Automated high-content imaging for cellular uptake, from the Schmuck cation to the latest cyclic oligochalcogenides

• Rémi Martinent,
• Javier López-Andarias,
• Dimitri Moreau,
• Yangyang Cheng,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2020, 16, 2007–2016, doi:10.3762/bjoc.16.167

• chemistry tools to deliver into living cells has seen a shift of attention from counterion-mediated uptake of cell-penetrating peptides (CPPs) and their mimics, particularly the Schmuck cation, toward thiol-mediated uptake with cell-penetrating poly(disulfide)s (CPDs) and cyclic oligochalcogenides (COCs

• results can be obtained from dose–response curves of the targeted delivery to selected cells and the cytotoxicity in the same experiment, even with poorly optimized cellular systems. Keywords: automation; cell-penetrating peptides; cellular uptake; cytosolic delivery; cytotoxicity; high-content imaging

• challenge is most pronounced with large substrates, such as proteins, oligonucleotides, or nanoparticles, due to the permeability barriers formed by the lipophilic core of the cell membrane [18][19]. In recent decades, the use of arginine-rich cell-penetrating peptides (CPPs) as carriers has emerged as an

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• William A. Donaldson Department of Chemistry, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881, USA 10.3762/bjoc.16.166 Abstract The spliceostatins/thailanstatins are a family of linear peptides/polyketides that inhibit pre-mRNA splicing, and as such act as potent cytotoxic

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

• Vladimir Kubyshkin

Beilstein J. Org. Chem. 2020, 16, 1837–1852, doi:10.3762/bjoc.16.151

• Vladimir Kubyshkin University of Manitoba, Dysart Rd. 144, Winnipeg, R3T 2N2, Canada 10.3762/bjoc.16.151 Abstract Fluorine-containing analogues of proline are valuable tools in engineering and NMR spectroscopic studies of peptides and proteins. Their use relies on the fundamental understanding of

• [49][50]. The presence of a fluorine-rich group in the structure is also beneficial for the NMR studies based on the detection of the 19F nucleus [51][52][53]. Limited attention has been given to the polarity effects in the proline analogues though. Few studies reported peptides containing proline

• complex structures: peptides and proteins. Results and Discussion Model compounds The study was originally set up following an assumption that a peptide containing a proline analogue would form a system of three dipoles. The peptide bond itself creates a strong dipole, with a direction that roughly aligns

A dynamic combinatorial library for biomimetic recognition of dipeptides in water

• Florian Klepel and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2020, 16, 1588–1595, doi:10.3762/bjoc.16.131

• Florian Klepel Bart Jan Ravoo Organic Chemistry Institute and Center for Soft Nanoscience, Westfälische Wilhelms-Universität Münster, Correnstraße 40, 48149 Münster, Germany 10.3762/bjoc.16.131 Abstract Small peptides are involved in countless biological processes. Hence selective binding motifs

• for peptides can be powerful tools for labeling or inhibition. Finding those binding motifs, especially in water which competes for intermolecular H-bonds, poses an enormous challenge. A dynamic combinatorial library can be a powerful method to overcome this issue. We previously reported artificial

• receptors emerging form a dynamic combinatorial library of peptide building blocks. In this study we aimed to broaden this scope towards recognition of small peptides. Employing CXC peptide building blocks, we found that cyclic dimers of oxidized CFC bind to the aromatic peptides FF and YY (K ≈ 229–702 M−1

A cyclopeptide and three oligomycin-class polyketides produced by an underexplored actinomycete of the genus Pseudosporangium

• Shun Saito,
• Kota Atsumi,
• Tao Zhou,
• Keisuke Fukaya,
• Daisuke Urabe,
• Naoya Oku,
• Md. Rokon Ul Karim,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 1100–1110, doi:10.3762/bjoc.16.97

• DSM 45348, using the AntiSMASH database [17], and identified in total 14 biosynthetic gene clusters for polyketides and non-ribosomal peptides. Intrigued by this, a strain available from the NBRC culture collections [18] was cultured and examined by HPLC–DAD analysis, which gave several peaks in the

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• Laila F. Awad Mohammed Salah Ayoup Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria, 21321, Egypt 10.3762/bjoc.16.91 Abstract Recent advances in the chemistry of peptides containing fluorinated phenylalanines (Phe) represents a hot topic in drug research

• the properties of peptides and proteins [5][6][7], influencing aspects such as protein folding, protein–protein interactions, ribosomal translation, lipophilicity, acidity/basicity, optimal pH, stability, thermal stability, and therapeutic properties [8][9][10]. This extends to metabolic properties of

• and activity of peptides in therapeutic vaccines and enzymes has been studied [19][26][27][28][29][30][31][32][33]. In this review we provide an overview for the various syntheses of FPhes and analogues. Five different categories of FPhe are represented and are classified I–V according to the position

Fabclavine diversity in Xenorhabdus bacteria

• Sebastian L. Wenski,
• Harun Cimen,
• Natalie Berghaus,
• Sebastian W. Fuchs,
• Selcuk Hazir and
• Helge B. Bode

Beilstein J. Org. Chem. 2020, 16, 956–965, doi:10.3762/bjoc.16.84

• caused by other compound(s) as both strains have the potential to produce further bioactive SMs, such as cabanillasin, PAX peptides, or rhabdopeptides [26][44][45][46], which will be studied in the future. Furthermore, the identification of fabclavine derivatives described here might support recent

Synthesis of new asparagine-based glycopeptides for future scanning tunneling microscopy investigations

• Laura Sršan and
• Thomas Ziegler

Beilstein J. Org. Chem. 2020, 16, 888–894, doi:10.3762/bjoc.16.80

• comparison with naturally occurring amino acids [14]. Thus, there is still a great effort in finding new potential drugs derived from glycopeptides [4][15]. By using preparative mass spectrometry (pMS) combined with STM on submolecular-resolution peptides and carbohydrates can be investigated regarding their

• investigation of the self assembly of such glycopeptides on metal surfaces will be performed via pMS and STM in further studies. Description of the starting materials 1a–f and 2a–f. Peptide coupling reactions, including the previous Fmoc cleavage. Cleavage of the fully protected peptides 6 and 7. Yields of the

Opening up connectivity between documents, structures and bioactivity

• Christopher Southan

Beilstein J. Org. Chem. 2020, 16, 596–606, doi:10.3762/bjoc.16.54

• peptides or polynucleotides, are also important to encompass. However, capture into structured records is more challenging for these larger therapeutic modalities than for small-molecules that can be merged on the basis of chemistry rules. Notwithstanding, space limitations mean that non-small molecule

Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• glycine-containing peptides using an in situ-formed heteroleptic copper complex, [Cu(I)(dmp)(xantphos)]PF6 (Scheme 25) [40]. Under blue light irradiation, glycine esters were readily alkylated using NHP esters in the presence of DABCO as a base. A large panel of NHP esters was introduced to ethyl N

Photocontrolled DNA minor groove interactions of imidazole/pyrrole polyamides

• Sabrina Müller,
• Jannik Paulus,
• Jochen Mattay,
• Heiko Ihmels,
• Veronica I. Dodero and
• Norbert Sewald

Beilstein J. Org. Chem. 2020, 16, 60–70, doi:10.3762/bjoc.16.8

• peptides or small molecules, thereby controlling geometry and functionality. E-to-Z photoisomerization usually is achieved upon irradiation at 350 nm (π–π* transition), while the Z-to-E isomerization proceeds photochemically upon irradiation at >400 nm (n–π* transition) or thermally. Photoswitchable

• substance, once located at the DNA target, with an external stimulus. Azobenzenes are photoswitchable molecules capable of generating significant structural changes in peptides or small molecules, thereby controlling their geometry and functionality upon irradiation [10][11][12][13]. While isomerization of

• pyrrole and imidazole carboxamides with higher binding affinities than the pyrrole analogs alone [33][34]. We selected 3-(3-(aminomethyl)phenyl)azophenylacetic acid as the linker between both polyamide strands because it was shown to induce hairpins in peptides upon E-to-Z photoisomerization [35][36

Light-controllable dithienylethene-modified cyclic peptides: photoswitching the in vivo toxicity in zebrafish embryos

• Sergii Afonin,
• Oleg Babii,
• Aline Reuter,
• Volker Middel,
• Masanari Takamiya,
• Uwe Strähle,
• Igor V. Komarov and
• Anne S. Ulrich

Beilstein J. Org. Chem. 2020, 16, 39–49, doi:10.3762/bjoc.16.6

• embryotoxicity of dithienylethene-modified peptides upon photoswitching, using 19 analogues based on the β-hairpin scaffold of the natural membranolytic peptide gramicidin S. We established an in vivo assay in two variations (with ex vivo and in situ photoisomerization), using larvae of the model organism Danio

• rerio, and determined the toxicities of the peptides in terms of 50% lethal doses (LD50). This study allowed us to: (i) demonstrate the feasibility of evaluating peptide toxicity with D. rerio larvae at 3–4 days post fertilization, (ii) determine the phototherapeutic safety windows for all peptides

• , (iii) demonstrate photoswitching of the whole-body toxicity for the dithienylethene-modified peptides in vivo, (iv) re-analyze previous structure–toxicity relationship data, and (v) select promising candidates for potential clinical development. Keywords: diarylethene photoswitch; gramicidin S

Synthesis of C-glycosyl phosphonate derivatives of 4-amino-4-deoxy-α-ʟ-arabinose

• Lukáš Kerner and
• Paul Kosma

Beilstein J. Org. Chem. 2020, 16, 9–14, doi:10.3762/bjoc.16.2

• identified as a major mechanism contributing to antimicrobial resistance of Gram-negative pathogenic bacteria. Inhibition of the corresponding enzymatic steps, specifically the transfer of 4-amino-4-deoxy-ʟ-arabinose, would thus restore the activity of cationic antimicrobial peptides and several

• cationic antimicrobial peptides with the negatively charged phosphate and carboxylate groups in LPS domains. Suitable inhibitors intercepting the attachment of Ara4N units to the lipid A and inner core region might restore sensitivity towards the cationic antimicrobial drugs as a novel approach to combat

Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis

• David C. B. Siebert,
• Roman Sommer,
• Domen Pogorevc,
• Michael Hoffmann,
• Silke C. Wenzel,
• Rolf Müller and
• Alexander Titz

Beilstein J. Org. Chem. 2019, 15, 2922–2929, doi:10.3762/bjoc.15.286

• resistances in clinically used bacterial targets, innovative antiinfective strategies comprising new antibiotic classes and virulence-attenuating compounds have been developed [3][4]. The argyrins 1–8 are a family of 8 naturally occurring cyclic peptides isolated by Sasse, Höfle and co-workers from the

• myxobacterium Archangium gephyra (Figure 1) [5][6]. These cyclic peptides have interesting biological activities such as cytotoxic activity presumably via proteasome inhibition and immunomodulatory effects, and they also show good antibiotic effects against P. aeruginosa [7][8][9]. The structure–activity

• relationship for the natural argyrins A–H revealed argyrin B as most potent derivative (2, IC50 0.08 µg/mL). In 1996, two cyclic peptides with a similar sequence but a proposed regioisomer of the methoxytryptophan were reported as antibiotics A21459A and B [7][10]. Later, it was shown that A21459A and B are

Fluorinated maleimide-substituted porphyrins and chlorins: synthesis and characterization

• Valentina A. Ol’shevskaya,
• Elena G. Kononova and
• Andrei V. Zaitsev

Beilstein J. Org. Chem. 2019, 15, 2704–2709, doi:10.3762/bjoc.15.263

• covalently conjugates thiol groups of cysteine residues in proteins or peptides by the thio-Michael addition to the double bond of the maleimide to form a corresponding succinimidyl thioether. Conjugation of the cysteine sulfhydryl group with maleimide moieties allows us to prepare the bioconjugates

Synthesis of novel sulfide-based cyclic peptidomimetic analogues to solonamides

• José Brango-Vanegas,
• Luan A. Martinho,
• Lucinda J. Bessa,
• Andreanne G. Vasconcelos,
• Alexandra Plácido,
• Alex L. Pereira,
• José R. S. A. Leite and
• Angelo H. L. Machado

Beilstein J. Org. Chem. 2019, 15, 2544–2551, doi:10.3762/bjoc.15.247

• ) circuit Agr (accessory gene regulator) [8][9][10][11]. Four native thiolactonic cyclopeptides, named autoinducing peptides (AIPs, Figure 1), were found to be the chemical signals for the QS circuit Agr. Their chemical structures are remarkably alike to solonamides, and the synthesis of new molecules

• cysteine sulfhydryl side chain to electrophilic Cβ of an O-acetylated Morita–Baylis–Hillman (MBH) adduct residue (Scheme 1). Despite reports describing the use of amino acid residues with nucleophilic side chains to prompt the macrocyclization of peptides and their mimetics, to the best of our knowledge

• . Cyclic thioether peptides have been found in the chemical skeletons of natural products and synthetic ones that display a wide variety of activities, including antibiotics [31], vascular cell adhesion molecule-1 antagonists [32] and anticardiolipin antibodies [33][34]. Two MBH adducts (2) (R = Me, heptyl

A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light

• Xavier Gómez-Santacana,
• Sabrina M. de Munnik,
• Tamara A. M. Mocking,
• Niels J. Hauwert,
• Shanliang Sun,
• Prashanna Vijayachandran,
• Iwan J. P. de Esch,
• Henry F. Vischer,
• Maikel Wijtmans and
• Rob Leurs

Beilstein J. Org. Chem. 2019, 15, 2509–2523, doi:10.3762/bjoc.15.244

• explored on GPCRs targeted endogenously by small molecules [3][4][11][16][17][18][19][20], small peptides [5][13] and larger peptides [7][21][22]. Most of the targeted GPCRs belong to the three rhodopsin-, secretin- and glutamate-like subfamilies and involve GPCRs that endogenously bind small-molecule

• ligands [10]. The ensuing photochromic GPCR ligands are usually orthosteric and the photoswitching generally affects the functional potency [4][11][23] and/or the binding affinity [3][4][5][11] of the ligand (Figure 1A). However, as mentioned, GPCRs that endogenously bind large molecules (large peptides

• by large peptides CXCL9, CXCL10 and CXCL10 and involved in inflammatory responses. In fact, the six compounds reported in that study represent the first photochromic small-molecule class that harbors a dynamic efficacy photoswitch (from antagonism to agonism) on a peptidergic GPCR (Figure 1B). Here

In search of visible-light photoresponsive peptide nucleic acids (PNAs) for reversible control of DNA hybridization

• Lei Zhang,
• Greta Linden and
• Olalla Vázquez

Beilstein J. Org. Chem. 2019, 15, 2500–2508, doi:10.3762/bjoc.15.243

• switching capacities and duplex formation were analyzed. Our group has recently demonstrated that photoresponsive peptides can affect the transcription of genes via inhibition of histone-modifying enzymes [37]. Repression of enzymes is achievable at nucleic acid level too. Therefore, in this project we

• cis ratio was also reported in photoswitchable peptides and DNA binders equipped with oF4Azo [47][48]. Regarding stability, the cis-PNA12(oF4Azo) (3) was stable at least for 24 h at 37 °C, while under the same conditions the thermodynamically unstable isomer of PNA12(HTI) (4) reverted after 6 h at

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids

• Gerardo M. Ojeda,
• Prabhat Ranjan,
• Pavel Fedoseev,
• Lisandra Amable,
• Upendra K. Sharma,
• Daniel G. Rivera and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 2447–2457, doi:10.3762/bjoc.15.237

• peptides and the formation of isoquinolones; so it is expected that in intermediate B the substrate behaves as a tridentate ligand for the Rh(III) center [37][62][63][64][65]. However, such a complexation must be reversible to allow a further ligand exchange with the acetylene to form intermediate C. The

Sugar-derived oxazolone pseudotetrapeptide as γ-turn inducer and anion-selective transporter

• Sachin S. Burade,
• Sushil V. Pawar,
• Tanmoy Saha,
• Navanath Kumbhar,
• Amol S. Kotmale,
• Manzoor Ahmad,
• Pinaki Talukdar and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2019, 15, 2419–2427, doi:10.3762/bjoc.15.234

• transporter for which an anion–anion antiport mechanism was established. Keywords: ion transport; oxazolone; peptidomimetics; pseudo-peptides; sugar amino acid; Introduction Tetrasubstituted α-amino acid (TAA)-derived peptidomimetics offer well-defined turn structures due to the presence of a

• stereochemically stable quaternary carbon center [1]. For example, TAA-derived peptides containing a cyclopropane ring and ʟ/ᴅ-dimethyl tartrate showed an α-turn and form 310-helical conformations in higher oligomers [2][3][4]. While, TAA-derived peptides having a tetrahydrofuran ring demonstrated a β-turn type

• conformation [5]. Amongst these, the use of sugar-derived TAAs in peptidomimetics is less explored. The linear tri-/tetrapeptides and spiro-peptides at the anomeric position of mannofructose are known [6][7][8]. Stick and co-workers have reported the synthesis of tetrasubstituted sugar furanoid amino acid

Bipolenins K–N: New sesquiterpenoids from the fungal plant pathogen Bipolaris sorokiniana

• Chin-Soon Phan,
• Hang Li,
• Simon Kessler,
• Peter S. Solomon,
• Andrew M. Piggott and
• Yit-Heng Chooi

Beilstein J. Org. Chem. 2019, 15, 2020–2028, doi:10.3762/bjoc.15.198

• array of secondary metabolites, including sesquiterpenes [1][2][3][4][5][6][7], sesquiterpene-xanthones [8], diterpenes [9], sesterterpenes [10], cochlioquinones and peptides [11]. Moreover, several of these secondary metabolites are known to play important roles in mediating the virulence of these

Design, synthesis and biological evaluation of immunostimulating mannosylated desmuramyl peptides

• Rosana Ribić,
• Ranko Stojković,
• Lidija Milković,
• Mariastefania Antica,
• Marko Cigler and
• Srđanka Tomić

Beilstein J. Org. Chem. 2019, 15, 1805–1814, doi:10.3762/bjoc.15.174

• -acetylmuramyl moiety with various acyl groups represents an important approach in the design of new immunologically active MDP analogues [17]. MDP analogues lacking the N-acetylmuramyl group are called desmuramyl peptides. Structure–activity studies of the MDP derivatives and analogues suggest that the ʟ-Ala-ᴅ

• -isoGln pharmacophore is essential for the immunostimulatory properties but the introduction of lipophilic substituent into MDP analogues can increase its adjuvant activity [12][18]. Up to now, our research was directed towards isomeric desmuramyl peptides containing lipophilic unnatural amino acid

• with derivatives lacking the adamantane moiety. Immunostimulating properties of synthesized derivatives were assessed in vivo using ovalbumin as an antigen. Results and Discussion Design Desmuramyl peptides enter into the cell by passive absorption and this process depends on lipophilicity [25

Synthesis and conformational preferences of short analogues of antifreeze glycopeptides (AFGP)

• Małgorzata Urbańczyk,
• Michał Jewgiński,
• Joanna Krzciuk-Gula,
• Jerzy Góra,
• Rafał Latajka and
• Norbert Sewald

Beilstein J. Org. Chem. 2019, 15, 1581–1591, doi:10.3762/bjoc.15.162

• analogues, which occasionally occurs in smaller natural AFGP (and furthermore proline is a precursor of the PP II helix) significantly decreased the inhibitory effect on the ice recrystallization of the compounds [19]. Here we present the synthesis of a series of model peptides comprising structural motifs

• -methylamide. The introduction of a methylamide function at the C-terminal end was performed on solid phase. In order to achieve this, the Fmoc-Sieber-PS resin was modified (Scheme 1A). This type of resin enabled cleavage of peptides under mild conditions, hence without destroying fragile O-glycosidic bond

• the resin by treatment with 7–10% TFA in DCM. The cleavage cocktail was co-evaporated with toluene with the purpose of avoiding high TFA concentrations. The crude products were precipitated in cold diethyl ether, if possible. Subsequently, the peptides were lyophilised in a mixture of water and

An azobenzene container showing a definite folding – synthesis and structural investigation

• Abdulselam Adam,
• Saber Mehrparvar and
• Gebhard Haberhauer

Beilstein J. Org. Chem. 2019, 15, 1534–1544, doi:10.3762/bjoc.15.156

• chemistry. Here, we present the synthesis of a foldable container consisting of two different types of Lissoclinum macrocyclic peptides which are connected via two azobenzene units. The container is controllable by light: irradiation with UV light causes a switching process to the compact cis,cis-isomer

• the chiral switchable container we intended to use the imidazole-containing peptides 2a (R = R’ = iPr) and 3a (R = R’ = iPr) as macrocycles (see Figure 1 and Scheme 1). Both feature two imidazole units which should be used to attach the azobenzene groups. Additionally, platform 2a has two valine units

• -isomer (Figure 8). Conclusion In conclusion, we were able to synthesize a foldable container consisting of two different types of Lissoclinum macrocyclic peptides which are connected via two azobenzene units. The synthesis of this container was achieved by a one pot reaction of the two imidazole

Efficiency Eff_syn of complex syntheses as multicomponent reactions, its algorithm and calculations based on concrete criteria

• Heiner Eckert

Beilstein J. Org. Chem. 2019, 15, 1425–1433, doi:10.3762/bjoc.15.142

• demonstrate the enormous influence of branching on the overall yield yoa and synthesis efficiency Effsyn. Fragment strategy: fragment linking in peptides synthesis In synthetic peptide chemistry, amino acids are sequentially built up to form long oligo/polypeptides. For reasons of transparency, we have

• to form a linear decapeptide (Scheme 4b); sequential synthesis of two non-identical peptides (1 heptapeptide and 1 tripeptide) and their linking to form a linear decapeptide (Scheme 4c); Calculation by means of the algorithm The results are impressive. A up to 2.5-fold yield can be achieved depending