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At least 19 recordsLinked to original sources
PubMed1997

Evidence for thiol-dependent production of oxygen radicals by 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz) and 3H-1,2-dithiole-3-thione: possible relevance to the anticarcinogenic properties of 1,2-dithiole-3-thiones.

1,2-Dithiole-3-thiones are an important class of anticarcinogens that selectively induce cellular production of chemoprotective phase II detoxification enzymes. It is important to identify chemical properties of anticarcinogens that are responsible for this enzyme induction. Previously, the ability of 1,2-dithiole-3-thiones to induce phase II enzymes has been attributed to their electrophilic character. We report here that the anticarcinogenic 1,2-dithiole-3-thiones, oltipraz (4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione, 1) and 3H-1,2-dithiole-3-thione (2), in conjunction with thiols, including the biological thiol glutathione, mediate the conversion of molecular oxygen to reactive oxygen radicals. Using a plasmid-based assay that monitors DNA cleavage, we find that 1 and 2, at micromolar concentrations, efficiently cleave DNA and that this cleavage can be suppressed by removal of molecular oxygen, addition of radical scavenging agents (mannitol, methanol, ethanol, and dimethyl sulfoxide), chelators of adventitious trace metals, and the peroxide-destroying enzyme catalase. Taken together, our data suggest that, in these reactions, molecular oxygen is converted to a peroxide species that undergoes a trace metal-catalyzed, Fenton-type reaction to generate oxygen radicals that cleave DNA. Reactive oxygen species are known to be capable of modulating gene expression in mammalian cells; thus, our studies indicate that oxygen radical production by 1,2-dithiole-3-thiones should be considered as a second chemical property, in addition to electrophilicity, that may play a role in the induction of protective phase II enzymes by this promising class of anticarcinogens.

Anaerobiosis↗
PubMed2005

On the homolytic cleavage of the N,O bond in N-(methoxy)pyridine-2(1H)-thione and N-(methoxy)thiazole-2(3H)-thione in thermally and photochemically induced reactions: a theoretical study.

The accuracy of theoretical approaches to describe electronic absorption spectra of N-(hydroxy)- and N-(methoxy)- derivatives of pyridine-2(1H)-thione and thiazole-2(3H)-thione are examined with the aim to identify methods that are applicable for a rational design of new photochemically active oxyl radical precursors. In addition, the mechanism of the photochemically induced methoxyl radical formation from N-(methoxy)pyridine-2(1H)-thiones and of N-(methoxy)thiazole-2(3H)-thiones is investigated by means of theoretical methods. The results of the study are applied in order to explain differences in photoreactions of N-(alkoxy)pyridine-2(1H)-thiones and the corresponding thiazole-2(3H)-thiones.

Hot Temperature↗
PubMed1987

Mechanism of protection against aflatoxin tumorigenicity in rats fed 5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) and related 1,2-dithiol-3-thiones and 1,2-dithiol-3-ones.

1,2-Dithiol-3-thiones, reported constituents of cruciferous vegetables, are five-membered cyclic sulfur-containing compounds with antioxidant, chemotherapeutic, and chemoprotective activities. The effects of dietary administration of a substituted 1,2-dithiol-3-thione, oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione], a potent antischistosomal agent, on aflatoxin B1 (AFB1) metabolism, DNA adduct formation, and hepatic tumorigenesis were examined in male F344 rats. Rats were fed graded doses of oltipraz (0.01-0.1%) for 4 wk. During the second and third wk of oltipraz feeding rats were gavaged with 250 micrograms of AFB1/kg five times a wk. Rats were finally restored to control diet 1 wk after cessation of AFB1 dosing. At 4 months focal areas of hepatocellular alteration were identified and quantitated by staining sections of liver for gamma-glutamyl transpeptidase activity. Treatment with oltipraz at all doses reduced by greater than 90% the volume of liver occupied by gamma-glutamyl transpeptidase-positive foci. Levels of AFB1 bound to hepatic DNA were reduced between 40 and 80% in animals fed increasing doses of dietary oltipraz (0.01-0.1%) for 1 wk prior to a single exposure to AFB1. Feeding of the higher levels of oltipraz led to marked increases in the specific activity of glutathione S-transferases, presumably serving to facilitate the detoxication of the ultimate electrophilic form of AFB1, the 8,9-oxide. At low dietary concentrations of oltipraz (0.01%), the only inductive effects seen were on the activities of selected cytochrome P-450 monooxygenases. Therefore, the protection afforded by oltipraz may be due to both the enhancement of electrophile detoxication pathways as well as modified oxidative metabolism of AFB1. In in vitro metabolism studies with hepatic post-mitochondrial supernatant, low-dose oltipraz pretreatment facilitated the oxidative production of aflatoxins P1 and Q1, but not M1, from AFB1. High-dose (0.1%) oltipraz pretreatment enhanced the primary metabolism of AFB1 to aflatoxins P1, M1, and Q1 as well as the formation of chloroform-insoluble metabolites. Feeding studies with a series of 1,2-dithiol-3-thione and 1,2-dithiol-3-one derivatives of oltipraz demonstrated that the inductive activity for cytochrome P-450-dependent monooxygenases and electrophile detoxication enzymes, such as glutathione S-transferases, could be readily separated by minor modifications of the 1,2-dithiol-3-thione structure. The unsubstituted 1,2-dithiol-3-thione nucleus strongly induced electrophile detoxication enzymes, but not the monooxygenases, and was the most effective inhibitor of the binding of AFB1 to hepatic DNA in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Aflatoxin B1↗
PubMed2002

Comparative (13)C and (31)P NMR studies of the ligand exchange reactions of auranofin with ergothionine, imidazolidine-2-thione and diazinane-2-thione.

The interaction of auranofin (Et(3)PAuSATg) with ergothionine (ErS), imidazolidine-2-thione (Imt) and diazinane-2-thione (Diaz) has been studied using (13)C and (31)P NMR spectroscopy. It is observed that these thiones are able to replace both Et(3)P and SATg(-) ligands simultaneously from gold(I) in auranofin forming >C [double bond] S-Au-SATg and [Et(3)P-Au-S [double bond] C<](+) type complexes. The displaced SATg(-) is oxidized to its disulfide (SATg)(2). However, some of the displaced Et(3)P is oxidized to Et(3)PO while the remaining reacts with thiones to form Et(3)P-S [double bond] C< species characterized by delta (31)P NMR of 1.0-1.5 ppm. The Et(3)PO resonance appeared in the 31P NMR spectrum, after 10 days of the addition of ErS, after 19 days of the addition of Imt and after 6 days of the addition of Diaz, to auranofin solution showing that the thiones react with auranofin very slowly.

Antirheumatic Agents↗
PubMed2001

Kinetic constraints for the thiolysis of 4-methyl-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (oltipraz) and related dithiole-3-thiones in aqueous solution.

This report summarizes an investigation of the reactions of biological and other thiols with the cancer chemopreventive oltipraz and other dithiolethiones. Analysis of the kinetics of reaction of 4-methyl-5-(pyrazin-2-yl)-1,2-dithiole-3-thione (oltipraz) 1 with monothiols and dithiols in the range of 0.75-20 mM in aqueous 15% ethanol, at pH 7.5 (0.1 M Tris buffer) and at 37 degrees C has been undertaken. A plot of k(obsd) against [thiol] shows that reactions of mono- and dithiols are first order in thiol concentration. The dependence on pH of these reactions shows that the active species is the thiolate anion. Specific second-order rate constants, k(2) (M(-1) s(-1)) for reaction of the thiolate anions with oltipraz have been determined to be cysteine, 0.040 +/- 0.001; 2-mercaptoethanol, 2.0 +/- 0.02; glutathione, 0.099 +/- 0.001; mercaptoacetic acid anion, 4.0 +/- 0.01; dithiothreitol, 1.33 +/- 0.02; 1,3-propanedithiol, 10 +/- 0.5; 1-mercaptopropane-3-ol, 6.5 +/- 0.1; 1-mercaptopropane-2,3-diol, 1.26 +/- 0.05. A plot of pK(a) against log k(2) for monothiols shows a linear dependence of k(2) on pK(a), beta(nuc) 1.1 +/- 0.07, which accounts for most of the reportedly enhanced reactivity of dithiols over monothiols. The pseudo-first-order rate constant for the solvolysis of oltipraz has been measured as 2.2 (+/-0.2) x 10(-8) s(-1). The kinetics of reaction of three other dithiole-3-thiones with glutathione has also been studied for comparison with oltipraz. The specific second-order rate constants, k(2) (M(-1) s(-1)) are 5-phenyl-1,2-dithiole-3-thione, 4.7 x 10(-)(4); 5-(4-methoxyphenyl)-1,2-dithiole-3-thione, 4.1 x 10(-4); and 1,2-dithiole-3-thione 0.08. Important implications for the mode of biological action of these compounds and the nature of the putative biological targets of the compounds are discussed.

Anticarcinogenic Agents↗
PubMed2005

Synthesis, structural characterization, and computational studies of novel diiodine adducts with the heterocyclic thioamides N-methylbenzothiazole-2-thione and benzimidazole-2-thione: implications with the mechanism of action of antithyroid drugs.

Reaction of N-methylbenzothiazole-2-thione (C8H7NS2 or NMBZT) with diiodine produced the charge-transfer (ct) complex [(NMBZT).I2] (1). NMBZT reacts with diiodine in the presence of FeCl3 in a molar ratio of 3:6:1 and forms the ionic complex [[(NMBZT)2I+].[FeCl4]-] (2) together with [[(NMBZT)2I+].[I7]-] (2a) iodonium salt. The reaction of benzimidazole-2-thione (C7H6N2S or MBZIM) with diiodine on the other hand results in the formation of the ct [[(MBZIM)2I]+[I3]-].[(MBZIM).I2] (3) compound. The compounds have been characterized by elemental analyses, DTA-TG, FT-Raman, FT-IR, UV-vis, and 1H NMR spectroscopies, and X-ray crystal structure determinations. Compound 1, C8H7I2NS2, is orthorhombic with a space group Pna2(1) and a = 12.5147(13) angstroms, b = 22.536(3) angstroms, c = 4.2994(5) angstroms, and Z = 4. Compound 2, C16H14Cl4FeIN2S4, is monoclinic, space group C2/c, a = 35.781(2) angstroms, b = 7.4761(5) angstroms, c = 18.4677(12) angstroms, beta = 107.219(1) degrees, and Z = 8. Compound 3, C21H18I6N6S3, monoclinic, space group P2(1)/n, a = 14.0652(11) angstroms, b = 22.536(3) angstroms, c = 4.2994(5) angstroms, beta = 99.635(7) degrees, and Z = 4, consists of two component moieties cocrystallized, one neutral which contains the benzimidazole-2-thione (MBIZM) ligand bonded with an iodine atom through sulfur, forming a compound with a "spoke" structure [(MBZIM)I2] 3a, while the other is the ionic complex [[(MBZII)2I+].[I3]-] (3b). The X-ray crystal structure of 1 shows a bond between the thione-sulfur atom and one of the iodine atoms in an essentially planar arrangement. In the cation of 2, an iodine is coordinated by two thione-sulfur atoms in a linear arrangement but the molecule is not planar. For the first time in the solid state a spoke-ionic mixed complex has been characterized in 3. One component of the structure is a molecular diiodine adduct, i.e., [(MBZIM)I2] (3a), with a linear coordination geometry in a decidedly planar arrangement, and the other component is an ionic adduct [[(MBZIM)2I]+.[I3]-] (3b) with the cation having an arrangement similar to that found for 1. Theoretical calculations using density functional (DFT) and ab initio Hartree-Fock theory have been carried out for 1 and 3a,b. The results are consistent with the experimental data. Conclusions on the behavior of a thioamide, when used as an antithyroid drug, have also been made.

Antithyroid Agents↗
PubMed2005

The identification of 1,3-oxazolidine-2-thiones and 1,3-thiazolidine-2-thiones from the reaction of glucose with benzyl isothiocyanate.

The structure of interaction products resulting from the reaction of unmodified glucose with benzyl isothiocyanate is reported. Prior to their identification, the main products of this reaction were isolated using solid-phase extraction (SPE) as well as preparative HPLC. They were then identified by NMR and MS as 3-benzyl-4-hydroxy-5-(D-arabino-1,2,3,4-tetrahydroxybutyl)-1,3-oxazolidine-2-thione, 3-benzyl-4-hydroxy-4-hydroxymethyl-5-(D-erythro-1,2,3-trihydroxypropyl)-1,3-oxazolidine-2-thione, N-benzyl-(D-gluco-4,5-dihydroxy-6-hydroxymethyl-tetrahydropyrano)[2,3-b]oxazolidine-2-thione and 3-benzyl-4-(N-benzyl amino)-5-(D-arabino-1,2,3,4-tetrahydroxybutyl)-1,3-thiazolidine-2-thione. The identity of the last compound was secured by X-ray crystal structure data.

Chromatography, High Pressure Liquid↗
PubMed1977

Synthesis and pharmacological properties of some 4-amino-5-substituted thiazole-2(3H)-thiones and thiazolo(4,5-d)pyrimidin-7(6H)-one-2(3H)-thiones.

4-Amino-5-substituted thiazole-2(3H)-thiones and thiazolo(4,5-d)-pyrimidin-7(6H)-one-2(3H)-thiones have been synthesized and screened for antimicrobial and pharmacological activities. Significant analgesic, antiinflammatory, anticonvulsant and antimicrobial properties have been found in some of the compounds synthesized. Analgesic and antiinflammatory activities are reported for the first time in thiazole-2(3H)-thiones.

Analgesics↗
PubMed2005

1,3-Dibenzoylimidazolidine-2-thione and 1,3-dibenzoyl-3,4,5,6-tetrahydropyrimidine-2(1H)-thione.

The title compounds, 1,3-dibenzoylimidazolidine-2-thione, C17H14N2O2S, (I), and 1,3-dibenzoyl-3,4,5,6-tetrahydropyrimidine-2(1H)-thione, C18H16N2O2S, (II), were obtained from the reactions of imidazolidine-2-thione and 1,4,5,6-tetrahydropyrimidine-2-thiol, respectively, with benzoyl chloride. Compounds (I) and (II) contain, respectively, imidazolidinethione [C=S = 1.6509 (14) A] and pyrimidinethione [C=S = 1.6918 (19) A] moieties bonded to two benzoyl rings. The molecules of (I) exhibit C2 symmetry, the C=S bond lying along the twofold rotation axis, while the molecules of (II) have mirror symmetry (Cs). The imidazolidine ring in (I) is essentially planar, while the pyrimidine ring in (II) adopts a boat conformation. Molecules of (I) are linked by weak intermolecular C-H...O interactions, while molecules of (II) are held together by van der Waals interactions.

Crystallography, X-Ray↗
PubMed2001

Synthesis and structure determination of some oxadiazole-2-thione and triazole-3-thione galactosides.

The syntheses of 5-pyridyl-3(beta-D-galactopyranosyl)-1,3,4-oxadiazole-2-thiones 3a-3c and 5-pyridyl-2(beta-D-galactopyranosyl)-4-benzyl-1,2, 4-triazole-3-thiones 6a-6c are reported. The existence of N-galactosides--not S-galactosides--was proven by IR and 15N NMR spectroscopy. The structures of the final products and the intermediates were elucidated by IR, 1H, 13C and 15N NMR spectroscopy and mass spectrometry.

Chromatography, Thin Layer↗
PubMed1992

Studies on the products of conversion of 4-ethoxycarbonylmethyl-1,2,4-triazoline-5-thione. VII. Synthesis of 4-beta-acetylaminoethyl derivatives of 1,2,4-triazoline-5-thione.

In the reaction of 4-ethoxycarbonylmethyl-1,2,4-triazoline-5-thione derivatives (Ia,b) with the primary amines the corresponding amides (IIa,b-IVa,b) have been formed. These amides were then undergone to reduction with LiAlH4 leading to the formation of corresponding amines (Va,b-VIIa,b). Then by means of the reaction with acetic anhydride these amines were transformed into corresponding acetylamine derivatives of 1,2,4-triazoline-5-thione (VIIIa,b-Xa,b).

Acetic Anhydrides↗
PubMed2001

Electron ionization mass spectra of 3,4-disubstituted-1,2,4-oxa(thia)diazole-5(4H)-thione(ones). Substituent effects on the mass spectrometric rearrangement of 3-aryl-4-(p-tolyl)-1,2,4-oxadiazole-5(4H)-thiones to the corresponding oxo compounds.

The fragmentation behaviour of ten 3,4-disubstituted 1,2,4-oxadiazole-5(4H)-thiones and seven 3,4-disubstituted 1,2,4-thiadiazole-5(4H)-ones studied here confirmed the earlier observations about the partial rearrangement of the former after ionization into the latter before further fragmentation. In the case of eight 3-(substituted phenyl)-4-(p-tolyl)-1,2,4-oxadiazole-5(4H)-thiones the fragmentations reflecting the above-mentioned molecular ion rearrangement show a clear correlation on the substituent sigma values. The electron-withdrawing substituents destabilize the molecular ion, so higher amounts of the rearranged ion [R(1)NCO](+.) are obtained. A good correlation of log[R(1)NCO](+) against sigma was obtained (r = 0.96). Only a satisfactory correlation prevailed for log([R(1)NCO](+)*/[R(1)NCS](+)*) against sigma(r = 0.87).

Journal Article↗
PubMed2002

Comparison of oxygen and sulfur effects on keto-enol chemistry in benzolactone systems: benzo[b]-2,3-dihydrofuran-2-one and -2-thione and benzo[b]-2,3-dihydrothiophene-2-one and -2-thione.

Carbon-acid ionization constants, Q(K)(a)(concentration quotient at ionic strength = 0.10 M), were determined by spectrophotometric titration in aqueous solution for benzo[b]-2,3-dihydrofuran-2-one (3, pQ(K)(a) = 11.87), benzo[b]-2,3-dihydrothiophene-2-one (2, pQ(K)(a) = 8.85), and benzo[b]-2,3-dihydrofuran-2-thione (1, pQ(K)(a) = 2.81). Rates of approach to keto-enol equilibrium were also measured for the latter two substrates in perchloric acid, sodium hydroxide, and buffer solutions, and the rate profiles constructed from these data gave the ionization constants of the enols ionizing as oxygen or sulfur acids pQ(E)(a) = 5.23 for 2 and pQ(E)(a) = 2.69 for 1. Combination of these acidity constants with the carbon-acid ionization constants according to the relationship Q(K)(a)/Q(E)(a) = K(E) then gave the keto-enol equilibrium constants pK(E) = 3.62 for 2 and pK(E) = 0.12 for 1. The fourth, all-sulfur, member of this series, benzo[b]-2,3-dihydrothiophene-2-thione (4), proved to exist solely as the enol in aqueous solution, and only the enol ionization constant pQ(E)(a) = 3.44 could be determined for this substance; the limits pK(E) < 1.3 and pQ(K)(a) < 2.1, however, could be set. The unusually high acidities and enol contents of these substances are discussed, as are also the relative values of the ketonization and enolization rate constants measured; in the latter cases, Marcus rate theory is used to determine intrinsic kinetic reactivities, free of thermodynamic effects.

Benzofurans↗
PubMed2005

Synthesis of 2,3-diaryltetrazole-5-thiones and theoretical studies on atomic charge distributions of 2,3-diphenyltetrazole-5-thione.

Four 2,3-diaryltetrazole-5-thiones have been synthesized in high yields using a new synthetic method under mild reaction conditions. Theoretical calculations of the structure, vibrational frequencies, and natural population analysis (NPA) of atomic charge distributions on 2,3-diphenyltetrazole-5-thione 1 have been performed by DFT-B3LYP, HF, and MP2 methods using several basis sets. According to the NPA results a new resonance hybrid structure of 1 has been proposed with an exocyclic sulfur atom and a tetrazole ring carrying negative charges and two phenyl rings having positive charges. On the basis of this new proposed structure, the calculated results can explain experimental facts logically. In addition, a new chemical property of 1 has been predicted: the protonation should occur not only on the exocyclic S atom, but also on the N atoms having negative charges.

Journal Article↗
PubMed2001

A new approach to 4-alkylthio-1,3-dithiole-2-thione: an unusual reaction of a zinc complex of 1,3-dithole-2-thione-4,5-dithiolate.

[see reaction]. A new and facile approach to 4-alkylthio-1,3-dithiole-2-thione starting from easily accessible reactants was described. This approach was based on the unusual reaction of a zinc complex of 1,3-dithiole-2-thione-4,5-dithiolate with electrophilic reagents in the presence of 3-picolyl chloride hydrochloride/or 4-picolyl chloride hydrochloride/or pyridine hydrochloride.

Journal Article↗
PubMed2006

Secondary interactions in gold(I) complexes with thione ligands. 5. Two ionic compounds of the form bis(thione)gold(I) bis(4-halobenzenesulfonyl)amide.

Bis(1,3-thiazolidine-2-thione-kappaS2)gold(I) bis(4-chlorobenzenesulfonyl)amide, [Au(C3H5NS2)2](C12H8Cl2NS2O4), has no imposed symmetry. Classical N-H...N and N-H...O hydrogen bonds link the residues to form chains parallel to the b axis. Weaker interactions involve C-H...O, C-H...Au and a number of X...Cl contacts (X = Cl, S or Au) clustered in the region y approximately equal to 1/4}. In bis(1-methylimidazolidine-2-thione-kappaS2)gold(I) bis(4-iodobenzenesulfonyl)amide, [Au(C4H8N2S)2](C12H8I2NS2O4), the Au atom of the cation and the N atom of the anion lie on the twofold axis (0, y, 1/4}) in the space group C2/c. The formula unit forms a self-contained ring with two symmetry-equivalent N-H...O hydrogen bonds, and weak C-H...X (X = O, I or S), Au...I and I...I contacts are observed. In both compounds, the anions display extended conformations.

Journal Article↗
PubMed1994

New classes of antimuscarinic agents endowed with selective antispasmodic properties. 1-Arylsulfonyl pyrrolidin-2-ones and 2-thiones, 1-arylsulfonyl piperidin-2-ones and 2-thiones and 1-arylsulfonyl hexahydro-2H-azepin-2-one.

A series of 1-arylsulfonylpyrrolidin-2-ones (and 2-thiones), 1-aryl sulfonylpiperidin-2-ones (and 2-thiones) and 1-arylsulfonyl hexahydro-2H-azepin-2-one were synthesized and submitted to a battery of binding assays. The compounds showed little or no affinity for the receptors tested other than muscarinic receptors labelled either with [3H]pirenzepine or with [3H]quinuclidinyl benzilate. When tested in the isolated guinea pig ileum, they antagonized the contractions induced by acetylcholine and behaved as competitive muscarinic antagonists. After parenteral administration in mice, most compounds inhibited carbachol-induced diarrhoea but were less effective in counteracting salivation and lacrimation and showed little or no mydriatic action, thus displaying selectivity at the intestinal level. The reference drugs tested, atropine, butyl scopolamine and cimetropium bromide were far less selective. maximal in vivo activity was obtained by introducing diethylamino or 1-piperidino or 1-hexahydroazepinyl groups in the 4-position of the phenyl ring while the enlargement of a 5- to a 6-membered lactam ring or its conversion into a thiolactam had a less marked effect. The most interesting compounds were further evaluated for their ability to antagonize carbachol-induced colonic hypermotility in the rat and arecoline-induced analgesia in mice. The effect on gastric acid secretion in the rat was also investigated. The overall in vivo data showed that compounds 14, 15, 26 and 27, i.e. those bearing a 1-hexahydroazepinyl group in the 4-position of the phenyl ring, were the most potent and selective compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗