cas 7652-46-2, N-ACETYL-L-CYSTEINE METHYL ESTER

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Highly stereoselective organocatalytic synthesis of pyrrolidinyl spirooxindoles containing halogenated contiguous quaternary carbon stereocenters
The highly stereoselective synthesis of pyrrolidine-fused spirooxindole derivatives bearing a carbon-halogen bond and contiguous quaternary carbon stereocenters was achieved via a [3 + 2] cycloaddition reaction. This method provided facile access to a collection of enantiomerically pure spiro[pyrrolidin-3,2′-oxindoles] containing halogenated contiguous quaternary carbon stereocenters in good to high yields (48–84%) and excellent stereoselectivity (up to >20:1 dr and >99% ee). The halogen-containing products can be stereoselectively transformed into sulfurated derivatives via nucleophilic substitution (SN2) reactions, indicating that they may serve as candidates in the development of covalent inhibitors with potential biological activity.
Chen, Fei-Yu,Han, Bo,Kang, Bin,Liu, Hong,Peng, Cheng,Xiang, Li,Zhan, Gu,Zhang, Shu-Cang
(2020)
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A simple, convenient method to synthesize cobalamins: Synthesis of homocysteinylcobalamin, N-acetylcysteinylcobalamin, 2-N-acetylamino-2- carbomethoxyethanethiolatocobalamin, sulfitocobalamin and nitrocobalamin
Glutathionylcobalamin, nitrocobalamin and sulfitocobalamin are important cobalamin metabolites isolable from human tissues. Herein we demonstrate that a procedure used to synthesize and isolate γ-glutamylcysteinylcobalamin and glutathionylcobalamin in aqueous solution in high yield and purity can be used to synthesize other novel, biologically relevant thiolatocobalamins, including d,l-homocysteinylcobalamin, N-acetyl-l-cysteinylcobalamin (Na+ salt) and 2-N-acetylamino-2-carbomethoxy-l-ethanethiolatocobalamin, as well as other non-alkylcobalamins, such as sulfitocobalamin (Na+ salt) and nitrocobalamin. This uncomplicated, general procedure will assist researchers in identifying unknown cobalamin metabolites isolated from biological samples, and researchers interested in studying the uptake and intracellular cobalamin processing mechanisms utilizing non-alkylcobalamin derivatives that are not yet commercially available. The X-ray structure and XAS spectrum of N-acetyl-l-cysteinylcobalamin are also presented. The Royal Society of Chemistry 2006.
Suarez-Moreira, Edward,Hannibal, Luciana,Smith, Clyde A.,Chavez, Roberto A.,Jacobsen, Donald W.,Brasch, Nicola E.
p. 5269 - 5277
(2006)
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COMPOUNDS AND IMPLANTS FOR TREATING OCULAR DISORDERS
The present disclosure relates to therapeutic compositions and therapies for use in the treatment of diseases and disorders of the eye. The present disclosure relates to curved, multilayer controlled-release ocular implant devices which include the therapeutic compositions of the present disclosure. The present disclosure related to methods for delivery of the therapeutic agents to the eye and the treatment of diseases and disorders of the eye.
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(2021/05/15)

Bioorthogonal Ligation and Cleavage by Reactions of Chloroquinoxalines with ortho-Dithiophenols
A bioorthogonal ligation and cleavage method via reactions of chloroquinoxalines (CQ) and ortho-dithiophenols (DT) is presented. Double nucleophilic substitutions of ortho-dithiophenols to chloroquinoxalines provide conjugates containing tetracyclic benzo[5,6][1,4]dithiino[2,3-b]quinoxaline with strong built-in fluorescence together with release of the other functional molecules. Three cleavable linkers were designed and successfully used in release of the molecules containing biotin from the protein conjugates. The CQ-DT bioorthogonal reactions can be applied for the bioorthogonal ligations, bioorthogonal cleavages, and trans-tagging of proteins, and show advantages of readily accessible unnatural orthogonal groups, appealing reaction kinetics (k2≈1.3 m?1 s?1), excellent biocompatibility of orthogonal groups, and high stability of conjugates. This complements previous bioorthogonal reactions and is a new route for protein-fishing applications and in-gel fluorescence analysis.
Fu, Hua,Li, Hongyun,Li, Youshan,Lou, Zhenbang,Yang, Haijun,Zhao, Yufen
supporting information
p. 3671 - 3677
(2020/02/04)

Protection of human retinal pigment epithelial cells from oxidative damage using cysteine prodrugs
Age-related macular degeneration (AMD) is one of the major causes of vision loss in the elderly in most developed countries. Among other causes, oxidative stress in the retinal pigment epithelium (RPE) has been hypothesized to be a major driving force of AMD pathology. Oxidative stress could be treated by antioxidant administration into the RPE cells. However, to achieve high in-vivo efficacy of an antioxidant, it is imperative that the agent be able to penetrate the tissues and cells. Evidence suggests that lipophilicity governs cellular penetrance. Out of many antioxidant candidates, N-acetyl-L-cysteine (a prodrug of L-cysteine) (NAC) is a potent antioxidant as the bioavailability of the parent drug, L-cysteine, determines the production of glutathione; the universal antioxidant that regulates ROS. To increase the lipophilicity, four ester derivatives of N-acetylcysteine: N-acetylcysteine methyl ester, N-acetylcysteine ethyl ester, N-acetylcysteine propyl ester, and N-acetylcysteine butyl ester were synthesized. To mimic in vitro AMD conditions, hydroquinone, a component of cigarette smoke, was used as the oxidative insult. Cytosolic and mitochondrial protection against oxidative stress were tested using cytosolic and mitochondrial specific assays. The results provide evidence that these lipophilic cysteine prodrugs provide increased protection against oxidative stress in human RPE cells compared with NAC.
Bulumulla, Chandima,Catchpole, Timothy,Christie, Abigail,Csaky, Karl G.,Kularatne, Ruvanthi N.,Stefan, Mihaela C.,Takacs, Alison
p. 386 - 394
(2020/04/17)

Visible-Light-Mediated S?H Bond Insertion Reactions of Diazoalkanes with Cysteine Residues in Batch and Flow
We describe the application of S?H bond insertion reactions of aryl diazoacetates with cysteine residues that enabled metal-free, S?H functionalization under visible-light conditions. Moreover, this process could be intensified by a continuous-flow photomicroreactor on the acceleration of the reaction (6.5 min residence time). The batch and flow protocols described were applied to obtain a wide range of functionalized cysteine derivatives and cysteine-containing dipeptides, thus providing a straightforward and general platform for their functionalizations in mild conditions. (Figure presented.).
Chen, Lin,Cui, Yu-Sheng,Duan, Xiu,Guo, Kai,Qin, Long-Zhou,Qiu, Jiang-Kai,Sun, Qi,Yuan, Xin,Zhuang, Kai-Qiang
supporting information
p. 5093 - 5104
(2020/09/23)

NOVEL COMPOUND EXHIBITING ANTI-OXIDATIVE OR ANTI-INFLAMMATORY ACTIVITY
The present invention relates to a novel compound exhibiting anti-oxidative or anti-inflammatory activity, a method of preparing the compound, a pharmaceutical composition for preventing or treating inflammatory diseases or the diseases caused by oxidation, which comprises the compound or a salt thereof as an active ingredient, and an anti-inflammatory or anti-oxidative cosmetic composition or food composition.
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(2019/07/29)

Labeling and Natural Post-Translational Modification of Peptides and Proteins via Chemoselective Pd-Catalyzed Prenylation of Cysteine
The prenylation of peptides and proteins is an important post-translational modification observed in vivo. We report that the Pd-catalyzed Tsuji-Trost allylation with a Pd/BIPHEPHOS catalyst system allows the allylation of Cys-containing peptides and proteins with complete chemoselectivity and high n/i regioselectivity. In contrast to recently established methods, which use non-native connections, the Pd-catalyzed prenylation produces the natural n-prenylthioether bond. In addition, a variety of biophysical probes such as affinity handles and fluorescent tags can be introduced into Cys-containing peptides and proteins. Furthermore, peptides containing two cysteine residues can be stapled or cyclized using homobifunctional allylic carbonate reagents.
Schlatzer, Thomas,Kriegesmann, Julia,Schr?der, Hilmar,Trobe, Melanie,Lembacher-Fadum, Christian,Santner, Simone,Kravchuk, Alexander V.,Becker, Christian F. W.,Breinbauer, Rolf
supporting information
p. 14931 - 14937
(2019/10/11)

Modulating Thiol p Ka Promotes Disulfide Formation at Physiological pH: An Elegant Strategy to Design Disulfide Cross-Linked Hyaluronic Acid Hydrogels
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.
Bermejo-Velasco, Daniel,Azémar, Alice,Oommen, Oommen P.,Hilborn, J?ns,Varghese, Oommen P.
p. 1412 - 1420
(2019/03/02)

Chemoselective Synthesis of N-Terminal Cysteinyl Thioesters via β,γ-C,S Thiol-Michael Addition
Dehydroalanine (ΔAla) is a highly electrophilic residue that can react efficiently with sulfur nucleophiles to furnish cysteinyl analogues. Herein, we report an efficient synthesis of N-terminal cysteinyl thioesters, suitable for S,N-acyl transfer, based on β,γ-C,S thiol-Michael addition. Both ionic and radical-based methodologies were found to be efficient for this process.
Petracca, Rita,Bowen, Katherine A.,McSweeney, Lauren,O'Flaherty, Siobhan,Genna, Vito,Twamley, Brendan,Devocelle, Marc,Scanlan, Eoin M.
supporting information
p. 3281 - 3285
(2019/05/10)

Selective Photoredox Trifluoromethylation of Tryptophan-Containing Peptides
For application in drug discovery and biomedicine, it is crucial to develop new biocompatible methods to modify polypeptides. Herein, a visible-light-induced photoredox trifluoromethylation of tryptophan-containing peptides is reported. Under a mild, biocompatible, and straightforward condition, this strategy could incorporate the trifluoromethyl group into tryptophan residue with excellent chemo- and site-selectivity. The use of lower photocatalyst loading in 2 mol-% and cheap CF3SO2Na salt represents a great catalytic activity and economic CF3 source. This direct trifluoromethylation strategy allows the ready study of fluorinated peptides exploiting 19F-NMR. Additionally, the development of this protocol enables the study of biochemical systems and potentially modulates the function of biomolecules. Careful mechanistic studies (Stern-Volmer fluorescence quenching, EPR, and radical inhibition/trapping experiments) indicate that the reaction would proceed with a radical–radical cross-coupling procedure.
Ding, Bo,Weng, Yue,Liu, Yunqing,Song, Chunlan,Yin, Le,Yuan, Jiafan,Ren, Yanrui,Lei, Aiwen,Chiang, Chien-Wei
p. 7596 - 7605
(2019/12/15)

Synthesis and cytotoxicity studies of novel NHC?-gold(I) complexes derived from lepidiline A
Ten novel N-heterocyclic carbene gold(I) complexes derived from lepidiline A (1,3-dibenzyl-4,5-dimethylimidazolium chloride) are reported here with full characterisation and biological testing. (1,3-Dibenzyl-4,5-diphenylimidazol-2-ylidene)gold(I) chloride (NHC?-AuCl) (1) was modified by substituting the chloride for the following: cyanide (2), dithiocarbamates (3-5), p-mercaptobenzoate derivatives (12-14) and N-acetyl-L-cysteine derivatives (15-17). All complexes were synthesised in good yields of 57-78%. Complexes 2, 12, 13, and 14 were further characterised by X-ray crystallography. Initial evaluation of the biological activity was conducted on all ten complexes against the multidrug resistant MCF-7topo breast cancer, HCT-116wt, and p53 knockout mutant HCT-116-/- colon carcinoma cell lines. Across the three cell lines tested, mainly single-digit micromolar IC50 values were observed. Nanomolar activity was exhibited on the MCF-7topo cell line with 3 displaying an IC50 of 0.28 μM ± 0.03 μM. Complexes incorporating a Au-S bond resulted in higher cytotoxic activity when compared to complexes 1 and 2. Theoretical calculations, carried out at the MN15/6-311++G(2df,p) computational level, show that NHC? is the more favourable ligand for Au(I)-Cl when compared to PPh3.
Curran, Danielle,Dada, Oyinlola,Müller-Bunz, Helge,Rothemund, Matthias,Sánchez-Sanz, Goar,Schobert, Rainer,Zhu, Xiangming,Tacke, Matthias
(2018/09/26)

Conformational study of L-methionine and L-cysteine derivatives through quantum chemical calculations and 3JHH coupling constant analyses
The understanding of the conformational behavior of amino acids and their derivatives is a challenging task. Here, the conformational analysis of esterified and N-acetylated derivatives of L-methionine and L-cysteine using a combination of 1H NMR and electronic structure calculations is reported. The geometries and energies of the most stable conformers in isolated phase and taking into account the implicit solvent effects, according to the integral equation formalism polarizable continuum model (IEF-PCM), were obtained at the ωB97X-D/aug-cc-pVTZ level. The conformational preferences of the compounds in solution were also determined from experimental and theoretical3 JHH coupling constants analysis in different aprotic solvents. The results showed that the conformational stability of the esterified derivatives is not very sensitive to solvent effects, whereas the conformational equilibrium of the N-acetylated derivatives changes in the presence of solvent. According to the natural bond orbital (NBO), quantum theory of atoms in molecules (QTAIM) and noncovalent interactions (NCI) methodologies, the conformational preferences for the compounds are not dictated by intramolecular hydrogen bonding, but by a joint contribution of hyperconjugative and steric effects.
Silva, Weslley G.D.P.,Braga, Carolyne B.,Rittner, Roberto
supporting information
p. 925 - 937
(2017/06/21)

Determination of the Absolute Configuration of (?)-Hydroxynitrilaphos and Related Biosynthetic Questions
The ongoing search for bioactive natural products has led to the development of new genome-based screening approaches to identify possible phosphonate producing microorganisms. From the identified phosphonate producers, several until now unknown phosphonic acid natural products were isolated, including (hydroxy)nitrilaphos (4 and 5) and (hydroxy)phosphonocystoximate (7 and 6). We present the synthesis of phosphonocystoximate via an aldoxime intermediate. Chlorination and coupling with methyl N-acetylcysteinate furnished 6 after global deprotection. The obtained experimental data confirm the previously assigned structure of the natural product. We were also able to determine the absolute configuration of (?)-hydroxynitrilaphos. Chiral resolution of diethyl cyanohydroxymethylphosphonate (24) with Noe's lactol furnished both enantiomers of 4. Conversion of (+)-24 to (R)-2-amino-1-hydroxyethylphosphonic acid by reduction of the cyano-group showed (?)-hydroxynitrilaphos ultimately to be S-configured. Further, we present a 13C-isotope labeling strategy for 4 and 5 that will possibly solve the question of whether hydroxynitrilaphos is a biosynthetic intermediate or a downstream product of hydroxyphosphonocystoximate biosynthesis.
Pallitsch, Katharina,Happl, Barbara,Stieger, Christian
p. 15655 - 15665
(2017/10/09)

Selective photocytotoxicity of anthrols on cancer stem-like cells: The effect of quinone methides or reactive oxygen species
Cancer stem cells (CSCs) are a subpopulation of cancer cells that share properties of embryonic stem cells like pluripotency and self-renewal and show increased resistance to chemo- and radiotherapy. Targeting CSC, rather than cancer cells in general, is a novel and promising strategy for cancer treatment. Novel therapeutic approaches, such as photodynamic therapy (PDT) have been investigated. A promising group of phototherapeutic agents are reactive intermediates - quinone methides (QMs). This study describes preparation of QM precursor, 2-hydroxy-3-hydroxymethylanthracene (2) and a detailed photochemical and photobiological investigation on similar anthracene derivatives 3 and 4. Upon photoexcitation with near visible light at λ > 400 nm 1 and 2 give QMs, that were detected by laser flash photolysis and their reactivity with nucleophiles has been demonstrated in the preparative irradiation experiments where the corresponding adducts were isolated and characterized. 3 and 4 cannot undergo photodehydration and deliver QM, but lead to the formation of phenoxyl radical and singlet oxygen, respectively. The activity of 1–4 was tested on a panel of human tumor cell lines, while special attention was devoted to demonstrate their potential selectivity towards the cells with CSC-like properties (HMLEshEcad). Upon the irradiation of cell lines treated with 1–4, an enhancement of antiproliferative activity was demonstrated, but the DNA was not the target molecule. Confocal microscopy revealed that these compounds entered the cell and, upon irradiation, reacted with cellular membranes. Our experiments demonstrated moderate selectivity of 2 and 4 towards CSC-like cells, while necrosis was shown to be a dominant cell death mechanism. Especially interesting was the selectivity of 4 that produced higher levels of ROS in CSC-like cells, which forms the basis for further research on cancer phototherapy, as well as for the elucidation of the underlying mechanism of the observed CSC selectivity based on oxidative stress activation.
Uzelac, Lidija,?kalamera, ?ani,Mlinari?-Majerski, Kata,Basari?, Nikola,Kralj, Marijeta
p. 558 - 574
(2017/06/23)

ANTIBACTERIAL AGENT
The invention provides a compound which is a peptide derivative of formula (1) as defined in the claims or a salt thereof: RG is H, -CH2-RGA or C1-12 hydrocarbyl optionally substituted with 1 to 4 substituents selected from -OR', -NO2, -CN, halogen and 5-6 membered heterocyclyl; or RG and RN1 together form a 5-6 membered heterocyclic ring which is optionally substituted with 1 to 3 substituents selected from Ra, -OR' and halogen; RGA is C1-11 hydrocarbyl optionally substituted with 1 to 4 substituents selected from -NR'R", -OR', -NO2, -CN, halogen and 5-6 membered heterocyclyl; RSis C1-16 hydrocarbyl, a 5-10 membered heterocyclyl or heteroaryl group, -(C1-4 alkylene)-RSA or -(C1-4 alkylene)-L-RSA; RSA is C1-16 hydrocarbyl, or a 5-10 membered heterocyclyl or heteroaryl group; L is -SO2-; and wherein RS and RSA are optionally substituted with a group Rb and/or from 1 to 5 substituents selected from Ra, -NR'R", -OR', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R", -0-C(0)R', -N(R')-C(0)R", -SR', -S(O)R', -S(O)2R', -S(O)2OR', -P(O)(OR')(OR"), =O, -SiR'R"R" and halogen; or Rs and an RC1 together form a 5-6 membered heterocyclyl ring which is optionally substituted with 1 to 3 substituents selected from Ra, -OR' and halogen; Rb is phenyl, benzyl, C3-6 cycloalkyl or 5-6 membered heterocyclyl; Q is -C(O)-N(RN2)-, -C(O)-C(R'R")-, -C(O)-O- -N(RN2)-C(O)-, -C(R'R")- C(O)-, -O-C(O)-, -C(R'R")-C(R"'R"")-, -C(R'R")-O- -O-C(R'R")-, -C(R'R")-N(RN2)-, -N(RN2)-C(R'R")- or -C(R')=C(R")-; Z is a group selected from -C(O)-O-RO and -CN4R' (tetrazolyl); RO is H or C1-12 hydrocarbyl optionally substituted with 1 to 4 substituents selected from -NR'R", -OR', -NO2, -CN, -C(O)R', -C(O)OR', -C(O)NR'R", -O-C(O)R', -N(R')- C(O)R", -SR', -S(O)R', -S(O)2R', -S(O)2OR', -P(O)(OR')(OR"), =O, halogen and 5-6 membered heterocyclyl; or RO and an RC2 together form a 5-6 membered heterocyclyl ring which is optionally substituted with 1 to 3 substituents selected from Ra, -OR' and halogen; each RN1 and RN2 is independently H or C1-4 alkyl; each RC1, RC2, R', R", R" and R"" is independently H or C1-4 alkyl and is optionally substituted with 1 to 3 substituents selected from halogen, -OH and -O-C1-4 alkyl; and each Ra is independently C1-4 alkyl which is optionally substituted with 1 to 3 halogen atoms.
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Page/Page column 30

(2016/12/07)

METHOD FOR THE PREPARATION OF N-ACETYL CYSTEINE AMIDE
The present application discloses an efficient process for the preparation of N-acetyl-L-cysteine amide (NACA) starting with N-acetyl-L-cysteine.
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Paragraph 0019; 0020; 0021

(2015/12/08)

STABILIZED MULTI-FUNCTIONAL ANTIOXIDANT COMPOUNDS AND METHODS OF USE
Disclosed are novel stable compounds having anti-oxidant properties and methods of using the compounds for the treatment of diseases or injuries associated with oxidative stress.
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Paragraph 00137; 00138

(2014/02/15)

Substrate-initiated synthesis of cell-penetrating poly(disulfide)s
Lessons from surface-initiated polymerization are applied to grow cell-penetrating poly(disulfide)s directly on substrates of free choice. Reductive depolymerization after cellular uptake should then release the native substrates and minimize toxicity. In the presence of thiolated substrates, propagators containing a strained disulfide from asparagusic or, preferably, lipoic acid and a guanidinium cation polymerize into poly(disulfide)s in less than 5 min at room temperature at pH 7. Substrate-initiated polymerization of cationic poly(disulfide)s and their depolymerization with dithiothreitol causes the appearance and disappearance of transport activity in fluorogenic vesicles. The same process is further characterized by gel-permeation chromatography and fluorescence resonance energy transfer.
Bang, Eun-Kyoung,Gasparini, Giulio,Molinard, Guillaume,Roux, Aurélien,Sakai, Naomi,Matile, Stefan
supporting information
p. 2088 - 2091
(2013/04/10)

Rapid cross-metathesis for reversible protein modifications via chemical access to se-allyl-selenocysteine in proteins
Cross-metathesis (CM) has recently emerged as a viable strategy for protein modification. Here, efficient protein CM has been demonstrated through biomimetic chemical access to Se-allyl-selenocysteine (Seac), a metathesis-reactive amino acid substrate, via dehydroalanine. On-protein reaction kinetics reveal a rapid reaction with rate constants of Seac-mediated-CM comparable or superior to off-protein rates of many current bioconjugations. This use of Se-relayed Seac CM on proteins has now enabled reactions with substrates (allyl GlcNAc, N-allyl acetamide) that were previously not possible for the corresponding sulfur analogue. This CM strategy was applied to histone proteins to install a mimic of acetylated lysine (KAc, an epigenetic marker). The resulting synthetic H3 was successfully recognized by antibody that binds natural H3-K9Ac. Moreover, Cope-type selenoxide elimination allowed this putative marker (and function) to be chemically expunged, regenerating an H3 that can be rewritten to complete a chemically enabled "write (CM)-erase (ox)-rewrite (CM)" cycle.
Lin, Yuya A.,Boutureira, Omar,Lercher, Lukas,Bhushan, Bhaskar,Paton, Robert S.,Davis, Benjamin G.
supporting information
p. 12156 - 12159
(2013/09/23)

Intramolecular hydrogen-bonding activation in cysteines: A new effective radical scavenger
The challenge of developing organic molecules with improved antioxidant activities for a competitive marketplace requires, given the great amount of possibilities, much laboratory work. Nowadays, the ability of methodologies based on quantum chemistry to determine the influence of different modifications on a molecule core provides a powerful tool for selecting the most useful derivatives to be synthesized. Here, we report the results of the assessment of antioxidant activity for quaternary amino acids, specifically for cysteine derivatives. The effect of introducing different substituents on the cysteine core is evaluated by using DFT to obtain an adequate structure-antioxidant activity relationship. This theoretical study shows a small panel of targets among which (R)-N-acetyl-2-methylcysteine methyl ester 15 exhibits special features and relevant antioxidant activity. The conformational 1H NMR study of this synthesized compound indicates the existence of an intramolecular C7 member ring involving S-H?OC substructure, which is reported for the first time in the literature for this amino acid unit. This unusual conformation seems to be the reason for the high antioxidant capacity experimentally found for this compound.
Haya, Luisa,Osante, I?aki,Mainar, Ana M.,Cativiela, Carlos,Urieta, Jose S.
p. 9407 - 9413
(2013/07/28)

OLEFIN METATHESIS REACTIONS OF AMINO ACIDS, PEPTIDES AND PROTEINS CONTAINING ALLYL SULFIDE GROUPS
A method for the modification of an amino acid, protein or peptide is disclosed. The method comprises reacting a carbon-carbon double bond-containing compound with an amino acid, a protein or a peptide containing an allyl sulfide group in the presence of a catalyst which promotes olefin metathesis, to form a modified amino acid, protein or peptide. Preferred carbon-carbon double bond-containing compounds include carbohydrates.
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(2012/07/27)

Hapalocyclamide: A novel phytotoxic hexapeptide of the cyanobacterium Hapalosiphon sp.
Hapalocyclamide, a novel oxazole-, thiazole- and thiazoline-containing cyclic hexapeptide, was isolated from the terrestrial cyanobacterium Hapalosiphon sp., and which showed phytotoxic activity on lettuce seedling growth. The gross structure of hapalocyclamide was established from spectroscopic data and chemical degradation. The absolute stereochemistry was determined by Marfey's analysis. Hapalocyclamide was established as cyclo-thiazole-l-alanine-oxazole-d-alanine-d-thiazoline-d-phenylalanine.
Koodkaew, Intira,Matsuyama, Shigeru,Sunohara, Yukari,Matsumoto, Hiroshi
experimental part
p. 977 - 979
(2012/03/26)

One-pot conversion of serine and α-methylserine derivatives to the corresponding cysteines and selenocystines by using chalcogenophosphate reagents
The one-pot reactions of N-acetylserine methyl ester and N-acetyl - methylserine methyl ester with Lawesson's or Woollins' reagent directly produced the corresponding cysteine or selenocysteine derivatives in moderate yields. The transformation would be initiated by phosphorylation of the hydroxy group, rather than chalcogenation of the amide group, and involve the oxazoline as a key intermediate. Copyright Taylor & Francis Group, LLC.
Makiyama, Akira,Komatsu, Itsuki,Iwaoka, Michio,Yatagai, Masanobu
scheme or table
p. 125 - 133
(2011/04/16)

Disulfide formation via sulfenamides
A phosphine-mediated one-step disulfide formation from S-nitrosothiols has been developed. This reaction can convert unstable S-nitrosothiols to stable disulfides via sulfenamide intermediates under very mild conditions. It has the potential to be used for the detection of S-nitrosothiols.
Pan, Jia,Xian, Ming
supporting information; experimental part
p. 352 - 354
(2011/03/17)

Rpe65 isomerase associates with membranes through an electrostatic interaction with acidic phospholipid headgroups
Opsins are light-sensitive pigments in the vertebrate retina, comprising a G protein-coupled receptor and an 11-cis-retinal-dehyde chromophore. Absorption of a photon by an opsin pigment induces isomerization of its chromophore to all-trans-retinal-dehyde. After a brief period of activation, opsin releases all-trans-retinaldehyde and becomes insensitive to light. Restoration of light sensitivity to the apo-opsin involves the conversion of all-trans-retinaldehyde back to 11-cis-retinal-dehyde via an enzyme pathway called the visual cycle. The critical isomerization step in this pathway is catalyzed by Rpe65. Rpe65 is strongly associated with membranes but contains no membrane- spanning segments. It was previously suggested that the affinity of Rpe65 for membranes is due to palmitoylation of one or more Cys residues. In this study, we re-examined this hypothesis. By two independent strategies involving mass spectrometry, we show that Rpe65 is not palmitoylated nor does it appear to undergo other post-translational modifications at significant stoichiometry. Instead, we show that Rpe65 binds the acidic phospholipids, phosphatidylserine, phosphatidylglycerol, and cardiolipin, but not phosphatidic acid. No binding of Rpe65 to basic phospholipids or neutral lipids was observed. The affinity of Rpe65 to acidic phospholipids was strongly pH-dependent, suggesting an electrostatic interaction of basic residues in Rpe65 with negatively charged phospholipid headgroups. Binding of Rpe65 to liposomes containing phosphatidylserine or phosphatidylglycerol, but not the basic or neutral phospholipids, allowed the enzyme to extract its insoluble substrate, all-trans- retinyl palmitate, from the lipid bilayer for synthesis of 11-cis-retinol. The interaction of Rpe65 with acidic phospholipids is therefore biologically relevant.
Yuan, Quan,Kaylor, Joanna J.,Miu, Anh,Bassilian, Sara,Whitelegge, Julian P.,Travis, Gabriel H.
experimental part
p. 988 - 999
(2010/12/18)

Development of a cysteine-catalyzed enantioselective rauhut-currier reaction
Herein, we report a full account of the development of an enantioselective Rauhut-Currier process that affords products in high yields and enantioselectivities using a cysteine-based catalyst. While traditional Morita-Baylis-Hillman catalysts were found to be essentially ineffective, various derivatives of protected cysteine were found to exhibit extraordinary reactivity and enantiotopic control. Extensive screening of reaction conditions led us to discover the enhanced effects of water as an additive and the chelating power of potassium in achieving higher enantiomer ratios. Mechanistic experiments also provided insight on the potential mechanism of the reaction in addition to possible transition states that provide the absolute stereochemistry formed in the observed products. Also included is a brief survey of the reaction scope involving different ring sizes as well as functionalized substrates.
Aroyan, Carrie E.,Dermenci, Alpay,Miller, Scott J.
experimental part
p. 5784 - 5796
(2010/10/19)

From disulfide- to thioether-linked glycoproteins
(Chemical Presented) Strengthening the bond: The introduction of a thiol tag in combination with chemoselective ligation to form a disulfide-linked bioconjugate is a selective and useful method for site-selective protein glycosylation. The phosphine-mediated desulfurization of such glycoconjugates to their reductant-resistant thioether-linked counterparts completes a convergent, site-selective synthesis of thioether-linked glycoproteins (see scheme).
Bernardes, Goncalo J. L.,Grayson, Elizabeth J.,Thompson, Sam,Chalker, Justin M.,Errey, James C.,El Oualid, Farid,Claridge, Timothy D. W.,Davis, Benjamin G.
supporting information; experimental part
p. 2244 - 2247
(2009/02/07)

Allyl sulfides are privileged substrates in aqueous cross-metathesis: Application to site-selective protein modification
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
Lin, Yuya A.,Chalker, Justin M.,Floyd, Nicola,Bernardes, Goncalo J. L.,Davis, Benjamin G.
supporting information; experimental part
p. 9642 - 9643
(2009/02/04)

Fast reductive ligation of S-nitrosothiols
(Chemical Equation Presented) Nitroso knows: A process has been developed which converts unstable S-nitrosothiols into stable sulfenamide analogues (see scheme).Reductive ligation proceeds rapidly in mixed organic solvent/water systems to give high yields. By applying this reaction, an efficient strategy for detecting S-nitrosylation in proteins and other biological systems is envisioned.
Wang, Hua,Xian, Ming
supporting information; experimental part
p. 6598 - 6601
(2009/03/12)

Enantioselective Rauhut-Currier reactions promoted by protected cysteine
We report highly enantioselective examples of the Rauhut-Currier cycloisomerization reaction (the "vinylogous Morita-Baylis-Hillman reaction"). The reaction is highly practical and is catalyzed by a commercially available derivative of the proteinogenic amino acid cysteine. Reactions are conducted in the presence of potassium tert-butoxide and a critical concentration of water in bulk acetonitrile. A mechanistic model is advanced that may account for reaction selectivity that is predicated on organizational chelation of K ion in the product-determining step in which the Cys derivative undergoes elimination. Copyright
Aroyan, Carrie E.,Miller, Scott J.
p. 256 - 257
(2007/10/03)

Concise Synthesis of Cyclothialidine Analogues with Ring Sizes from 12 to 15: Novel Macrocyclization Protocol Involving Reductive Thiolation
The DNA gyrase inhibitor cyclothialidine was shown to be an interesting lead structure for the search of new antibacterials. During extensive work elucidating the structure-activity relations, it was demonstrated that variation of the lactone ring size of its bicyclic core was tolerated. Indeed, even 'seco' analogues exhibited DNA gyrase inhibitory activity. These derivatives were subsequently found to be conveniently accessible by a reductive thiolation approach. Application of this methodology to cyclic systems established an alternative, concise, and flexible synthetic access to congeners of cyclothialidine of varying ring size which so far had been prepared by Mitsunobu lactonization of the corresponding seco acids.
Geiwiz, J.,Goetschi, E.,Hebeisen, P.
p. 1698 - 1704
(2007/10/03)

Acetyl bromide-alcohols as convenient reaction systems for: a) Removal of N-tert-Boc, N-Cbz and N-Ac protective groups, b) Esterifications and transesterifications, c) Debenzylation of aryl-O-benzyl ethers
Hydrogen bromide generated in situ by the addition of acetyl bromide to alcohols is a useful reagent for esterifications and transesterifications; N- tert-Boc, N-Cbz, and N-Ac deprotections; and debenzylation reactions.
Lesk,Nudelman
p. 1405 - 1408
(2007/10/03)

3,4-Epoxyprecocenes as Models of Cytotoxic Epoxides: Synthesis of the Cis Adducts Occuring in the Glutathione Metabolic Pathway
The adducts of 3,4-epoxyprecocene II (1b) with N-acetyl-L-cysteine, and glutathione (GSH), in which a formal syn addition of the thiol reagent to the oxirane has taken place, with the atom linked to the benzylic position of the benzopyranyl skeleton of 1b, have been synthesized.A stereochemical correlation between the two sets of diastereomeric cis adducts 3, 5, and 6 formed, i.e. the 3R,4S and 3S,4R series, has been established by spectroscopic, chromatographic, and enzymatic means.To assign the absolute configuration of these adducts, a synthesis of chiral 1b(3R,4R), using the cysteinyl moiety itself as reagent for resolution of the precursor racemic bromohydrin 7, has been developed.Regarding the influence of the reaction conditions on the stereochemical course of the oxirane cleavage, the addition of methyl esters of L-cysteine or its N-acetyl derivative to 1b in neutral organic solvents led to the corresponding cis adducts 4 and 2, respectively, with a high degree of stereoselectivity.On the other hand, in aqueous media the stereochemical outcome of the reaction of GSH with epoxide 1b depends on the solvent polarity and pH.Thus, while above pH13 the trans diastereomeric pair of adducts is almost quantitatively formed, a significant proportion of the corresponding cis conjugates is obtained within the pH range 8.5-10.5 (up to 24percent).This result suggests that the cis conjugates could also exert a role in the detoxification mechanisms of highly reactive epoxides.
Conchillo, Antonio,Camps, Francisco,Messeguer, Angel
p. 1728 - 1735
(2007/10/02)

Comparative Sulfhydryl Reaction Pathways of Chlorooxirane and Chloroacetaldehyde
Two bifunctional alkylating agents, chlorooxirane (1) and chloroacetaldehyde (2), which are putative metabolites of vinyl chloride (VC), are expected to be detoxified via S-(formylmethyl)glutathione as the common intermediate.This paper compares the behavior of 1 and 2 in their reactions with to model thiols in aqueous and chloroform media to evaluate the above hypothesis.In aqueous media, 1 and 2 react with N-acetylcysteine (3a) or its methyl ester 3b to form the same S-acetaldehyde 4a or 4b, which, upon standing, cyclized to the dihydro-1,4-2H-thiazine derivatives6a and 6b.In chloroform, the above products were obtained for both 1 and 2 via different pathways: the reaction of 3b and 2 formed initially the thiohemiacetal 7 at 0 deg C, which rearranged to the aldehyde 4b after warming or treatment with triethylamine.Another thiol, 3,4-dichlorobenzenethiol (8), used for trapping alkylating metabolites from VC as the S-acetaldehyde 9, was found to react with 1 but not 2 in aqueous solution to produce 9, whose identity was verified by an independently synthesized sample.The reaction of the thiol 8 and 1 in chloroform yielded 9 sluggishly; the reaction of 8 and 2 gave the thiohemiacetal 11, which rearranged to the aldehyde 9 when heated at 50 deg C or treated with pyridine.
Joseph, J. T.,Elmore, J. D.,Wong, John L.
p. 471 - 474
(2007/10/02)

Studies on the Reactivity of Bicyclomycin with Nucleophilic Amino Acid Derivatives
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Abuzar, Syed,Kohn, Harold
p. 4000 - 4003
(2007/10/02)

Formation of Thiocarbonyl Compounds in the Reaction of Ebselen Oxide with Thiols
Reaction of α-toluenethiol with Ebselen oxide, 2, affords dibenzyl disulfide and seleno sulfide 5, R = PhCH2.In the course of this reaction, thiobenzaldehyde is formed and can be trapped with cyclopentadiene in 90percent yield.Reaction of 2-propene-1-thiol with 2 afforded thioacrolein dimer in 69percent yield and seleno sulfide 5, R = CH2-CH=CH2.Trapping, stereochemical, and isotopic exchange studies were used to determine if in the reaction of 2 with 1-heptanethiol, cyclohexanethiol, and N-acetyl-D,L-cysteine thiocarbonyl compounds heptanethial, cyclohexanethione, and 2-acetamino-3-thioxopropanoic acid (α-thioformyl-N-acetylglycine), respectively, are also formed.These studies showed that free thiocarbonyl compounds are not formed in these reactions.
Glass, Richard S.,Farooqui, Firdous,Sabahi, Mahmood,Ehler, Kenneth W.
p. 1092 - 1097
(2007/10/02)

Methyl mercapturate episulfonium ion: A model reactive metabolite of dihaloethanes
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Henkel,Amato
p. 1279 - 1282
(2007/10/02)

Styrene derivatives, their use as antiallergic agents and intemediate epoxides for their synthesis
Alkenes of the formula (I) and epoxides (II) used to make them are useful as anti-inflammatory and antiallergic pharmaceuticals: STR1 wherein R1 =H or CH3 ; R2 =phenyl, substituted phenyl, benzyl or a cysteinyl moiety; R4 and R5 =alkyl; n=O or 1; and R3 is as described.
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(2008/06/13)

A NOTE ON THE SYNTHESIS OF METHACRYLATE-DERIVED MERCAPTURIC ACID METHYL ESTERS
The synthesis, TLC data and spectral characteristics of mercapturic acid methyl esters derived from five industrially important methacrylates and methacrylamide are described.
Kopecky, Jan,Smejkal, Jaroslav,Linhart, Igor,Hanus, Vladimir,Pech, Pavel
p. 1123 - 1128
(2007/10/02)

INTRINSIC REACTIVITIES IN THE ALKYLATIONS OF PROTECTED AMINO ACIDS BY (R)- AND (S)-METHYLOXIRANE
A comparative study is described of the reactions between protected amino acids and the enantiomeric methyloxiranes .At 45 deg C in methanol the relative rates of the reactions with either (1a) or (1b) are (5a) ca. (3a) > (2a>.The reaction of (1a)/(1b) with (2a) is dramatically accelerated (>/= 100-fold) by triethylamine, because of the conversion of (2a) into its thiolate.The products from (1a)/(1b) + (2a) thiolate are (R,αR)- and (S,αR)-N-acetyl-S-(2-hydroxy-propyl)-L-cysteine methyl ester .These products undergo a slow further reaction with methyloxirane leading via a β-elimination to N-acetyldehydroalanine methyl ester and bis-(2-hydroxypropyl) sulphide.The products from (1a)/(1b) + (3a) are (R,αS)- and (S,αS)-N-(2-hydroxypropyl)-L-valine methyl ester .These products also undergo a slow further reaction with methyloxirane leading to an NN-bis-(2-hydroxypropyl)valine methyl ester and derived morpholone (R,R,αS)-NN-bis-(2-hydroxypropyl)valine methyl ester (3f) and δ-lactone (3h)>.The reactions of (1a) or (1b) with (5a) give, via the products of mono-N-alkylation in the imidazole ring α-benzoyl-Nτ-(2-hydroxypropyl)-L-histidine methyl ester (5d) and its N?-isomer (5e) from (1b) + (5a)>, a mixture α-benzoyl-N?Nτ-bis-(2-hydroxypropyl)-L-histidinylimidazolium carboxylates (6d) + (6e) from excess of (1b) + (5a)>.The generation of methoxide during the reactions described is responsible for the β-elimination leading to a dehydroalanine derivative and for the epimerisation during the formation of (6d) + (6e).Kinetic studies show that for none of the substrates (2a), (3a), or (5a) is there significant enantioselectivity in their reactions with the enantiomers of methyloxirane.The relevance of the present study to the toxicology of methyloxiranes is discussed.
Ellis, Martin K.,Golding, Bernard T.,Watson, William P.
p. 1737 - 1744
(2007/10/02)