Aqueous olefin metathesis: recent developments and applications

• Valerio Sabatino and
• Thomas R. Ward

Beilstein J. Org. Chem. 2019, 15, 445–468, doi:10.3762/bjoc.15.39

• shock protein from M. Jannaschii (MjHSP) [71]. The authors reported a HG-II-type catalyst modified on its NHC backbone with an α-bromoacetyl unit (68) that is reacted with the unique cysteine of the modified MjHSP variant (G41C) to afford ArM 4 (Scheme 15). The hybrid catalyst ArM 4 was then tested for

• variant of the β-barrel protein FhuA [73][74]. To do so, the authors duplicated multiple β-barrel strands to enlarge the cavity of the protein. HG-type catalysts bearing a maleimide moiety with different spacer lengths (69–71) were covalently anchored to a cysteine of the expanded nitrobindin variant

• -selective protein modification through aqueous CM [83], thus expanding the catalytic repertoire of protein modification with transition-metal catalysts [84][85][86][87]. A variant of subtilisin from Bacillus lentus containing a single cysteine (SBL-S156C) was modified by direct allylation to install an

Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells

• Rainer Kufka,
• Robert Rennert,
• Goran N. Kaluđerović,
• Lutz Weber,
• Wolfgang Richter and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2019, 15, 96–105, doi:10.3762/bjoc.15.11

• -1)-βA),F7,L17,P34]-hNPY (8), was synthesized by reacting the tubugi-1-SSPy (3) with the free thiol function of a β-alanine–cysteine dipeptide (βAC) linked to the side chain of Lys4 of the targeting peptide. For this purpose, 1 mol equiv of the tubugi-1-SSPy building block 3 and one molar equivalent

Lectins of Mycobacterium tuberculosis – rarely studied proteins

• Katharina Kolbe,
• Sri Kumar Veleti,
• Norbert Reiling and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2019, 15, 1–15, doi:10.3762/bjoc.15.1

• human C-type mannose receptor 2, the sequence identity was 28%. Identical amino acids are highlighted in grey, amino acids with a small/polar side chain: orange, hydrophobic side chain: green, charged side chain: red, aromatic amino acids and cysteine: violet. β-Sheets of the secondary structure are

Green synthesis of new chiral 1-(arylamino)imidazo[2,1-a]isoindole-2,5-diones from the corresponding α-amino acid arylhydrazides in aqueous medium

• Nadia Bouzayani,
• Jamil Kraїem,
• Sylvain Marque,
• Yakdhane Kacem,
• Abel Carlin-Sinclair,
• Jérôme Marrot and
• Béchir Ben Hassine

Beilstein J. Org. Chem. 2018, 14, 2923–2930, doi:10.3762/bjoc.14.271

• (3d), (L)-cysteine phenylhydrazide (3g), (L)-tyrosine phenylhydrazide (3j), (L)-alanine 4-chlorophenylhydrazide (3k), (L)-phenylglycine 4-chlorophenylhydrazide (3l) and (L)-phenylalanine 4-chlorophenylhydrazide (3m) were synthesized for the first time in this work. Verardo et al. [29] have shown that

Olefin metathesis catalysts embedded in β-barrel proteins: creating artificial metalloproteins for olefin metathesis

• Daniel F. Sauer,
• Johannes Schiffels,
• Takashi Hayashi,
• Ulrich Schwaneberg and
• Jun Okuda

Beilstein J. Org. Chem. 2018, 14, 2861–2871, doi:10.3762/bjoc.14.265

• post-expressional protein modifications [10][11][12]. For example, a single cysteine mutant of subtilisin from Bacilus lentus (SBL-S156C) was modified via sulfide bond formation with allyl cysteine displaying an allyl function on the protein surface. This allyl group was modified with a GH-type

• . Engineered variants of NB were used to construct artificial metatheases [56]. The cavity of NB was enlarged by introducing five mutations compared to the NB wild-type. Two histidines were substituted by leucine or alanine. Furthermore, a cysteine was introduced allowing covalent anchoring, and the two

• wild-type protein). For covalent anchoring, a cysteine residue was introduced at position 545 [59]. This position is suggested to be in a conformationally stable environment within the β-barrel structure. Additionally, mutation N548V was introduced to enable access of the metal catalyst to position

Novel solid-phase strategy for the synthesis of ligand-targeted fluorescent-labelled chelating peptide conjugates as a theranostic tool for cancer

• Sagnik Sengupta,
• Mena Asha Krishnan,
• Premansh Dudhe,
• Ramesh B. Reddy,
• Bishnubasu Giri,
• Sudeshna Chattopadhyay and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2018, 14, 2665–2679, doi:10.3762/bjoc.14.244

• amino acid cysteine is also cumbersome and challenging. Recently, Low et al. reported synthesis of various targeted conjugates in which fluorescent tag [37] has been attached in a solution phase reaction. Also, they have reported the synthesis of ligand-conjugated peptides containing a radiotracer

• commonly available and less expensive cysteine-labelled 2-chlorotrityl resin (Figure 1b). The methodology is general and can be significantly useful for acid-sensitive resins that contain acid-labile orthogonal amino acids with 4-methoxytrityl (Mmt) and 4-methyltrityl (Mtt) protecting groups. Results and

• . This is compensated by introduction of dibasic amino acid like diaminopropionic acid (Dap), acidic amino acids like aspartic acid (Asp) and polar cysteine amino acid (Cys) that makes up the chelating core. In the case of FR targeted fluorescent conjugate 17, the targeting ligand, folic acid, is

Non-native autoinducer analogs capable of modulating the SdiA quorum sensing receptor in Salmonella enterica serovar Typhimurium

• Matthew J. Styles and
• Helen E. Blackwell

Beilstein J. Org. Chem. 2018, 14, 2651–2664, doi:10.3762/bjoc.14.243

• sub-micromolar IC50 (318 nM). Compound 11 was originally designed by the Meijler lab to react with a cysteine in the AHL-binding pocket of LasR, thereby acting as an irreversible inhibitor [44]. SdiA does have a cysteine in the binding pocket (Cys45, see Figure 1D), but it is positioned near carbons 3

• identified that can be used for developing second-generation AHL-type ligands with enhanced potencies in SdiA: using electrophilic groups to target the cysteine in the SdiA binding pocket (taking a possible cue from 11); delineating the SARs for activity by the POHL class, with an eye toward examining bulky

• ), and a cysteine that potentially could be involved in inhibition (purple, see discussion below). Overview of SdiA agonism and antagonism single-point screening results in the S. Typhimurium reporter. Agonists are indicated in green. Antagonists are indicated in red. Compounds with less than 10% agonism

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• -CoA) is then transferred to an active-site cysteine of the β-ketoacyl-ACP synthase III (FabH)-type enzyme PqsD [26][27]. Subsequently, another CoA-activated substrate comes into play. In analogy to fatty acid synthesis, malonyl-CoA is reacted with the enzyme-bound thioester to yield 2

• formed by action of the heterodimeric complex PqsBC. This time, CoA-activated octanoic acid is used to preload an active-site cysteine of PqsC with the fatty acid via a thioester linkage [30][31]. The previously produced 2-ABA is then consumed to from HHQ under decarboxylative condensation [30]. Finally

• docking [51]. These inhibitors appeared to bind in the substrate channel in a slightly remote position from the active site cysteine and, hence, termed channel blockers [51]. Optimised hits exhibited a potency in the single-digit micromolar range (12, Figure 6). However, it has been found that similar

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• the aryl substitution resulted in a flat SAR with only little variation in potency among the substituents analyzed [30][36][37][38][39]. Just recently, in an attempt to search for new pharmacophores, Titz et al. have reported the synthesis of the epoxyheptose derivative 11 targeting a cysteine residue

Functionalization of graphene: does the organic chemistry matter?

• Artur Kasprzak,
• Agnieszka Zuchowska and
• Magdalena Poplawska

Beilstein J. Org. Chem. 2018, 14, 2018–2026, doi:10.3762/bjoc.14.177

• -cysteine has been proposed or discussed. Most plausibly, the attack of cysteine’s highly nucleophilic sulfur on GO’s epoxides did occur in this case [30][31], based on the changes observed in the IR spectrum of the product. The material’s structure would include free amino and carboxyl groups forming the

β-Hydroxy sulfides and their syntheses

• Mokgethwa B. Marakalala,
• Edwin M. Mmutlane and
• Henok H. Kinfe

Beilstein J. Org. Chem. 2018, 14, 1668–1692, doi:10.3762/bjoc.14.143

• converted to the epoxide 123, which upon thiolysis with a strategically protected cysteine, gave the regioisomeric hydroxy sulfides 124 and 125 (Scheme 43). Each of these was then converted to natural pteriatoxin A (7) and its analog 126. Epoxide opening to yield β-hydroxy sulfides of unnatural (artificial

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• in sufficient levels to pump inside the cell efficacious doses of the drug. The peptide-carrier should be constructed in such way that the conjugation with a drug or/and a fluorophore is feasible. Conjugation usually occurs on lysine, cysteine and glutamic acid [34] via orthogonal coupling or on the

• than their parent linear counterparts [38]. Cyclic peptides are usually synthesized by reacting the N-terminus with the C-terminus or by exploiting specific functional groups of certain amino acids present in the sequence. A representative example is the sulfhydryl group of cysteine-containing peptides

• /or in the acidic cellular compartments of cancer cells and consequently release the active drug. Additionally, disulfide linkers are often adopted in PDCs, since they are cleaved by reducing agents like cysteine and glutathione, present in high concentrations in malignant cells. Linkers bearing

Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin–GnRH-III conjugates developed for targeted drug delivery

• Sabine Schuster,
• Beáta Biri-Kovács,
• Bálint Szeder,
• Viktor Farkas,
• László Buday,
• Zsuzsanna Szabó,
• Gábor Halmos and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 756–771, doi:10.3762/bjoc.14.64

• . For instance, lysosomal cysteine proteases also known as cathepsins show a broad substrate specificity [43]. Nearly all human cysteine proteases belong to the group of endopeptidases, whereby cathepsin B is also a carboxydipeptidase and cathepsin X displays carboxymono- and dipeptidase activity [44

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• such intermediates. By selecting the appropriate reaction conditions (various pH and temperatures), they were able to alkylate free amino acids, e.g., glycine (Gly), L-serine (Ser), L-cysteine (Cys), L-lysine (Lys), L-tyrosine (Tyr) and glutathione (Glu) in aqueous solution to isolate 55 (Scheme 8

Recent developments in the asymmetric Reformatsky-type reaction

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 325–344, doi:10.3762/bjoc.14.21

• Reformatsky reaction between L-cysteine-derived thiazolidinic aldehyde 14 and (R)-α-chloroacetyl-2-oxazolidinone 15, leading to the corresponding β-hydroxy amide 16 in both remarkable yield (95%) and diastereoselectivity (>98% de), as shown in Scheme 6. The latter was subsequently converted into the expected

Photocatalytic formation of carbon–sulfur bonds

• Alexander Wimmer and
• Burkhard König

Beilstein J. Org. Chem. 2018, 14, 54–83, doi:10.3762/bjoc.14.4

• apply cysteine-containing glutathione for the reaction with a series of highly functionalized alkenes to form the respective sulfide adducts with yields up to 99%. This concept attracted attention from different fields of chemistry. Boyer and co-workers for example applied the redox mediator accelerated

• aryl diazonium salts to give the corresponding diaryl sulfide in high yields. Very recently, Noël and co-workers applied the above-mentioned concepts for the selective arylation of cysteine and cysteine-containing peptides in batch as well as in a photomicroreactor (Scheme 18) [49]. They were able to

• efficiently couple a series of functionalized aryls with the thiol moiety of cysteine, applying the organic photocatalyst Eosin Y. The respective aryl diazonium salts were generated in situ from the respective anilines, tert-butyl nitride and catalytic amounts of p-toluenesulfonic acid. Also in 2017, Fu and

Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

• Matthias Wünsch,
• David Schröder,
• Tanja Fröhr,
• Lisa Teichmann,
• Sebastian Hedwig,
• Nils Janson,
• Clara Belu,
• Jasmin Simon,
• Shari Heidemeyer,
• Philipp Holtkamp,
• Jens Rudlof,
• Lennard Klemme,
• Alessa Hinzmann,
• Beate Neumann,
• Hans-Georg Stammler and
• Norbert Sewald

Beilstein J. Org. Chem. 2017, 13, 2428–2441, doi:10.3762/bjoc.13.240

• , these propargylamines have been frequently used as precursors for the synthesis of diverse bioactive compounds. Their conversion into triazoles is best investigated, since triazoles as amide bond surrogates are found in several inhibitors of proteases such as cathepsin S [1][2][3][4][5][6], cysteine

• propargylamines without an acidifying Cα-substituent. Synthesis of propargylamines containing polar or acidic functional groups The synthesis of propargylamines with polar substituents to mimic polar amino acids such as serine (alcohol), cysteine (thiol) or glutamine (carboxamide) requires special protective

• ][99]. Selective cleavage of the tert-butyl group was not yet accomplished without affecting the tert-butyl sulfinamide protection group of the amine. A cysteine-analogous alkyne could be synthesized starting from benzylmercaptan. Unfortunately, only extremely low yields were achieved and N-sulfinyl

Selective enzymatic esterification of lignin model compounds in the ball mill

• Ulla Weißbach,
• Saumya Dabral,
• Laure Konnert,
• Carsten Bolm and
• José G. Hernández

Beilstein J. Org. Chem. 2017, 13, 1788–1795, doi:10.3762/bjoc.13.173

• recently investigated the resilience of enzymes under ball milling conditions. The results from these studies have shown that biocatalysts such as cysteine and serine proteases tolerated the milling conditions and catalyzed the mechanoenzymatic peptide and amide bond formation after short milling times

2-Methyl-2,4-pentanediol (MPD) boosts as detergent-substitute the performance of ß-barrel hybrid catalyst for phenylacetylene polymerization

• Julia Kinzel,
• Daniel F. Sauer,
• Marco Bocola,
• Marcus Arlt,
• Tayebeh Mirzaei Garakani,
• Andreas Thiel,
• Klaus Beckerle,
• Tino Polen,
• Jun Okuda and
• Ulrich Schwaneberg

Beilstein J. Org. Chem. 2017, 13, 1498–1506, doi:10.3762/bjoc.13.148

• of the cysteine function of 2 (Cys545) using the fluorescence dye ThioGlo® 1 (fluorescent thiol reagent, Figure S2, Supporting Information File 1). More than 90% of the cysteines are occupied, showing a very high coupling efficiency of the rhodium catalyst. Further, the biohybrid conjugate was

• the β-barrel membrane channel protein FhuA WT co-crystallized with the detergent n-octyl-2-hydroxyethyl sulfoxide [24]. The N-terminal cork domain (residue 1-160) blocking the channel was removed. The amino acid exchanges of the hybrid catalyst model FhuA ΔCVFtev, namely cysteine at position 545

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

• using the same one-pot strategy [78]. In a follow up work by Novoa et al. [79] by using NEt3 and DMC, S-linked glycopeptides at cysteine residues on a solid phase could also be obtained. This methodology or very similar variations thereof is now being utilized by several laboratories for various

• products to form disulfides. However, it was found that treatment of the crude reaction mixture with PBu3 reduced the disulfides allowing for smoother isolation. Importantly, in a second step the unprotected thiol was able to ligate a selenylsulfide-activated single-cysteine mutant protein (subtilisin

From chemical metabolism to life: the origin of the genetic coding process

• Antoine Danchin

Beilstein J. Org. Chem. 2017, 13, 1119–1135, doi:10.3762/bjoc.13.111

• . Remarkably, most coenzymes –necessary effectors of metabolism, the existence of which is a prerequisite for any plausible scenario of origin– are today synthesised from simple carbon molecules and amino acids. Among those, 4′-phosphopantetheine (cysteine condensed with pantothenate, a derivative of valine

Conformational study of L-methionine and L-cysteine derivatives through quantum chemical calculations and ³J_HH coupling constant analyses

• Weslley G. D. P. Silva,
• Carolyne B. Braga and
• Roberto Rittner

Beilstein J. Org. Chem. 2017, 13, 925–937, doi:10.3762/bjoc.13.94

• 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

• analysis; cysteine; methionine; NMR spectroscopy; quantum chemical calculations; Introduction Amino acids constitute the building blocks of proteins and peptides, which play an important role in numerous biological processes [1][2]. However, their studies in both isolated and condensed phases have been

• been more widely reported, mainly in gas phase [3][4][5][6][7][8]. Among the 20 amino acids incorporated into proteins, L-methionine (L-Met) and L-cysteine (L-Cys) are the only two containing sulfur. The former is an initiator amino acid in the protein synthesis of all eukaryotics cells [9], whereas

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

• biosynthetic cycle is KS-catalyzed chain extension. This reaction occurs by nucleophilic attack of an enolate generated by decarboxylation of an ACP-bound extender unit onto the starter unit or chain extension intermediate attached to the active site cysteine of the KS domain. The face of the enolate which is

Posttranslational isoprenylation of tryptophan in bacteria

• Masahiro Okada,
• Tomotoshi Sugita and
• Ikuro Abe

Beilstein J. Org. Chem. 2017, 13, 338–346, doi:10.3762/bjoc.13.37

• Masahiro Okada Tomotoshi Sugita Ikuro Abe Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan 10.3762/bjoc.13.37 Abstract Posttranslational isoprenylation is generally recognized as a universal modification of the cysteine residues in peptides and

• posttranslational isoprenylation of tryptophan in bacteria. In particular, this review will focus on current findings which have not been available at the time we published a review on this topic previously [3]. Review Posttranslational isoprenylation of cysteine Posttranslational isoprenylation is generally

• referred to as the farnesylation or geranylgeranylation of the thiol group of the C-terminal cysteine residue in peptides and proteins [4][5][6][7]. The isoprenylation of cysteine was first found in the peptide pheromones of basidiomycetous yeast [8][9][10]. Two peptide pheromones, tremerogen A-10 and

Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934

• Veronika Ulrich,
• Clara Brieke and
• Max J. Cryle

Beilstein J. Org. Chem. 2016, 12, 2849–2864, doi:10.3762/bjoc.12.284

• nm, respectively, as well as a broad minor peak at λ = 548 nm (Figure 2a). The peaks at λ = 420 and 450 nm are caused by different protonation states of the thiol side chain of the proximal heme ligand cysteine: P450 enzymes displaying a protonated thiol ligand (as indicated by a peak at λ = 420 nm

• cysteine residue Cys342, which is a region of poorly defined electron density. The I helix contains the conserved residues responsible for controlling protonation during oxygen activation of the P450 catalytic cycle (Asp235 and Gln236) [34]. Residues projecting into the active site are Thr86 in the B–C