[Contributions to the chemistry of phosphine alkylenes. I. On the reaction of phosphine alkylenes with dialkyl-and diaryl-chlorophosphines].
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Alkynes↗
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Tertiary phosphines and phosphine oxides containing a 2-haloethyl group.
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Antineoplastic Agents↗
[Contribution to the study of the action of phosphine (PH3). On the question of so-called chronic phosphine poisoning].
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Animals↗
Evaluation of phosphinates as potential pretreatments for nerve agents.
To assess the utility of phosphinates as pretreatments against nerve agents, experiments were conducted to determine whether oximes can reactivate phosphinate-inhibited guinea pig acetylcholinesterase (AChE) and whether the toxicity of phosphinates is reduced by treatment with atropine and/or oxime. Three phosphinates, 4-nitrophenyl methyl(phenyl) phosphinate (MPP), 4-nitrophenyl chloromethyl(phenyl) phosphinate (CMPP), and 4-nitrophenyl 2-methoxyphenyl(methyl) phosphinate (MPMP), were used in these experiments. In the first group of experiments, 2-PAM or HI-6 was administered, im, 2 min after peak inhibition of whole blood AChE activity by the phosphinates. Both oximes significantly reactivated MPP- or CMPP-inhibited AChE; however, HI-6 was the better reactivator in both cases. Oximes were ineffective against MPMP. Efficacy studies revealed that neither HI-6 nor 2-PAM potentiated the toxic effects of MPP or CMPP and that atropine/oxime therapy provided greater protection (up to 100 LD50s) against either phosphinate than any single therapy. The reactivation and efficacy data, especially for CMPP, support the concept that oxime sensitive phosphinates may be useful as pretreatments against nerve agent intoxication.
Acetylcholinesterase↗
Determination of phosphine by adsorption sampling with modified silica gel and colorimetry of phosphate.
A method for determining phosphine was developed using adsorption sampling followed by colorimetric measurement. Two types of adsorbent used in this study were prepared from silica gel by impregnation with potassium permanganate (1% w/w) or (mercury(II) chloride and sodium chloride) (0.2 + 0.2% w/w). Each adsorbent (150 mg) packed in a glass tube had the capacity to adsorb 0.3 ppm of phosphine in 3 l of test gas passing through at a rate of 300 ml/min without breakthrough. The adsorbed phosphine was desorbed into solutions as phosphate and the recovered phosphate was determined by ICP-AES or by one of two kinds of colorimetric methods for phosphate based on the molybdenum blue method, i.e., the colorimetric method following JIS K 0102 and that following the NIOSH Manual of analytical method, No. S 332. When 0.01 ppm of phosphine in 3 l of test gas was adsorbed on the potassium permanganate adsorbent and determined by the JIS method, 93.8% of the phosphine was recovered as phosphate with a CV of 12.9% (n = 3). This method was applicable to field surveys of phosphine in workplaces. The other method with the mercury(II) chloride adsorbent followed by the NIOSH method resulted in lower recovery of phosphate in low phosphine concentration range. ICP-AES was less sensitive than the colorimetries. The effect of coexistent arsenite or silicate on the colorimetry of phosphate was assessed.
Adsorption↗
Chemical reactivity of labile sulfur of iron-sulfur proteins. The reaction of triphenyl phosphine.
The reaction of triphenyl phosphine to iron-sulfur proteins from adrenal cortex mitochondria, spinach chloroplasts, and Clostridium pasteurianum was investigated. As ethanol concentrations in the reaction mixture increased, the rate of the reaction decreased. In the simultaneous presence of 1 M KC1 and 5 M urea, the reaction rate reached at maximum. Under these conditions the initial rates of the decolorization reaction by the phosphine were found to be 8.7, 0.88, and 1.8 nmol of ferredoxin per min at 25 degrees C for adrenal, spinach, and clostridial ferredoxins, respectively. The kinetic curves for the reaction of the phosphine sulfide formation, the loss of labile sulfur, and the deterioriation of visible absorption showed a similar pattern with a comparable rate. During this reaction, the complete reduction of ferric ions present in ferredoxin was observed with a fast rate under either aerobic or anaerobic conditions. These results suggest that the iron atoms in ferredoxin are first reduced by the intramolecular reductants in the presence of triphenyl phosphine with the concomitant formation of S2-2, which then reacts with triphenyl phosphine resulting in the formation of triphenyl phosphine sulfide.
Adrenal Cortex↗
Phosphinic peptide analogues as potent inhibitors of Corynebacterium rathayii bacterial collagenase.
Pseudo-substrate analogues of collagenase from Corynebacterium rathayii, in which the scissile peptide bond is replaced by a phosphinic moiety, were synthesized and evaluated as inhibitors of this enzyme. The phosphinic tetrapeptide, Z-Phe-psi(PO2CH2)-Gly-Pro-Nle (1), was found to be a potent inhibitor of collagenase with a Ki value of 8 nM. Increasing the length of the phosphinic-containing inhibitors from tetra- to hepta-peptide size further improves the potency of these compounds. The heptapeptide analogue, Z-Phe-Gly-Pro-Phe-psi(PO2CH2)-Gly-Pro-Nle-OMe, with a Ki value of 0.6 nM, is the most potent inhibitor reported to date for bacterial collagenases. A comparison between the phosphinic analogue Z-Phe-psi(PO2CH2)-Gly-Pro-Nle (1) and the phosphonamide peptide Z-Phe-psi(PO2NH)-Gly-Pro-Nle (2) shows that for bacterial collagenase the replacement of a CH2 by an NH group results only in a modest increase in affinity from Ki = 8 nM for compound 1 to Ki = 6 nM for compound 2. Most of the phosphorus-containing inhibitors of this series are slow- or slow-tight-binding inhibitors with second-order rate constants for association and dissociation varying respectively for the kon values from 1 x 10(3) to 26 x 10(3) M-1.s-1 and for the koff values from 3 x 10(-4) to 2 x 10(-5) s-1. Interestingly, the lower affinity of the molecule containing a D residue in the P1 position of the inhibitor, compared with the molecule with an L residue in this position, is mainly the consequence of a lower rate constant for association of these D stereoisomers with the enzyme. This study demonstrates that phosphinic peptide analogues are potent inhibitors of a bacterial collagenase. The development of new phosphinic peptides should lead to the discovery of potent inhibitors of other zinc metalloproteases. Details of how the analogues were synthesized are given in Supplementary Publication SUP 50176 (14 pages), which has been deposited with the British Library Document Supply Centre, Boston Spa, Wetherby, W. Yorkshire LS23 7BQ, from whom copies can be obtained on the terms indicated in Biochem. J. (1994) 297, 9.
Amino Acid Sequence↗
[PH3 residues in hazelnuts, soybeans and wheat following phosphine fumigation with non-constant concentrations].
In model tests hazelnuts, soy beans and wheat were fumigated with phosphine (PH3) at non constant concentrations. The influence of different concentration characteristics on the fumigation and the decomposition of phosphine residues was investigated in accordance with the fumigation technique. At the beginning the concentration increases, and after attaining the maximum gradually decreases to zero. The level of residues during the fumigation as well as the behaviour of residues during the storage of the fumigated products was monitored with a gas chromatographic method. The residues correlate with the concentration of phosphine, they also pass through a peak. The rate of decomposition of residues which had been formed in the phase of increasing concentration is greater than the rate of residues of equal magnitude which had been formed during the decreasing phase. When the concentration is even the maximum residue occurs later than the maximum concentration; when there is a steep trend both maximums coincide. This behaviour can be explained by the sorption and diffusion of phosphine. A comparison is made with the phosphine concentration which occurs during fumigation in practice. The parameters which produce a constant concentration trend with only one maximum and a non constant trend with an often increasing and decreasing concentration are discussed. The different behaviour of residues in these cases is described. Conclusions are drawn for the practice of fumigation.
Chromatography, Gas↗
Phosphinic acid inhibitors of D-alanyl-D-alanine ligase.
We report the synthesis of a series of phosphinic acid dipeptide analogues, NH2CH(R1)PO(OH)CH2CH(R2)CO2H, related to DAla-DAla. The best of these compounds are potent, essentially irreversible inhibitors of DAla-DAla ligase, and their preferred stereochemistry was shown by chiral synthesis of (1(S)-aminoethyl)(2(R)-carboxy-1-n-propyl)phosphinic acid, 12b, and by X-ray crystallography of its derivative benzyl [1(S)-[(benzyloxycarbonyl)-amino]ethyl](2(R)-carbomethoxy-1-propyl) phosphinate, 13, to correspond to the stereochemical configuration of DAla-DAla at both centers. A mechanism for the inhibition of DAla-DAla ligase by these compounds is proposed to involve an ATP-dependent formation of phosphorylated inhibitor within the enzyme's active site. The antibacterial activities of these compounds are modest although their spectra include both Gram-positive and Gram-negative susceptible organisms. The best antibacterial activity was shown by (1(S)-aminoethyl) [2-carboxy-2(R)-(methylthio)-1-ethyl]phosphinic acid, 3e, whose MIC's range from 4-128 micrograms/mL on nine of a panel of 11 bacterial organisms. Combination of one of the more active phosphinic acids 12b with the alanine racemase inhibitor fluoro-D-alanine enhances the antibacterial spectrum of the latter on several strains of bacteria and inhibits fluoro-D-alanine's self-reversal, which normally occurs at concentrations several fold higher than its MIC level. This inhibition of fluoro-D-alanine self-reversal is consistent with an involvement of DAla-DAla ligase inhibition in the antibacterial activity of these compounds.
Adenosine Triphosphate↗
The interaction of phosphine with haemoglobin and erythrocytes.
1. Phosphine progressively converts oxyhaemoglobin to methaemoglobin and hemichrome species, with the product formed being time- and concentration-dependent. 2. The reaction of phosphine with oxyhaemoglobin leads to the formation of phosphite and phosphate. 3. Incubation of rat erythrocytes with various concentrations of phosphine results in the progressive uptake of phosphine by the erythrocytes in a temperature-dependent first-order process. 4. Uptake of phosphine by erythrocytes causes crenation, but conversion of oxyhaemoglobin to methaemoglobin and hemichrome could not be demonstrated.
Animals↗
Spectrophotometric determination of phosphine residues in rice.
Phosphine residues were determined in 2 types of rice samples, raw polished and parboiled. The yellow chromophore due to phosphine from raw polished rice had 2 absorption maxima, a strong one at 370-380 nm and a weaker one at 400-410 nm. The chromophore from parboiled rice also had 2, one at 390-400 nm and the other at 410-420 nm. A closed system containing rice and a phosphine tablet or powder yielded 93-99% recovery of fortified phosphine. At any given dose of phosphine, parboiled rice retained a higher amount of residue after aeration than did raw polished rice.
Chromatography, Gas↗
Simple spectrophotometric method for determination of phosphine residues in wheat.
A method has been developed for determination of phosphine residues in wheat, based on the reaction of phosphine with silver nitrate in aqueous solution to form an egg-yellow chromophore with an absorption maximum at 400 nm. At this wavelength, there is a linear relationship between absorbance and concentration of phosphine in the range 10-100 ng/mL. Phosphine-fumigated wheat is soaked in a known volume of AgNO3 solution, and the absorbance of the filtrate is read against a blank at 400 nm. The method is sensitive, with lower detection and estimation limits of 0.008 and 0.01 micrograms PH3, respectively. Recovery of added phosphine from a closed system was 85-100%. Accuracy for this method has been compared with that for the gas chromatographic method.
Pesticide Residues↗
Gas-liquid chromatography and flame photometric detection of phosphine in wheat.
A screening method using gas-liquid chromatography with flame photometric detection has been developed for determining phosphine in wheat. Phosphine is measured as the sum of physically bound intact phosphine and that derived from residual aluminum phosphide. Wheat is extracted in a closed, partially evacuated glass system by refluxing with 10% sulfuric acid. Liberated gases are swept into a gas-collection flask fitted with rubber septa to permit gas sampling. Aliquots of collected gas are injected into a gas chromatograph. Phosphine is quantitated by peak area as determined by an electronic integrator. Recoveries varied with concentration: 67% was recovered at 0.10 ppm and 98% was recovered at 19 ppm. For concentrations less than 1.5 ppm, the coefficient of variation was 9.95%. Using flame photometric detection, phosphine concentrations as low as 0.04 ppm were easily determined in wheat.
Chromatography, Gas↗
Determination of genotoxic and other effects in mice following short term repeated-dose and subchronic inhalation exposure to phosphine.
Phosphine is an important fumigant in the grain industry and has been reported to be genotoxic in occupationally exposed fumigators. This study reports on the effects of phosphine inhalation exposure at up to, and exceeding, occupational relevant levels in a subchronic (0.3, 1.0 and 4.5 ppm, 13 weeks) and a short term repeated-dose (5.5 ppm, 2 weeks) study in both sexes of Balb-c mice. The following end-points were examined: micronucleus induction in bone marrow, peripheral blood, spleen lymphocytes and skin keratinocytes, mutations at the hypoxanthine-guanine phosphoribosyl transferase locus in lymphocytes, and weight gain and relative organ weights (kidneys, lungs, liver, heart, brain and spleen). After subchronic exposure, there was a highly significant negative linear correlation between proportional weight gain and exposure in both sexes (multiple linear regression, r = -0.56, P < 0.0001), with female mice showing a greater effect. Females also showed an increase in relative organ weights at the highest test dose, in contrast to males where there was a slight decrease. A statistically significant increase in micronucleus frequency was seen in the bone marrow and spleen lymphocytes of both sexes, but only at the highest concentration. The short term repeated-dose study revealed a slight decrease in weight gain in both sexes, with a greater effect in females. It is concluded that phosphine is weakly genotoxic in both sexes of mice, and has an effect on weight gain. However, the weak genotoxic effect may not be biologically significant as it was seen only in the subchronic study and only at the highest test concentration of 4.5 +/- 0.8 ppm (approaching the LD50). Although such exposure conditions are unlikely to be encountered in an occupational environment, caution should continue to be exercised in the use of phosphine until more data become available.
Animals↗
Inhibition of human immunodeficiency virus-1 protease by a C2-symmetric phosphinate. Synthesis and crystallographic analysis.
The human immunodeficiency virus type 1 (HIV-1) protease is a potential target of acquired immune deficiency syndrome (AIDS) therapy. A highly potent, perfectly symmetrical phosphinate inhibitor of this enzyme, SB204144, has been synthesized. It is a competitive inhibitor of HIV-1 protease, with an apparent inhibition constant of 2.8 nM at pH 6.0. The three-dimensional structure of SB204144 bound to the enzyme has been determined at 2.3-A resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (= sigma parallel F(o) magnitude to - Fc parallel/sigma magnitude of F(o)), of 0.178. The inhibitor is held in the enzyme active site by a set of hydrophobic and hydrophilic interactions, including an interaction between Arg8 and the center of the terminal benzene rings of the inhibitor. The phosphinate establishes a novel interaction with the two catalytic aspartates; each oxygen of the central phosphinic acid moiety interacts with a single oxygen of one aspartic acid, establishing a very short (2.2-2.4 A) oxygen-oxygen contact. As with the structures of penicillopepsin bound to phosphinate and phosphonate inhibitors [Fraser, M. E., Strynadka, N. C., Bartlett, P. A., Hanson, J. E., & James, M. N. (1992) Biochemistry 31, 5201-14], we interpret this short distance and the stereochemical environment of each pair of oxygens in terms of a hydrogen bond that has a symmetric single-well potential energy curve with the proton located midway between the two atoms.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗
Human genotoxicity: pesticide applicators and phosphine.
Fumigant applicators who, 6 weeks to 3 months earlier, were exposed to phosphine, a common grain fumigant, or to phosphine and other pesticides had significantly increased stable chromosome rearrangements, primarily translocations in G-banded lymphocytes. Less stable aberrations including chromatid deletions and gaps were significantly increased only during the application season, but not at this later time point. During fumigant application, measured exposure to phosphine exceeds accepted national standards. Because phosphine is also used as a dopant in the microchip industry and is generated in waste treatment, the possibility of more widespread exposure and long-term health sequelae must be considered.
Chromosome Aberrations↗
Steroid phosphorus compounds. V--Mass spectrometry of phosphinic esters of monohydroxy steroids.
The mass spectra of the dimethylphosphinic, dimethylthiophosphinic and dimethylphosphinous ester derivatives of several monohydroxy steroids are reported. The fragmentations of the derivatized steroids largely depend on the nature of the phosphorus-containing ester group. Phenolic ester derivatives exhibit the base peak at the molecular ion, whereas the spectra of the secondary phosphinic esters are dominated by very intense protonated phosphinic acid ions [Me2P(XH)(OH)]+ at m/e 95 (X =O) or at m/e 111 (x = s). The present results also indicate the low ionization potential for the phosphinic ester group. Due to their good gas chromatographic properties, these steroid derivatives appear to be particularly suitable for gas chromatographic mass spectrometric analysis of biochemical materials.
Androsterone↗
Nutritional and toxicological effects of long-term ingestion of phosphine-fumigated diet by the rat.
The fumigation of stored foodstuffs with phosphine (PH3) is likely to become widely used in the future because of its technological efficiency and the rapid desorption of the fumigant. In a long-term feeding study of a phosphine-fumigated diet, rats were monitored for weight gain, food intake, plasma chemistry, haematology and urinary changes. Histopathological studies, including organ-weight determinations, were carried out after treatment of the rats for 1 and 2 yr. The results show that ingestion of a phosphine-fumigated diet by the rat for 2 yr does not cause any marked modification of growth, food intake, nitrogen balance, body composition, functional behaviour or the incidence or type of tumours.
Animals↗