Reaction of chloro(triphenylmethyl)disulfide with 1,3-dienes: synthesis of cyclic di- and terasulfides.

Chloro(triphenylmethyl)disulfide (3) reacts with 2,3-dimethyl-1,3-butadiene (4) to yield cyclic disulfide 5 (a product consistent with the trapping of diatomic sulfur) as well as the cyclic tetrasulfide 6.     

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.     

Dopamine selective molecularly imprinted polymers via post-imprinting modification

A novel synthetic dopamine receptor bearing bidentate binding sites were prepared by covalent imprinting using a disulfide linkage which is cleaved and oxidized to a non-covalent sulfoxide recognition group. The used templates have dopamine-like structures connected to an allyl moiety via a disulfide and to a 4-vinylphenyl group via a cyclic boronic diester. After the polymerization, the ester bonds were hydrolyzed and the disulfide bond was reduced to remove the template moiety from the polymer matrix, followed by the oxidation to transform the thiol residues into sulfonic acid (post imprinted process). The imprinted polymer adsorbed dopamine selectively in aqueous solution with the two-point interaction, i.e. the formation of cyclic boronic diester and electrostatic interaction with the sulfonic acid residue.     

Methane formation by reaction of a methyl thioether with a photo-excited nickel thiolate--a process mimicking methanogenesis in archaea

The formation of a sulfuranyl radical intermediate followed by methyl transfer to the nickel(I) center of coenzyme F430 and generation of the disulfide has been proposed as a possible mechanism for the formation of methane catalyzed by methyl coenzyme M reductase in methanogenic archaea. In order to test this hypothesis, a sterically shielded, bifunctional model substrate that contained a methyl thioether and a sulfhydryl functional group, which could form a five-membered cyclic sulfuranyl radical according to the postulated mechanism, was synthesized. The corresponding thiolate reacted with Ni(II) salts to give a diamagnetic, square-planar Ni(II) dithiolate complex, which was characterized by X-ray diffraction. Upon irradiation of this complex with light of lambda > 300 nm, methane and the cyclic disulfide were formed, whereas irradiation of the thiolate in the absence of nickel gave only traces of methane and no cyclic disulfide. The observed products are consistent with the postulated mechanism via a sulfuranyl radical, and the role of light is interpreted as the formation of a Ni(I)/thiyl radical pair upon excitation of a charge-transfer band of the Ni(II) dithiolate. In the presence of a large excess of thiolate, the diamagnetic complex was transformed into a paramagnetic, five- or six-coordinate complex that proved to be more active in the generation of both methane and the cyclic disulfide, than the square-planar diamagnetic dithiolate.     

Synthesis and ring‐opening polymerization of co‐cyclic(aromatic aliphatic disulfide) oligomers

An effective approach was presented for the synthesis of co‐cyclic(aromatic aliphatic disulfide) oligomers by catalytic oxidation of aromatic and aliphatic dithiols with oxygen in the presence of a copper‐amine catalyst. The aromatic dithiols can be 4,4′‐oxybis(benzenethiol), 4,4′‐diphenyl dithiol, 4,4′‐diphenylsulfone dithiol. The aliphatic dithiols can be 1,2‐ethanedithiol, 2,3‐butanedithiol, 1,6‐hexane dithiol. The co‐cyclic(aromatic aliphatic disulfide) oligomers were characterized by gradient HPLC, MALDI‐TOF‐MS, GPC, ¹H‐NMR, TGA, and DSC techniques. The glass transition temperatures of these co‐cyclics ranged from ?11.3 to 56.6°C. In general, these co‐cyclic(aromatic aliphatic disulfide) oligomers are soluble in common organic solvents, such as CHCl₃, THF, DMF, DMAc. These co‐cyclic oligomers readily underwent free radical ring‐opening polymerization in the melt at 180°C, producing linear, tough and high molecular weight poly(aromatic aliphatic disulfide)s. The glass transition temperatures of these polymers ranged from ?3.7 to 107.8°C that are higher than those of corresponding co‐cyclics. Copyright © 2003 John Wiley & Sons, Ltd.     

Application and Structural Analysis of Triazole‐Bridged Disulfide Mimetics in Cyclic Peptides

Ruthenium‐catalysed azide–alkyne cycloaddition (RuAAC) provides access to 1,5‐disubstituted 1,2,3‐triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied. We report synthetic strategies to install various triazole linkages into cyclic peptides through backbone cyclisation and RuAAC cross‐linking reactions. These linkages were evaluated in four serine protease inhibitors based on sunflower trypsin inhibitor‐1. NMR and X‐ray crystallography revealed exceptional consensus of bridging distance and backbone conformations (RMSD<0.5 Å) of the triazole linkages compared to the parent disulfide molecules. The triazole‐bridged peptides also displayed superior half‐lives in liver S9 stability assays compared to disulfide‐bridged peptides. This work establishes a foundation for the application of 1,5‐disubstituted 1,2,3‐triazoles as disulfide mimetics.     

PHOTOLYSIS OF SOME CYCLIC DISULFIDES*

Abstract— Photolysis of liquid pentarnethylene disuliide, liquid tetramethylene disulfide and liquid l, 4-butanedithiol has been studied. Photolysis of the cyclic disulfides by irradiation in their lowest energy absorption band produces the corresponding dithiol; photolysis of alkali-doped cyclic disulfide at the same irradiation wavelength as above produces the corresponding cyclic monosulfide. It is suggested that photolysis of undoped liquids proceeds via -S-S- scission, whereas that of the doped liquids is supposed to involve initial -CS- scission. Photolysis of the dithiol produces the corresponding cyclic monosulfide, the rate of such production being considerably enhanced in the presence of alkali. Much of the above data and suggestions are rationalized using a simple MO formalism, which also involves an attempted interpretation of much of the electronic spectra of the various compounds. Product identification was made by study of the short wavelength absorption spectrum of the vapor in equilibrium with the photolysed material.     

Application and Structural Analysis of Triazole-Bridged Disulfide Mimetics in Cyclic Peptides

Ruthenium-catalysed azide–alkyne cycloaddition (RuAAC) provides access to 1,5-disubstituted 1,2,3-triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied. We report synthetic strategies to install various triazole linkages into cyclic peptides through backbone cyclisation and RuAAC cross-linking reactions. These linkages were evaluated in four serine protease inhibitors based on sunflower trypsin inhibitor-1. NMR and X-ray crystallography revealed exceptional consensus of bridging distance and backbone conformations (RMSD<0.5 Å) of the triazole linkages compared to the parent disulfide molecules. The triazole-bridged peptides also displayed superior half-lives in liver S9 stability assays compared to disulfide-bridged peptides. This work establishes a foundation for the application of 1,5-disubstituted 1,2,3-triazoles as disulfide mimetics.     

Basic Al2O3 as an Efficient Heterogeneous Reagent for the Synthesis of Symmerical Dialkyl Trithiocarbonates

This work deals with reaction of alkyl halides with carbon disulfide in the presence of basic alumina as heterogeneous and reusable reagent. It afforded symmetrical dialkyl trithiocarbonate in moderate to excellent isolated yields. Reaction of 1,2‐dichloro ethane with carbon disulfide also proceeded in a similar manner to give a five‐membered cyclic trithiocarbonate without formation of any polymeric by‐product.     

Synthesis of new cyclic dialkoxy disulfides

Five new cyclic dialkoxy disulfides have been synthesized and fully characterized. An X-ray structure was obtained for the 2,3-furandimethylene dialkoxy disulfide.     

Thioctic acid modification of oligonucleotides using an H-phosphonate

The H-phosphonate of a derivative of thioctic acid (TA) was synthesised and used to introduce a disulfide moiety at the 5′-end of oligonucleotides. This method overcomes the difficulties experienced with the phosphoramidite approach when employing a cyclic disulfide in the starting alcohol. The disulfide-modified oligonucleotides are subsequently used in metallic nanoparticle (Au and Ag) and surface functionalisation for sensitive, sequence specific analytical detection strategies.     

Highly efficient chemical fixations of carbon dioxide and carbon disulfide by cycloaddition to aziridine under atmospheric pressure

Cycloaddition of aziridine with carbon dioxide was successfully catalyzed by alkali metal halide or tetraalkylammonium halide to give the corresponding 5-membered cyclic urethane, 1,3-oxazolidin-2-one, selectively. The reaction can be performed at ambient temperature under atmospheric pressure. Analoguous reaction of aziridine with carbon disulfide also successfully gave the corresponding 5-membered cyclic dithiourethane, 1,3-thioxazolidine-2-thione.     

Fragmentation of peptide disulfides under conditions of negative ion mass spectrometry: Studies of oxidized glutathione and contryphan

The fragmentation of positive and negative ions of peptide disulfides under mass spectrometric conditions yields distinctly different product ion distributions. A negative ion upon collision induced dissociation yields intense product ions, which correspond to cleavage at the disulfide linkage. The complete assignment of the product ions obtained upon fragmentation of oxidized glutathione in an ion trap is presented. The cleavage at the disulfide site is mediated by abstraction of CalphaH and CbetaH protons resulting in product ions derived by neutral loss of H2S2 and H2S. The formation of peptide thioaldehydes and persulfides at the cysteine sites is established. Dehydroalanine formation at the Cys residue is predominant. The case of a contryphan, a cyclic peptide disulfide derived from Conus snail venom, illustrates the utility of negative ion mass spectrometry in disulfide identification. Complementary information is derived by combining the fragmentation patterns obtained from positive and negative ions of disulfide containing peptides.     

Cyclic and linear amidine catalysts for the efficient synthesis of cyclic trithiocarbonates from carbon disulfide and episulfides under mild conditions

Cyclic and linear amidines effectively catalyzed the reaction of carbon disulfide and episulfides under mild conditions, such as ordinary pressure and ambient temperature, to give the corresponding cyclic trithiocarbonates in high yields.     

Direct electrochemistry of bovine heart cytochrome c facilitated by cysteine derivatives and analogues. Some effects of facilitator structure

Bovine heart cytochrome c electrochemistry was investigated by cyclic voltammetry using gold electrodes modified by self-assembled monolayers of cysteine and some of its derivatives, including glutathione. Glutathione shows a peculiar dependence of the facilitating ability on the oxidation state of the sulfur functionality. Whereas the disulfide form acts as an efficient facilitator, the thiol form is completely inactive. This behavior was accounted for by the lower stability of adsorbed thiol layers as compared to disulfide layers. Apparently, small molecules of cysteine derivative form rather stable adsorbed layers with a high degree of dimer formation. Conversely, reduced glutathione is not able to turn into the disulfide form in the adsorbed layer. Consequently, only the layer produced by the adsorption of the disulfide form itself is stable enough for promoting direct electron transfer reactions of cyt c. Electronic Publication     

磺胺甲恶唑在二硫化钼纳米片修饰电极上的电化学行为

采用了研磨后超声和离心分离方法制备了二硫化钼纳米片,通过原子力显微镜(AFM)和扫描电子显微镜(SEM)对不同离心速度分离的二硫化钼纳米片进行了表征。使用循环伏安法(CV)和差分脉冲伏安法(DPV)在磺胺甲恶唑溶液中对二硫化钼纳米片修饰的玻碳电极进行了电化学行为研究。结果显示,磺胺甲恶唑在二硫化钼修饰电极的循环伏安图上有一对氧化还原峰。其峰电流值与扫描速度的平方根成正比,是扩散控制过程。DPV扫描结果显示,磺胺甲恶唑的峰电流与其浓度之间存在着明显的线性关系。研磨超声方法制备出的二硫化钼纳米片层材料在电极上能够加速电子的转移和传输,从而有效提高峰电流值,为进一步研制准确测定磺胺甲恶唑电化学传感器提供了一种可选择的材料和电化学分析方法。     

Copolymerization of elemental sulfur with cyclic(arylene disulfide) oligomers

Copolymerization reactions between cyclic(arylene disulfide) oligomers were studied. The cyclic disulfide oligomers derived from 4,4′-isopropylidene bisbenzenethiol gave soluble polysulfanes via copolymerization with S₈. The copolymerization reactions were studied both in solution and melt by GPC and NMR. Solution copolymerization reactions can only form polysulfanes with up to three to four sulfur linkages; however, melt copolymerization reactions gave polysulfanes with up to seven sulfur linkages (average). The melt copolymerization reactions between cyclic disulfide oligomers derived from 4,4′-thiobis(benzenethiol) and S₈ were studied using DSC, TGA, and DMTA. With increasing contents of sulfur in the polysulfanes, T_gs, 5% weight losses by TGA, and tan δ decreased. With seven sulfur linkages in the polymer, it is a rubber with a T_g of 12°C, a 5% weight loss by TGA of 249°C, and tan δ of 44°C, respectively. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35 : 2961–2968, 1997     

Disulfide bond decay during matrix-assisted laser desorption/ionization time-of-flight mass spectrometry experiments

In our laboratory, we have been studying the reductive processes that occur during matrix-assisted laser desorption/ionization (MALDI) experiments. Recently, we have finished an analysis of the DHB matrix effect on the azo group in cyclic peptides. However, deep understanding of disulfide bond behaviour during a mass spectrometry (MS) experiment is much more important in proteomics as its reduction can cause serious errors in protein spectra interpretation. Therefore, we have focused on intra- and intermolecular disulfide bonds as well as disulfide bonds connecting cysteine and 2-thio-5-nitrobenzoic acid (TNB, Ellman's reagent modification) in model peptides during MALDI MS measurements. While the reduction was not observed for intra- and intermolecular cysteine-cysteine disulfide bonds, the disulfide connection between cysteine and TNB was always affected. It was proved that TNB and Ellman's reagent can act as a matrix itself. The results obtained enabled us to propose a reaction mechanism model which is able to describe the phenomena observed during the desorption/ionization process of disulfide-containing molecules.     

Recognition of the dihydrogenophosphate anion on a gold electrode derivatized with an amidoferrocenylalkylthiolate ligand

A dialkyl disulfide derivative with an amidoferrocenyl termini was synthesized and coordinated as an alkylthiolate ligand to the surface of a gold electrode which was shown by cyclic voltammetry. This derivatized electrode behaved as an electrochemical redox sensor allowing the recognition of the dihydrogenophosphate anion.