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PubMed1993

Comparison of DNA adduct formation by means of synchronous scanning and by isotope tracers: in-vitro study on formation of DNA adducts in human lymphocytes exposed to benzo(a)pyrene.

The P-450 complex transforms polyaromatic hydrocarbons (PA) into active intermediates that may cause mutations due to DNA adduct formation. The present communication compares the rate of DNA adduct formation in human lymphocytes incubated for varying times with different concentrations of benzo(a)pyrene (B(A)P). In the presence of B(A)P the cultures were standardized as to medium and lectin concentration. Then the cells were exposed to increasing levels of cold and 3H-labelled B(A)P for varying times. B(A)P adducted to DNA was estimated both by synchronous scanning (SS) and by counting radioactivity. SS revealed a synchronous signal at 382 nm, corresponding to data available from the literature, and the peak height declined linearly with dose of B(A)P. However, it appeared that the signal height decreased if the DNA was successively extracted with chloroform. Five times extraction gave rise to a stable content of B(A)P of about 25% of the B(A)P originally found in the DNA. This DNA could only be traced with the radioactive tracer, since the concentration of adducted B(A)P was below the lower level of detection by the SS method. Even at low B(A)P levels the carcinogen exists in two forms in DNA: as 'free' non-adducted (extractable with lipid solvents) and an adducted form. Time variation showed that the DNA was incorporated linearly with both forms of B(A)P for up to 2 hours, then the take-up was constant. Concentration variation showed linear incorporation up to 1 microM B(A)P. The present data may explain conflicting data on the extent to which lymphocytes adduct B(A)P to DNA. The lipid-soluble planar B(A)P of DNA may, like photosensitizers, intercalate between the two DNA strands. Like the intercalation of acridines into DNA, which is known to cause frameshift mutations, the intercalation of B(A)P may also have mutagenic consequences.

Benzo(a)pyrene↗
PubMed2005

Pyruvate formate-lyase activating enzyme: elucidation of a novel mechanism for glycyl radical formation.

Pyruvate formate lyase activating enzyme is a member of a novel superfamily of enzymes that utilize S-adenosylmethionine to initiate radical catalysis. This enzyme has been isolated with several different iron-sulfur clusters, but single turnover monitored by EPR has identified the [4Fe-4S](1+) cluster as the catalytically active cluster; this cluster is believed to be oxidized to the [4Fe-4S](2+) state during turnover. The [4Fe-4S] cluster is coordinated by a three-cysteine motif common to the radical/S-adenosylmethionine superfamily, suggesting the presence of a unique iron in the cluster. The unique iron site has been confirmed by Mossbauer and ENDOR spectroscopy experiments, which also provided the first evidence for direct coordination of S-adenosylmethionine to an iron-sulfur cluster, in this case the unique iron of the [4Fe-4S] cluster. Coordination to the unique iron anchors the S-adenosylmethionine in the active site, and allows for a close association between the sulfonium of S-adenosylmethionine and the cluster as observed by ENDOR spectroscopy. The evidence to date leads to a mechanistic proposal involving inner-sphere electron transfer from the cluster to the sulfonium of S-adenosylmethionine, followed by or concomitant with C-S bond homolysis to produce a 5'-deoxyadenosyl radical; this transient radical abstracts a hydrogen atom from G734 to activate pyruvate formate lyase.

Acetyltransferases↗
PubMed2005

How principles of domain formation in model membranes may explain ambiguities concerning lipid raft formation in cells.

Sphingolipid and cholesterol-rich liquid ordered lipid domains (lipid rafts) have been studied in both eukaryotic cells and model membranes. However, while the coexistence of ordered and disordered liquid phases can now be easily demonstrated in model membranes, the situation in cell membranes remains ambiguous. Unlike the usual situation in model membranes, under most conditions, cell membranes rich in sphingolipid and cholesterol may have a "granular" organization in which the size of ordered and/or disordered domains is extremely small and domains may be of borderline stability. This review attempts to explain the origin of the divergence between of our understanding of rafts in model membranes and in cells, and how the physical properties of model membranes can help explain many of the ambiguities concerning raft formation and properties in cells. How physical principles of ordered domain formation relate to limitations of detergent insolubility and cholesterol depletion methods used to infer the presence of rafts in cells is also discussed. Possible modifications of these techniques that may increase their reliability are considered. It will be necessary to study model membrane systems more closely approximating cell membranes in order gain a complete understanding of raft properties in cells. Very high concentrations of membrane cholesterol and proteins may explain key physical characteristics of domains in cellular membranes, and are the two of the most obvious factors requiring additional study.

Animals↗
PubMed2005

Film formation from monodisperse acrylic lattices 2. Influence of drying temperature on the film formation process.

The influence of drying temperature on the properties of latex films was investigated by gravimetry, turbidimetry (i.e., analysis of transmission spectra and interference), atomic force microscopy and measurement of water vapor permeability. Several pitfalls in the determination of water content of dried films that absorb water after being submerged in it have been proposed, such as fading boundaries, remaining water after drying and change of particle sizes. At moderately higher temperatures film formation is improved. This improvement follows from the formation of smoother film surfaces (AFM), lower water vapor permeabilities and smaller values for delta lambda(min). On the other hand, defects as cracks and channels also are created, especially at high temperatures. It appears, however, that these channels do not run from the one surface of a film to the other.

Journal Article↗
PubMed2006

Foot formation in Hydra: a novel gene, anklet, is involved in basal disk formation.

We isolated a novel gene by a differential-display RT-PCR method comparing basal disk tissue and peduncle tissue in a species of Hydra, Pelmatohydra robusta, and we referred to it as anklet. The putative anklet product has a signal sequence in its N-terminus, and it has one MAC/PF domain and one EGF domain. In normal hydra, the expression of anklet was restricted in the periphery of the basal disk and the lowest region of the peduncle. In foot-regenerating animals, anklet was first expressed in the newly differentiated basal disk gland cells at the regenerating basal end, and then expression became restricted at the periphery of the regenerated basal disk and in the lowest region of the peduncle. This spatially specific expression pattern suggested that the product of the anklet gene plays a role in basal disk formation. We therefore examined the role played by the protein product of the anklet gene by suppressing the transcription level of anklet using an RNA-mediated interference (RNAi) method. Suppression of the level of expression of the anklet gene led to a decrease in basal disk size in normal hydra, and to a delay in basal disk regeneration in foot-amputated animals. These results suggested that anklet is involved in the formation and maintenance of the basal disk in hydra.

Amino Acid Sequence↗
PubMed2006

Prooxidant action of rhodizonic acid: transition metal-dependent generation of reactive oxygen species causing the formation of 8-hydroxy-2'-deoxyguanosine formation in DNA.

Rhodizonic acid, a six-membered cyclic hydroxyquinone, produced reactive oxygen species as a complex with transition metals. Addition of rhodizonic acid with ferrous ion caused an inactivation of aconitase the most sensitive enzyme to oxidative stress in permeabilized yeast cells. The iron-dependent inactivation of aconitase implies the rhodizonic acid/iron-mediated generation of reactive oxygen species. Spectrophotometric analysis of the interaction of rhodizonic acid with FeSO4 showed that addition of superoxide dismutase could inhibit the oxidation of rhodizonic acid, suggesting that reactive oxygen species produced from rhodizonic acid is superoxide radical. Rhodizonic acid further acted as a prooxidant causing a copper-dependent DNA damage. Treatment of DNA from plasmid pBR322 and calf thymus with rhodizonic acid plus copper caused strand scission and the formation of 8-hydroxy-2'-deoxyguanosine in DNA. Addition of catalase protected DNA from the rhodizonic acid-mediated strand scission, indicating that hydroxyl radical may participate in the DNA damage. Rhodizonic acid also showed a potent copper-reducing activity. These results indicate that copper ion reduced by rhodizonic acid may participate in the formation of superoxide radical that converts to hydrogen peroxide and hydroxyl radical. Other cyclic hydroxyquinones such as four-membered squaric acid and five-membered croconic acid did not show any prooxidant and reducing effects. Cytotoxic effects of tetrahydroquinone the precursor of rhodizonic acid may be related to the prooxidant properties of rhodizonic acid formed in cells.

Copper↗
PubMed2003

Role of the plasminogen system in basal adhesion formation and carbon dioxide pneumoperitoneum-enhanced adhesion formation after laparoscopic surgery in transgenic mice.

OBJECTIVE: To evaluate the role of plasminogen activator inhibitor-1 (PAI-1), urokinase plasminogen activator (uPA), and tissue-type plasminogen activator (tPA) in adhesion formation after laparoscopic surgery. DESIGN: Prospective, randomized study. SETTING: Academic research center. ANIMAL(S): Seventy female wild-type and transgenic knockout mice for PAI-1 (PAI-1(-/-)), uPA (uPA(-/-)) or tPA (tPA(-/-)). INTERVENTION(S): Standardized lesions to induce peritoneal adhesions were performed during laparoscopy. To evaluate basal adhesions and pneumoperitoneum-enhanced adhesions, the pneumoperitoneum was maintained for 10 minutes or 60 minutes, respectively. Peritoneal biopsy samples were obtained during and after 60 minutes of carbon dioxide pneumoperitoneum. MAIN OUTCOME MEASURE(S): Adhesions were blindly scored after 7 days. Concentrations of PAI-1 and tPA were measured by using enzyme-linked immunosorbent assay. RESULT(S): In PAI-1, uPA, and tPA wild-type mice, pneumoperitoneum enhanced adhesions. Compared with wild-type mice, basal adhesions were fewer in PAI-1(-/-) mice and more in uPA(-/-) and tPA(-/-) mice. Pneumoperitoneum did not enhance adhesions in these transgenic mice. PAI-1 concentration increased after 60 minutes of pneumoperitoneum whereas tPA concentration did not change. CONCLUSION(S): Impaired fibrinolysis increases basal adhesions. The absence of pneumoperitoneum-enhanced adhesions in PAI-1(-/-), uPA(-/-), and tPA(-/-) mice and the increase in PAI-1 expression indicate that PAI-1 up-regulation by carbon dioxide pneumoperitoneum is a mechanism of pneumoperitoneum-enhanced adhesion formation.

Animals↗
PubMed1999

Novel microtiter plate format for testing germ tube formation and proposal of a cost-effective scheme for yeast identification in a clinical laboratory.

The germ tube test is most widely used for presumptive identification of Candida albicans. Conventional testing is relatively time-consuming due to the hands-on time involved in preparing and viewing each isolate. In order to reduce work-load and costs we have developed a novel microtiter plate test format that offers several advantages: (i) use of removable strips of microtiter wells placed in lockwell frames, (ii) only one pipetting step for each isolate, (iii) direct micromorphological evaluation using an inverse microscope, (iv) use of a novel synthetic germ tube test medium, (v) reduction of the inoculum, permitting testing of minute colonies, (vi) thus, testing of different colonies in potentially mixed primary cultures of clinical specimens is encouraged and facilitated. Implementing this microtiter based germ tube test with simultaneous trehalase test for presumptive identification of Torulopsis (Candida) glabrata, we propose an identification scheme including this test format. This has been implemented in our routine laboratory permitting cost-effective presumptive identification of almost all clinically relevant yeast species.

Candida↗
PubMed2005

G Protein betagamma dimer formation: Gbeta and Ggamma differentially determine efficiency of in vitro dimer formation.

The Gbeta and Ggamma subunit of the heterotrimeric G proteins form a functional dimer that is stable once assembled in vivo or in vitro. The requirements, mechanism, and specificity of dimer formation are still incompletely understood, but represent important biochemical processes involved in the specificity of cellular signaling through G proteins. Here, seven Gbeta and 12 FLAG-epitope-tagged Ggamma subunits were separately synthesized in vitro using a rabbit reticulocyte lysate expression system. The translation products were combined and dimers isolated by immunoprecipitation. Gbeta1 and Gbeta4 formed dimers with all Ggamma subunit isoforms, generally with Gbeta/Ggamma stoichiometries between 0.2:1 and 0.5:1. Gbeta5, Gbeta5L, and Gbeta3s did not form significant amounts of dimer with any of the gamma subunit isoforms. Gbeta2 and Gbeta3 formed dimers with selected Ggamma isoforms to levels intermediate between that of Gbeta1/Gbeta4 and Gbeta3s/Gbeta5/Gbeta5L. We also expressed selected Gbetagamma in HEK293 cells and measured PLCbeta2 activity. Gbetagamma dimer-dependent increases in IP3 production were seen with most Gbeta1, Gbeta2, and Gbeta5 combinations, indicating functional dimer expression in intact cells. These results define the complete set of G protein betagamma dimers that are formed using a single biochemical assay method and suggest that there are Gbeta isoform-specific factors in rabbit reticulocyte lysates that determine the efficacy of Gbetagamma dimer formation.

Animals↗
PubMed1998

Quantification of Outer-Sphere Macrochelate Formation in the Ternary cis-Diammine-Platinum(II)-Bis-2'-deoxyguanosine 5'-Monophosphate Complex, cis-(NH(3))(2)Pt(dGMP)(2)(2)(-), and Formation of Quaternary Mixed Metal Ion Species with Magnesium(II), Copper(II), or Zinc(II) in Aqueous Solution.

The acid-base properties of cis-(NH(3))(2)Pt(dG)(2)(2)(-), where both dG(2)(-) (=2'-deoxyguanosine 5'-monophosphate) are N7-coordinated to the same Pt(II) [the complex is abbreviated as Pt(dG)(2)(2)(-)], are summarized [on the basis of potentiometric pH titration data from B. Song et al. (Metal-Based Drugs 1996, 3, 131-141)] and a micro acidity constant scheme is developed which allows quantification of the intrinsic acidity of the two P(O)(2)(OH)(-) groups present in this ternary complex (I = 0.1 M, NaNO(3); 25 degrees C). On the basis of comparisons with the corresponding acid-base properties of cis-(NH(3))(2)Pt(dCMP.H-N3)(2) [(dCMP.H)(-) = phosphate-monoprotonated 2'-deoxycytidine 5'-monophosphate] it is concluded that intramolecular, outer-sphere macrochelates form via Pt(NH(3)).O(3)P hydrogen bonds. The formation degree of these macrochelates is quantified; it amounts in aqueous solution in each case (in its lower limit) to about 40% for the various possibilities which exist for the formation of these chelates in the cis-(NH(3))(2)Pt(dG)(2) complexes. The stability constants of the mixed metal ion complexes, M[Pt(H;dG)(dG)](+) and M[Pt(dG)(2)], were also determined via potentiometric pH titrations. On the basis of previous measurements with simple phosphate monoesters and phosphonate derivatives, i.e., R-PO(3)(2)(-) with R being a noncoordinating residue (Sigel, H.; et al., Helv. Chim. Acta 1992, 75, 2634-2656), it is shown that the stability of the two mixed metal ion complexes is largely governed by the basicity of the phosphate groups (as quantified via the mentioned microconstants) indicating that the effect of the N7-bound Pt(II) on the phosphate-metal ion binding properties is relatively small. These results suggest that, e.g., a metal ion bound to a nucleobase residue in a nucleotide or in a nucleic acid affects only slightly the metal ion binding capabilities of its phosphate residue or its phosphate backbone.

Journal Article↗
PubMed1993

Montmorillonite catalysis of RNA oligomer formation in aqueous solution. A model for the prebiotic formation of RNA.

Oligomers of adenylic acid of up to the 11-mer in length are formed by the reaction of the phosphorimidazolide of adenosine (ImpA) in pH 8 aqueous solution at room temperature in the presence of Na(+)-montmorillonite. These oligomers are joined by phosphodiester bonds in which the 3',5'-linkage predominates over the 2',5'-linkage by a 2:1 ratio. Reaction of a 9:1 mixture of ImpA, A5'ppA results in the formation of oligomers with a 3:1 ratio of 3',5'- to 2',5'-linked phosphodiester bonds. A high proportion of these oligomers contain the A5'ppA grouping. A5'ppA reacts much more rapidly with ImpA than does 5'-ADP (ppA) or 5'-ATP (pppA). The exchangeable cation associated with the montmorillonite effects the observed catalysis with Li+, Na+, NH4+, and Ca2+ being the more effective while Mg2+ and Al3+ are almost ineffective catalysts. 2',5'-Linked oligomers, up to the tetramer in length, are formed using UO2(2+)-montmorillonite. The structure analysis of individual oligomer fractions was performed by selective enzymatic and KOH hydrolytic studies followed by HPLC analysis of the reaction products. It is concluded from the composition of the oligomers that the rate of addition ImpA to a 3'-terminus containing a 2',5'-linkage is slower than the addition to a nucleoside joined by a 3',5'-linked phosphodiester bond. The potential importance of mineral catalysis of the formation of RNA and other oligomers on primitive Earth is discussed.

Adenosine Monophosphate↗
PubMed1994

Effect of phosphate activating group on oligonucleotide formation on montmorillonite: the regioselective formation of 3',5'-linked oligoadenylates.

The effects of amine structure on the montmorillonite-catalyzed oligomerization of the 5'-phosphoramidates of adenosine are investigated. 4-Aminopyridine derivatives yielded oligoadenylates as long as dodecamers with a regioselectivity for 3',5'-phosphodiester bond formation averaging 88%. Linear and cyclic oligomers are obtained and no A5'ppA-containing products are detected. Oligomers as long as the hexanucleotide are obtained using 2-aminobenzimidazole as the activating group. A predominance of pA2'pA is detected in the dimer fraction along with cyclic 3',5'-trimer; no A5'ppA-containing oligomers were detected. Little or no oligomer formation was observed when morpholine, piperidine, pyrazole, 1,2,4-triazole, and 2-pyridone are used as phosphate-activating groups. The effects of the structure of the phosphate activating group on the oligomer structure and chain lengths are discussed.

4-Aminopyridine↗
PubMed2001

Kinetic analysis of the stepwise formation of a long-range DNA interstrand cross-link by a dinuclear platinum antitumor complex: evidence for aquated intermediates and formation of both kinetically and thermodynamically controlled conformers.

Reported here is a detailed study of the kinetics and mechanism of formation of a 1,4 GG interstrand cross-link by [(trans-PtCl(NH(3))(2))(2)(mu-NH(2)(CH(2))(n)NH(2))](2+) (1,1/t,t (n = 6), 1), the prototype of a novel class of platinum antitumor complexes. The reaction of the self-complementary 12-mer duplex 5'-[d(ATATGTACATAT)(2)] with (15)N-1 has been studied at 298 K, pH 5.4, by [(1)H,(15)N] HSQC 2D NMR spectroscopy. Initial electrostatic interactions with the duplex are observed for 1 and the monoaqua monochloro species (2). Aquation of 1 to yield 2 occurs with a pseudo-first-order rate constant of (4.15 +/- 0.04) x 10(-5) s(-1). 2 then undergoes monofunctional binding to the guanine N7 of the duplex to form 3 (G/Cl) with a rate constant of 0.47 +/- 0.06 M(-(1) s(-1). There is an electrostatic interaction between the unbound [PtN(3)Cl] group of 3 and the duplex, which is consistent with H-bonding interactions observed in the molecular model of the monofunctional (G/Cl) adduct. Closure of 3 to form the 1,4 GG interstrand cross-link (5) most likely proceeds via the aquated (G/H(2)O) intermediate (4) (pseudo-first-order rate constant = (3.62 +/- 0.04) x 10(-5) s(-1)) followed by closure of 4 to form 5 (rate constant = (2.7 +/- 1.5) x 10(-3) s(-1)). When closure is treated as direct from 3 (G/Cl) the rate constant is (3.39 +/- 0.04) x 10(-5) s(-1). Closure is ca. 10-55-fold faster than that found for 1,2 GG intrastrand cross-link formation by the diaqua form of cisplatin. Changes in the (1)H and (15)N shifts of the interstrand cross-link 5 indicate that the initially formed conformer (5(i)) converts irreversibly into other product conformer(s) 5(f). The NMR data for 5(i) are consistent with a molecular model of the 1,4 GG interstrand cross-link on B-form DNA, which shows that the NH(2) protons have no contacts except with solvent. The NMR data for 5(f) show several distinct NH(2) environments indicative of interactions between the NH(2) protons and the DNA. HPLC characterization of the final product showed only one major product peak that was confirmed by ESI-FTICR mass spectroscopy to be a cross-linked adduct of (15)N-1 and the duplex. The potential significance of these findings to the antitumor activity of dinuclear platinum complexes is discussed.

Antineoplastic Agents↗
PubMed2006

Conversion of methanol into hydrocarbons over zeolite H-ZSM-5: ethene formation is mechanistically separated from the formation of higher alkenes.

The widely debated reaction mechanism for the conversion of methanol to hydrocarbons over acidic zeolite H-ZSM-5 has been investigated using isotopic labeling. The mechanistic findings for H-ZSM-5 are clearly different from those previously described at a detailed level for H-beta and H-SAPO-34 catalysts. On the basis of the current set of data, we can state that, for H-ZSM-5, ethene appears to be formed exclusively from the xylenes and trimethylbenzenes. Moreover, propene and higher alkenes are to a significant extent formed from alkene methylations and interconversions. This implies that ethene formation is mechanistically separated from the formation of higher alkenes, an insight of utmost importance for understanding and possibly controlling the ethene/propene selectivity in methanol-to-alkenes catalysis.

Journal Article↗
PubMed1996

Reactivity of Zirconocene Azametallacyclobutenes: Insertion of Aldehydes, Carbon Monoxide, and Formation of alpha,beta-Unsaturated Imines. Formation and Trapping of [Cp(2)Zr=O] in a [4 + 2] Retrocycloaddition(1).

Azametallacyclobutene Cp(2)ZrN-t-BuCEt=CEt (1) underwent an insertion reaction with CO to form the acyl complex 2 (Cp(2)Zr(N-t-BuCEtCEtCO), 67% yield). The addition of acetone to azametallacyclobutene 3 (Cp(2)Zr(NArCMeCPh), Ar = 2,6-dimethylphenyl) yielded the N-bonded enamine and O-bonded enolate complex of zirconocene 4 (Cp(2)Zr(NArCMeCPhH)(OCMeCH(2)), 76% yield). The addition of aldehydes RCOH to metallacycle 3 resulted in the insertion of the aldehyde into the Zr-C bond to form complexes Cp(2)Zr(NArCMeCPhCRHO) (8a) and Cp(2)Zr(NArCMeCPhC(i-Pr)HO (9) in 85% (R = Ph) and 73% yields, respectively. Similarly, treatment of metallacycle 10 (Cp(2)Zr(NArCEtCEt)) with benzaldehyde yielded the insertion product 11 (Cp(2)Zr(NArCEtCEtCPhHO)) in 56% isolated yield. The structure of complex 11 was confirmed by an X-ray crystallographic study. Heating the insertion products 8a and 9 led to elimination of the alpha,beta-unsaturated imines 13 and 14a (ArN=CMeCPh=CRH) in 53% and 72% yields, respectively, and the formation of oxozirconocene oligomer (Cp(2)ZrO)(n)(). The oxozirconocene monomer was trapped by dimethylzirconocene, preventing the formation of oligomer and resulting in the isolation of product 15. A kinetic study of this retrocycloaddition produced the following activation parameters: DeltaH() = 26.5 kcal/mol, DeltaS() = 3.48 eu. A Hammett sigma/rho study showed that electron-donating groups alpha to the metallacycle oxygen accelerate the retrocycloaddition (rho = -0.8).

Journal Article↗
PubMed2006

Contact formation dynamics: Mapping chemical bond formation between a molecule and a metallic probe.

We present a study that maps out chemical bond formation between a Pt-inked probe and a single 1,3-cyclohexadiene (1,3-CHD) molecule on Si(100). By separating the mechanical and electronic contributions to the current during the approach to contact, we show that there are significant forces between the probe and the C=C of the molecule and we track the relaxation of the molecule, the emergence of a chemical bond feature in the LDOS, and the quenching of specific molecular vibrations during bond formation.

Binding Sites↗
PubMedDate not supplied

Formation, stability, and rearrangements of the glutathione conjugates of butadiene monoxide: evidence for the formation of stable sulfurane intermediates.

Butadiene monoxide, a toxic metabolite of 1,3-butadiene, is a substrate for the human placental glutathione (GSH) S-transferase. The products have been identified as S-(2-hydroxy-3-buten-1-yl)glutathione (I) and S-(1-hydroxy-3-buten-2-yl)glutathione (II). S-(4-hydroxy-2-buten-1-yl)glutathione (III), which was formed chemically, was not detected. 1H NMR analysis of II was consistent with its structure, but spectra of I indicated a 1:1 equilibrium between I and the sulfurane tautomer (IVB) formed by intramolecular displacement of the hydroxyl group by the sulfur atom. The ratio of I to IVB did not change whether the spectrum was obtained at pH 3, 7, or 9 in the presence or absence of LiClO4. Incubations of I at pH 7 or 9 for 5 days at 25 degrees C or for 7 h at 50 degrees C, in the presence or absence of nucleophiles plus LiClO4, did not affect the HPLC profile of I. Storage of I at -20 degrees C for 30 weeks, reflux at pH 7.8 for 5 h in the presence of GSH, or incubations at pH 2 for 5 h at 55 degrees C in the presence of GSH or 2-mercaptoethanol, however, resulted in the conversion of I to III (10-30%). Treatment of I with H2O2 resulted in formation of the corresponding sulfoxide (V) and sulfone (VI), which blocked the formation of III. NMR and chemical reactivity studies of III indicated an initial 1:1 equilibrium between III and the five-membered ring sulfurane (VIIB) formed by intramolecular displacement of the hydroxyl group by the sulfur atom.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Stability↗
PubMed2000

Formation of N-nitrosamines and N-nitramines by the reaction of secondary amines with peroxynitrite and other reactive nitrogen species: comparison with nitrotyrosine formation.

Reactive nitrogen species, including nitrogen oxides (N(2)O(3) and N(2)O(4)), peroxynitrite (ONOO(-)), and nitryl chloride (NO(2)Cl), have been implicated as causes of inflammation and cancer. We studied reactions of secondary amines with peroxynitrite and found that both N-nitrosamines and N-nitramines were formed. Morpholine was more easily nitrosated by peroxynitrite at alkaline pH than at neutral pH, whereas its nitration by peroxynitrite was optimal at pH 8.5. The yield of nitrosomorpholine in this reaction was 3 times higher than that of nitromorpholine at alkaline pH, whereas 2 times more nitromorpholine than nitrosomorpholine was formed at pH <7.5. For the morpholine-peroxynitrite reaction, nitration was enhanced by low concentrations of bicarbonate, but was inhibited by excess bicarbonate. Nitrosation was inhibited by excess bicarbonate. On this basis, we propose a free radical mechanism, involving one-electron oxidation by peroxynitrite of secondary amines to form amino radicals (R(2)N(*)), which react with nitric oxide ((*)NO) or nitrogen dioxide ((*)NO(2)) to yield nitroso and nitro secondary amines, respectively. Reaction of morpholine with NO(*) and superoxide anion (O(2)(*)(-)), which were concomitantly produced from spermine NONOate and by the xanthine oxidase systems, respectively, also yielded nitromorpholine, but its yield was <1% of that of nitrosomorpholine. NO(*) alone increased the extent of nitrosomorpholine formation in a dose-dependent manner, and concomitant production of O(2)(*)(-) inhibited its formation. Reactions of morpholine with nitrite plus HOCl or nitrite plus H(2)O(2), with or without addition of myeloperoxidase or horseradish peroxidase, also yielded nitration and nitrosation products, in yields that depended on the reactants. Tyrosine was nitrated easily by synthetic peroxynitrite, by NaNO(2) plus H(2)O(2) with myeloperoxidase, and by NaNO(2) plus H(2)O(2) under acidic conditions. Nitrated secondary amines, e.g., N-nitroproline, could be identified as specific markers for endogenous nitration mediated by reactive nitrogen species.

Aniline Compounds↗