6493-73-8

3,4-Dichloro-1,2,5-thiadiazole is introduced as a safe and efficient sulfur transfer reagent. By applying this commercially available reagent, the symmetrical trisulfides and ethanedinitrile were simultaneously obtained by reacting various thiols with this reagent at room temperature. This reagent is non-toxic, inexpensive, and commercially available. In addition, no higher-order polysulfides were detected in all cases after the completion of the reaction. The short reaction times (20–50 min), excellent selectivity, and high yield of the trisulfides are some attractive merits of this reagent for the preparation of trisulfides. The reaction is one-pot, and isolation-purification of intermediates is not required. The procedure was readily scaled up to 5 grams. A mechanism is presented to explain the chemistry.

The bulbous root garlic (Allium sativum) with a strong taste and pungent odor is used widely in culinary preparations and folk medicine. Silver and gold nanoparticles (NPs) synthesized using this ingredient have also shown medicinal and therapeutic potency. Garlic contains organosulfur compounds, such as diallyl sulfide (DAS), diallyl disulfide (DADS) and diallyl trisulfide (DATS). These compounds are of crucial significance as anticancer drugs. Reported here is a synthesis of a series of DATS with varying substituents and plausible application as capping as well as reducing agent to synthesize gold nanoparticles (TS-GNPs). In the process, it was discovered that among the selected DATs, only 1,3-di(but-1-ene)trisulfane could serve the purpose because of structural reasons. The reason for this intriguing selectivity has been investigated in detail using the experimental findings and theoretical calculations of the frontier molecular orbitals (FMO). Graphic abstract: Synthesis of a series of medicinally important symmetrical organic trisulfides as a structural analogue of diallyl trisulfides (DATS) in an attempt to construct organosulfur compound induced gold nanoparticles (GNPs), has been reported. Only 1,3-Di(but-1-ene)trisulfane in the lot is capable of reducing the chloroauric acid to synthesize the protected GNPs.[Figure not available: see fulltext.].

Temperature-and solvent-induced selective synthesis of trisulfides and disulfides is demonstrated. A remarkable selectivity was achieved using Na2S as a sulfur-Transfer agent under mild, greener, catalyst-free and additive-free conditions. This study reveals trisulfides as a better model than disulfides in general for a sustained release of H2S and potent anti-cancer activities.

Investigations into hydrogen sulfide (H2S) signaling pathways have demonstrated both the generation and importance of persulfides, which are reactive sulfur species that contain both reduced and oxidized sulfur. These observations have led researchers to suggest that oxidized sulfur species, including sulfane sulfur (S0), are responsible for many of the physiological phenomena initially attributed to H2S. A common method of introducing S0 to biological systems is the administration of organic polysulfides, such as diallyl trisulfide (DATS). However, prior reports have demonstrated that commercially-available DATS often contains a mixture of polysulfides, and furthermore a lack of structure-activity relationships for organic polysulfides has limited our overall understanding of different polysulfides and their function in biological systems. Advancing our interests in the chemical biology of reactive sulfur species including H2S and S0, we report here our investigations into the rates and quantities of H2S release from a series of synthetic, pure benzyl polysulfides, ranging from monosulfide to tetrasulfide. We demonstrate that H2S is only released from the trisulfide and tetrasulfide, and that this release requires thiol-mediated reduction in the presence of cysteine or reduced glutathione. Additionally, we demonstrate the different effects of trisulfides and tetrasulfides on cell proliferation in murine epithelial bEnd.3 cells.

A strategy to deliver a well-defined persulfide species in a biological medium is described. Under near physiological conditions, the persulfide prodrug can be activated by an esterase to generate a “hydroxymethyl persulfide” intermediate, which rapidly collapses to form a defined persulfide. Such persulfide prodrugs can be used either as chemical tools to study persulfide chemistry and biology or for future development as H2S-based therapeutic reagents. Using the persulfide prodrugs developed in this study, the reactivity between S-methyl methanethiosulfonate (MMTS) with persulfide was unambiguously demonstrated. Furthermore, a representative prodrug exhibited potent cardioprotective effects in a murine model of myocardial ischemia-reperfusion (MI/R) injury with a bell shape therapeutic profile.

Thioamides are prepared in moderate-to-good yields from the benzylamines or benzylamine derivatives by treatment with elemental sulfur under microwave and solvent-free conditions at 170.C in 15 min.

Reaction of the complex [(TPA)Zn(H2O)]2+ [TPA = tris(2-pyridylmethyl)amine] with hydrogen sulfide in aqueous buffered solution gives the corresponding monomeric hydrogensulfido complex [(TPA)Zn(SH)] +, which was fully characterized, including by XRD. This complex is stable at neutral pH, but decomposes under basic conditions to yield the free ligand and zinc sulfide, and under acidic conditions to give hydrogen sulfide and the starting aqua complex. In organic solvents, the coordinated sulfur atom reacts with electrophiles such as methylmethanethiosulfonate to yield methyltrisulfide. Reaction with the hydroxo complex [(TpPh,Me)Zn(OH)] [TpPh,Me = hydridotris{(5-methyl-3-phenyl)pyrazolyl}borate] promotes the formation of the unsymmetrical dinuclear μ-sulfido species [(TPA)Zn-S-Zn(TpPh,Me)]+, which, upon treatment with one molar equivalent of trifluoroacetic acid, dissociates into [(Tp Ph,Me)Zn(SH)] and [(TPA)Zn(CF3CO2)] +, resulting in the transfer of the hydrogensulfido ligand from one zinc center to another.

Elemental sulfur (S8) reacts reversibly with the copper(I) complex [(TMPA′)CuI]+ (1), where TMPA′ is a TMPA (tris(2-pyridylmethyl)amine) analogue with a 6-CH2OCH 3 substituent on one pyridyl ligand arm, affording a spectroscopically pure end-on bound disulfido-dicopper(II) complex [{(TMPA′)CuII}2(μ-1,2-S2 2-)]2+ (2) {ν(S-S) = 492 cm-1; ν(Cu-S)sym = 309 cm-1}; by contrast, [(TMPA)Cu I(CH3CN)]+ (3)/S8 chemistry produces an equilibrium mixture of at least three complexes. The reaction of excess PPh3 with 2 leads to formal "release" of zerovalent sulfur and reduction of copper ion to give the corresponding complex [(TMPA′)-CuI(PPh3)]+ (11) along with S=PPh3 as products. Dioxygen displaces the disulfur moiety from 2 to produce the end-on Cu2O2 complex, [{(TMPA′)Cu II}2(μ-1,2-O22-)]2+ (9). Addition of the tetradentate ligand TMPA to 2 generates the apparently more thermodynamically stable [{(TMPA)CuII}2(μ-1,2-S 22-)]2+ (4) and expected mixture of other species. Bubbling 2 with CO leads to the formation of the carbonyl adduct [(TMPA′)CuI-(CO)]+ (8). Carbonylation/sulfur- release/CO-removal cycles can be repeated several times. Sulfur atom transfer from 2 also occurs in a near quantitative manner when it is treated with 2,6-dimethylphenyl isocyanide (ArNC), leading to the corresponding isothiocyanate (ArNCS) and [(TMPA′)CuI(CNAr)]+ (12). Complex 2 readily reacts with PhCH2Br: [{(TMPA′)Cu II}2(μ-1,2-S22-)]2+ (2) + 2 PhCH2Br → [{(TMPA′)-CuII(Br)} 2]2+ (6) + PhCH2SSCH2Ph. The unprecedented substrate reactivity studies reveal that end-on bound μ-1,2-disulfide-dicopper(II) complex 2 provides a nucleophilic S 22- moiety, in striking contrast to the electrophilic behavior of a recently described side-on bound μ-η2: η2-disulfido-dicopper(II) complex, [{(N3)Cu II}2(μ-η2:η2-S 22-)]2+ (5) with tridentate N3 ligand. The investigation thus reveals striking analogies of copper/sulfur and copper/dioxygen chemistries, with regard to structure type formation and specific substrate reactivity patterns.

New bis-aromatic and heterocyclic trisulfide derivatives 5, 7-10 were synthesized by optimizing lead dibenzyl trisulfide natural product (4) to evaluate their anti-tumor activities. Five compounds 5-7, 9, and 10 exhibited potent anti-tumor activities against eight different tumor cell lines with low cytotoxicity against HepG2. Initial SAR was discussed, and MOA of these anti-microtubule agents was suggested based on cell kinetic response patterns observed on RT-CES system.

The present invention provides substituted di-, tri-, tetra- and penta-sulfide compounds and compositions, and methods of using the same for the treatment and/or prevention of a cell proliferative disorder. The present invention also provides methods for preparing trisulfide compounds and compositions.

Anhydrous sodium oligosulfide was prepared by the heterogeneous reaction of metal sodium and elemental sulfur in aprotic solvents. The oligosulfide consisted of a mixture of several Na2Sn (n = 2 - 8). Organic oligosulfides (R2Sn, n ≥ 2) including moisture-sensitive one were synthesized by the reaction with organic halides in high yeilds under mild conditions.

The reaction of triphenylmethanesulfenyl chloride (3a) with acyclic disulfides 4 or 5 give the respective trisulfides 1 or 2 in moderate to good yield and selectivity. A mechanism is advanced to explain the chemistry.

The reactions between a series of alkyl halides RX: X = I, R = CH3 (1), C3H7 (2); X = Br, R = C4H9 (3), 2-C4H9 (4), 3-C5H11 (5), PhCH2 (6); X = Cl, R = PhCH2 (7), C6H13 (8), and electrogenerated S1/3- ions (S62- ?S3.-) have been investigated by spectroelectrochemistry in N,N-dimethylacetamide at 20°C. RX substrates react in two steps: (i) nucleophilic substitution of S1/3- ions (SN2 process) yielding RSx- ions (x = 5.2, R = alkyl; x = 4.8, R = PhCH2); (ii) subsequent substitutions of RSx- ions lead to RSzR polysulfanes (z ≈ 3.5), probably through partial disproportionation of the anionic species. On a preparative scale, mixtures of CH3SzCH3 (z = 2-6, z = 3.9) or PhCH2Sz CH2Ph (z = 2-5, z = 3.7) were obtained from chemical reactions between 1, 6 and S62- ions, or electrochemical syntheses. Kinetic studies at 20°C of the reactions between S3.- ions and substrates 4, 5, 7 and 8 imply that the dianions S62- are the nucleophilic agents in the first step rather than S3.- radical anions.

At a working potential of about +2.0 V (vs SCE) the carbon-sulfur electrode is a source of the electrogenerated cation S2+. In organic media, this electrophile reacts with thiols (or thiolates) to give a mixture of polysulfides of which the trisulfide is the main product. The reaction between electrogenerated Sy2- and alkyl halides is less selective. Elsevier,.

Unsymmetrical di- tri- and tetrasulfides can be prepared in a one-pot reaction using SO2Cl2 SCl2 and S2Cl2 respectively to permit coupling of the appropriate thiols.

In contrast to the behaviour of disulphides RS2R, the mono-desulphurisation of tri- or tetra-sulphides RSnR (R = benzyl, p-tolyl; n= 3, 4) by triphenylphosphine in hydroxylic solvents (methanol-benzene or water- 2-propanol-benzene) mainly affords Ph3PS with only small (n = 3) or very small (n = 4) amounts of Ph3PO.Ph3PO was virtually absent in the reaction products of Ph3P with 2Sn (n = 2, 3) or with elemental sulphur in alcoholic or aqueous media.Reaction rates for the formation of Ph3PS or Ph3PO decrease in the order: RS4R > RS3R >> RS2R (R = benzyl or p-tolyl) and hydroxylic >> aprotic solvents; the dependence on R is: (EtO)2P(S) >> p-tolyl > benzyl.Addition of a thiol impedes the formation of Ph3PO; low pH's have an opposite effect.The results are rationalised in terms of basicity of anions RSp- (p = 1 to n-1), relative softness of terminal or central S in RSnR and Broensted acidity of the solvent.An alternative is proposed to the Bartlett's mechanism for the reaction of S8 with Ph3P, in which the intermediate zwitterion Ph3P+S4- collapses by fast intramolecular nucleophilic displacement, affording Ph3PS and highly reactive S7.

The reaction of XeF2 with cysteine derivatives RSCH2CH(NHR)COOR, i.e., S-benzyl-N-trifluoroacetyl-L-cysteine methyl ester, S-benzyl-N-carbobenzoxy-L-cysteine p-nitrophenyl ester, and S-methyl-N-trifluoroacetyl-L-cysteine methyl ester is described.The fluorinated products PhCHFSCH2CH(NHR)COOR, PhCH2SCHFCH(NHR)COOR, and FCH2SCH2CH(NHR)COOR were identified by 1H and 19F nuclear magnetic resonance spectroscopy.PhCH2SCHFCH(NHR)COOR loses HF within 24 hours to give Z- and E-PhCH2SCH=C(NHR)COOR.If the reaction with XeF2 is carried out in the presence of moisture the sulfoxide RS(O)CH2CH(NHR)COOR and sulfone RSO2CH2CH(NHR)COOR are produced.

The bridgehead enone (16) was converted into the allylic trisulphide (22)/(23) in a completely stereospecific manner, and the thermal and reduction chemistry of some allylic trisulphides was examined.

Bis(tributyltin) sulfide acts efficiently to transfer the sulfur atom as S(2-) to a variety of halide substrates to afford the corresponding symmetrical sulfides in good overall yield.

Thiols react with diimidazolylsulfide under mild conditions to give simmetrical trisulfides in good yield and high purity.

Tris(dialkylamino)phosphines effect a rapid desulfurization of trisulfides to disulfides under mild conditions.The reaction mechanism involves a bimolecular process, proceeding by the rate-determining formation of a phosphonium salt intermediate.The central sulfur atom of a diaryl trisulfide is removed in the process, while a dialkyl trisulfide loses a terminal sulfur atom to the aminophosphine.

Reaction of N,N'-thionyldiimidazole with thiols effects the formation of disulfides and trisulfides.These results are rationalized by assuming that the thiols react with N,N'-thionyldiimidazole to produce the disulfides and N,N'-thiobisimidazole which subsequently reacts with the starting thiols to give the trisulfides.

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