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Intramolecular 1,3-dipolar nitrone cycloaddition onto an enantiomerically pure ketene dithioacetal dioxide using a three-carbon tether gave the corresponding 5,5-disubstituted isoxazolidine as a single diastereomer in good yield. This reaction has been used as the key step in an asymmetric synthesis of the naturally occurring antibiotic, (-)-cispentacin. An asymmetric synthesis of 4-amino-pyrrolidine-3-carboxylic acid has also been carried out using the intramolecular nitrone cycloaddition as the stereocontrolling step.

The enantiomeric resolution of a series of 20 asymmetric sulfoxides was systematically investigated by HPLC using multimodal elution with amylose trisR(S)-1-phenylethylcarbamate], amylose tris(3,5-dimethoxyphenylcarbamate) and amylose and cellulose tris(3,5-dimethylphenylcarbamate) phases. The sulfoxide series was composed of aromatic, olefinic and ketosulfoxides, sulfinyl acids and esters. This work has shown that enantioselectivity and enantioresolution of the polysaccharide-based columns can be achieved by changing the type and composition of the mobile phase, widening the applicability of these chiral phases.

FT IR and Raman spectroscopic studies of pure diethylsulfoxide (DESO) in the liquid and in the solid states and its solutions in various solvents have been performed. Analysis of SO- and CH-stretching regions in a wide range of concentration shows that the bands may be fitted satisfactorily by considering seven components. In addition, fundamental frequencies have been assigned using ab initio calculations at the RHF/3-21G* levels. The results obtained confirm a viewpoint on a self-associative structure of DESO, and support the hypothesis of the existence of different types of intermolecular associates including both dipole-dipole and hydrogen bonding mechanisms.

S(R)()-Podolactone D (1), a new norditerpene dilactone having a methylsulfoxide moiety, was isolated from the leaves of Podocarpus macrophyllus D. Don var. maki Endl. along with known podolactone D (2, S(S)()-podolactone D). The structures and absolute configurations of compounds 1 and 2 were elucidated by spectral methods (HREIMS, IR, (1)H, (13)C, and 2D NMR) and finally confirmed by single-crystal X-ray analyses. The cytotoxic effects of compounds 1 and 2 on P388 murine leukemia cells were also examined.

Onion (Allium cepa L.) is botanically included in the Liliaceae and species are found across a wide range of latitudes and altitudes in Europe, Asia, N. America and Africa. World onion production has increased by at least 25% over the past 10 years with current production being around 44 million tonnes making it the second most important horticultural crop after tomatoes. Because of their storage characteristics and durability for shipping, onions have always been traded more widely than most vegetables. Onions are versatile and are often used as an ingredient in many dishes and are accepted by almost all traditions and cultures. Onion consumption is increasing significantly, particularly in the USA and this is partly because of heavy promotion that links flavour and health. Onions are rich in two chemical groups that have perceived benefits to human health. These are the flavonoids and the alk(en)yl cysteine sulphoxides (ACSOs). Two flavonoid subgroups are found in onion, the anthocyanins, which impart a red/purple colour to some varieties and flavanols such as quercetin and its derivatives responsible for the yellow and brown skins of many other varieties. The ACSOs are the flavour precursors, which, when cleaved by the enzyme alliinase, generate the characteristic odour and taste of onion. The downstream products are a complex mixture of compounds which include thiosulphinates, thiosulphonates, mono-, di- and tri-sulphides. Compounds from onion have been reported to have a range of health benefits which include anticarcinogenic properties, antiplatelet activity, antithrombotic activity, antiasthmatic and antibiotic effects. Here we review the agronomy of the onion crop, the biochemistry of the health compounds and report on recent clinical data obtained using extracts from this species. Where appropriate we have compared the data with that obtained from garlic (Allium sativum L.) for which more information is widely available., (Copyright 2002 John Wiley & Sons, Ltd.)

Using a mixed nitrogen/sulfur ligand possessing a single internal hydrogen bond donor (N,N-bis-2-(methylthio)ethyl-N-(6-amino-2-pyridylmethyl)amine (bmapa)), we prepared and structurally and spectroscopically characterized a series of zinc complexes possessing a single alcohol ([(bmapa)Zn(MeOH)](ClO(4))(2) (1)), formamide ([(bmapa)Zn(DMF)](ClO(4))(2) (3), [(bmapa)Zn(NMF)](ClO(4))(2) (4)), or sulfoxide ([(bmapa)Zn(DMSO)](ClO(4))(2) (7), [(bmapa)Zn(TMSO)](ClO(4))(2) (8)) ligand. X-ray crystallographic characterization was obtained for 1.MeOH, 3, 4, 7.DMSO, and 8. To enable studies of the influence of the single hydrogen bond donor amino group of the bmapa ligand on the chemistry of zinc/neutral oxygen donor binding interactions, analogous alcohol ([(bmpa)Zn(MeOH)](ClO(4))(2) (2)), formamide ([(bmpa)Zn(DMF)](ClO(4))(2) (5), [(bmpa)Zn(NMF)](ClO(4))(2) (6)), and sulfoxide ([(bmpa)Zn(DMSO)](ClO(4))(2) (9), [(bmpa)Zn(TMSO)](ClO(4))(2) (10)) complexes of the bmpa (N,N-bis-2-(methylthio)ethyl-N-(2-pyridylmethyl)amine) ligand system were generated and characterized. Of these, 2, 5, 6, and 9.2DMSO were characterized by X-ray crystallography. Solution spectroscopic methods ((1)H and (13)C NMR, FTIR) were utilized to examine the formamide binding properties of 3-6 in CH(3)CN and CH(3)NO(2) solutions. Conclusions derived from this work include the following: (1) the increased donicity of formamide and sulfoxide donors (versus alcohols) makes these competitive ligands for a cationic N/S-ligated zinc center, even in alcohol solution, (2) the inclusion of a single internal hydrogen bond donor, characterized by a heteroatom distance of approximately 2.80-2.95 A, produces subtle structural perturbations in N/S-ligated zinc alcohol, formamide, or sulfoxide complexes, (3) the heteroatom distance of a secondary hydrogen-bonding interaction involving the oxygen atom of a zinc-coordinated alcohol, formamide, and sulfoxide ligand is reduced with increasing donicity of the exogenous ligand, and (4) formamide displacement on a N/S-ligated zinc center is rapid, regardless of the presence of an internal hydrogen bond donor. These results provide initial insight into the chemical factors governing the binding of a neutral oxygen donor to a N/S-ligated zinc center.

Herein, we report the results from two experiments that are consistent with sulfoxidation and N-dealkylation involving two different enzyme substrate complexes and thus two different active oxygen species that do not interchange. The first experiment involves the use of a mutant that may increase the amount of the hydroperoxy-iron species (FeIIIO2H).1 This mutant increases the amount of sulfoxidation relative to the amount of N-dealkylation by 4-fold. In a second experiment, deuterium substitution on the N-methyl groups of substrate does not result in an increase in sulfoxidation. This later result is consistent with N-dealkylation and sulfoxidation being mediated by two different active oxygen species. While the data indicate two active oxygen species, they do not distinguish between the different possibilities for the active oxygen species.

A gas chromatographic-mass spectrometric method for the determination of S-methyl-L-cysteine sulfoxide (1), S-propyl-L-cysteine sulfoxide (2), and S-propenyl-L-cysteine sulfoxide (3), specific marker compounds in the genus Allium, is described. The target amino acids were converted to the tert-butyldimethylsilyl derivatives. The products were silylated on the amino and carboxyl groups and on an additional oxygen atom and were separated on a nonpolar capillary column. That incorporation of three tert-butyldimethylsilyl groups had occurred was verified by mass spectrometry, which gave an m/z 302 fragment as base peak (amino acid side chain eliminated ion) and m/z 436 (1), 464 (2), or 462 (3) as major peaks (tert-butyl function eliminated ion), by electron impact ionization. The detection limits for 1 and 2 under selected ion monitoring at m/z 436 (1) and m/z 464 (2), respectively, were determined to be 0.3 and 1.8 ng per injection. To clean up the analytes from the solvent extract of onion, as a representative food material, onion, the sample solution was subjected to combined solid phase extraction. The eluate from a Sep-Pak C(18) cartridge was applied to a Bond Elut SCX cartridge (H(+) form), followed by washing with 0.1 M hydrochloric acid and elution with 0.5 M ammonia. From a simulated matrix solution containing 5% sucrose, 1 and 2 were extracted quantitatively, and the detection yield was approximately 75%. The contents of 1, 2, and 3 in commercial onion were estimated to be 0.3, 3.1, and 3.0 mg, respectively, per gram of fresh weight.

The H64D/V68A and H64D/V68S mutants of Myoglobin are found to oxidize thioanisole with high enantioselectivity and reactivity. These mutants are also capable of enantioselective binding of alpha-methylbenzylamine, which mimics an expected sulfoxidation intermediate. The kinetic study of the amine binding shows that the Fe-O bond cleavage in the intermediate may be the chiral discrimination step of the sulfoxidation.

A method has been developed for the oxidation of sulfides to sulfoxides on polystyrene resin. The polystyrene bound sulfoxide may be used in Swern oxidation reactions, and the used reagent may be regenerated by oxidation with tert-butylhydrogen peroxide.

Lyophilized horseradish peroxidase (HRP) exhibits poor stereoselectivity in the sulfoxidation of thioanisole when the enzyme is either redissolved in water or suspended in organic solvents. However, when HRP is co-lyophilized in the presence of lyoprotectants or ligands, its stereoselectivity, although still low in most organic solvents, increases up to 4-fold if assayed in secondary or tertiary alcohols (but not in their linear isomers). A mechanistic hypothesis is presented explaining this puzzling phenomenon on the basis of a model of the active site of the enzyme-substrate complex derived from its X-ray crystal structure by means of molecular dynamics and energy minimization.

The C2-hydroxyglycosylation reaction employing the reagent combination of a diaryl sulfoxide and triflic anhydride offers a novel method for glycal assembly whereby a hydroxyl functionality is stereoselectively installed at the C2-position of a glycal donor with concomitant glycosylation of a nucleophilic acceptor. Mechanistic investigations into this reaction revealed a novel process for sulfonium-mediated oxidation of glycal enol ethers in which the sulfoxide oxygen atom is stereoselectively transferred to the C2-position of the glycal. (18)O-labeling studies revealed that the S-to-C2 oxygen-transfer process involves initial formation of a C1[bond]O linkage followed by O-migration to C2, leading to the generation of an intermediate glycosyl 1,2-anhydropyranoside that serves as an in situ glycosylating agent. These findings are consistent with the initial formation of a C2-sulfonium[bond]C1-oxosulfonium pyranosyl species upon activation of the glycal donor with Aryl(2)SO x Tf(2)O.

On the basis of model imidazole inhibitors of cytokine release, a series of novel pyridinyl pyrimidine derivatives was prepared and tested on their ability to inhibit the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) from peripheral blood mononuclear cells (PBMC) and human whole blood. In the pyrimidine series, structure-activity relationships (SARs) similar to those of the imidazole series were found, although generally pyrimidine compounds were less potent. Modification of the substituent at the 2 position of the pyrimidine led to the most active compound 14 which inhibited release of TNF-alpha (IC(50) = 3.2 microM) and IL-1beta (IC(50) = 2.3 microM) from PBMC as effectively as the model imidazole inhibitor ML 3163 (TNF-alpha, IC(50) = 3.7 microM; IL-1beta, IC(50) = 0.9 microM). Screening in an isolated enzyme assay revealed both imidazole and pyrimidine compounds as inhibitors of p38 MAP (mitogen-activated protein) kinase.

[reaction: see text] A novel electrochemical sulfoxide imination process is described. Our approach starts with a highly selective nitrene transfer from N-aminophthalimide to a variety of sulfoxides. This oxidative treatment is followed by reductive N-N bond cleavage under the controlled current conditions, which leads to a range of parent NH sulfoximines. In addition to solving the challenging problem of removing the N-phthalimido group, the overall process avoids the use of toxic oxidants and metal additives.

A series of four S-allyl D-thiopyranosides, alpha- and beta-manno and xylo, were oxidized with MCPBA at low temperature to give seven of the eight possible sulfoxides, whose configuration at sulfur was determined either directly by X-ray crystallography or by correlation with closely related structures. For the axial thioglycosides oxidation leads very predominantly to the (R)(S)-diastereomer in the xylo series and exclusively so in the manno series; the configuration at C2 is of little importance in determining the stereoselectivity of oxidation of axial thioglycopyranosides. In the equatorial series the configuration at C2 has a significant effect on the outcome of the reaction as, although both series favored the (S)(S)-sulfoxide, selectivity was significantly higher in the case of the beta-mannoside than of the beta-xyloside. The two alpha-xylo sulfoxides have different conformations of the pyranoside ring with the (R)(S)-isomer adopting the (1)C(4) chair and the (S)(S)-diastereomer the (4)C(1). Each pair of diastereomeric sulfoxides was thermally equilibrated in C(6)D(6) and in CD(3)OD. In the mannose series the kinetic isomers are also thermodynamically preferred. In the xylose series, on the other hand, the nature of the thermodynamic isomer in both the alpha- and beta-anomers is a function of solvent with a switch observed on going from C(6)D(6) to CD(3)OD. The results are rationalized in terms of the exo-anomeric effect, steric shielding provided by H3 and H5 in the axial series, the interaction of the C2-O2 and sulfoxide dipoles, and increased steric interactions on hydrogen bonding of the sulfoxides to CD(3)OD.

[structure: see text] The first enantioselective total synthesis of (-)-Centrolobine is described. The key reaction is the synthesis of the cis-disubstituted tetrahydropyran framework by intramolecular cyclization of the enantiopure hydroxyketone 3 with Et3SiH and TMSOTf. The stereoselective reduction of the beta-ketosulfoxide 4 is the source of chirality. Revision of the absolute configuration of (-)-Centrolobine is proposed.

Ortholithiation and reaction with (-)-menthyl p-toluenesulfinate introduces a sulfoxide substituent ortho to the stereogenic Ar-CO axis of an aromatic amide. The sulfoxide exerts a powerful conformational bias on the axis, such that after rapid equilibration at ambient temperature essentially only one of two diastereoisomeric Ar-CO atropisomers is populated. Sulfoxide-lithium exchange by treatment with t-BuLi regenerates the ortholithiated amide in an enantiomerically pure and conformationally stable form. Rapid electrophilic trapping of the organolithium therefore generates highly enantiomerically enriched atropisomeric tertiary aromatic amides. The overall process, involving temporary substitution of lithium to sulfoxide to lithium, amounts to a dynamic resolution under thermodynamic control.

The polyoxomolydate of the Keggin structure, PMo12O403-, catalyzes, under anaerobic conditions, oxygen transfer from sulfoxides to alkylarenes such as xanthene and diphenylmethane to yield xanthen-9-one and benzophenone, respectively. With use of 17O and 18O labeled phenylmethylsulfoxide it was shown that the sulfoxide is complexed by the polyoxometalate and the oxygen is transferred from the sulfoxide to the alkylarene. There is a good correlation between the reaction rate and the heterolytic benzylic C-H bond energy indicating a hydride transfer reaction from the alkylarene to the polyoxometalate-sulfoxide complex. In the case of triphenylmethane the resulting carbocation reacts to yield 9-phenylfluorene as the major product. The reaction kinetics supports such a reaction pathway.

Methods are described for the synthesis of the 2'-tributylstannyl derivative of 2',3'-didehydro-2',3'-dideoxyuridine (d4U). Two approaches were investigated: radical-mediated desulfonylative stannylation of the 2'-benzenesulfonyl derivative of d4U and sulfoxide-metal exchange reaction of the 2'-benzenesulfinyl derivative. The latter approach was found to give the desired 2'-stannyl derivative in good yield. It was also shown that manipulations of the stannyl group allowed the introduction of a variety of carbon-substituents to the 2'-position by applying the Stille reaction. The whole reaction sequence has opened up a highly general entry to 2'-carbon-substituted analogues of d4U.

The oxidation of a series of para-substituted phenyl methyl sulfides was carried out with several oxo(salen)iron (salen = N,N'-bis(salicylidine)ethylenediaminato) complexes in acetonitrile. The oxo complex [O=Fe(IV)(salen)](*+), generated from an iron(III) [bond] salen complex and iodosylbenzene, effectively oxidizes the organic sulfides to the corresponding sulfoxides. The formation of [O [double bond] Fe(IV)(salen)](*+) as the active oxidant is supported by resonance Raman studies. The kinetic data indicate that the reaction is first-order in the oxidant and fractional-order with respect to sulfide. The observed saturation kinetics of the reaction and spectral data indicate that the substrate binds to the oxidant before the rate-controlling step. The rate constant (k) values for the product formation step determined using Michaelis-Menten kinetics correlate well with Hammett sigma constants, giving reaction constant (rho) values in the range of -0.65 to -1.54 for different oxo(salen)iron complexes. The log k values observed in the oxidation of each aryl methyl sulfide by substituted oxo(salen)iron complexes also correlate with Hammett sigma constants, giving positive rho values. The substituent effect, UV-vis absorption, and EPR spectral studies indicate oxygen atom transfer from the oxidant to the substrate in the rate-determining step.

Peroxoiron species have been proposed to be involved in catalytic cycles of iron-dependent oxygenases and in some cases as the active intermediates during oxygen-transfer reactions. The catalytic properties of a mononuclear iron complex, [Fe(II)(pb)(2)(CH(3)CN)(2)] (pb=(-)4,5-pinene-2,2'-bipyridine), have been compared to those of its related dinuclear analogue. Each system generates specific peroxo adducts, which are responsible for the oxidation of sulfides to sulfoxides. The dinuclear catalyst was found to be more reactive and (enantio)selective than its mononuclear counterpart, suggesting that a second metal site affords specific advantages for stereoselective catalysis. These results might help for the design of future enantioselective iron catalysts.

The synthesis of cis-monochloro(dimethylsulfoxide)(metforminuro) platine(II) was investigated. It crystallizes in the monoclinic system, space group P 2(1)/c with Z=4. The cell parameters are: a=9.173(2); b=11.286( 2); c=12.556( 3) (A); b=99.69(2) degrees. The structure of this compound was refined to R=0.031 and wR=0.038 using 1461 independent reflexions with I>3 s(I). The platinum coordination is square planar, built up from one Cl, one O from the dimethylsulfoxide, and one bidentate chelating ligand (metforminure anion) via the two imine nitrogen atoms in cis position. The negative charge of the metforminure ligand ensures the electric neutrality in the complex. The crystal packing is characterized by four hydrogen bonds, one of which is bifurcated (involving Cl atom (intramolecular bonding) and O(i) (intermolecular bonding; symmetry code i: x, 3/2-y; 1/2+z).

New chiral sulfoxide-1,3-oxazoline ligands have been developed as chiral ligands for Lewis acid-catalyzed asymmetric Diels-Alder reactions. The use of chiral sulfinyl 1,3-oxazoline ligands in copper(II)-catalyzed asymmetric Diels-Alder reactions provided an endo cycloadduct as a major product with moderate enantioselectivity. A rationale is proposed for the mechanism of the asymmetric induction.

Horseradish peroxidase exhibits a meager stereoselectivity (E) in the sulfoxidation of thioanisole (1a) in 99.8% (v/v) methanol. The E value, however, is greatly enhanced when the enzyme forms a complex with benzohydroxamic acid (2a). These findings are rationalized by means of molecular dynamics simulations and energy minimization which correctly explain (i) why the free enzyme is not stereoselective, (ii) why 2a inhibits peroxidase-catalyzed sulfoxidation of 1a but the enzymatic formation of one enantiomer of the sulfoxide product is inhibited much more than that of the other, thereby raising peroxidase's E, and (iii) why in the presence of 2a the enzyme favors production of the S sulfoxide of 1a. The generality of the observed ligand-induced stereoselectivity enhancement is demonstrated with other hydrophobic hydroxamic acids, as well as with additional thioether substrates.

In conformational analysis, the systematic search method completely maps the space but suffers from the combinatorial explosion problem because the number of conformations increases exponentially with the number of free rotation angles. This study introduces a new methodology of conformational analysis that controls the combinatorial explosion. It is based on a dimensional reduction of the system through the use of principal component analysis. The results are exactly the same as those obtained for the complete search but, in this case, the number of conformations increases only quadratically with the number of free rotation angles. The method is applied to a series of three drugs: omeprazole, pantoprazole, lansoprazole-benzimidazoles that suppress gastric-acid secretion by means of H+, K+-ATPase enzyme inhibition.

Previous models for mechanisms of enzymatic sulfoxidation have been somewhat limited by a lack of knowledge of the essential features of substrate-enzyme versus product-enzyme relationships. Computerized methods for modeling ligand-protein (substrate-enzyme) interactions can overcome some of these limitations. Specifically, CoMFA (comparative molecular field analysis) provided a useful general approach in which to evaluate substrate-enzyme and product-enzyme relationships. The present investigation examined the relationship between substrate and product structure in predicting enantioselective sulfoxidation reactions using CoMFA for two species of microorganisms that have been used as models for mammalian metabolism, Mortierella isabellina and Helminthosporium sp. The overall enantioselectivity observed was based on the composite stereoselectivity of sulfoxide formation, sulfone formation (from the sulfoxide), and sulfoxide reduction back to the achiral substrate (sulfide).

Patients with complications of peptic ulcers, high grade reflux oesophagitis, or Zollinger Ellison syndrome need a sufficient permanent acid suppression. In appropriate indications they receive proton pump inhibitors (PPI) intravenously or via perfusion over a longer period, if an oral application is not possible. PPIs are prodrugs, which should be converted into the active principle in the acidic canaliculus at pH 1 of the parietal cell. Otherwise they would be activated prematurely. Immediate chemical degradation causes discolouration. Aim of the study was to compare pH stabilities of the intravenous formulations of Omeprazole (different solutions for infusion and injection) and Pantoprazole (one solution for injection and infusion). The solutions prepared accordingly to the official instructions, were exposed to four different light conditions. Both manufacturers (AstraZeneca Osterreich GmbH, Byk Osterreich Pharma Ges.m.b.H.) state reference solutions for acceptable discolouration. Those were prepared according to the European Pharmacopeia. Discolouration of solutions were evaluated as criterion for stability of the PPI prodrugs. If change of colour is at least of the extent of the corresponding reference solution, further use is no longer permitted. Optical alterations under different light conditions were compared and documented photographically with standardized illumination. Intensity and spectral composition of light as well as temperature had only minor influence on discolouration as measure of degradation of the prodrugs. Both formulations for injection fulfill the specifications for pH stability within the stated time frames mentioned in the summaries of product characteristics (SPC). Comparing both products, after a short period (1 hour) Omeprazole injectable formulation showed a substantial optical discolouration. After 6 hours these changes were more intense than the reference solution BG5 allows. Pantoprazole showed optical alteration to a notable later time point. After 24 hours discolouration reached the reference colour B6. Injectable formulation of Pantoprazole is about three times more stable than that of Omeprazole. Infusion solution of Omeprazole shows no optical alteration within the stated time frame due to high dilution and pH value. Assuming that 100 ml of the infusion solution contains 40 mg Omeprazole. It takes 5 hours for the volume to be infused at a dose regimen of 8 mg/h. Therefor 5 x 100 ml/24 h are needed.

Simple high performance liquid chromatography (HPLC) methods for the analysis of 4-chlorophenyl methyl sulphide (CPMS), diphenyl sulphide (DPS) and their corresponding sulphoxide and sulphone metabolites in rat liver microsomes are described. The assay methods are based on a reversed phase HPLC column (Spherisorb(R) 5 ODS, 15 x 0.46 cm) using a mixture of water and tetrahydrofuran (THF) as mobile phase at a flow rate of 0.5 ml/min and ultraviolet detection at 260 nm. The compounds were extracted into diethyl ether (2 x 5 ml) from rat liver microsomal incubation mixture (2 ml) and the recoveries were more than 80%. The calibration curves for determining the sulphoxide and sulphone of CPMS or DPS were linear (r > or =0.995) in the range of 0-50 microg/ml and the assays were reproducible with low inter- and intra-assay variation of less than 13.5%. The lower limit of quantitation (LOQ) was 0.1 microg/ml for CPMSO and 0.025 microg/ml for CPMSO(2), diphenyl sulphoxide (DPSO) and diphenyl sulphone (DPSO(2)). The HPLC methods were successfully applied to measure enzymically formed CPMSO, CPMSO(2), DPSO and DPSO(2) in rat liver microsomes and to characterise the Michaelis-Menten kinetics associated with the metabolism of CPMS and DPS and their corresponding sulphoxides. About 20% of the initial CPMS (0.5 mM) concentration in the incubation was converted to the sulphoxide although the sulphone was not detected under these optimum incubation conditions. Similarly, about 15-20% of DPS was converted to the sulphoxide while less than 0.1% of DPS was converted to DPSO(2). Eadie-Hofstee plot of CPMS sulphoxidation was biphasic. This suggests that the sulphoxidation of CPMS is a consequence of at least two enzyme systems, one characterized by low affinity and high capacity (K(m)=0.1 mM; V(max)=2.1 nmoles/mg protein/min) and the other by high affinity and low capacity (K(m)=0.05 mM; V(max)=1.5 nmoles/mg protein/min). On the other hand, the Eadie-Hofstee plot of DPS sulphoxidation was monophasic with an apparent V(max) and K(m) of 1.8 nmoles/mg protein/min and 0.036 mM, respectively.

The one-electron oxidation of methionine (Met) plays an important role in the redox reactions of Met in peptides and proteins under conditions of oxidative stress, e.g., during the metal-catalyzed oxidation of beta-amyloid peptide (beta A). However, little information is available with regard to mechanisms and product formation during the metal-catalyzed oxidation of Met. Here, we demonstrate that two-electron oxidation of Met in Fenton reactions, carried out aerobically by [Fe(II)(EDTA)](2-) and H(2)O(2) (EDTA = ethylenediaminetetra acetate) is the consequence of two consecutive one-electron transfer reactions carried out by either free or complexed hydroxyl radicals, followed by the reaction of an intermediary sulfur-nitrogen bonded radical cation (sulfuranyl radical) with O(2). The model peptide Met-Met represents an ideal substrate for these investigations as its one-electron oxidation, followed by reaction with molecular oxygen, produces unique intermediates, azasulfonium diastereomers, which can be chemically isolated before hydrolysis to sulfoxide occurs.

Exploration of the SAR around selective NK2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK1 and NK2 antagonists. ZD6021 inhibited binding of [3H]-NKA or [3H]-SP to human NK1 and NK2 receptors, with high-affinity (K(i)=0.12 and 0.62nM, respectively). In functional assays ZD6021 had, at 10(-7)M, in human pulmonary artery pK(B)=8.9 and in human bronchus pK(B)=7.3, for NK1 and NK2, respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED(50)=0.5mg/kg, and NK2 mediated bronchoconstriction, ED(50)=13mg/kg.

[reaction: see text]. Treatment of the allenyl sulfoxides and sulfones possessing a proper delta-hydroxy appendage at the C-1 position with potassium tert-butoxide effected endo mode ring closure at the sp-hybridized carbon center of the allenyl moiety to provide the five- to eight-membered oxacycles in high yields.

The rhenium(V) monooxo complexes (hoz)2Re(O)Cl (1) and [(hoz)2Re(O)(OH2)][OTf] (2) have been synthesized and fully characterized (hoz = 2-(2'-hydroxyphenyl)-2-oxazoline). A single-crystal X-ray structure of 2 has been solved: space group = P1, a = 13.61(2) A, b = 14.76(2) A, c = 11.871(14) A, alpha = 93.69(4) degrees, beta = 99.43(4) degrees, gamma = 108.44(4) degrees, Z = 4; the structure was refined to final residuals R = 0.0455 and Rw = 0.1055. 1 and 2 catalyze oxygen atom transfer from aryl sulfoxides to alkyl sulfides and oxygen-scrambling between sulfoxides to yield sulfone and sulfide. Superior catalytic activity has been observed for 2 due to the availability of a coordination site on the rhenium. The active form of the catalyst is a dioxo rhenium(VII) intermediate, [Re(O)2(hoz)2]+ (3). In the presence of sulfide, 3 is rapidly reduced to [Re(O)(hoz)2]+ with sulfoxide as the sole organic product. The transition state is very sensitive to electronic influences. A Hammett correlation plot with para-substituted thioanisole derivatives gave a reaction constant rho of -4.6 +/- 0.4, in agreement with an electrophilic oxygen transfer from rhenium. The catalytic reaction features inhibition by sulfides at high concentrations. The equilibrium constants for sulfide binding to complex 2 (cause of inhibition), K2 (L x mol(-1)), were determined for a few sulfides: Me2S (22 +/- 3), Et2S (14 +/- 2), and tBu2S (8 +/- 2). Thermodynamic data, obtained from equilibrium measurements in solution, show that the S=O bond in alkyl sulfoxides is stronger than in aryl sulfoxides. The Re=O bond strength in 3 was estimated to be about 20 kcal x mol(-1). The high activity and oxygen electrophilicity of complex 3 are discussed and related to analogous molybdenum systems.

Trans complexes such as trans-[PtCl(2)(NH(3))(2)] have historically been considered therapeutically inactive. The use of planar ligands such as pyridine greatly enhances the cytotoxicity of the trans geometry. The complexes trans-[PtCl(R'R''SO)(A)(2)]NO(3) (R'R''SO = substituted sulfoxides such as dimethyl (Me(2)SO), methyl benzyl (MeBzSO), and methyl phenyl sulfoxide (MePhSO) and A = NH(3), pyridine (py) and 4-methylpyridine or picoline (pic)) were prepared for comparison of the chemical reactivity between ammine and pyridine ligands. The X-ray crystal structure determination for trans-[PtCl(Me(2)SO)(py)(2)]NO(3) confirmed the geometry with S-bound Me(2)SO. The crystals are orthorhombic, space group P2(1)2(1)2(1), with cell dimensions a = 7.888(2) A, b = 14.740(3) A, c =15.626(5) A, and Z = 4. The geometry around the platinum atom is square planar with l(Pt-Cl) = 2.304(4) A, l(Pt-S) = 2.218(5) A, and l(Pt-N) = 2.03(1) and 2.02(1) A. Bond angles are normal with Cl-Pt-S = 177.9(2) degrees, Cl-Pt-N(1) = 88.0(4) degrees, Cl-Pt-N(2) = 89.3(5) degrees, S-Pt-N(1) = 93.8(4) degrees, S-Pt-N(2) = 88.9(4) degrees, and N(1)-Pt-N(2) = 177.2(6) degrees. The intensity data were collected with Mo Kalpha radiation with lambda = 0.710 69 A. Refinement was by full-matrix least-squares methods to a final R value of 3.80%. Unlike trans-[PtCl(2)(NH(3))(2)], trans-[PtCl(2)(A)(2)] (A = py or pic) complexes do not react with Me(2)SO. The solvolytic products of cis-[PtCl(2)(A)(2)] (A = py or pic) were characterized. Studies of displacement of the sulfoxide by chloride were performed using HPLC. The sulfoxide was displaced faster for the pyridine complex relative to the ammine complex. Chemical studies comparing the reactivity of trans-[PtCl(R'R''SO)(amine)(2)]NO(3) with a model nucleotide, guanosine 5'-monophosphate (GMP), showed that the reaction gave two principal products: the species [Pt(R'R''SO)(amine)(2)(N7-GMP)], which reacts with a second equivalent of GMP, forming [Pt(amine)(2)(N7-GMP)(2)]. The reaction pathways were different, however, for the pyridine complexes in comparison to the NH(3) species, with sulfoxide displacement again being significantly faster for the pyridine case.

C-Glycosides derived from alpha-L-fuco-, alpha-D-gluco-, beta-D-gluco-, and alpha-D-mannopyranose have been synthesized from the corresponding glycosyl phenyl sulfoxide through phenylsulfinyl-lithium exchange, to generate an anomeric carbanion, and subsequent reaction with a carbon electrophile. The reactions were stereospecific and proceeded with retention of the configuration at the anomeric center. Improved yields of C-glycosides were obtained by an inverse addition protocol. Trapping of the anomeric carbanion with aldehydes gave best results. Reaction with ketones, chloroformates, nitriles, and alkyl halides was also explored. Mechanistic aspects of the reaction are discussed.

While excellent methods exist for the oxidation of sulfides to sulfoxides R1R2S-->R1R2SO, the azaversion of this atom transfer redox process, i.e., R1R2S-->R1R2S=N-SO2R3, has been less reliable. In sulfilimine synthesis, sulfoxide has been an inevitable byproduct in all cases to date, and the yields of sulfilimine have varied widely. A nearly ideal procedure for the sulfide to sulfonyl sulfilimine transformation is described. Almost quantitative yields are achieved from a diverse set of sulfides and a broad range of the readily available sulfonyl nitrenoid sources known as chloramine salts (R3SO2NClNa), essentially by simply stirring them together in acetonitrile.

Mid-infrared vibrational unpolarised absorption and vibrational circular dichroism (VCD) spectra of CCl4 solutions of tert-butyl methyl sulfoxide (1) are reported. The spectra are compared to ab initio density functional theory (DFT) calculations carried out using two functionals, B3PW91 and B3LYP, and two basis sets, 6-31G* and TZ2P. The VCD spectra are calculated using Gauge-invariant atomic orbitals (GIAOs). The analysis of the VCD spectrum confirms the R(-)/S(+) absolute configuration of 1. The advantages and disadvantages of VCD spectroscopy in determining the absolute configurations of chiral sulfoxides are discussed.

alpha-Aminoalkylcuprates prepared from alpha-lithio carbamates and CuCN.2LiCl participate in 1,4-addition reactions with alpha, beta-unsaturated esters, thiol esters, imides, and nitriles in poor to excellent yields depending upon the electron-withdrawing substituent and the substitution pattern of the unsaturated substrate. These reagents also undergo conjugate addition reactions with alpha,beta-alkynyl esters, sulfoxides, and nitriles and with alpha,beta-beta,gamma-unsaturated allenyl esters. Excellent stereocontrol is achieved in the conjugate additions of alpha-aminoalkylcuprates to the allenyl esters, while poor stereoselectivity results in the conjugate additions to the alkynyl derivatives. Deprotection and cyclization of the alkynyl adducts affords pyrrolin-2-ones, while similar treatment of the allenyl adducts affords 4-alkylidine- pyrrolidin-2-ones and pyrrolizidinones.

The synthesis and biological activity of a series of 2-[(4-methylthiopyridin-2-yl)methylsulfinyl]benzimidazoles are described. These compounds have potent inhibitory effects against the protein tyrosine phosphatase activity of CD45. Enzymatic analysis with several phosphatases revealed that compound 5a had high specificity for CD45 compared with serine/threonine phosphatases (PP1, PP2A), tyrosine phosphatases (LAR, PTP1B and PTP-S2) and dual phosphatase (VHR).

Carbonate radical (*CO3-) is a selective oxidant that may be important in limiting the persistence of a number of sulfur-containing compounds in sunlit natural waters. Thioanisole, dibenzothiophene (DBT), and fenthion were selected to investigate the degradation pathway initiated by *CO3-; electron-rich sulfur compounds are particularly reactive towards the *CO3-. Using HPLC, GC, GC-MS and LC-MS for structural confirmation, the major photodegradation products of thioanisole and DBT were the corresponding sulfoxides. The sulfoxide products were further oxidized through reaction with *CO3- to the corresponding sulfone derivatives. Fenthion showed a similar pathway with appearance of fenthion sulfoxide as the major product. The proposed mechanism involves abstraction of an electron on sulfur to form a radical cation, which is then oxidized by dissolved oxygen. Each of the sulfur probes were further investigated in a sunlight simulator under varying matrix conditions. The highest rate constants occurred in the *CO3- matrix, and the lowest occurred in a matrix of dissolved organic carbon (DOC) and bicarbonate. In synthetic and natural field water, thioanisole photodegraded faster than under direct photolysis, with half-lives of 75.1 and 85.8 min, respectively. Fenthion photodegraded more rapidly than thioanisole. DBT photodegraded rapidly in a *CO3- matrix with a half-life of 24.8 min, while the half-life of direct photolysis was 350 min. Photodegradation products of each compound were also investigated. Ultimately, *CO3- was found to contribute toward the photodegradation of sulfur-containing compounds in natural waters.

The thionium ions 10 generated by Pummerer reaction of N-aryl-N-methyl-3-(phenylsulfinyl)propionamides 4 caused not only an electrophilic cyclization reaction producing 2-quinolones 8, but also the formation of the vinyl sulfides 5 and 6 in favor of the latter reaction. On the other hand, the treatment of the vinyl sulfides 5 and 6 with p-toluenesulfonic acid induced cyclization to afford the 2-quinolones 8 in excellent to moderate yields, depending on the electronic properties of the aromatic ring, thus providing a convenient method for the synthesis of methoxy-2-quinolones.

Peroxidase-catalyzed asymmetric sulfoxidations, while synthetically attractive, suffer from relatively low reaction rates due to poor substrate solubilities in water and from appreciable spontaneous oxidation of substrates (especially aryl alkyl sulfides) with H(2)O(2). In this work, we found that both of these shortcomings could be alleviated by switching from aqueous solutions to certain nearly anhydrous (99.7%) organic solvents as sulfoxidation reaction media. The rates of spontaneous oxidation of the model prochiral substrate thioanisole in several organic solvents were observed to be some 100- to 1000-fold slower than in water. In addition, the rates of asymmetric sulfoxidation of thioanisole in isopropyl alcohol and in methanol catalyzed by horseradish peroxidase (HRP) were determined to be tens to hundreds of times faster than in water under otherwise identical conditions. This dramatic activation is due to a much higher substrate solubility in organic solvents than in water and occurs even though the intrinsic reactivity of HRP in isopropyl alcohol and in methanol is hundreds of times lower than in water. Sulfoxidation of thioanisole catalyzed by four other hemoproteins (soybean peroxidase, myoglobin, hemoglobin, and cytochrome c) is also much faster in isopropyl alcohol than in water., (Copyright 2000 John Wiley & Sons, Inc. Biotechnol Bioeng 70: 353-357, 2000.)

A series of diaryl and alkylaryl sulfoxide-containing nitrogen mustards were synthesized and evaluated for their hypoxia-selective cytotoxicity against V-79 cells in vitro as well as for their metabolism profiles with the rat S-9 fractions. In general, the diaryl sulfoxides (4, 5, and 7-9) showed much greater hypoxia selectivity (11-27-fold) than the alkylaryl sulfoxides (approximately 3-fold) (1 and 3). The fused diphenyl sulfoxides (10 and 11), on the other hand, showed very low hypoxia selectivity (1.3-3-fold). Compound 10 was highly cytotoxic under both aerobic and anaerobic conditions, while 11 showed low cytotoxicity under both conditions. The bioreduction of 8 by the rat S-9 fraction under anaerobic conditions was inhibited by menadione and enhanced by benzaldehyde, acetaldehyde, or 2-hydroxypyrimidine suggesting the involvement of aldehyde oxidase in the reduction of the sulfoxides. Bioreductive metabolism studies of selected model sulfoxides suggested that diaryl sulfoxides are better substrates for aldehyde oxidase than alkylaryl sulfoxides.

Two short and convergent routes have been devised for the preparation of enantiomerically pure acyclic epoxy vinyl sulfoxides. These substrates undergo highly regio- and stereoselective S(N)2' displacements with lithium cyanocuprates to give alpha'-alkylated, gamma-oxygenated Z alpha,beta-unsaturated sulfoxides in moderate to good yields and with good to excellent diastereoselectivities. The absolute configuration of the newly formed carbon-carbon bond is primarily controlled by the chiral sulfur atom, which in a nonreinforcing situation can override the intrinsic anti tendency of the vinyl oxirane moiety and forces the cuprate to undergo syn addition. The hydroxy vinyl sulfoxide functionality of the resulting adducts should allow for subsequent asymmetric transformations thus enhancing the synthetic usefulness of this methodology.

The flavor precursors of 17 species belonging to the Alliaceae family were analyzed by HPLC, and results were evaluated with respect to the classification of species into their genus, subgenus, and section. Identification and quantification of these precursors were carried out by synthetic and natural reference materials. In addition, nine of these species were investigated in terms of their alliinase activity. Alliinase (EC 4.4.1.4) catalyzes the conversion of odorless (+)-S-alk(en)yl-L-cysteine sulfoxides into volatile thiosulfinates. Cysteine sulfoxides as well as alliinase activity were found in all investigated samples, and (+)-S-methyl-L-cysteine sulfoxide was most abundant. (+)-S-Propyl-L-cysteine sulfoxide was detected in only a few, not closely related, species. Analysis of the crude protein extract of nine species gave evidence that alliinase activities of samples were similar in terms of pH and temperature optimum, K(M) value, and substrate specificity. For all investigated protein extracts, the highest specific alliinase activity was found for (+)-S-(2-propenyl)-L-cysteine sulfoxide (alliin). The substrate specificity of these enzymes was not related to relative abundance of the cysteine sulfoxides. However, SDS-PAGE yielded some significant differences among species in terms of their total protein compositions. Species belonging to different subgenera exhibited a specific protein pattern with molecular masses between 13 and 35 kDa.

Approaches to the rational design of vanadium-based semi-synthetic enzymes and biomimetic models as catalysts for enantioselective oxidations are reviewed. Incorporation of vanadate ion into the active site of phytase (E.C. 3.1.3.8), which in vivo mediates the hydrolysis of phosphate esters, afforded a semi-synthetic peroxidase. It catalyzed the enantioselective oxidation of prochiral sulfides with H2O2 affording the S-sulfoxide, e.g. in 66% ee at quantitative conversion of thioanisole. Under the reaction conditions the semi-synthetic vanadium peroxidase was stable for more than 3 days with only a slight decrease in turnover frequency. Amongst the transition-metal oxoanions that are known to be potent inhibitors of phosphatases, only vanadate resulted in a semi-synthetic peroxidase when incorporated into phytase. In a biomimetic approach, vanadium complexes of chiral Schiff base complexes were encapsulated in the super cages of a hydrophobic zeolite Y. Unfortunately, these ship-in-a-bottle complexes afforded only racemic sulfoxide in the catalytic oxidation of thioanisole with H2O2.

The Pummerer reaction of imidosulfoxides bearing tethered alkenyl groups has been employed for the synthesis of several alkaloids. The required imidosulfoxides necessary for the cascade sequence were easily obtained by heating the appropriate amide with (ethylsulfeny)acetyl chloride followed by sodium periodate oxidation. The initially formed thionium ion, obtained by treating the imidosulfoxide with acetic anhydride and p-toluenesulfonic acid, reacts with the neighboring imido group, and the resulting oxonium ion undergoes subsequent deprotonation to produce an isomünchnone dipole. This mesoionic betaine intermediate undergoes ready intramolecular dipolar cycloaddition across the neighboring pi-bond. Exposure of the resulting cycloadducts to additional acetic anhydride leads to ring opening and formation of a 5-acetoxy-substituted 2(1H)-pyridone. This six-ring heterocyclic system constitutes a valuable building block for the synthesis of a variety of pyridine, quinolizidine, and clavine alkaloids. The cyclization-deprotonation-cycloaddition cascade has been successfully applied to the synthesis of the naturally occurring alkaloids onychnine, dielsiquinone, (+/-)-lupinine, (+/-)-anagyrine, (+/-)-pumiliotoxin C, and (+/-)-costaclavine.

BOF-4272, (+/-)-8-(3-methoxy-4- phenylsulfinylphenyl)pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one, is a new drug intended for the treatment of hyperuricemia. This report describes the detailed metabolic pathways of BOF-4272 in the dog. The metabolic pathways were investigated using the metabolites found in plasma, urine, and feces after intravenous or oral administration of BOF-4272, as well as the metabolites found in the liver S9 incubation mixture after the addition of BOF-4272 or BOF-4269. BOF-4269 (the sulfide metabolite of BOF-4272) was the only metabolite detected in plasma and feces after the intravenous or oral administration of BOF-4272. BOF-4269 was detected in dog plasma after a lag time following the oral administration of BOF-4272, and the Cmax and AUC0-t of BOF-4269 were higher in fed dogs than in fasted dogs after the oral administration of BOF-4272. A small amount of BOF-4269 was detected in dog plasma immediately after the intravenous administration of BOF-4272. Only BOF-4276 (the sulfone metabolite of BOF-4272) was detected in the S9 incubation mixture after the addition of BOF-4272. Mainly BOF-4272 was detected and small amounts of BOF-4276 and M-1 (the hydroxy metabolite of BOF-4269) were detected in the S9 incubation mixture after the addition of BOF-4269. These findings suggest that BOF-4272 is mainly metabolized to BOF-4269 by the intestinal flora in dogs, whereas little of this drug is metabolized to BOF-4269 in the dog liver. In conclusion, this work has allowed us to formulate the proposed metabolic pathways of BOF-4272 in the dog.