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Conformations of disulfide and diselenide were compared in (Boc-Cys/Sec-NHMe)2 and (Boc-Cys/Sec-OMe)2 using X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, density functional theory (DFT), and circular dichroism (CD) spectroscopy. Conformations of disulfide/diselenide in polypeptides are defined based on the sign of side chain torsion angle χ3 (–CH2–S/Se–S/Se–CH2–); negative indicates left-handed and positive indicates right-handed orientation. In the crystals of (Boc-Cys-OMe)2 and (Boc-Sec-OMe)2, the disulfide exhibits a left-handed and the diselenide a right-handed orientation. Characterization of cystine and selenocystine derivatives in solution using 1H-NMR, natural abundant 77Se NMR, 2D-ROESY, and chemical shift analysis coupled to DMSO titration has indicated the symmetrical nature and antiparallel orientation of Cys/Sec residues about the disulfide/diselenide bridges. Structural calculations of cystine and selenocystine derivatives using DFT further support the antiparallel orientation of Cys/Sec residues about disulfide/diselenide. The far-ultraviolet (UV) region CD spectra of cystine and selenocystine derivatives have exhibited the negative Cotton effect (CE) for disulfide and positive for diselenide confirming the difference in the conformational preference of disulfide and diselenide. In the previously reported polymorphic structure of (Boc-Sec-OMe)2, the diselenide has right-handed orientation. In the X-ray structures of disulfide and diselenide analogues of Escherichia coli protein encoded by curli specific gene C (CgsC) retrieved from Protein Databank (PDB), disulfide has left-handed and the diselenide right-handed orientation. The current report provides the evidence for the local conformational difference between a disulfide and a diselenide group under unconstrained conditions, which may be useful for the rational replacement of disulfide by diselenide in polypeptide chains.

A new catalytic protocol for the synthesis of selenoesters from aryl iodides and diaryl diselenides has been developed, where formic acid was employed as an efficient, low-cost, and safe substitute for toxic and gaseous CO. This protocol presents a high functional group tolerance, providing access to a large family of selenoesters in high yields (up to 97%) while operating under mild reaction conditions, and avoids the use of selenol which is difficult to manipulate, easily oxidizes, and has a bad odor. Additionally, this method can be efficiently extended to the synthesis of thioesters with moderate-to-excellent yields, by employing for the first time diorganyl disulfides as precursors.

A method for the photoinduced evolution of atomic oxygen from pyridazine N-oxides was developed. This underexplored oxygen allotrope mediates arene C-H oxidation within complex, polyfunctional molecules. A water-soluble pyridazine N-oxide was also developed and shown to promote photoinduced DNA cleavage in aqueous solution. Taken together, these studies highlight the utility of pyridazine N-oxides as photoactivatable O(3P) precursors for applications in organic synthesis and chemical biology.

The present invention discloses a green disulfide synthesis method, belonging to the field of green chemical and organic synthesis technology. Under room temperature, open, neutral conditions, rapid preparation of parent nuclei is alkanes, olefins, aromatic hydrocarbons, oxazole, thiazole, pyrazole, imidazole, etc. and their derivatives of symmetrical disulfide, the catalyst is MBrx(M is Fe2+,Fe3+,Ce3+, etc., x is 2-3), the only oxidant isH2O2. The present invention is reacted by using commercially available and low-cost reagents (e.g., FeBr2,CeBr3 andH2O2,etc.) and common organic solvents, the steps are concise, the operation is convenient, the reaction is rapid, the reaction conditions are mild, the room temperature is open, and no further purification can be obtained pure disulfide, more advantageous than all previous methods, is expected to be in organic synthesis, medicine, Pesticides and electronics and other industries are widely used.

Proteins with a functionalized C-terminus such as a C-terminal thioester are key to the synthesis of larger proteins via expressed protein ligation. They are usually made by recombinant fusion to intein. Although powerful, the intein fusion approach suffe

Lantibiotics are a class of peptide antibiotics with activity against most Gram-positive bacteria. Lanthionine (Lan) and β-MeLan are unusual thioether-bridged, non-proteinogenic amino acids, which are characteristic features of lantibiotics. In this paper, we report the facile stereoselective synthesis of β-methyllanthionines with orthogonal protection by nucleophilic ring opening of aziridines. This method leads to an expedient access to β-methyllanthionines and allows production of over 30 g of β-methyllanthionine in a single batch.

The disulfide bond plays a crucial role in protein biology and has been exploited by scientists to develop antibody-drug conjugates, sensors, and for the immobilization other biomolecules to materials surfaces. In spite of its versatile use, the disulfide chemistry suffers from some inevitable limitations such as the need for basic conditions (pH > 8.5), strong oxidants, and long reaction times. We demonstrate here that thiol-substrates containing electron-withdrawing groups at the β-position influence the deprotonation of the thiol group, which is the key reaction intermediate in the formation of disulfide bonds. Evaluation of reaction kinetics using small molecule substrate such as l-cysteine indicated disulfide formation at a 2.8-fold higher (k1 = 5.04 × 10-4 min-1) reaction rate as compared to the conventional thiol substrate, namely 3-mercaptopropionic acid (k1 = 1.80 × 10-4 min-1) at physiological pH (pH 7.4). Interestingly, the same effect could not be observed when N-acetyl-l-cysteine substrate (k1 = 0.51 × 10-4 min-1) was used. We further grafted such thiol-containing molecules (cysteine, N-acetyl-cysteine, and 3-mercaptopropionic acid) to a biopolymer namely hyaluronic acid (HA) and determined the pKa value of different thiol groups by spectrophotometric analysis. The electron-withdrawing group at the β-position reduced the pKa of the thiol group to 7.0 for HA-cysteine (HA-Cys); 7.4 for N-acetyl cysteine (HA-ActCys); and 8.1 for HA-thiol (HA-SH) derivatives, respectively. These experiments further confirmed that the concentration of thiolate (R-S-) ions could be increased with the presence of electron-withdrawing groups, which could facilitate disulfide cross-linked hydrogel formation at physiological pH. Indeed, HA grafted with cysteine or N-acetyl groups formed hydrogels within 3.5 min or 10 h, respectively, at pH 7.4. After completion of cross-linking reaction, both gels demonstrated a storage modulus G′ ≈ 3300-3500 Pa, which indicated comparable levels of cross-linking. The HA-SH gel, on the other hand, did not form any gel at pH 7.4 even after 24 h. Finally, we demonstrated that the newly prepared hydrogels exhibited excellent hydrolytic stability but can be degraded by cell-directed processes (enzymatic and reductive degradation). We believe our study provides a valuable insight on the factors governing the disulfide formation and our results are useful to develop strategies that would facilitate generation of stable thiol functionalized biomolecules or promote fast thiol oxidation according to the biomedical needs.

Monoamino cyclic tellurides with a five- or six-membered ring structure and their derivatives were developed as a new class of catalyst for the oxidation of organothiols to organodisulfides in a glutathione peroxidase-like catalytic reaction. Quantitative conversion and high reaction rate were achieved by performing the reaction in an organic-aqueous segmented microflow system. Importantly, the process circumvented product purification, which is a major limitation of current organodisulfide synthetic methods.

A method of preventing or inhibiting L-cystine crystallization is disclosed, using the compounds of formula I: [in-line-formulae]R1a—[O]v-(-A-L-)m-A-[O]v—R1b [/in-line-formulae] wherein A, L, R1a, R1b, m, and v are as described herein. The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of conditions that are causally related to L-cystine crystallization, such as comprising (but not limited to) kidney stones.

We report herein the synthesis of silver nanoparticles (Ag NPs), their characterization, and anion and cation sensing properties. Freshly prepared amide-triazole Ag NPs (3a-Ag NPs and 3b-Ag NPs) could detect fluoride and cations such as Hg2+ and Cd2+ in aqueous media with a color change from pink to brown. The cysteine-based Ag NPs 5b-Ag NPs showed a colorimetric response towards H2PO4-, whereas 6-Ag NPs showed a colorimetric response towards H2PO4- and HSO4- in aqueous media.

Melt polycondensation approach is developed for new classes of reduction responsive disulfide containing functional polyesters based on l-cystine amino acid resources under solvent free process. l-Cystine was converted into multi-functional ester-urethane monomer and subjected to thermoselective transesterification at 120 °C with commercial diols in the presence of Ti(OBu)4 to produce polyesters with urethane side chains. The polymers were produced in moderate to high molecular weights and the polymers were found to be thermally stable up to 250 °C. The β-sheet hydrogen bonding interaction among the side chain urethane unit facilitated the self-assembly of the polyester into amyloid-like fibrils. The deprotection of urethane unit into amine functionality modified the polymers into water soluble cationic polyester spherical nanoparticles. The reduction degradation of disulfide bond was studied using DTT as a reducing agent and the high molecular weight polymers chains were found be chopped into low molecular weight oligomers. The cytotoxicity of cationic disulfide nanoparticle was studied in MCF-7 cells and they were found to be biocompatible and non-toxic to cells upto 50 μg/mL. The custom designed reduction degradable and highly biocompatible disulfide polyesters from l-cystine are useful for futuristic biomedical applications.

A new method for the synthesis of secondary thiocarbamates from readily available isocyanides and thiosulfonates with broad functional group tolerance is reported. The reaction proceeds under mild reaction conditions in isopropanol and is catalyzed by inexpensive sodium iodide.

The reversible metathesis of disulfide bonds is generally induced by a combination of a reducing agent and base or by irradiation with ultraviolet light. Here we report that ultrasound irradiation is suitable for generating clean equilibrium mixtures of disulfides within one hour or one day, depending on the sonication source. Preliminary mechanistic investigations suggest that the solvent plays an active role in producing initiator radicals.

Selenocysteine is a valuable component of both natural selenoproteins and designer biocatalysts; however the availability of such proteins is hampered by technical limitations. Here we report the first general strategy for the production of selenoproteins via genetically-encoded incorporation of a synthetic photocaged selenocysteine residue in yeast cells, and provide examples of light-controlled protein dimerization and targeted covalent labeling in vitro.

Multiple applications of isothioureas as fine chemicals (or their precursors) are known, but a general sustainable method for their synthesis was hitherto unavailable. We report a novel general approach towards S-alkyl and S-aryl isothioureas through a copper(I)-catalyzed three-component reaction between amines, isocyanides, and thiosulfonates. The formal synthesis of a superpotent sweetener further illustrates the applicability of our method. Safety first! A direct synthesis of isothioureas by a copper-catalyzed three-component reaction from readily available substrates (see scheme) avoids the toxic, flammable, and highly reactive reagents required in classical approaches. The reaction also enables the straightforward synthesis of S-aryl isothioureas, which are difficult to obtain by other methods.

A method of preventing or inhibiting L-cystine crystallization using the compounds of formula (I) is disclosed, wherein A, L, R1a, R1b, and m are as described herein. The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of conditions that are causally related to L-cystine crystallization, such as comprising (but not limited to) kidney stones.

Olefin metathesis has recently emerged as a viable reaction for chemical protein modification. The scope and limitations of olefin metathesis in bioconjugation, however, remain unclear. Herein we report an assessment of various factors that contribute to productive cross-metathesis on protein substrates. Sterics, substrate scope, and linker selection are all considered. It was discovered during this investigation that allyl chalcogenides generally enhance the rate of alkene metathesis reactions. Allyl selenides were found to be exceptionally reactive olefin metathesis substrates, enabling a broad range of protein modifications not previously possible. The principles considered in this report are important not only for expanding the repertoire of bioconjugation but also for the application of olefin metathesis in general synthetic endeavors.

(Figure Presented) A phosphine-free palladium catalyst for aqueous Suzuki-Miyaura cross-coupling is presented. The catalyst is active enough to mediate hindered, ortho-substituted biaryl couplings but mild enough for use on peptides and proteins. The Suzuki-Miyaura couplings on protein substrates are the first to proceed in useful conversions. Notably, hydrophobic aryl and vinyl groups can be transferred to the protein surface without the aid of organic solvent since the aryl- and vinylboronic acids used in the coupling are water-soluble as borate salts. The convenience and activity of this catalyst prompts use in both general synthesis and bioconjugation.

Allyl sulfides undergo efficient cross-metathesis in aqueous media with Hoveyda-Grubbs second generation catalyst 1. The high reactivity of allyl sulfides in cross-metathesis was exploited in the first examples of cross-metathesis on a protein surface. S-Allylcysteine was incorporated chemically into the protein, providing the requisite allyl sulfide handle. Preliminary efforts to genetically incorporate S-allylcysteine into proteins are also reported. Copyright

An efficient and robust oxidative elimination of cysteine to dehydroalanine has been discovered. The reaction is induced by O-mesitylenesulfonylhydroxylamine (MSH) and is compatible with methionine. The key elimination has been executed on protein surfaces and allows ready access to different post-translationally modified proteins through conjugate addition of sulfur nucleophiles to dehydroalanine. Treatment of the resulting thioether with MSH results in regeneration of dehydroalanine, allowing a "functional switch" by subsequent addition of a different thiol. Copyright

Recent studies have demonstrated that arginase plays important roles in pathologies such as asthma or erectile dysfunctions. We have synthesized new ω-borono-α-amino acids that are analogues of the previously known arginase inhibitors S-(2-boronoethyl)-l-cysteine (BEC) and 2-amino-6- boronohexanoic acid (ABH) and evaluated them as inhibitors of purified rat liver arginase (RLA). In addition to the distance between the B(OH)2 and the α-amino acid functions, the position of the sulfur atom in the side chain also appears as a key determinant for the interaction with the active site of RLA. Furthermore, substitution of the alkyl side chain of BEC by methyl groups and conformational restriction of ABH by incorporation of its side chain in a phenyl ring led to inactive compounds. These results suggest that subtle interactions govern the affinity of inhibitors for the active site of RLA.

N-Boc derivatives of Met, Cys, and Trp, the properties of which resemble those of the respective amino acid residues present in proteins, are efficiently oxidized by methyltrioxorhenium and H2O2. A high regioselectivity for the oxida

(Chemical Equation Presented) Quorum sensing is a process by which bacteria sense cell density. This cell-cell communication process is mediated by autoinducers. A cross-species messenger, autoinducer-2 (Al-2) is produced from S-ribosyl-L-homocysteine by the LuxS enzyme. A proposed mechanism for LuxS is an aldose-ketose isomerization of S-ribosylhomocysteine followed by a β-elimination. We report here the synthesis of two substrate analogues, S-anhydroribosyl-L-homocysteine and S-homoribosyl-L-cysteine, which prevent the initial and final step of the mechanism, respectively.

The synthesis of the S1-N10 nine-membered lactone core 28 of enf-griseoviridin is reported. Starting from cystine derivative 25, encompassing a terminal ynoate, treatment under Zn/AcOH conditions led to the formation of lactone 28 in 12% yield. Therefore, the lactone moiety of enf-griseoviridin is obtained in 10.7% overall yield for two steps. An access to the corresponding 5-epi-griseoviridin lactone 29 is also described.

A cationic rhodium(I)/PPh3 complex is an effective catalyst for dehydrogenation of primary or secondary alkanethiols to symmetrical disulfides under inert atmosphere. The dependence of reactivity on the structure of thiols is examined in detail.

Efficient synthesis of cystine, selenocystine, and their higher homologues like homo and bishomo amino acid derivatives from natural amino acid derivatives using tetrathiomolybdate and tetraselenotungstate reagents under mild and neutral conditions is reported. The generality of the reaction has been studied by capping various groups to amino and carboxyl components of canonical amino acids.

Synthesis of the lactone core 17 of 8-epi-griseoviridin is reported. Thioethynyl derivative 11 was easily prepared via an anionic coupling reaction between acetylenic compound 9 and sulfone 10. After desilylation of 11, saponification of the resulting hydroxy ester 12 followed by a Mitsunobu macrolactonization furnished the unusual triple-bond-containing nine-membered lactone 13 in 50% yield for the last two steps (39% after recrystallization). Stannylation under Magriotis conditions led to the pure regio- and stereocontrolled vinyltin 14 (80% yield). After a Sn/I exchange, palladium-catalyzed carbonylation delivered either the ester lactone 16 in 67% yield or the propargyl amide 17 in 65% yield. Synthesis of propargyl amide 17 of the lactone core of 8-epi-griseoviridin was achieved in 11.9% overall yield from commercial L-cystin dimethyl ester (nine steps).

S-allyloxycarbonylaminomethyl derivatives of thiols in general and cysteine in particular are readily deprotected by palladium catalysed hydrostannolysis with tributyltin hydride in the presence of acetic acid. They are perfectly stable in the basic conditions (piperidine/DMF) of Fmoc group removal but tend to decompose, albeit slowly, in the acidic conditions (TFA/CH2Cl2) of t-Bu and Boc groups removal.

S-Allocam derivatives of thiols in general and cysteine in particular are selectively and readily deprotected through palladium catalyzed hydrostannolysis. They are perfectly stable in the basic conditions of Fmoc-removal, but only marginally stable in the acidic conditions of t-Bu, Boc removal.

Phthalimidomethyl group is employed as a protecting group of thiols.This group can be introduced to thiols under mild reaction conditions and be removed by treatment with hydrazine hydrate followed by mercuric acetate or cupric acetate.

A general one-pot, two-stage procedure is described for the preparation of the title compounds from the free amino acids in near quantitative yields.

The 4-methoxybenzyl thioether protecting group is deblocked efficiently by oxidation with the homogeneous electron transfer agent tris(4-bromophenyl)ammoniumyl (2.+) leading to the disulfide in high yields.S-(4-methoxybenzyl)cysteine derivatives like 9 in this way can be transformed into the corresponding cystine derivatives like 10 in 90percent yield.Many N and carboxy protecting groups like the Boc and Z group and tert-butyl or benzyl ester functions are stable under the cleavage conditions.On the other hand the 4-methoxybenzyl thioether protecting group is totally unaffected by the conditions for oxidative deblocking of the S-trityl functions by either iodine or rhodanolysis.This opens up new opportunities for the directed synthesis of cystinyl peptides with more than one intra- or interchain disulfide bridge.Application of the new method to the synthesis of a cystine peptide with one intrachain S-S-bridge and a double-chain biscystinyl peptide is reported.

The total syntheses of sparsomycin (1), a naturally occurring antibiotic and antitumor substance, and its three stereomers 65-67 are described for the first time.In a convergent approach, the carboxylic acid 2 and the amine 3 were synthesized followed by amide formation (Scheme I).The acid 2 was prepared (23percent yield) from 6-methyluracil (12) by coupling the aldehyde 19 with the phosphorane 20 (Scheme III).The synthesis of the amine 3, especially challenging because of the monoxodithioacetal moiety, was accomplished by the reaction of a cysteine α-halo sulfoxide derivative 8 with sodium methylmercaptide (Scheme II, route B).Alternatively, oxidation of the dithioacetals 23-26 was unsatisfactory, yielding predominantly the undesired regioisomers 27B-30B (Table I).Procedures are given for the preparation and separation of the α-halo sulfoxide diastereomers 33,35, 36-41, and 52-54.By use of these procedures, the amino alcohol monoxodithioacetals 3 and 60 were prepared in five steps (40percent yield) from the D-cystine derivative 59 having the SC chirality of sparsomycin (Scheme VII).Finally, sparsomycin (1) and the SC diastereomer 67 were prepared (40percent yield) by mixed anhydride coupling of 2 with 3 and 60, respectively (Schemes I and X).In addition, syntheses of the RC enantiomer 65 and corresponding diastereomer 66 are described (Scheme IX).The CD spectra of 1 and its three stereomers are also discussed.