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

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

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

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