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

Carbohydrate PEGylation, an approach to improve pharmacological potency

• M. Eugenia Giorgi,
• Rosalía Agusti and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 1433–1444, doi:10.3762/bjoc.10.147

• ]. Several methods have been developed for site-directed PEGylation. One of the most popular involves the reaction of the thiol group in one or two cysteine residues with appropriate PEG derivatives. The cysteine could be originally present in the protein or introduced by mutagenesis [27][28]. The C-terminus

Automated solid-phase peptide synthesis to obtain therapeutic peptides

• Veronika Mäde,
• Sylvia Els-Heindl and
• Annette G. Beck-Sickinger

Beilstein J. Org. Chem. 2014, 10, 1197–1212, doi:10.3762/bjoc.10.118

• ]. Chemical synthesis of lipidated peptides is mostly performed by SPPS using the Fmoc/t-Bu strategy allowing for selective and efficient modification. Fatty acids can be incorporated into the peptide sequence at the N-terminus [98], at lysine [99] or cysteine side chains [100] and by esterification [101]. A

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• of amide bonds by 1,2,3-triazoles, especially the 1,4-disubstituted isomer, provided a wide variety of biological active peptidomimetics. Peptidomimetics containing these triazole cores can serve as blood components [77], anticancer medications [78], inhibitors of cysteine [79] and HIV-1 proteases

• expected compound 109 (Scheme 34). Thiazoles In several natural products, the thiazole ring can be found as a backbone linker, probably resulting from easy cyclization/oxidation of cysteine residues. These compounds show interesting antifungal and antibiotic [95][96], algicidal [97], and antitumor [98][99

Synthesis of nucleotide–amino acid conjugates designed for photo-CIDNP experiments by a phosphotriester approach

• Tatyana V. Abramova,
• Olga B. Morozova,
• Vladimir N. Silnikov and
• Alexandra V. Yurkovskaya

Beilstein J. Org. Chem. 2013, 9, 2898–2909, doi:10.3762/bjoc.9.326

• solvent systems (see below) and spots were visualized by UV irradiation, ninhydrin (for amine groups) or cysteine/aqueous sulfuric acid (for nucleosides and tryptophan) solution. Evaporations were performed under reduced pressure at 40 °C. The preparative silica gel column chromatography was performed

Advancements in the mechanistic understanding of the copper-catalyzed azide–alkyne cycloaddition

• Regina Berg and
• Bernd F. Straub

Beilstein J. Org. Chem. 2013, 9, 2715–2750, doi:10.3762/bjoc.9.308

• agent, the water-soluble tris(2-carboxyethyl)phosphine (TCEP; often prepared and used as its hydrochloride salt TCEP·HCl) can be employed [45][46][47][48][49][50][51][52][53][54][55], which is especially suitable for applications in biological systems because it also protects cysteine residues in

Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties

• Catalin V. Maftei,
• Elena Fodor,
• Peter G. Jones,
• M. Heiko Franz,
• Gerhard Kelter,
• Heiner Fiebig and
• Ion Neda

Beilstein J. Org. Chem. 2013, 9, 2202–2215, doi:10.3762/bjoc.9.259

• . With an IC50 value of 9.4 µM, compound 7 was the most active, probably because maleimide is able to rapidly bind to the cysteine-34 position of circulating albumin, transported as an albumin conjugate (macromolecular drug), and then released in the target tissue by acid related cleavage or enzymatic

Isotopically labeled sulfur compounds and synthetic selenium and tellurium analogues to study sulfur metabolism in marine bacteria

• Nelson L. Brock,
• Christian A. Citron,
• Claudia Zell,
• Martine Berger,
• Irene Wagner-Döbler,
• Jörn Petersen,
• Thorsten Brinkhoff,
• Meinhard Simon and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2013, 9, 942–950, doi:10.3762/bjoc.9.108

• -serine to L-cysteine. Elemental sulfur, hydrogen sulfide, or thiosulfate can be funneled via the lithotrophic sulfur oxidation (Sox) pathway to sulfate [18][19][20][21][22]. Analogous degradation steps for the selenium and tellurium derivatives of DMSP (dimethylseleniopropionate, DMSeP, and

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• units have been employed in developing bicycle-based peptidomimetics, the thiomethylene unit is quite attractive as the synthesis into such systems is simplified, because the amino acid cysteine can be used. This bicyclic constraint was initially developed by Nagai and Sato [41]. In this constrained

• accomplished through the condensation of α-alkylaldehyde proline derivatives 34a–c with either D-cysteine or D-homocysteine derivatives to give diastereoisomeric mixtures of thiazolidines 35, 37 and 38 and thiazines 36, respectively (Scheme 2). Formation of the lactam ring from the thiazine and thiazolidines

Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• , 1700 4th Street, San Francisco, CA, 94158, USA Cellular Ultra-Structure Laboratory, Oswaldo Cruz Institute (IOC), FIOCRUZ, Rio de Janeiro, RJ, Brazil 21040-362 10.3762/bjoc.9.3 Abstract Inhibition of the Trypanosoma cruzi cysteine protease cruzain has been proposed as a therapeutic approach for the

• investigated are cruzain [7][8][9][10], the major cysteine protease active in the parasite, and T. cruzi CYP51 (TcCYP51), a 14-α-demethylase enzyme of the cytochrome P450 family required for ergosterol biosynthesis [11][12][13][14]. TcCYP51 is analogous to the fungal enzyme targeted by the azole class of

• intracellular replication and differentiation of the T. cruzi parasite [17]. A variety of small-molecule cruzain inhibitors have been described, the majority of which act irreversibly by reaction with the catalytic cysteine in the enzyme active site [18][19][20][21][22][23][24][25][26][27]. One of the earliest

S-Fluorenylmethyl protection of the cysteine side chain upon N^α-Fmoc deprotection

• Johannes W. Wehner and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2012, 8, 2149–2155, doi:10.3762/bjoc.8.242

• led to the fluorenylmethyl-protected thioether 8 in high yield. The suggested mechanism for this reaction comprises the addition of the cysteine thiolate on the exocyclic double bond of dibenzofulvene, which is formed during Fmoc deprotection. The influence of base concentration on this

• transprotection reaction was studied. Keywords: Fmoc protecting group; glycoamino acids; N-Fmoc→S-Fm transprotection; protecting groups; Introduction In the course of our work on the synthesis of glycoamino acids, we have recently used L-cysteine as a scaffold for the synthesis of various glycoclusters [1][2][3

• oxidiation of the cysteine moiety into the respective cystine form. Indeed, preparation of glycoamino acid derivatives such as 3-dimer, an oxidized cysteine, or cystine derivative, is facile and can be realized via different synthetic routes. However, as we employed the fluorenylmethoxycarbonyl (Fmoc

Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology

• Jan Anderl,
• Hartmut Echner and
• Heinz Faulstich

Beilstein J. Org. Chem. 2012, 8, 2072–2084, doi:10.3762/bjoc.8.233

• protected as tert-butyl ethers (tyrosine), tert-butyloxycarbonyl derivatives (lysine), trityl derivatives (cysteine, glutamine), and as (2,2,4,6,7-pentamethyl)dihydrobenzofuran-5-sulfonyl derivative (arginine). Coupling was performed by using a 4-fold excess of each of the protected amino acids and the