Disulfides, imines, and metal coordination within a single system: interplay between three dynamic equilibria

We report a system in which three distinct dynamic linkages, disulfide (S-S), imine (C=N), and coordinative (N-->metal) bonds were shown to be capable of simultaneous reversible exchange. The "disulfide layer" of the system under study consists of two homo-disulfides, bis(4-aminophenyl) disulfide 1 and bis(4-methoxyphenyl) disulfide 2 that equilibrate in the presence of catalytic amount of triethylamine to favor the formation of a hetero-disulfide product, 4-aminophenyl-4'-methoxyphenyl disulfide 3. The addition of 2-formylpyridine and a metal salt strongly perturbed this 1+2<-->3 equilibrium through the formation of metal complexes incorporating disulfide 1 as a subcomponent. CuI perturbed the equilibrium by a factor of 3.3, and FeII by a factor of 179, in both cases in favor of the homo-disulfides. The disulfide equilibrium could be further modified, following metal-complex formation, by coordinative (transmetallation: substitution of FeII for CuI) or covalent (imine exchange: the substitution of one amine residue for another) exchange. Thus, although the three kinds of dynamic linkages were demonstrated to be mutually compatible, changes at one kind of linkage could be used to predictably perturb an equilibrium involving another.     

双(O,O-二烃基硫代磷酰基)二硫物与二氯化汞的反应

双(O,O-二乙基硫代磷酰基)二硫物(Ⅰ)及双(O,O-二正丁基硫代磷酸基)二硫物(Ⅰ)与二氯化汞于室温下在乙醇中反应,视反应物的摩尔比为1:1或1:2.     

Catalytic enantioselective conjugate additions using enantiopure β-amino disulfides and β-amino thiolates

The enantioselective conjugate addition of diethylzinc to chalcone catalysed by nickel(II) using an enantiopure β-amino thiolate 2 or β-amino disulfide 1 to achieve ee's of up to 50% is described.     

Three-component reaction between amines,carbon disulfide and electron-deficient derivatives of chloropyridine or chlorobenzene: synthesis of 3,6-diazaspiro[4.5]deca-2,7,9-trien-6-ium chloride and dithioylcarbamates derivatives

In this study, three-component reaction of some primary and secondary amines with carbon disulfide in the presence of electron-deficient derivatives of chloropyridine or chlorobenzene in the CH₃CN as a solvent is reported. The reaction of primary amines with carbon disulfide and electron-deficient compounds of chloropyridine or chlorobenzene after 6–8 h afforded the three-component addition product. The reaction of secondary amines with carbon disulfide and electron-deficient compounds of chloropyridine or chlorobenzene after 3–4 h afforded the two-component addition product. The product(s) of reactions were purified by recrystallization or column chromatography and their structures were identified by spectroscopy techniques such as ¹H-NMR, ¹³C-NMR, IR, UV and elemental analysis. The reactions were carried out under mild conditions and without using a catalyst.     

Structure and properties of biodegradable wheat gluten/attapulgite nanocomposite sheets

Wheat gluten (WG) and Attapulgite (ATP) was mixed in acidic solution and freeze-dried, thermally compression-molded to form nanocomposite sheet. The influences of reduction and sonication on structure of wheat gluten were examined by Raman spectrum. The variation of disulfide bonding in wheat gluten show that the sonication is more effective than reduction on the breakage of disulfide bonds, whereas the content of disulfide bonds in the WG sheet molded by sonicated WG powder is the highest in the molded sheets. FT-IR analysis displays that the bands in the range of 1700-1600 cm⁻¹ shift to higher frequency after mixing WG and ATP powders and molding the nanocomposite. The tensile and bending properties of the WG sheet increase with addition of ATP powder, and the properties of the sheet molded by sonicated WG powder decrease for the reduction of the disulfide bonding, but the properties of the sheet can be improved by addition of ATP. The WG/ATP nanocomposite images observed by SEM and TEM show that rod-like ATP particles are evenly dispersed in WG matrix, but the crystal structure of ATP is impervious. The viscoelasticity of the WG sheet declines with addition of ATP particle, and that the α-relaxation of the WG sheet molded by sonicated WG powder shift to high temperature and become broad. Both mass and bending strength of 7 wt% WG/ATP nanocomposite sheet show a decline over a soil exposure time of 20 days.     

AN UNUSUAL ADDITION AND RING-CLOSURE REACTION OF 1-(2-BROMOETHYL)-2,3-DIHYDRO- 3-PROPYL-1,3,2-BENZO-DIAZAPHOSPHORIN-4(1H)-ONE 2-OXIDE WITH CARBON DISULFIDE FOR A NEW AND CONVENIENT SYNTHESIS OF THE FUSED PHOSPHORUS HETEROCYCLIC COMPOUND

ABSTRACT

The reaction of 1-(2-bromoethyl)-2,3-dihydro-3-propyl-1,3,2-benzodiazaphosphorin-4(1H)-one 2-oxide with carbon disulfide takes an alternative pathway in the use of different bases. The sodium hydride mediated reaction leads to the formation of the tricyclic fused 1,2,3,4,4a,4b,5,6-octahydro-6-oxo-5-propyl-4-thia-3,4b,4a-thiazphosphaphenanthridine 4a-oxide via addition of H-P bond across the double bond of carbon disulfide followed by intramolecular cyclization. In the presence of triethylamine, refluxing a mixture of 1-(2-bromoethyl)-2,3-dihydro-3-propyl-1,3,2-benzodiazaphosphorin-4(1H)-one 2-oxide with carbon disulfide in benzene takes an unusual course with formation in excellent yield of the first example of fused phosphorus heterocyclic 4-[1′-(β-bromoethyl)-4′-oxo- 3′-propyl-1′,2′,3′,4′-tetrahydro-1,3,2-benzodiazaphosphorin-2′- sulfide]-1,2,3,4,4a,4b,5,6-octahydro-6-oxo-5-propyl-3,4b, 4a-thiazphosphaphenanthridine 4a,2′-dioxide, which was confirmed by spectroscopic methods, microanalyses and single crystal X-ray structure determination.     

Concerning the gas chromatographic determination of amphetamine as (1-phenyl-isopropyl)-isothiocyanate

Amphetamine (I) reacts spontaneously at room temperature with carbon disulfide to form (1-phenyl-isopropyl)-isothiocyanate, which was identified by UV.-, IR.- and mass spectrometry. This reaction is used for the analytical determination of I by gas chromatography. The characteristic peak shift which occurs after addition of carbon disulfide differentiates I from N-methylamphetamine (II). The method is applied to urine analysis of I and II (which partially metabolizes to I) and might be useful in doping control.     

On the easy oxidation of (R)-2-[N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid to its disulfide dimer

The physical and spectroscopic data of (R)-2-[N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid are reviewed and the synthesis of (R)-di-[2-(N-(1-phenylethyl)amino]-1-cyclopentenedithiocarboxylic acid disulfide is described. The product resulting from the conjugate addition of the dithioacid to 2(5H)-furanone is also characterised.     

Rhodium-catalyzed disulfide exchange reaction

A system of RhH(PPh3)4, trifluoromethanesulfonic acid, and (p-tol)3P catalyzes the disulfide exchange reaction. Treatment of two symmetrical dialkyl disulfides with the catalyst provides an equilibrium mixture of three disulfides within 15 min in refluxing acetone. The catalyst is active after reaching the equilibrium, and addition of a disulfide to the mixture changes the ratio of the products. The use of 4 mol equiv excess of one of the disulfides provides the unsymmetrical disulfide in a yield exceeding 80%. Disulfide-containing peptides also undergo an exchange reaction. The reactions of diaryl disulfides and dialkyl disulfides are even faster, and reach equilibrium within 5 min at room temperature in the presence of the rhodium complex and 1,2-bis(diphenylphosphino)ethane (dppe). This exchange reaction is considerably affected by the substituents on the disulfides. Treatment of diphenyl disulfide, di(p-tolyl) disulfide, and bis(sec-butyl) disulfide yields phenyl p-tolyl disulfide at room temperature with unchanged bis(sec-butyl) disulfide; random disproportionation occurs at reflux. The rhodium catalysis can be used for the exchange reaction of disulfides and diselenides giving selenosulfides as well as disulfides and ditellurides giving tellurinosulfides.     

Determination of Stability Constants of Cadmium(II) Complexes with Diallyl Disulfide,Dimethyl Disulfide and Diallyl Sulfide Using Differential Pulse Voltammetry

The study of the binding of heavy metal ions by organosulfur compounds of garlic is especially important for the understanding of many biological systems. Cadmium is a non-essential heavy metal known to be one of the most toxic environmental pollutant.Interactions between cadmium and diallyl disulfide (DADS), dimethyl disulfide (DMDS) and diallyl sulfide (DAS) were investigated by differential pulse voltammtery. Determination of the stability constants of cadmium(II) with DADS, DMDS and DAS complexes was based on the DeFord–Hume methodology that calculated from the dependence of the shift of cadmium( II) peak potential upon addition of the ligands DADS, DMDA and DAS separately. The results of this study provide evidence of the formation of 1: 1 and 1: 2 complexes between cadmium(II) and DADS, DMDS and DAS with stability constants (β) in the range of ca. 10^5.8–10^6.2 and 10^9.6–10^10.6 respectively.     

Effect of cysteine on bovine serum albumin (BSA) denaturation induced by solar ultraviolet (UVA, UVB) irradiation.

Long-term exposure to natural sun-light (UVA, UVB) induced fluorescence and caused disulfide bond formation in bovine serum albumin (BSA). The addition of cysteine enhanced the bond formation to such an extent that a solution of BSA was transformed into an insoluble gel. The disulfide bonds in the gels are derived from internal-SH groups of protein. This reaction occurred even if cysteine was added after exposure to ultraviolet (UV)-irradiation. Fluorescent substances seem to be involved in this reaction. On the other hand, low concentrations of cysteine (less than 5 mM) inhibited both fluorescence and disulfide bond formation. The addition of glutathione to BSA produced the same effect as that of cysteine. The addition of thiourea to BSA solution inhibited fluorescence, but did not inhibit disulfide bond formation. We assume that external-SH compounds such as cysteine and glutathione, which have high reactivity with hydroxyl radicals (.OH), act not only as free-radical scavengers, but also as radical mediators in the polymerization of protein through disulfide cross-links induced by UV-irradiation. Solar UVA as well as UVB irradiation are shown to have the same effect on the protein polymerization.     

氯化血红素催化氧化巯基形成二硫键

对氯化血红素催化氧化巯基形成二硫键的反应进行了研究,发现N,N-二异丙基乙胺(DIEA)的加入可以提高氯化血红素的催化活性,并降低其在氧化过程中的自聚现象.在室温及少量DIEA存在下,将氯化血红素和巯基乙酸甲酯按摩尔比1∶4混合于p H=8.0的水溶液中,敞口搅拌反应20 min,可以催化空气氧化90%的巯基乙酸甲酯形成相应的分子间二硫键产物.该催化氧化体系还可应用于多肽合成中,在相同条件下,只需2 h即可完成还原型催产素和利那洛肽的氧化环合,生成高产率的催产素和利那洛肽环肽.与传统的氧化方法相比,氯化血红素催化氧化的方法具有高效、环保的优点,为多肽合成中二硫键的形成提供了一种新方法.     

Self-assembly of a diblock copolymer with pendant disulfide bonds and chromophore groups: a new platform for fast release

An amphiphilic block copolymer comprising poly(ethylene glycol) (PEG) and poly(2-(methacryloyl)oxyethyl-2'-hydroxyethyl disulfide) (PMAOHD) blocks was synthesized by atom transfer radical polymerization (ATRP). Pyrenebutyric acid was conjugated to the block copolymer by esterification, and a block copolymer with pendant disulfide bonds and pyrenyl groups (PEG-b-P(MAOHD-g-Py)) was obtained. (1)H NMR and gel permeation chromatography (GPC) results demonstrated the successful synthesis of the block copolymer. The cleavage of the disulfide bonds and the degrafting of the pyrenyl groups were investigated in THF and a THF/methanol mixture. Fluorescence spectroscopy, GPC, and (1)H NMR results demonstrated fast cleavage of the disulfide bonds by Bu(3)P in THF. Fluorescence results showed the ratio of the intensity of the excimer peak to the monomer peak decreased rapidly within 20 min. GPC traces of the block copolymer moved to a long retention time region after addition of Bu(3)P, indicating the cleavage of the disulfide bonds and the degrafting of the pyrenyl groups. PEG-b-P(MAOHD-g-Py) can self-assemble into micelles with poly(MAOHD-g-Py) cores and PEG coronae in a mixture of methanol and THF (9:1 by volume). The dissociation of the micelles in the presence of Bu(3)P was investigated. After cleavage of the disulfide bonds in the micellar cores, a pyrene-containing small molecular compound and a block copolymer with pendant thiol groups were produced. Transmission electron microscopy (TEM), dynamic light scattering (DLS), and (1)H NMR were employed to track the dissociation of the polymeric micelles. All the techniques demonstrated the dissociation of the micelles and the fast release of pyrenyl groups from the micelles.     

A Closed Metallomolecular Cage that can Open its Aperture by Disulfide Exchange

A closed metallomolecular cage based on the tris(saloph) framework, in which its aperture can be opened by disulfide exchange, was designed. At the apertures of the molecular cage, bridging diamine ligands having a disulfide bond were introduced to close the cage structure. These bridging ligands efficiently blocked the uptake of a guest, Cs⁺, but the presence of a thiolate anion significantly accelerated the guest uptake. This clearly means that this cage complex became open by the addition of the thiolate anion, because the cage closure becomes more dynamic due to the disulfide exchange reaction.     

Racemic and Quasi‐Racemic X‐ray Structures of Cyclic Disulfide‐Rich Peptide Drug Scaffolds

Cyclic disulfide‐rich peptides have exceptional stability and are promising frameworks for drug design. We were interested in obtaining X‐ray structures of these peptides to assist in drug design applications, but disulfide‐rich peptides can be notoriously difficult to crystallize. To overcome this limitation, we chemically synthesized the L ‐ and D ‐forms of three prototypic cyclic disulfide‐rich peptides: SFTI‐1 (14‐mer with one disulfide bond), cVc1.1 (22‐mer with two disulfide bonds), and kB1 (29‐mer with three disulfide bonds) for racemic crystallization studies. Facile crystal formation occurred from a racemic mixture of each peptide, giving structures solved at resolutions from 1.25 Å to 1.9 Å. Additionally, we obtained the quasi‐racemic structures of two mutants of kB1, [G6A]kB1, and [V25A]kB1, which were solved at a resolution of 1.25 Å and 2.3 Å, respectively. The racemic crystallography approach appears to have broad utility in the structural biology of cyclic peptides.     

Studies on the refolding of the reduced-denatured insulin with size exclusion chromatography

The refolding of the reduced-denatured insulin from bovine pancreas was investigated with the size exclusion chromatography (SEC). It was shown that the reduced-denatured insulin originally denatured with 7.0 mol L^?1 guanidine hydrochloride (GuHCI) or 8.0 mol L^?1 urea could not be refolded with a non-oxidized mobile phase. Although the oxidized and reduced glutathione (GSSG and GSH) were employed in the oxidized mobile phase, the reduced-denatured insulin still could not be renatured. However, in the presence of 2.0 mol L^t-1 urea in the oxidized mobile phase employed, the reduced-denatured insulin can be refolded with SEC, and the aggregation of denatured insulin can be diminished by urea. In addition, the disulfide exchange of reduced-denatured insulin also can be accelerated with GSSG/GSH in the oxidized mobile phase. The three disulfide bridges of insulin were formed correctly and the reduced-unfolded insulin can be renatured completely. The results were further tested with reversed-phase liquid chromatography (RPLC) and hydrophobic interaction chromatography (HIC).     

Characterization of disulfide linkages and disulfide bond scrambling in recombinant human macrophage colony stimulating factor by fast-atom bombardment mass spectrometry of enzymatic digests

Fast-atom bombardment mass spectrometry was used to study disulfide bonding patterns in heat-denatured human recombinant macrophage colony stimulating factor (rhM-CSF). The heat-denaturated protein was studied by analysis of the pattern of peptides in the proteolytic digests. Native rhM-CSF is a homodimer with intramolecular disulfide linkages between Cys7–Cys90, Cys48–Cys139, and Cys102–Cys146 and intermolecular linkages between Cys31-Cys31, and the pairs Cys157 and Cys159. Brief heating for 1 min leads to partial disulfide bond scrambling. In addition to the native disulfide bonds between Cys7–Cys90, Cys48–Cys139, and Cys31-Cys31, nonnative disulfide bonds were detected between Cys48–Cys90 and Cys48–Cys102. When heated for 5 min the disulfide bonds of rhM-CSF are completely scrambled and lead to nonnative intramolecular disulfide bonds between Cys48–Cys102 and Cys90–Cys102 and one intermolecular disulfide bond between Cys102–Cys102.     

Unexpected catalyzed C=C bond cleavage by molecular oxygen promoted by a thiyl radical.

Olefin oxidation with molecular oxygen, promoted by a transition metal catalyst and a thiophenol, involved C=C bond cleavage into the corresponding carbonyl derivatives. This new reaction proceeds under one atmosphere of oxygen, at room temperature, in the presence of an excess of thiophenol and a catalyst such as MnL(2) 3a or VClL(2) 3c. It was applied to aromatic and aliphatic olefins, as well as to functionalized or unfunctionalized acyclic compounds, providing the corresponding ketones and aldehydes in up to 98% yield. The synthetic interest of this catalytic oxidation was illustrated by a one-step preparation of the fragrance (-)-4-acetyl-1-methylcyclohexene 7e in 73% isolated yield. The C=C bond cleavage probably results from a catalyzed decomposition of the beta-hydroperoxysulfide intermediate 12 that is formed by the radical addition of thiophenol to the olefin in the presence of oxygen. Although an excess of the thiophenol was used, it was transformed into the disulfide which could then be reduced without purification in 83% overall yield, thereby allowing for recycling. In addition, the C=C bond cleavage under oxygen could be promoted by catalytic quantities of the thiyl radical, generated by photolysis of the disulfide; thus, in the presence of 0.1 equiv of bis(4-chlorophenyl) disulfide 4b and 5% of the manganese complex 3a, trans-methylstilbene 1b gave, under radiation, benzaldehyde 6a and acetophenone 7a in up to 95% yield. This new reaction offers an alternative to the classical C=C bond cleavage procedures, and further developments in the fields of bioinorganic and environmental chemistry are likely.     

Cyanoacetylene and Its Derivatives: XXVIII. Reactions of 2-Mercaptobenzothiazole with Nitriles of αα,ββ-Acetylene γγ-Hydroxyacids and with 3-Phenyl-2-propynonitrile

Nucleophilic addition of 2-mercaptobenzothiazole to 4-alkyl-4-hydroxy-2-alkynonitriles at 1:1 ratio in the presence of 4-6 wt% of Et₃N occurs regio- and stereospecifically to afford (Z)-4-alkyl-3-(benzothiazolyl-2-thio)-4-hydroxy-2-alkenonitriles (yield 40-51%). In the presence of 1.3 wt% of Dabco the thiazole and 4-hydroxy-4-methyl-2-pentynonitrile (1:1) give rise to a mixture of 2-alkenonitrile and 2-(3,3,6,6-tetramethyl-2-cyanomethyl-5-cyanomethylene-1,4-oxathian-2-yl)thiobenzothiazole. At the use of 4-6 wt% of LiOH arises an intractable mixture containing 1,4-oxathiane, benzothiazol-2-one, 2-[1-(5,5-dimethyl-2-cyanomethyl)-4-cyanomethylene-1,3-oxathiolan-2-yl)-1-methylethyl]thiobenzothiazole, bis(2,2,5,5-tetramethyl-6-cyanomethyl-3-cyanomethylene-1,4-oxathian-6-yl) disulfide, bis[1-(5,5-dimethyl-2-cyanomethyl-4-cyanomethylene-1,3-oxathiolan-2-yl)-1-methylethyl] disulfide, and 3-[1-(5,5-dimethyl-2-cyanomethyl-4-cyanomethylene-1,3-oxathiolan-2-yl)-1-methylethyl]benzothiazol-2-one (according to ¹H and ¹³C NMR data). 2-mercaptobenzothiazole adds to 3-phenyl-2-propynonitrile in the presence of 7 wt% of KOH with regio- and stereospecific formation of (Z)-3-(benzothiazolyl-2-thio)-3-phenyl-2-propenonitrile (88%).     

Kinetic analyses of disulfide formation between thiol groups attached to linear poly(acrylamide)

Kinetic analyses were carried out for formation of disulfide crosslinkages between thiol groups on linear polymers, poly(acrylamide‐co‐N‐acrylcysteamine) (P‐SH). Disulfide crosslinkages were formed by auto‐oxidation of pendant thiol groups or through the thiol‐disulfide exchange reaction induced by addition of disulfide compounds gluthathione. In the auto‐oxidation reaction, the rate constant for disulfide formation highly depended on pH values of the reaction mixtures and the P‐SH concentrations. Gelation rate is too slow to enclose living cells into hydrogel under physiological pH 7.4. The hydrogel formation rate can be accelerated by addition of disulfides, such as oxidized glutathione. In the later case, oxygen in the reaction mixture is not consumed. The thiol‐disulfide exchange reaction is much more suitable for the cell encapsulation than the thiol auto‐oxidation reaction. These findings give a basis for enclosure of living cells in a hydrogel. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011