Synthesis of acylglycerol derivatives by mechanochemistry

• Karen J. Ardila-Fierro,
• Andrij Pich,
• Marc Spehr,
• José G. Hernández and
• Carsten Bolm

Beilstein J. Org. Chem. 2019, 15, 811–817, doi:10.3762/bjoc.15.78

• Chemosensation, Institute for Biology II, RWTH Aachen University, D-52074 Aachen, Germany 10.3762/bjoc.15.78 Abstract In recent times, many biologically relevant building blocks such as amino acids, peptides, saccharides, nucleotides and nucleosides, etc. have been prepared by mechanochemical synthesis. However

• peptides to endure mechanical stress in nature has allured scientists to evaluate the mechanical stability of proteins by using single-molecule nanomechanical techniques (e.g., magnetic and optical tweezers or atomic force microscopy) [3][4]. Additionally, the resilience of the peptide bond to mechanical

• loads has led to mechanoenzymatic transformations [5][6][7], and to synthesize amino acid derivatives [8][9][10] and peptides [11][12][13] by ball milling and extrusion techniques. Similarly, mechanochemical derivatizations of sugars and sugar derivatives such as cyclodextrins (CDs) have proven

Solid-phase synthesis of biaryl bicyclic peptides containing a 3-aryltyrosine or a 4-arylphenylalanine moiety

• Iteng Ng-Choi,
• Àngel Oliveras,
• Lidia Feliu and
• Marta Planas

Beilstein J. Org. Chem. 2019, 15, 761–768, doi:10.3762/bjoc.15.72

• Iteng Ng-Choi Angel Oliveras Lidia Feliu Marta Planas LIPPSO, Departament de Química, University of Girona, Maria Aurèlia Capmany 69, Girona 17003, Spain 10.3762/bjoc.15.72 Abstract A methodology for the solid-phase synthesis of biaryl bicyclic peptides containing a Phe-Phe, a Phe-Tyr or a Tyr

• resulting biaryl monocyclic peptidyl resin leading to the formation of the expected biaryl bicyclic peptide. This study provides the first solid-phase synthesis of this type of bicyclic compounds being amenable to prepare a diversity of synthetic or natural biaryl bicyclic peptides. Keywords: borylation

• ; cross-coupling; cyclization; macrocycles; solid-phase synthesis; Introduction Monocyclic and bicyclic peptides are acquiring a relevant interest in current drug discovery. They display improved biological properties over their acyclic counterparts and, at the same time, they are suitable to modulate

Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

• Jan Hendrik Lang and
• Thomas Lindel

Beilstein J. Org. Chem. 2019, 15, 577–583, doi:10.3762/bjoc.15.53

• satisfying. After Boc removal at 22, HATU/HOAt-mediated coupling with Boc-protected L-alanine afforded dipeptide 26, which was saponified and coupled with TIPS-protected threonine methyl ester (obtained with TIPSCl/DBU/MeCN) to provide tripeptide 27 (Scheme 5). Peptides 26 and 27 were obtained in nearly

Synthesis and SAR of the antistaphylococcal natural product nematophin from Xenorhabdus nematophila

• Frank Wesche,
• Hélène Adihou,
• Thomas A. Wichelhaus and
• Helge B. Bode

Beilstein J. Org. Chem. 2019, 15, 535–541, doi:10.3762/bjoc.15.47

• pathogenic against humans, they are widely used as biocontrol agents in agriculture [9]. Natural products produced by bacteria play an important role in the bacteria/nematode/insect life cycle and most natural products are non-ribosomal peptides (NRP), e.g., rhabdopeptides [10][11] and polyketide–NRP hybrids

Selectivity in multiple multicomponent reactions: types and synthetic applications

• Ouldouz Ghashghaei,
• Francesca Seghetti and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2019, 15, 521–534, doi:10.3762/bjoc.15.46

• [21], supramolecular structures (cryptands, cages, cryptophanes, podands, etc.) [22][23][24], cyclic/macrocyclic peptides [25] and other complex structures in a straightforward manner (Scheme 5). The diversity in these systems arises not only from combining a variety of building blocks (from simple

• aromatic and aliphatic substrates to peptides, steroids, sugars, etc.) [26], but also from the different MCRs used. Although the Ugi 4CR is the most commonly used transformation in this context, interesting examples exploiting other MCRs have been reported (Scheme 6) [27][28]. However, when the first MCR

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

• exploit biocompatible conditions. This review focuses on the progress made in aqueous olefin metatheses and their applications in chemical biology. Keywords: aqueous catalysis; artificial metalloenzymes; chemical biology; green chemistry; olefin metathesis; ruthenium catalysts; stapled peptides

• -metathesis reaction of allyl sulfide 99. Preparation of BODIPY-containing profluorescent probes 102 and 104. Metathesis-based ethylene detection in live cells. First example of stapled peptides via olefin metathesis. RCM of challenging substrate 17 in air and in the presence of water. RCM of N,N

Synthesis of C₃-symmetric star-shaped molecules containing α-amino acids and dipeptides via Negishi coupling as a key step

• Sambasivarao Kotha and
• Saidulu Todeti

Beilstein J. Org. Chem. 2019, 15, 371–377, doi:10.3762/bjoc.15.33

• the structural and chemical nature of protein–protein interactions, synthetic peptides and unnatural AAAs [8][9][10][11][12][13][14][15] can be useful as molecular tools. Moreover, C3-symmetric peptides are valuable in studying the molecular interactions involving proteins that are derived from

• electroluminescent devices [33]. To address these challenges, we [34] and others [35][36] have synthesized functionalized C3-symmetric molecules containing amino acids and peptides. The Negishi cross coupling [37][38] is a reliable synthetic method, which involves palladium or nickel-catalyzed coupling of organozinc

• knowledge only a limited number of reports is available for the synthesis of C3-symmetric peptides (Figure 1) [8][41]. To fill this gap, we have explored a new synthetic strategy to star-shaped C3-symmetric AAA derivatives and peptides by using trimerization and the Negishi cross coupling as key steps

Chemical structure of cichorinotoxin, a cyclic lipodepsipeptide that is produced by Pseudomonas cichorii and causes varnish spots on lettuce

• Hidekazu Komatsu,
• Takashi Shirakawa,
• Takeo Uchiyama and
• Tsutomu Hoshino

Beilstein J. Org. Chem. 2019, 15, 299–309, doi:10.3762/bjoc.15.27

• ) is between βCH of Thr-18 (δH 5.23, m) and CO of Val-22 (δc 170.5, s). Detailed analyses of the 2D NMR data (1H,1H-COSY, TOCSY and NOESY) and 1H,13C correlations (HMQC and HMBC)) of the peptides and proteins [16][17][18], which are illustrated in Figure 4, allowed us to construct the complete backbone

• 22-B [13], corpeptin A and B [19], fuscopeptin [20] and tolaasin I [21][22], which are typical lipodepsipeptides produced by Pseudomonas sp., and they are structural analogues of cichorinotoxin. All of these peptides have a lipophilic fatty acid moiety connected to dhThr1-D-Pro2, and the amino acids

• is likely that the hydrophilic Ser21, embedded in the macrocycle of the peptide, is crucial for the necrosis activity. The peptides in the macrocycle, listed in Supporting Information File 1, Figure S15, consist of 5 or 8 amino acids, and of these, at least two of the hydrophilic amino acids are

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• 3-hydroxy- (2), 4-hydroxy- (3) and 3,4-dihydroxyglutamic acid (4) to summarize achievements in this area. The protected forms of 3-hydroxyglutamic acid are of significant value as intermediates in the synthesis of complex peptides. Review 3-Hydroxyglutamic acid The reports on the optical resolution

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

• , PDCs are smaller in size – which may improve tissue and cell permeability, allows a more flexible and cost-efficient production, and in many cases small peptides are less antigenic [16]. Generally, a useful PDC must exhibit at least four major skills that are all required for the selective and potent

• receptor binding of the peptide–tubulysin A conjugate [K4(C(TubA)-βA-),F7,P34]-pNPY (IC50 = 47.6 nM) was detected to be slightly reduced. However, when testing the functional receptor activation – using an second messenger (IP) accumulation assay, Ahrens and co-workers found all three peptides and PDC

• 100 nM, i.e., around two magnitudes higher than at the Y1 receptor subtype. Furthermore the authors illustrated the Y1 receptor subtype-specific endocytotic internalization of the aforementioned peptides [32]. These findings indicate the highly affine receptor binding, effective NPY Y1 receptor

N-Arylphenothiazines as strong donors for photoredox catalysis – pushing the frontiers of nucleophilic addition of alcohols to alkenes

• Fabienne Speck,
• David Rombach and
• Hans-Achim Wagenknecht

Beilstein J. Org. Chem. 2019, 15, 52–59, doi:10.3762/bjoc.15.5

• only in stationary low concentrations. In the past, we used electron mediators as additives (triethylamine) [19][26] or peptides with substrate-binding sites [31][32] to overcome this problem. For the current work, we propose a radical ion pair in a solvent cage that undergoes an extremely fast proton

Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

• Laura Carro

Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

• antibacterial effects. In addition to small molecules, peptides have also been investigated as disruptors of protein–protein interactions in the sliding clamp. A structure-based approach, using the natural pentapeptide QL(S/D)LF (8, Figure 3) as a template, led to the identification of the short peptide P6 (16

• peptides for their ability to disrupt PPIs in the β-sliding clamp of Staphylococcus aureus. In this elegant study, from a library of 900,000 cyclic peptides, which was intracellularly generated using the split-intein circular ligation of peptides and proteins (SICLOPPS) technology [66], three hits

• , peptides III-5, III-6 and III-7 (18–20, Figure 5), were identified to be able to disrupt the DnaN–DnaN (β-clamp–β-clamp) interaction. Interestingly, III-5 (18) and III-6 (19) were able to inhibit the growth of Staphylococcus aureus with MIC values of approximately 50 μg/mL while their linear counterparts

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

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

• Gram-positive bacteria. While Gram-positive bacteria often use peptides as signal molecules, Gram-negative bacteria employ N-acylhomoserine lactones (AHLs) with subtle differences in their chemical structure, as well as other types of autoinducers (Figure 5). Interestingly, the signaling molecule

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• melanoma cells was increased by [4Lys(Ac)]-GnRH-III(Dau=Aoa), while the GnRH-III(Dau=Aoa) and [4Lys(Bu)]-GnRH-III(Dau=Aoa) decreased this activity. Conclusion: Internalization and cytotoxicity of the conjugates showed that GnRH-III peptides could guard Dau to melanoma cells and promote antitumor activity

• 2.5% water (v/v/v) for 2.5 h at room temperature (rt) and then precipitated with ice-cold diethyl ether followed by purification on RP-HPLC. Daunorubicin was attached to the purified peptides via oxime linkage that was formed under slightly acidic conditions (0.2 M NH4OAc buffer at pH 5) at rt

Nucleoside macrocycles formed by intramolecular click reaction: efficient cyclization of pyrimidine nucleosides decorated with 5'-azido residues and 5-octadiynyl side chains

• Jiang Liu,
• Peter Leonard,
• Sebastian L. Müller,
• Constantin Daniliuc and
• Frank Seela

Beilstein J. Org. Chem. 2018, 14, 2404–2410, doi:10.3762/bjoc.14.217

• analysis of the cyclic ketones muscone and civetone [1]. Other classical examples are cyclic peptides such as valinomycin and cyclic oligosaccharides like cyclodextrins [2][3][4]. The literature has been recently reviewed [5]. Also, oligonucleotides form cyclic structures commonly existing in plasmid DNA

• and deprotection steps are necessary to control the cyclization process. Preorganization of the molecules can help to make cyclization more efficient. Azide–alkyne "click" chemistry has been executed to generate cyclic peptides [11][12][13], cyclic oligonucleotides [14][15][16][17] and other

Tetrathiafulvalene – a redox-switchable building block to control motion in mechanically interlocked molecules

• Hendrik V. Schröder and
• Christoph A. Schalley

Beilstein J. Org. Chem. 2018, 14, 2163–2185, doi:10.3762/bjoc.14.190

• lasso, a structural motif which was also recently found in nature for peptides with high antibacterial efficacy [71]. In 12, the TTF molecule is not implemented in the thread but in the wheel component. In the neutral state, strong hydrogen bonding between the crown ether wheel and the dialkylammonium

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• -trifluoromethylamines, which are attractive due to their low basicity, ability to act as amide bioisosteres [42] and higher metabolic stability. The number of medicinal chemists who specialise in peptides has been increasing in recent years. This is largely due to the increasing interest in macrocyclic peptides. A key

• structural characteristic of peptides is the disulfide bridge formed by cysteines. This functional group is much more prevalent in peptide medicinal chemistry. Noël et al. have published a protocol for the aerobic oxidation of thiols to disulfides, using Eosin Y photocatalysis and TMEDA (Scheme 3) [43]. The

• , in a similar manner to the amide coupling by Leow. The demonstrated oxidation of the free thiols to a disulfide to afford oxytocin (3c) as the product in quantitative yield shows the value of this procedure. Medicinal chemists who specialise in creating artificial peptides could find much use for

Artificial bioconjugates with naturally occurring linkages: the use of phosphodiester

• Takao Shoji,
• Hiroki Fukutomi,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 1946–1955, doi:10.3762/bjoc.14.169

• ’-phosphitylation; phosphodiester bonds; Introduction Peptides and oligonucleotides are of exceptional importance since they are promising pharmaceutical candidates for the treatment of a range of diseases that are beyond traditional small molecule drugs [1][2][3][4][5][6][7]. Due to their iterative structures

• artificial building blocks with various functions are available, expanding chemical libraries of peptides and oligonucleotides significantly [8][9][10][11][12][13][14][15]. Furthermore, thus designed and synthesized peptides and oligonucleotides can be conjugated with each other to integrate their

• solvents, and washing the precipitates with polar solvents simultaneously rinses away excess amino acids or nucleosides and coupling reagents. We have demonstrated multistep syntheses of up to 28-mers for peptides and 21-mers for oligonucleotides without column purification. In all cases, the C-terminal

Diazirine-functionalized mannosides for photoaffinity labeling: trouble with FimH

• Femke Beiroth,
• Tomas Koudelka,
• Thorsten Overath,
• Stefan D. Knight,
• Andreas Tholey and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1890–1900, doi:10.3762/bjoc.14.163

• -functionalized mannosides as high-affinity FimH ligands and performed an extensive study on photo-crosslinking of the best ligand (mannoside 3) with a series of model peptides and FimH. Notably, we have employed high-performance mass spectrometry to be able to detect radiation results with the highest possible

• labeling studies with more complex substrates. Irradiation of mannoside 3 and model peptides In analogy to our earlier work, we first used a series of model peptides (M2, M3, M7, M8, T3, and S17, cf. Table 2) for the photolabeling experiments with mannoside 3. These model peptides were chosen rather

• the peptides in a 1:1 ratio. After irradiation with UV light, two new signals were detected in nano-LC–ESIMS experiments in comparison to the original peptide spectra (Table 2). It should be noted that whereas we could monitor photodecomposition of the photolabels by 19F NMR spectroscopy (cf. [29

A hemicryptophane with a triple-stranded helical structure

• Augustin Long,
• Olivier Perraud,
• Erwann Jeanneau,
• Christophe Aronica,
• Jean-Pierre Dutasta and
• Alexandre Martinez

Beilstein J. Org. Chem. 2018, 14, 1885–1889, doi:10.3762/bjoc.14.162

• a better understanding of the properties of this biological system and giving rise to numerous applications ranging from artificial collagenous biomaterials to peptides for therapeutic uses [3][4][5]. Recently, molecular cages presenting a triple helical structure have aroused a considerable

Defining the hydrophobic interactions that drive competence stimulating peptide (CSP)-ComD binding in Streptococcus pneumoniae

• Bimal Koirala,
• Robert A. Hillman,
• Erin K. Tiwold,
• Michael A. Bertucci and
• Yftah Tal-Gan

Beilstein J. Org. Chem. 2018, 14, 1769–1777, doi:10.3762/bjoc.14.151

• the CSP signal that they produce (CSP1 and CSP2, Figure 1) and their cognate receptors (ComD1 and ComD2, respectively), with minimal cross-talk between the groups [28]. The two CSP signals share approximately 50% homology and differ mainly in hydrophobic residues in the central region of the peptides

• (in addition to upregulation of ComX). ComD modulation can therefore be quantified by measuring β-gal activity. The peptides were first screened for their ability to activate/inhibit the ComD1 and ComD2 receptors at high concentration (10 µM). Only analogs that exhibited greater than 75% activation

• of 0.2 M. Reactions were run at 50 W at a temperature of 75 °C for 8 minutes, followed by 2 × 3 min deprotection with 20% piperidine in DMF. Peptide purification. Crude peptides were purified with RP-HPLC. The crude peptide was dissolved in ACN/H2O (1:4) and purified in 2.0–2.4 mL portions on either

Synthesis and photophysical studies of a multivalent photoreactive Ru^II-calix[4]arene complex bearing RGD-containing cyclopentapeptides

• Sofia Kajouj,
• Lionel Marcelis,
• Alice Mattiuzzi,
• Adrien Grassin,
• Damien Dufour,
• Pierre Van Antwerpen,
• Didier Boturyn,
• Eric Defrancq,
• Mathieu Surin,
• Julien De Winter,
• Pascal Gerbaux,
• Ivan Jabin and
• Cécile Moucheron

Beilstein J. Org. Chem. 2018, 14, 1758–1768, doi:10.3762/bjoc.14.150

• is also faced by complexes anchored on cell-penetrating peptides. In order to provide a selective cell targeting, we developed a multivalent system composed of a photoreactive ruthenium(II) complex tethered to a calix[4]arene platform bearing multiple RGD-containing cyclopentapeptides. Extensive

• reactive-oxygen-species-dependent apoptosis. Another strategy for the design of cell penetrating photoreactive RuII complexes consists of tethering the complex to a vector that allows a cellular uptake. In this context, OsII, RhIII and RuII complexes were anchored to cell penetrating peptides (CPP) such as

• the Ru complex and the cyclic peptides by the calixarene should be an advantage by preventing any negative effect of the RGD peptidic units on the photochemistry of the complex and, alternatively, prevents any influence of the complex on the affinity of the RGD patterns to interact with the targeted

Design, synthesis and structure of novel G-2 melamine-based dendrimers incorporating 4-(n-octyloxy)aniline as a peripheral unit

• Cristina Morar,
• Pedro Lameiras,
• Attila Bende,
• Gabriel Katona,
• Emese Gál and
• Mircea Darabantu

Beilstein J. Org. Chem. 2018, 14, 1704–1722, doi:10.3762/bjoc.14.145

• s-triazine units (branch-cells, T-0 or cores T-2, Scheme 3 and Scheme 4). According to H. Kessler (in 1982, [62]), this parameter is appropriate for describing amide protons solvation in p→π conjugated systems, such as –N(H)–C(=O)– ↔ –N+(H)=C(–O−)– in peptides and proteins, in water. Later on (in

Natural and redesigned wasp venom peptides with selective antitumoral activity

• Marcelo D. T. Torres,
• Gislaine P. Andrade,
• Roseli H. Sato,
• Cibele N. Pedron,
• Tania M. Manieri,
• Giselle Cerchiaro,
• Anderson O. Ribeiro,
• Cesar de la Fuente-Nunez and
• Vani X. Oliveira Jr.

Beilstein J. Org. Chem. 2018, 14, 1693–1703, doi:10.3762/bjoc.14.144

• membranes increased significantly when treated with lead peptides compared to controls. Biophysical features such as helicity, hydrophobicity, and net positive charge were identified to play an important role in the anticancer activity of the peptides. Indeed, abrupt changes in peptide hydrophobicity and

• conformational propensity led to peptide inactivation, whereas increasing the net positive charge of peptides enhanced their activity. We present peptide templates with selective activity towards breast cancer cells that leave normal cells unaffected. These templates represent excellent scaffolds for the design

• of selective anticancer peptide therapeutics. Keywords: breast cancer; decoralin; MCF-7 cells; peptide design; selective anticancer peptides; structure–activity relationships; Introduction Approximately 12% of U.S. women develop breast cancer according to the U.S. Breast Cancer website (http