The adsorption and decomposition of dimethyl methylphosphonate (DMMP) have been examined on four different metal oxide surfaces:  aluminum oxide, magnesium oxide, lanthanum oxide, and iron oxide. Aluminum, magnesium, and lanthanum oxides are observed to behave in much the same way, with initial binding of the PO species to the surface at an acid site, followed by stepwise elimination of the methoxy groups, beginning at temperatures as low as 50 °C, which combine with surface hydrogens to yield methanol that evolves from the surface. The final product observed for these oxides is a surface-bound methylphosphonate, with the P−CH3 bond intact, which is resistant to further oxidation even in the presence of 70 Torr of oxygen at 300−400 °C. Adsorption on iron oxide yields a different sequence of events, with the initial adsorption occurring again with the PO moiety binding to an acid site, although there is some indication of the formation of a second type of surface complex. The primary interaction on iron oxide appears to be much stronger than with the other oxides, and probably involves the unidentate coordination of the DMMP to a Lewis acid site on the surface. Nonselective elimination of both the methoxy and the phosphorus-bound methyl groups begins only after heating above 200 °C, but occurs with total elimination of the methyl and methoxy groups observed after heating above 300 °C in vacuum. The ease with which iron oxide cleaves the P−CH3 bond is attributed to the availability of multiple oxidation states to the iron atom. Participation of the Fe(III)/Fe(II) redox couple in the reaction provides a low-energy path for oxidative cleavage of the P−CH3 bond. The other oxide surfaces cannot provide a similar path, and on these surfaces the P−CH3 bond is resistant to cleavage. The use of infrared diffuse reflectance techniques, observing, in particular, the methyl stretch region of the infrared spectrum, has allowed the almost complete characterization of the decomposition processes which occur after DMMP adsorbs on aluminum oxide, magnesium oxide, lanthanum oxide, and iron oxide.

Rare adverse reactions to drugs that are of unknown etiology, or idiosyncratic reactions, can produce severe medical complications or even death in patients. Current hypotheses suggest that metabolic activation of a drug to a reactive intermediate is a necessary, yet insufficient, step in the generation of an idiosyncratic reaction. We review evidence for this hypothesis with drugs that are associated with hepatotoxicity, one of the most common types of idiosyncratic reactions in humans. We identified 21 drugs that have either been withdrawn from the U.S. market due to hepatotoxicity or have a black box warning for hepatotoxicity. Evidence for the formation of reactive metabolites was found for 5 out of 6 drugs that were withdrawn, and 8 out of 15 drugs that have black box warnings. For the other drugs, either evidence was not available or suitable studies have not been carried out. We also review evidence for reactive intermediate formation from a number of additional drugs that have been associated with idiosyncratic hepatotoxicity but do not have black box warnings. Finally, we consider the potential role that high dosages may play in these adverse reactions.

The adsorption and decomposition reactions of dimethyl methylphosphonate (DMMP) on a commercial γ-Al 2 O 3 , a γ-Al 2 O 3 -supported iron oxide, and a sol-gel-prepared alumina have been examined at temperatures from 25 to 400 °C. The capacities of these solids for the decomposition of DMMP have been measured, and the identities and amounts of the decomposition products determined over the entire temperature range. The alumina surfaces yield higher total amounts of decomposition products than the supported iron oxide material, with the sol-gel alumina showing very high activity. When corrected for surface area, however, the supported iron oxide material shows an activity equal to that of the γ-Al 2 O 3 support. The sol-gel alumina shows a higher activity at all temperatures up to saturation of the surface, presumably because of the presence of transitional phases that yield more reactive surface sites. At 25 °C, the commercial γ-Al 2 O 3 shows a total decomposition capacity of 117 µmol/g, the alumina-supported iron oxide material a capacity of 93 µmol/g, and the sol-gel alumina a capacity of 208 µmol/g. At 100 °C, these capacities increase by about a factor of 3, and at 200 °C and above, all of the materials show some capacity for sustained decomposition of DMMP.

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The adsorption of dimethyl methylphosphonate (DMMP) on alumina-supported iron oxide has been examined. DMMP reacts on adsorption at room temperature, apparently through cleavage of the phosphorus−carbon bond. This bond is observed to be extremely resistant to cleavage when DMMP is adsorbed on oxides such as alumina, magnesia, and lanthana. The phosphorus−methoxy bonds, which are the most readily cleaved on the other oxides, appear at least initially to remain intact on the alumina-supported iron oxide. The hypothesis proposed to account for the unusual activity of the iron oxide surface is an oxidation pathway involving the Fe(II)/Fe(III) redox couple.

The adsorption and decomposition reactions of dimethyl methylphosphonate (DMMP) on cerium oxide supported on aluminum oxide have been examined at 25 °C. Experiments were carried out that involved dosing the reactive adsorbent with small doses of DMMP, followed by quantitative determination of the decomposition products. The results suggest that the formation reactions of methanol and dimethyl ether are competitive processes involving the same surface intermediate, which is most likely a surface methoxy species. Based on the observed results, it is proposed that the formation of dimethyl ether is due to the combination of two surface methoxy groups, while an important, if not the dominant, reaction producing methanol involves a surface methoxy group interacting with a vapor phase or physisorbed DMMP molecule. The presence of significant amounts of methoxy fragments formed upon DMMP adsorption is supported by results from diffuse reflectance spectroscopy, which also show that those groups are primarily associated with the cerium oxide domains. FT-Raman spectroscopy shows that the most active cerium oxide domains are highly dispersed two-dimensional domains or very small (<1 nm) crystallites. Somewhat larger (<6 nm) three-dimensional crystallites add to the decomposition yield, but less strongly. The FT-Raman evidence also supports the formation of a relatively narrow particle size distribution of cerium oxide crystallites on the alumina support surface from the sample preparation method. The alumina-supported cerium oxide reactive adsorbents developed as part of this study are the most active that have been reported in the literature for ambient temperature applications, decomposing approximately 775 µmol of DMMP per gram of adsorbent at 25 °C, and strongly or irreversibly adsorbing an additional 400 µmol, for a total capacity at room temperature of 1.1-1.2 mmol of DMMP per gram.

Near-IR FT-Raman spectra of B12 imidazole derivatives and cobalamins in aqueous solution were compared since there is now strong evidence that, in human B12-dependent enzymes, the 5,6-dimethylbenzimidazole (DMBz) is replaced by imidazole from a histidine in the protein. Derivatives studied include methylcobalamin [MeCbl (DMBz base-on) and MeCbl+ (base-off by acidification to protonate the DMBz)], methylaquacobinamide (MeCbi+) [Cbi's have the DMBz-bearing nucleotide loop removed by hydrolysis], and Me(N-acetylhistidine)Cbi [coordinated through imidazole in Me(N-AcHis)Cbi at pH 10 and imidazolate in Me(N-AcHis)Cbi- in 1 M NaOH]. Several marker bands changed with changes in the axial ligand trans to the methyl group. The frequency of the Co−CH3 stretching mode at ∼505 cm-1 (assigned by isotopic shift using −CD3) was similar for all MeCbl and MeCbi species; thus, the trans ligand, including the very powerful electron-donating imidazolate species, has little effect on Co−C bond strength. In contrast, the peak height of the Co−CH3 band, relative to the corrin long-axis mode band at 1495 cm-1, consistently increased 2-fold upon coordination of an N-donor ligand to MeCbi+ and MeCbl+. This intensity change appears to be a useful means of assessing ligand replacement reactions. With increasing trans ligand donor ability, the frequency of the corrin in-phase double-bond stretching mode along the short axis at ∼1545 cm-1 increased, but the frequencies of the corresponding long-axis mode at ∼1495 cm-1 and the corrin band at ∼1570 cm-1 were unchanged. The frequency of a corrin band at ∼1600 cm-1 increased slightly to 1603 cm-1 from the base-on to the base-off MeCbl form; the band is also at 1603 cm-1 for MeCbi+, Me(N-AcHis)Cbi, and Me(N-AcHis)Cbi-. A decrease in the frequency of the ∼1570 cm-1 band coincident with acid-catalyzed H-to-D exchange at the corrin C10 in acidic D2O solutions (confirmed by 1H NMR spectroscopy) was evidence that it is a corrin band. However, the frequency and intensity of this band were relatively insensitive to the trans ligand. This diverse dependence of the corrin-band frequencies on changes in trans axial ligand bulk suggests that in these B12 derivatives there are no large structural distortions. Differences in electron donation by the trans ligands have the greater influence on the spectra. A band at ∼1315 cm-1 was found to be characteristic of unprotonated DMBz; it is absent when DMBz is removed (Cbi's) or protonated (MeCbl+) but present in all other Cbl's, including base-off (CN)2Cbl-. An ∼30 cm-1 shift to lower frequency of the overlapping amide I bands of cobalt corrinoids between H2O and D2O was caused by amide NH2 to ND2 exchange. The frequency shift of ∼10 cm-1 of this band between H2O and ethanol was consistent with a small redistribution of resonance forms of the amide group between solvents. Since the band for the CD3 symmetric stretch of the Co−CD3 group lies in a region of the spectrum (∼2105 cm-1) that is devoid of other bands, it may be useful in studies of enzyme-bound Me-d 3-Cbl...

Australine [(1R,2R,3R,7S,7aR)-3-(hydroxymethyl)-1,2,7-trihydroxypyrrolizid ine] is a polyhydroxylated pyrrolizidine alkaloid that was isolated from the seeds of the Australian tree Castanospermum australe and characterized by NMR and X-ray diffraction analysis [Molyneux et al. (1988) J. Nat. Prod. (in press)]. Since swainsonine and catanospermine are polyhydroxylated indolizidine alkaloids that inhibit specific glycosidases, we tested australine against a variety of exoglycosidases to determine whether it would inhibit any of these enzymes. This alkaloid proved to be a good inhibitor of the alpha-glucosidase amyloglucosidase (50% inhibition at 5.8 microM), but it did not inhibit beta-glucosidase, alpha- or beta-mannosidase, or alpha- or beta-galactosidase. The inhibition of amyloglucosidase was of a competitive nature. Australine also inhibited the glycoprotein processing enzyme glucosidase I, but had only slight activity toward glucosidase II. When incubated with cultured cells, this alkaloid inhibited glycoprotein processing at the glucosidase I step and caused the accumulation of glycoproteins with Glc3Man7-9(GlcNAc)2-oligosaccharides.