Synthesis of acylhydrazino-peptomers, a new class of peptidomimetics, by consecutive Ugi and hydrazino-Ugi reactions

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2016, 12, 2865–2872, doi:10.3762/bjoc.12.285

• compared to a natural peptide. Indeed, these compounds have shown to be a useful class of peptidomimetics with interesting biological activities [21][22][23], including antiviral [25][26] and cysteine protease inhibition [27][28][29][30]. Hydrazinopeptides [31][32][33][34][35][36] (peptide analogs in which

O-Alkylated heavy atom carbohydrate probes for protein X-ray crystallography: Studies towards the synthesis of methyl 2-O-methyl-L-selenofucopyranoside

• Roman Sommer,
• Dirk Hauck,
• Annabelle Varrot,
• Anne Imberty,
• Markus Künzler and
• Alexander Titz

Beilstein J. Org. Chem. 2016, 12, 2828–2833, doi:10.3762/bjoc.12.282

• was available for molecular replacement and the protein contains only one methionine and no cysteine residues, which is insufficient to consider incorporation of selenomethionine in the protein for the structure elucidation. Its carbohydrate-binding specificity was determined and a preference for O

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

• Michaela Prothiwa,
• Dávid Szamosvári,
• Sandra Glasmacher and
• Thomas Böttcher

Beilstein J. Org. Chem. 2016, 12, 2784–2792, doi:10.3762/bjoc.12.277

• developed a library of cysteine reactive chemical probes with an alkyne handle for fluorescence tagging and report the selective and highly sensitive in vitro labelling of the active site cysteine of this important enzyme. Interestingly, only one type of probe, with a reactive α-chloroacetamide was capable

• (Figure 1B) [14]. For the condensation step of an anthraniloyl residue with malonyl-CoA by PqsD, a cysteine residue (Cys112) is involved in the formation of a covalent thioester intermediate. We were speculating that activity-based electrophilic probes may be applicable to target this enzyme in vitro

• , Cys112, is engaging in the catalytic process forming a covalent reaction intermediate. We thus aimed at exploring the possibility to selectively label the active site cysteine residue using chemical probes. Activity-based protein profiling (ABPP) has become a powerful tool to study protein function and

Interactions between cyclodextrins and cellular components: Towards greener medical applications?

• Loïc Leclercq

Beilstein J. Org. Chem. 2016, 12, 2644–2662, doi:10.3762/bjoc.12.261

• ., alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, cysteine and methionine), they can be easily included inside the CDs. This complexation leads to modification of the protein. For sake of clarity, only some typical examples are reported in this section. In their paper on the

• NMR signals corresponding to Trp residues were shifted upon the addition of G1-β-CD due to encapsulation of the tryptophan residues in the G1-β-CD cavity [92]. In addition, the 1H NMR signals for cysteine 64 and isoleucine 98 were also influenced to a considerable extent with the addition of G1-β-CD

Economical and scalable synthesis of 6-amino-2-cyanobenzothiazole

• Jacob R. Hauser,
• Hester A. Beard,
• Mary E. Bayana,
• Katherine E. Jolley,
• Stuart L. Warriner and
• Robin S. Bon

Beilstein J. Org. Chem. 2016, 12, 2019–2025, doi:10.3762/bjoc.12.189

• preparation of luciferins 3 involves straightforward condensation of CBTs 1 with D-cysteine (2) (Scheme 1). For BLI applications, luciferins are often generated in vivo from CBTs [4][5][6][7], which are easier to modify and handle due to their higher stability, cell permeability, and reactivity than the full

• bioorthogonal reaction (k ≈ 10 M−1s−1) [9] for site-specific labelling or immobilisation of proteins 4, either at an N-terminal cysteine residue or at a 1,2-aminothiol group incorporated into a non-natural amino acid (Scheme 1) [10][11]. In addition, CBT derivatives have been used for the synthesis of polymeric

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• peptidyl carrier protein (PCP) of the downstream NRPS module is loaded with an L-cysteine, which serves as a sulphur donor. From 177, sulphur is transferred by the NifS-like cysteine desulphurase TlmS to the tRNA-specific and adenosine triphosphate (ATP)-dependent 2-thiouridylase TlmJ, which is thereby

Artificial Diels–Alderase based on the transmembrane protein FhuA

• Hassan Osseili,
• Daniel F. Sauer,
• Klaus Beckerle,
• Marcus Arlt,
• Tomoki Himiyama,
• Tino Polen,
• Akira Onoda,
• Ulrich Schwaneberg,
• Takashi Hayashi and
• Jun Okuda

Beilstein J. Org. Chem. 2016, 12, 1314–1321, doi:10.3762/bjoc.12.124

• contains a cysteine residue at position 545 for conjugation [31], an NHC ligand containing a maleimide function was prepared (Scheme 1). The imidazolium salt 3 was synthesized by nucleophilic substitution of mesityl imidazol 1 with maleimide derivative 2. These salts were used to generate the Cu(I) NHC

• using the established anchoring strategy, the Cu(I) and Cu(II) complexes (4 and 10–12) were anchored covalently inside the β-barrel structure. After anchoring, the protein was refolded by dialysis (Scheme 3). Anchoring of all complexes was successful. Titration of the free cysteine with the fluorescence

• dye ThioGlo® indicated that more than 95% of the cysteine residues were conjugated for each catalyst. Renaturing of the protein was successful in the case of the terpy ligand framework (for clarity of the location of the catalyst, see Figure S1 in Supporting Information File 1). After 3 days of

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• -2-ylphosphonates showed cysteine protease inhibition activities. 2.2.9 Heterocyclic bisphosphonates: A modified Kabachnik–Fields reaction of the substituted amine 135 with triethyl orthoformate followed by reaction with sodium diethylphosphite afforded bisphosphonate intermediate 136 that was

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• -translationally modified into the final product, and a heterotrimeric complex that is responsible for both heterocyclisation of serine and cysteine residues, and subsequent oxidation of (ox/thi)azolines into (ox/thi)azoles (Figure 3A). This catalytic complex consists of “C” and “D” proteins (annotated as McbB and

• McbD, respectively, for microcin B17) that cooperate to catalyse heterocyclisation of specific serine and cysteine residues in McbA, and a flavin-dependent dehydrogenase (the “B-protein”, McbC for microcin B17) that oxidises these heterocycles. These early in vitro studies indicated that the “C-protein

• then be attacked by an adjacent serine or cysteine side chain, thus releasing phosphate/AMP and generating the heterocycle. This order of steps was not advocated by either the Naismith or Mitchell groups as it requires a disfavoured 5-endo-trig cyclisation, although this mode of cyclisation is

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• without significantly affecting the reaction (93–97% yield, 92:8 to 96:4 er). The authors also explored further elaboration of the products to access enantioenriched cysteine analogues. The Glorius lab has made use of N-heterocyclic carbene (NHC) catalysts for intermolecular Stetter reactions between

Gold-catalyzed direct alkynylation of tryptophan in peptides using TIPS-EBX

• Gergely L. Tolnai,
• Jonathan P. Brand and
• Jerome Waser

Beilstein J. Org. Chem. 2016, 12, 745–749, doi:10.3762/bjoc.12.74

• context, the modification of natural peptides and proteins is highly attractive, and it has been the target of intensive research in the last decades (Figure 1) [6][7][8][9][10][11]. The functionalization of highly reactive cysteine, lysine and the N-terminus has been particularly successful [12][13][14

• using a linker is used, for example an alkylation reaction of cysteine. The direct introduction of an alkyne onto the biomolecule would be interesting to profit from modified electronic and spectroscopic properties. However, the direct alkynylation of peptides or proteins is usually based on the use of

• instantaneous. It was highly chemoselective for thiols in the presence of other nucleophilic functional groups. The alkynylation could be therefore applied to cysteine-containing peptides. The scope of the reaction could be later extended to a broad range of aliphatic and aromatic alkynes [35]. In 2015, the

Biosynthesis of α-pyrones

• Till F. Schäberle

Beilstein J. Org. Chem. 2016, 12, 571–588, doi:10.3762/bjoc.12.56

• mechanism for CorB and MxnB closely resembles each other, but certain differences have also been proposed, as will be discussed here. First, one chain is transferred and covalently linked to the active-site cysteine. This results in an activation of the cysteine-tethered chain. In the second step, the other

• chain is placed into the proximal cavity, orienting the α-carbon in a position suitable for the nucleophilic attack by the cysteine-tethered, activated chain. Thereby, the second chain is still attached to the ACP, the phosphopantetheine residue reaching into the T-shaped catalytic cavity, enabling the

• catalytic cysteine. Subsequently, lactonization can take place. It is assumed that an enolate exists as an intermediate in the formation of the C–O bond [88]. Even though for both enzymes no experimental evidences for the chronological order of the two condensation reactions exist, it can be expected that

Mycothiol synthesis by an anomerization reaction through endocyclic cleavage

• Shino Manabe and
• Yukishige Ito

Beilstein J. Org. Chem. 2016, 12, 328–333, doi:10.3762/bjoc.12.35

• stereochemistry of the glucosamine and cysteine moieties [21][22]. Hung also reported the utility of the 2-azido-2-deoxyglycosyl donor and resolved inositol isomers in a recent MSH synthesis [23]. Knapp et al. reported an intramolecular aglycone delivery method in order to achieve complete α-stereoselectivity [24

• synthesis of MSH was completed as follows (Scheme 5): the carbamate and acetyl groups were removed by alkaline hydrolysis to give known compound 8 [24]; then, benzyl groups were removed by H2/Pd(OH)2/C in AcOH/dioxane/H2O. Although it was reported that the cysteine moiety was introduced by 1-[bis

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• the product of a polyketide biosynthetic gene cluster [24]. To test whether N-acetylcysteine could be a biosynthetic precursor of the unusual 1,5-oxathiocane structure, feeding experiments using both (2S)- and (2R)-N-((2H3)acetyl)cysteine were performed. The deuterium atoms of both precursors were

• experiments are rare, but can provide interesting insights into the biosynthesis of sulfur containing natural products. Besides the recently presented synthetic developments towards 36S-labeled SAM and methionine [77], also [34S]cysteine has been made accessible by synthesis from elemental 34S8 and used to

• . Oxygen atoms originating from water are labeled as Oa, whereas 18O labels in the hydroxy group of chorismate are annotated as Ob. The XanB2-reaction was not investigated (missing label). Incorporation of sulfur into tropodithietic acid (72) via cysteine. Biosynthetic proposal for the starter unit of

Active site diversification of P450cam with indole generates catalysts for benzylic oxidation reactions

• Paul P. Kelly,
• Anja Eichler,
• Susanne Herter,
• David C. Kranz,
• Nicholas J. Turner and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2015, 11, 1713–1720, doi:10.3762/bjoc.11.186

• were identified in seven sub-libraries (Figure 1, bottom). Among this new population, structural and functional diversity was evident as can be seen from the grid structure (Figure 1, bottom) representing all active variant combinations identified across libraries I–VII. Cysteine, asparagine and

Pyridinoacridine alkaloids of marine origin: NMR and MS spectral data, synthesis, biosynthesis and biological activity

• Louis P. Sandjo,
• Victor Kuete and
• Maique W. Biavatti

Beilstein J. Org. Chem. 2015, 11, 1667–1699, doi:10.3762/bjoc.11.183

• studies performed on this topic. Riddick showed the oxidation product of tryptophan (61) (kynurenine (62)) as the precursor for the biosynthesis of pyridoacridines (Figure 6) [74]. Kynurenine (62) with acetic acid forms the quinolinone 63, which in presence of amino acids such as cysteine, asparagine

• decarboxylated to give kynuramine (65). The latter, by reaction with dopamine, forms the benzo-3,6-phenanthroline intermediate 68, which in turn gave shermilamine B (67) upon reaction with cysteine (Figure 8) [76]. The compounds 13-didemethylaminocycloshermilamine D (31) and demethyldeoxyamphimedine (9) (Figure

•  9) were presumably formed by reaction of a related benzophenanthroline (styelsamine D, 6) with cysteine and formaldehyde, respectively [47]. This reaction was followed by cyclization and oxidation to afford the alkaloids (Figure 9). The analysis of different biosynthesis pathways clearly suggested

A novel and widespread class of ketosynthase is responsible for the head-to-head condensation of two acyl moieties in bacterial pyrone biosynthesis

• Darko Kresovic,
• Florence Schempp,
• Zakaria Cheikh-Ali and
• Helge B. Bode

Beilstein J. Org. Chem. 2015, 11, 1412–1417, doi:10.3762/bjoc.11.152

• using stable isotope labeled precursors [7] suggested a two-chain biosynthesis mechanism for photopyrone biosynthesis (Scheme 1): First, thioester-activated 9-methyldecanoic acid 14 is covalently bound to an active site cysteine. Deprotonation of the α-carbon of 14 results in the formation of a

Orthogonal dual-modification of proteins for the engineering of multivalent protein scaffolds

• Michaela Mühlberg,
• Michael G. Hoesl,
• Christian Kuehne,
• Jens Dernedde,
• Nediljko Budisa and
• Christian P. R. Hackenberger

Beilstein J. Org. Chem. 2015, 11, 784–791, doi:10.3762/bjoc.11.88

• canonical amino acids, particularly cysteine. For example, SPI was used to introduce a NCAA such as azidohomoalanine (Aha) in a methionine-(Met)-auxotroph in combination with the chemical modification of the natural amino acid cysteine [30][31]. These handles were, e.g., addressed by CuAAC and disulfide

• cysteine has some drawbacks including the high tendency for disulfide bond formation or cross reaction with other cysteine residues, reaction reversibility, and occasionally side-reactions with basic side chains, e.g., lysines [33]. Specifically, in the current paper we use in the current paper the oxime

Regulation of integrin and growth factor signaling in biomaterials for osteodifferentiation

• Qiang Wei,
• Theresa L. M. Pohl,
• Anja Seckinger,
• Joachim P. Spatz and
• Elisabetta A. Cavalcanti-Adam

Beilstein J. Org. Chem. 2015, 11, 773–783, doi:10.3762/bjoc.11.87

• peptide, a prodomain and a mature domain. The proproteins dimerize after the signal peptide has been removed and are enzymatically cleaved to yield the biologically active dimeric mature protein [57]. The amino acid sequence of BMPs and their "cystine knot" motif, which is composed of seven cysteine units

• , is highly conserved [50]. Six of the seven cysteine residues Cys14/Cys79, Cys47/Cys113, and Cys43/Cys111 form intramolecular disulfide bonds to stabilize the monomer, whereas the seventh cysteine (Cys78) contributes to the formation of an intermolecular bond between the two monomers for dimerization

• focal adhesion and actin fibers is hindered (b). Reprinted with permission from [29]. Copyright 2009 American Chemical Society. (a) BMP-2 homodimer. 3D-Structure of a BMP-2 homodimer (blue and pink) with cysteine residues, highlighted in yellow to show the intra- and intermolecular disulfide bonds

Exploring monovalent and multivalent peptides for the inhibition of FBP21-tWW

• Lisa Maria Henning,
• Sumati Bhatia,
• Miriam Bertazzon,
• Michaela Marczynke,
• Oliver Seitz,
• Rudolf Volkmer,
• Rainer Haag and
• Christian Freund

Beilstein J. Org. Chem. 2015, 11, 701–706, doi:10.3762/bjoc.11.80

• highest frequency in the phage display experiment (RPPCGYPLP), did not show any binding to either WW domain in ITC experiments, possibly reflecting the potential of the cysteine residue to form an unspecific complex with glutathione-S-transferase. Similarly, the peptide RPPPPHFPQ could not be confirmed as

Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications

• Tor E. Kristensen

Beilstein J. Org. Chem. 2015, 11, 446–468, doi:10.3762/bjoc.11.51

• related compounds, such as various amino alcohols and the thiol-functional amino acid cysteine. While the basic methodology underlying this approach has been known for decades, it has evolved through recent developments connected to amino acid-derived chiral organocatalysts to become a more widely

• asymmetric organocatalysis picked up momentum quite rapidly. Through a series of disclosures, during the time period from 2010 to 2012, Xiangkai Fu and co-workers detailed the preparation of amphiphilic organocatalysts from serine, threonine and cysteine by acidic O-acylation, as well as their use in

• asymmetric organocatalysis [54][55][56][57][58][59][60][61]. Chemoselective O-acylation of serine, threonine and cysteine in CF3CO2H with a range of acyl chlorides, followed by crystallization of the product directly from the reaction mixture by addition of Et2O, furnished a comprehensive collection of

Natural phenolic metabolites with anti-angiogenic properties – a review from the chemical point of view

• Qiu Sun,
• Jörg Heilmann and
• Burkhard König

Beilstein J. Org. Chem. 2015, 11, 249–264, doi:10.3762/bjoc.11.28

• the amino acid cysteine, producing aliphatic secondary metabolites with thiol functionalities instead of phenolic ones. Nevertheless, this class contains thio-analogs of the naturally occurring o-catechol substructure, and thus, it has been included in this review. Zhang and Xu et al. [51] have

Sacrolide A, a new antimicrobial and cytotoxic oxylipin macrolide from the edible cyanobacterium Aphanothece sacrum

• Naoya Oku,
• Miyako Matsumoto,
• Kohsuke Yonejima,
• Keijiroh Tansei and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2014, 10, 1808–1816, doi:10.3762/bjoc.10.190

• cysteinyl residues in proteins, thereby affecting redox-controlled signal transduction pathways [19]. The induction of membrane blebbing has been reported for lipophilic inhibitors of protein phosphatase 2A, which is a cysteine-dependent phosphatase [20][21]. However, 1 did not inhibit this enzyme (data not

Synthesis and bioactivity of analogues of the marine antibiotic tropodithietic acid

• Patrick Rabe,
• Tim A. Klapschinski,
• Nelson L. Brock,
• Christian A. Citron,
• Paul D’Alvise,
• Lone Gram and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2014, 10, 1796–1801, doi:10.3762/bjoc.10.188

• TDA. The introduction of sulfur proceeds via nucleophilic attack of S-thiocysteine to the Michael acceptor of tropone-2-carboxylic acid coenzyme A ester and oxidative elimination of cysteine. The second sulfur atom is introduced by analogous attack to the vinylogous Michael acceptor. The volatiles

Bifunctional dendrons for multiple carbohydrate presentation via carbonyl chemistry

• Davide Bini,
• Francesco Nicotra and
• Laura Cipolla

Beilstein J. Org. Chem. 2014, 10, 1686–1691, doi:10.3762/bjoc.10.177

• dendrons in quantitative yields. The glycosylated dendrons can be exploited for further chemoselctive thiol–ene reactions with matrices suitably functionalized with thiol groups, i.e., cysteine residues in proteins. Experimental General methods All chemicals were purchased from Sigma-Aldrich and used