.

In vivo protection by amifostine and DRDE-07 against sulphur mustard toxicity.

The study was aimed at investigating the prophylactic efficacy of orally administered amifostine and a newly synthesized compound, S-2(2-amino-ethylamino)ethyl phenyl sulphide (DRDE-07), against dermally applied sulphur mustard (SM) in mice and rats. The LD50 values of amifostine and DRDE-07 were determined following oral and intraperitoneal routes and the LD50 of SM diluted in PEG-300 was determined following dermal route. Amifostine or DRDE-07 (equivalent to their 0.05 LD50, 0.10 LD50 and 0.20 LD50) dissolved in water was fed to mice and rats and, after 30 min, various doses of SM were applied to the hair-clipped area of the skin and were observed for 14 days for mortality. The protection index (PI) was calculated as a ratio of LD50 with treatment to LD50 without treatment. The estimated percutaneous LD50 of SM was found to be 8.1 and 2.4 mg///kg for female mice and male rats, respectively. A dose-related protection was observed with all the three doses of both compounds. Thirty minutes prior, the administration of amifostine in female mice offered a PI of 3.0 at the lowest pretreatment dose (52.5 mg// kg) followed by PI of 6.7 and 9.5 at 105 and 210 mg// /kg pretreatment doses, respectively. DRDE-07 offered better protection against SM in female mice, i.e., a PI of 4.8 at pretreatment dose of 62.5 mg// /kg, a PI of 12.0 at the dose of 124.7 mg///kg and a PI of 27.0 at the dose of 249.4 mg/kg. In male rats, DRDE-07 gave a PI of about 3.0 at all the three pretreatment doses (80, 160 and 320 mg///kg), whilst amifostine offered a PI of 3.1 at the highest pretreatment dose (452 mg///kg). The present study showed that oral administration of both amifostine and DRDE-07 was effective as a prophylactic agent for protecting against SM toxicity, and that DRDE-07 offered better protection.

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.

Poly-Schiff bases. V. Synthesis and characterization of novel soluble fluorine-containing polyether azomethines

A new dialdehyde monomer, 4,4′-(hexafluoroisopropylidine) bis(p-phenoxy) benzaldehyde, was prepared; it led to a number of novel poly-Schiff bases in reactions with different diamines, such as 4,4′-diaminidiphenyl ether, 4,4′-(isopropylidine) bis(p-phenoxy) dianiline, 4,4′-(hexafluoroisopropylidine) bis(p-phenoxy) dianiline, and benzidine. The polymers were characterized with viscosity measurements, nitrogen analyses, and IR and 1H NMR spectroscopy. These poly-Schiff bases showed good thermal stability up to 491 °C for 10% weight loss in thermogravimetric analysis under air and high glass-transition temperatures up to 215 °C in differential scanning calorimetry. These polymers were soluble in a wide range of organic solvents, such as CHCl3, dimethylformamide (DMF), dimethyl sulfoxide, and 1-methyl-2-pyrrolidon (NMP), and were insoluble in toluene and acetone. Thin films of these polymers cast from DMF exhibited tensile strengths up to 38 MPa.

The Efficacy of Monoisoamyl Ester of Dimercaptosuccinic Acid in Chronic Experimental Arsenic Poisoning in Mice

Abstract The therapeutic efficacy of monoisoamyl meso-2,3-dimercaptosuccinic acid (MiADMSA), a new monoester of 2,3-dimercaptosuccinic acid on arsenic induced oxidative stress in liver and kidneys, alterations in hematopoietic system and depletion of arsenic burden was assessed, in mice. Three different doses of MiADMSA (25, 50 or 100 mg/kg) for five consecutive days were administered in chronically arsenic exposed mice (10 ppm in drinking water for six months). Oral administration of MiADMSA particularly at a dose of 50 mg/kg, produced relatively more pronounced beneficial effects on the inhibited blood δ-aminolevulinic acid dehydratase (ALAD), biochemical variables indicative of hepatic and renal oxidative stress and depletion of arsenic concentration in blood, liver and kidneys, compared with intraperitoneal administration of the drug. The treatment with MiADMSA although, produced essential metals imbalance which could be a restrictive factor for the possible therapeutic use of this compound in chronic arsenic poisoning and thus require further exploration.

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 OF 2-PHENYLPERFLUOROPROPENE AND 1,1,1,3,3,3-HEXAFLUORO-2-PHENYLPROPANE

Abstract We describe the optimisation of reaction conditions for the synthesis of 2-phenylperfluoropropene and its HF addition product 1,1,1,3,3,3-hexafluoro-2-phenylpropane from 1,1,1 -trifluoroacetophenone by the reaction with sodium chlorodifluoroacetate and triphenylphosphine in dimethylformamide. The formation of olefin and the addition product has been studied over a range of temperature ( 50–150 °C ) as a function of time.

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.