Recent applications of click chemistry for the functionalization of gold nanoparticles and their conversion to glyco-gold nanoparticles

• Vivek Poonthiyil,
• Thisbe K. Lindhorst,
• Vladimir B. Golovko and
• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 11–24, doi:10.3762/bjoc.14.2

• synthesized in two steps (Scheme 5). Herein, the treatment of methyl-terminated triethylene glycol monolayer-protected AuNPs (Me-EG3-AuNPs) with ω-carboxy tetraethylene glycol thiols (HOOC-EG4-SH) gave carboxy-functionalized AuNPs (HOOC-EG4-AuNPs). Peptide coupling of these HOOC-EG4-AuNPs with a DBCO-amine

• synthesize peptide-decorated AuNPs [59] and nanomaterial hybrids containing single walled carbon nanotubes and AuNPs [60]. AuNP surface modification by CuAAC The distinct advantages of CuAAC over NCAAC, such as improved regioselectivity and rates of the reaction, motivated several groups to use CuAAC for the

Halogen-containing thiazole orange analogues – new fluorogenic DNA stains

• Aleksey A. Vasilev,
• Meglena I. Kandinska,
• Stanimir S. Stoyanov,
• Stanislava B. Yordanova,
• David Sucunza,
• Juan J. Vaquero,
• Obis D. Castaño,
• Stanislav Baluschev and
• Silvia E. Angelova

Beilstein J. Org. Chem. 2017, 13, 2902–2914, doi:10.3762/bjoc.13.283

• been conjugated to a variety of molecules, including peptides [29], proteins [30], DNA [17], and DNA analogues such as peptide nucleic acid (PNA) [16][31]. TO-based chromophores assembled as a structural scaffold inside nucleic acids (TO-tethered nucleic acids) have attracted considerable attention [32

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

• Susanne Huhmann,
• Anne-Katrin Stegemann,
• Kristin Folmert,
• Damian Klemczak,
• Johann Moschner,
• Michelle Kube and
• Beate Koksch

Beilstein J. Org. Chem. 2017, 13, 2869–2882, doi:10.3762/bjoc.13.279

• of peptides as therapeutics. One strategy to increase the proteolytic stability of peptides is the modification with fluorinated amino acids. This study presents a systematic investigation of the effects of fluorinated leucine and isoleucine derivatives on the proteolytic stability of a peptide that

• was designed to comprise substrate specificities of different proteases. Therefore, leucine, isoleucine, and their side-chain fluorinated variants were site-specifically incorporated at different positions of this peptide resulting in a library of 13 distinct peptides. The stability of these peptides

• this study when positioned N-terminal to the cleavage site. These results provide valuable information for the application of fluorinated amino acids in the design of proteolytically stable peptide-based pharmaceuticals. Keywords: fluorinated amino acids; hexafluoroleucine; peptide drugs; protease

The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands

• Yaochun Xu,
• Isabelle Correia,
• Tap Ha-Duong,
• Nadjib Kihal,
• Jean-Louis Soulier,
• Julia Kaffy,
• Benoît Crousse,
• Olivier Lequin and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2017, 13, 2842–2853, doi:10.3762/bjoc.13.276

• CF3-threonine containing pentapeptides interact with the amyloid peptide Aβ1-42 in order to reduce the protein–protein interactions mediating its aggregation process. Keywords: aggregation; beta-sheet; fluorine; peptide; unnatural amino acid; Introduction It is estimated that 20% of administered

• attracting increasing interest as around 100 peptides are on the pharmaceutical market [2]. Peptide fluorination has appeared as a general and effective strategy to enhance the stability against enzymatic, chemical and thermal denaturation while generally retaining the original structure and biological

• a fluorinated substituent incorporated in the side-chain of amino acids on peptide conformations has recently raised attention [9]. While the effect of fluorinated analogs of hydrophobic aliphatic and aromatic amino acids has been prominently studied, the influence of fluorinated polar amino acids

Development of a fluorogenic small substrate for dipeptidyl peptidase-4

• Futa Ogawa,
• Masanori Takeda,
• Kanae Miyanaga,
• Keita Tani,
• Ryuji Yamazawa,
• Kiyoshi Ito,
• Atsushi Tarui,
• Kazuyuki Sato and
• Masaaki Omote

Beilstein J. Org. Chem. 2017, 13, 2690–2697, doi:10.3762/bjoc.13.267

• different, ideally, non-fluorescence and intensive fluorescence, respectively. On the basis of the structural features of 1, we expected that its fluorescence would disappear as a result of peptide derivatization of the amino group, because electron donation by the amino group would be attenuated and the

• peptide [18]. Additionally, DPP-4 is a significant biomarker for the progress of diabetes, and several chromogenic or fluorogenic substrates for DPP-4 have been developed [19][20][21]. We therefore evaluated 1 as a fluorogenic probe for DPP-4 activity using the peptide analogue H-Gly-Pro-1 as a substrate

• hydrazine, without disturbing the peptide bond structure, to give H-Gly-Pro-1. DPP-4 activity measurement The fluorescence spectra of 1 and H-Gly-Pro-1 were recorded to confirm their fluorescence profiles; the spectra are shown in Figure 3. As expected, H-Gly-Pro-1 was non-fluorescent because of the

Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres

• Myriam Drouin and
• Jean-François Paquin

Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262

• reacted easily in a SN2 reaction to give a more functionalized molecule. For example, treatment of the chlorinated monofluoroalkene with NaN3 provided the corresponding N3-containing monofluoroalkene. The azide group underwent a 1,3-dipolar cycloaddition to give a 1,2,3-triazole, which is also a peptide

• bond isostere [6]. Using this strategy, a mutant tripeptide containing two different peptide bond isosteres could be synthesized (Figure 3). In 2016, Konno and co-workers developed a stereoselective chromium-mediated C–F bond cleavage followed by a C–C bond formation to access (Z)-monofluoroalkenes

• interaction with the NS5A protein. This fluorinated peptide isostere showed activity in the picomolar range against one genotype and did not exhibit any cytotoxicity (Figure 4). Pannecoucke and co-workers synthesized three heptapeptides, Gly-Gly-ψ[(Z)-CF=CH]-Phe-Ser-Phe-Arg-Phe-NH2, Gly-ψ[(Z)-CF=CH]-Gly-Phe

Pyrene–nucleobase conjugates: synthesis, oligonucleotide binding and confocal bioimaging studies

• Artur Jabłoński,
• Yannic Fritz,
• Hans-Achim Wagenknecht,
• Rafał Czerwieniec,
• Tytus Bernaś,
• Damian Trzybiński,
• Krzysztof Woźniak and
• Konrad Kowalski

Beilstein J. Org. Chem. 2017, 13, 2521–2534, doi:10.3762/bjoc.13.249

• [4], pyrene-modified peptide nucleic acids (PNA) [5], locked nucleic acids (LNA) [6][7], invader LNA [8], and twisted intercalating nucleic acids (TINA) [9]. Furthermore pyrene-modified nucleotides have been used for the construction of DNA-based multichromophore systems [10][11][12][13], as cancer

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

• fluorination of peptide scaffolds. One of these methods involves esterification of the C-terminus of peptides using a diazomethane species. Here, we provide an investigation of the physicochemical consequences of peptide esterification with partially fluorinated ethyl groups. Derivatives of N-acetylproline are

• undergo variable hydrolysis in biologically relevant buffers. The hydrolytic stability can be tailored over a broad pH range by varying the number of fluorine atoms in the ester moiety or by introducing adjacent charges in the peptide sequence. Keywords: conformation; ester bond; hydrolysis; peptides

• measurements can be used to study ligand–protein [12] and protein–protein interactions [13]; membrane proteins [14][15][16] and membrane-associated peptides [17][18]; equilibria among conformations of RNA [19], DNA [20], and peptide nucleic acids (PNA) [21]; and many others. Particularly recent is the

One-pot syntheses of blue-luminescent 4-aryl-1H-benzo[f]isoindole-1,3(2H)-diones by T3P^® activation of 3-arylpropiolic acids

• Melanie Denißen,
• Alexander Kraus,
• Guido J. Reiss and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2017, 13, 2340–2351, doi:10.3762/bjoc.13.231

• class particularly attractive for the development of novel sensors and fluorescent dyes [38], for instance 6-chloro-2,3-naphthaleneimide derivatives were successfully used for labeling amino acids, and for studying peptide protein interactions [39]. Even the superficial attachment to a binding domain

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

• Raju Cheerlavancha,
• Ahmed Ahmed,
• Yun Cheuk Leung,
• Aggie Lawer,
• Qing-Quan Liu,
• Marina Cagnes,
• Hee-Chan Jang,
• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2017, 13, 2316–2325, doi:10.3762/bjoc.13.228

• University, Nanchang, China School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia 10.3762/bjoc.13.228 Abstract Backbone-extended amino acids have a variety of potential applications in peptide and protein science, particularly if the geometry of the amino acid is controllable. Here we

• diastereoisomers of this fluorinated δ-amino acid adopt distinct conformations in solution, suggesting that these molecules might have value as shape-controlled building blocks for future applications in peptide science. Keywords: amino acids; conformation; deoxyfluorination; fluorine; stereochemistry

• ; Introduction The incorporation of unnatural amino acids into a peptide structure can potentially reduce conformational disorder and hence improve the binding affinity of the peptide for its biological target. For example, conformationally rigid amino acids such as 1 (Figure 1) have been shown to dramatically

Synthesis and application of trifluoroethoxy-substituted phthalocyanines and subphthalocyanines

• Satoru Mori and
• Norio Shibata

Beilstein J. Org. Chem. 2017, 13, 2273–2296, doi:10.3762/bjoc.13.224

• ][91] or a peptide [92]. For example, TFEO-Pcs conjugated with peptides (15) have been reported [93]. A3B type TFEO-Pc was successfully condensed with peptides by palladium-catalyzed cross-coupling reactions in good yield (Scheme 5). These TFEO-Pc-peptide conjugates, which show a sharp Q band in the UV

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• in the expression of normal cell surface components. The subset of the human γδ T cells that express the Vγ9Vδ2 receptor recognize and present non-peptide antigens including prenyl pyrophosphate antigens also identified as phosphoantigens. These Vγ9Vδ2 T cells are involved during bacterial or

• diethyl phosphonate groups [204], other mild conditions, developed in the context of peptide chemistry, were reported. It is based on the use of trimethylsilyl trifluoromethanesulfonate (TMS-OTf) as silylating agent, trifluoroacetic acid (TFA) as acidic reagent, and dimethylsulfide (DMS) and m-cresol to

• avoid side reactions (from SN1 or SN2 mechanism) [204] that can involve the functional groups present in the amino acid or peptide. These conditions were applied to prepare the compound 82 from 81 [205][206] (Figure 24). 4. From dichlorophosphine (R–PCl2) or dichlorophosphine oxide (R–P=OCl2) Aryl- and

A mechanochemical approach to access the proline–proline diketopiperazine framework

• Nicolas Pétry,
• Hafid Benakki,
• Eric Clot,
• Pascal Retailleau,
• Farhate Guenoun,
• Fatima Asserar,
• Chakib Sekkat,
• Thomas-Xavier Métro,
• Jean Martinez and
• Frédéric Lamaty

Beilstein J. Org. Chem. 2017, 13, 2169–2178, doi:10.3762/bjoc.13.217

• and Discussion First we studied the preparation of simple Pro–Pro DKP as a model compound. The use of ball milling in peptide synthesis has drawn some attention in the recent years [20][21][22][23][24][25][26][27][28]. We took advantage of our extensive experience in peptide mechanosynthesis [20][23

• alternative approach, we tested the optimal conditions developed previously for peptide mechanosynthesis [25], starting with unactivated amino acids together with a coupling agent. We had indeed reported two successful examples of couplings involving proline amino esters. The initial conditions, using 1-ethyl

• . This was in agreement with the experimental formation of only 15a. As mentioned above, another possibility to exploit meso pyrrolidine cis-11 would be to desymmetrize [43] the ester functions by selective hydrolysis. The corresponding carboxylic acid could then be engaged in a peptide coupling. Pig

Synthesis of 2-aminosuberic acid derivatives as components of some histone deacetylase inhibiting cyclic tetrapeptides

• Shital Kumar Chattopadhyay,
• Suman Sil and
• Jyoti Prasad Mukherjee

Beilstein J. Org. Chem. 2017, 13, 2153–2156, doi:10.3762/bjoc.13.214

• therefore the variation in the carbonyl functionality may have implications in drug design. Moreover, Asu and its congener 2-aminopimelic acid have been used as ethylenic equivalent of a disulfide linkage [4]. Other applications of Asu in peptide engineering and as a building block are of notable importance

Preactivation-based chemoselective glycosylations: A powerful strategy for oligosaccharide assembly

• Weizhun Yang,
• Bo Yang,
• Sherif Ramadan and
• Xuefei Huang

Beilstein J. Org. Chem. 2017, 13, 2094–2114, doi:10.3762/bjoc.13.207

• are intrinsically sensitive to factors including protective groups on the glycan ring, reaction solvent, and additives present. As a result, further experimentation and analysis are needed to enable robust syntheses and achieve automation with comparable efficiencies of automated peptide and nucleic

Peptide synthesis: ball-milling, in solution, or on solid support, what is the best strategy?

• Ophélie Maurin,
• Pascal Verdié,
• Gilles Subra,
• Frédéric Lamaty,
• Jean Martinez and
• Thomas-Xavier Métro

Beilstein J. Org. Chem. 2017, 13, 2087–2093, doi:10.3762/bjoc.13.206

• Abstract While presenting particularly interesting advantages, peptide synthesis by ball-milling was never compared to the two traditional strategies, namely peptide syntheses in solution and on solid support (solid-phase peptide synthesis, SPPS). In this study, the challenging VVIA tetrapeptide was

• build more efficient and sustainable peptide syntheses in the near future. Keywords: ball-mill; green chemistry; mechanochemistry; peptide synthesis; SPPS; Introduction Peptides play a central role both in biological mechanisms and in therapeutic solutions of the future [1][2]. Pharmaceutical

• to improve their in vivo bioavailability and stability. This progresses empowered the potential of therapeutic peptides, suggesting a production surge in the future. Besides this high potential, actual peptide production techniques suffer from major environmental issues [4][5][6]. Indeed, large

Intramolecular glycosylation

• Xiao G. Jia and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2017, 13, 2028–2048, doi:10.3762/bjoc.13.201

• which can be formed more readily than a glycosidic bond. ... The glycosylation reaction then becomes an intramolecular process and hence could be expected to proceed more easily.” The authors then refer to a known phenomenon in the field of peptide chemistry “where two components to be coupled had been

• linker showed very high efficiency, and will be highlighted below. Another early development discussed below is the peptide-templated synthesis. Beyond these influential early studies that led to further developments, this topic was comprehensively overviewed and for early developments the reader should

• that affected the removal of the template and all benzyl protecting groups followed by acetylation of the resulting hydroxy groups. Peptide tether/template Short peptide chains have also been investigated as templates for glycosylation. The general underpinning idea is to streamline the oligosaccharide

Solid-state mechanochemical ω-functionalization of poly(ethylene glycol)

• Michael Y. Malca,
• Pierre-Olivier Ferko,
• Tomislav Friščić and
• Audrey Moores

Beilstein J. Org. Chem. 2017, 13, 1963–1968, doi:10.3762/bjoc.13.191

• manufacturing, drug development and nanotechnology. PEG derivatives are being increasingly used to covalently modify small molecule and peptide drugs, as well as bioactive nanomaterials in order to improve solubility in biological serum, reduce immunogenicity, and enhance pharmacokinetic profiles. Herein we

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

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

Chemical systems, chemical contiguity and the emergence of life

• Terrence P. Kee and
• Pierre-Alain Monnard

Beilstein J. Org. Chem. 2017, 13, 1551–1563, doi:10.3762/bjoc.13.155

• characteristics of various biomolecules, e.g., the catalytic activity of RNAs and their evolution potential [9][10][11], as well as processes that were essential for their syntheses, such as Fischer–Tropsch-like reactions [12], non-enzymatic RNA [13] or peptide polymerization [14]. Moreover, it has also allowed

• chemical systems also implies the existence of chemical contiguity. Many aspects of cellular biochemistry, e.g., in bioenergetics, glycolysis, the Krebs cycle or the intricate peptide formation systems, pre-suppose a form of chemical contiguity in their emergence. The Oxford English Dictionary defines

• catalysis was demonstrated yet, amino acid and peptide-derivatized fatty acids (synthesized via a prebiotically plausible route) have been shown to associate with fatty acid vesicles. Vesicles with arginine-derivatized fatty acids could even electrostatically recruit RNA from the surrounding medium [70

A new member of the fusaricidin family – structure elucidation and synthesis of fusaricidin E

• Marcel Reimann,
• Louis P. Sandjo,
• Luis Antelo,
• Eckhard Thines,
• Isabella Siepe and
• Till Opatz

Beilstein J. Org. Chem. 2017, 13, 1430–1438, doi:10.3762/bjoc.13.140

• chain [12]. In order to reduce the number of linear steps, the protected guanidino group was included in the side chain building block in our case. This strategy would allow to assemble the complete peptide core in a solid-phase synthesis and to perform the solution-phase coupling without a large excess

• alcohol 12 was subjected to ozonolysis and Pinnick oxidation to furnish the protected GHPD acid 3 in an overall yield of 14.3%. The peptide core was synthesized manually according to a standard SPPS Fmoc protocol using HATU and NMM in NMP [16]. For protection of the threonine unit, it was converted into a

• the doubly acylated product, several other uncharacterized byproducts were formed. Nevertheless, O-deallylation with Pd(PPh3)4 and BH3·NHMe2 gave a high conversion to the deprotected peptide [1]. The cyclization with PyBOP, HOBt and DIPEA in DMF led again to the formation of numerous byproducts. In

Synthesis of the heterocyclic core of the D-series GE2270

• Christophe Berini,
• Thibaut Martin,
• Pierrik Lassalas,
• Francis Marsais,
• Christine Baudequin and
• Christophe Hoarau

Beilstein J. Org. Chem. 2017, 13, 1407–1412, doi:10.3762/bjoc.13.137

• as readily available starting material. Keywords: antibiotic; bromination; BSC; C–H arylation; cross-coupling; Hantzsch synthesis; thiopeptide; Introduction Thiopeptide antibiotics are a class of peptide-derived macrocycles which contain many thiazole and thiazoline units, with almost 90 structures

Framing major prebiotic transitions as stages of protocell development: three challenges for origins-of-life research

• Ben Shirt-Ediss,
• Sara Murillo-Sánchez and
• Kepa Ruiz-Mirazo

Beilstein J. Org. Chem. 2017, 13, 1388–1395, doi:10.3762/bjoc.13.135

• promoters and regulators [48][49][50], i.e., beyond their traditionally ascribed role as selectively permeable enclosures that keep concentrations above critical threshold values. One could mention here, for instance, their catalytic effects on diverse reactive processes (like peptide formation – [51][52

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

• obtain oligonucleotide–PEG–peptide conjugates [55][56]. The Fmoc protecting group was first removed and the peptide was assembled on the exposed amino function. Since the peptide moiety did not contain acid labile side chain protections, the oligonucleotide sequence could then be assembled by the