Heck- and Suzuki-coupling approaches to novel hydroquinone inhibitors of calcium ATPase

• Robert J. Kempton,
• Taylor A. Kidd-Kautz,
• Soizic Laurenceau and
• Stefan Paula

Beilstein J. Org. Chem. 2019, 15, 971–975, doi:10.3762/bjoc.15.94

• tether to BHQ that terminated in a leucine moiety to obtain target 14. Similar to related compounds based on the structure of the natural product thapsigargin, 14 displayed inhibitory potency against SERCA activity. This makes 14 a suitable candidate for the future attachment of a deactivating peptide to

• cytotoxic agent. The problem of concomitant toxicity to healthy cells has been circumvented by attaching a short peptide (His-Ser-Ser-Lys-Leu-Gln-Leu) to a tether at TG’s C-8 position (1b). This modification renders the inhibitor inactive [3]. Prostate cancer cells produce on their surface the serine

• protease PSA (prostate-specific antigen) that is capable of cleaving the peptide bond between Gln and Leu, thereby producing an active TG analogue that can enter the cancer cell and kill it by triggering apoptosis. Apoptosis occurs as the result of elevated cytosolic calcium levels, which are caused by

Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• formaldehyde allowed the rapid production of eight functionalized macrocycles (Scheme 30). Another method using repetitive Ugi reactions has been described for the macrocyclization of peptides [48]. The approach was based on double Ugi-4CR involving a peptide diacid, a diisocyanide, methylamine and

• paraformaldehyde (Scheme 31a). Subsequently, it was observed that varying the amine component (C-protected amino acids) allowed the obtention of exocyclic elements of diversity as observed in macrocycles 162a and b (Scheme 31b). The process allows the increase of the peptide sequence as well as the inclusion of

Mechanochemistry of supramolecules

• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2019, 15, 881–900, doi:10.3762/bjoc.15.86

• shaking and stirring [89]. Peptide-chain containing distal thiol groups underwent an aerial oxidation process to give different disulfide-containing macromolecules. They observed that under mechanical shaking conditions preferentially the cyclic hexamer 33 is formed, whereas stirring resulted in formation

• interactions of alternating hydrophilic and hydrophobic units in the peptide chains played the vital role in the system. Friščić and Aav with co-workers reported the first solvent-free mechanochemical synthesis of hemicucurbiturils [90] through the anion template effect of dynamic covalent chemistry [47][91

• thermodynamic control. Preferential formation of hexamer 33 under mechanochemical shaking via non-covalent interactions of peptide chains. Anion templated mechanochemical synthesis of macrocycles cycHC[n] by validating the concept of dynamic covalent chemistry. Hydrogen-bond-assisted [2 + 2]-cycloaddition

Efficient synthesis of pyrazolopyridines containing a chromane backbone through domino reaction

• Razieh Navari,
• Saeed Balalaie,
• Saber Mehrparvar,
• Fatemeh Darvish,
• Frank Rominger,
• Fatima Hamdan and
• Sattar Mirzaie

Beilstein J. Org. Chem. 2019, 15, 874–880, doi:10.3762/bjoc.15.85

• Razieh Navari Saeed Balalaie Saber Mehrparvar Fatemeh Darvish Frank Rominger Fatima Hamdan Sattar Mirzaie Peptide Chemistry Research Center, K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran, Tel: +98-21-23064226, Fax: +98-21-22889403 Medical Biology Research Center

Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides

• Maryam Khalesi,
• Azim Ziyaei Halimehjani and
• Jürgen Martens

Beilstein J. Org. Chem. 2019, 15, 852–857, doi:10.3762/bjoc.15.82

• for the Ugi reaction. This article provides a facile and convenient one-pot procedure for the synthesis of peptide-like heterocyclic molecules containing 2-pyrrolidone (γ-lactam), amide and ester functional groups with good to excellent yields. Keywords: amino acid-based isocyanides; levulinic acid

• prominent and studied MCRs is the Ugi reaction. The Ugi four-component condensation reaction (U-4CC) between an aldehyde, an amine, a carboxylic acid and an isocyanide provides a rapid preparation of α-aminoacyl amide or pseudo-peptide derivatives. These biologically active peptide-like molecules can be

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

• biomolecules that constitute the cell do also experience the effects of the mechanical forces. For example, from the moment a nascent peptide begins growing in the ribosome, such peptide experiences mechanical signals that regulate the speed of protein synthesis [2]. Not surprisingly, the natural ability of

• 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

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

• 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

• -terminal groups of the peptide and their putative target. This method has been used for the macrocyclization of peptides through, for example, copper-catalyzed azide–alkyne cycloadditions [14], ring-closing olefin metathesis [13] or the formation of an aryl–aryl bond between the side chain of two aromatic

• , the cyclization of linear peptides through aryl–aryl bond formation confers a relative conformational constraint on the peptide scaffold. Moreover, the resulting biaryl motif is able to participate in π–π interactions with aromatic and hydrophobic residues, and also in π-cation interactions with

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

• assembled by solution-phase synthesis and an open-chain analogue of the natural product was obtained. Keywords: jasplakinolide; marine natural products; Negishi coupling; polyketides; stereoselective synthesis; Introduction Our program on the synthesis of biologically active natural products with peptide

• Suberites japonicus (Thiele) has been synthesized only once, with relay ring-closing metathesis being the key step [9]. Characteristically, seragamides A–E exhibit a L-threonine unit at the C-terminus of the peptide moiety. There is a considerable body of work on the synthesis of the C12 polyketide section

• with literature data we converted 7 to the free carboxylic acid carrying a TBS-protected hydroxy group at C8 by silylation with TBSOTf/2,6-lutidine, followed by saponification with LiOH. To investigate whether polyketide 7 could be coupled in an unprotected form with the peptide fragment of seragamide

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

• moiety itself are required for bioactivity [16]. These findings suggest a specific interaction of this electrophilic moiety with a nucleophile. Such an interaction was previously reported for the macrocyclic peptide cyclotheonamide A, isolated from marine sponge Theonella sp. Cyclotheonamide A is

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

• consecutive reactions lead to adducts displaying a diversity of substituents at several positions, which, in principle, can be located at will, in a controlled manner. For instance, the combination of a Petasis 3CR with an Ugi 4CR led to a peptide structure with six diversity points arising directly from the

• illustrate a repetitive Ugi 4CR-deprotection-Ugi 4CR protocol to obtain peptide nucleic acid (PNA) oligomers (Scheme 13A) [49], peptidic tetrazoles and hydantoinimides (Scheme 13B) [50], respectively. Incidentally, the later processes take place in solid phase, which enhances their synthetic suitability. The

Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists

• Constantinos G. Neochoritis,
• Maryam Kazemi Miraki,
• Eman M. M. Abdelraheem,
• Ewa Surmiak,
• Tryfon Zarganes-Tzitzikas,
• Beata Łabuzek,
• Tad A. Holak and
• Alexander Dömling

Beilstein J. Org. Chem. 2019, 15, 513–520, doi:10.3762/bjoc.15.45

• . The aforementioned artificial macrocycles combine the indole ring, a motif found in many bioactive molecules with the drug-like properties of a non-peptide macrocycle. We hypothesize that these chimeric derivatives of an indole and a macrocycle will offer new potential on specific PPIs and other

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

• interesting applications in plant biology. Olefin metathesis is also used to cross-link peptide fragments. This technology is known as peptide stapling [92]. Blackwell et al. engineered the first stapled peptide in 1998 by introducing two non-natural amino acids bearing a terminal alkene in a peptide sequence

• (e.g., 105, 106) [93]. The cross-linking of the two amino acids by metathesis results in a more rigid and stabilized alpha helix (products 107 and 108, Scheme 23). Although the reaction cannot be classified as aqueous metathesis (the reaction is carried out in CHCl3 and the peptide remains attached to

• the solid phase), this technology has been exploited to disrupt protein–protein interactions (PPIs) in cancer cells [94][95][96]. Aileron Therapeutics recently launched a stapled peptide platform aiming at developing molecules like ALRN-6924, a stapled peptide that interacts with p53 inhibitors MDMX

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

• peptide dendrimers. Keywords: amino acids; cyclotrimerization; Negishi coupling; peptide; Introduction Optically active C3-symmetric molecules are valuable synthons to design dendrimers, chiral ligands, polymers, and supramolecules [1][2][3][4]. In this regard, 1,3,5-triarylbenzene derivatives are

• /petroleum ether) to afford the C3-symmetric mono- and dipeptide derivatives 11, 12 and 13, respectively. Peptide derivative 11 Colorless solid; yield 86% (89 mg, starting from 100 mg of 10); Rf = 0.46 (7:3 ethyl acetate/petroleum ether); mp 156–158 °C; [α]D25 +25.07 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ

• , 2928, 1606, 1596, 1434, 783, 505 cm−1. Exemplar C3-symmetric peptide scaffolds reported in the literature. Preparation of compound 7 from L-serine (3). Preparation of the trimerized product 9. Synthesis of compound 11 via Negishi cross-coupling reaction. Synthesis of C3-symmetric trimers 12, 13 and 14

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

• white solid. Its IR spectrum (KBr tablet, Supporting Information File 1, Figure S1) showed strong and broad absorption bands at 1535 cm−1 and 1660 cm−1, indicating that cichorinotoxin has amide groups and that it is a peptide. In addition, a band at 1740 cm−1 (medium) was also observed, suggesting that

• of the fragment ions in the FABMS spectrum of cichorinotoxin (Figure 1) showed the presence of the following peptide segment: Pro-Ala-Ala-Ala-Val-Ala-dhThr-Ala-Val (Figure 2). As described below, this toxin has a 3-hydroxydecanoic acid moiety as a fatty acid. Furthermore, the amino group at the N

• peptide part is cyclized through an ester linkage between two of the amino acid residues (Thr18 and Val22). Thus, cichorinotoxin is classified as a cyclic lipodepsipeptide. To determine the stereochemistry of the amino acids (D or L), we tried to isolate partial fragments by acid hydrolysis. The toxin was

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

• biological activity. Indeed, the interest in 3-hydroxyglutamic acid started many years ago by the discovery of this amino acid in hydrolysates of an antibiotic peptide S-520 [24]. It has been proved recently that it was actually the isomer (2S,3R)-2 and it is a fragment of a cyclohexapeptide [25]. (2R,3S)-2

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

• Pharmaceuticals GmbH, Leberstr. 20, A-1110 Vienna, Austria 10.3762/bjoc.15.11 Abstract Tubugi-1 is a small cytotoxic peptide with picomolar cytotoxicity. To improve its cancer cell targeting, it was conjugated using a universal, modular disulfide derivative. This allowed conjugation to a neuropeptide-Y (NPY

• )-inspired peptide [K4(C-βA-),F7,L17,P34]-hNPY, acting as NPY Y1 receptor (hY1R)-targeting peptide, to form a tubugi-1–SS–NPY disulfide-linked conjugate. The cytotoxic impacts of the novel tubugi-1–NPY peptide–toxin conjugate, as well as of free tubugi-1, and tubugi-1 bearing the thiol spacer (liberated from

• potency of the liberated tubugi-1 that, however, still bears the thiol spacer (tubugi-1-SH) was restored and up to 10-fold higher compared to the entire peptide–toxin conjugate. The conjugate shows toxic selectivity to tumor cell lines overexpressing the hY1R receptor subtype like, e.g., the hard to treat

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

• host proteins and cell types, for example the invariant N-acetyl-D-glucosamine or N-acetyl-D-galactosamine residues that attach N- or O-glycans, respectively, to the peptide side chains, the large variety and possible permutations of “capping” residues (for example D-mannopyranosides, D

Cross metathesis-mediated synthesis of hydroxamic acid derivatives

• Shital Kumar Chattopadhyay,
• Subhankar Ghosh and
• Suman Sil

Beilstein J. Org. Chem. 2018, 14, 3070–3075, doi:10.3762/bjoc.14.285

• important demonstration of the protocol is the preparation of the unusual amino acid component of the bioactive cyclic peptide Chap-31. Keywords: α-amino acid; catalysis; cross metathesis; hydroxamates; Introduction Cross-metathesis reactions (CM) have rapidly grown [1][2][3] to be a reliable method for

• ] and the didehydrohydroxamate TSA (2) [24], display useful anticancer properties through inhibition of histone deacetylase enzymes (HDAc) and are used as FDA-approved drugs. Similarly, the cyclic peptide Chap-31 (3) [25] with a terminal hydroxamic acid residue has shown promising anticancer activity

• synthesis of the unusual amino acid component of the important anticancer cyclic peptide compound Chap-31, we attempted the cross-metathesis reaction of N-benzyloxyacryl amide 5 with the homoallylglycine derivative 4k (Table 1, entry 11) and the bis-homoallyl glycine derivative 4l (Table 1, entry 12) [32

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

• the peptide-binding pocket of the β-clamp, they carried out a fluorescence anisotropy titration screening of the Rockefeller University chemical library containing 30,600 polar organic compounds which led to the discovery of RU7 (9, Figure 3) with an inhibition constant of 10 μM. Pleasingly, it was

• 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

• , Figure 5) with enhanced affinity for the β-clamp (IC50 = 1.12 μM, measured by surface plasmon resonance). This acetylated peptide was used as a lead and further modified at the second position, where the leucine residue was replaced by a cyclohexyl-L-alanyl group (Cha), and also on the terminal

Synthesis of pyrrolidine-based hamamelitannin analogues as quorum sensing inhibitors in Staphylococcus aureus

• Jakob Bouton,
• Kristof Van Hecke,
• Reuven Rasooly and
• Serge Van Calenbergh

Beilstein J. Org. Chem. 2018, 14, 2822–2828, doi:10.3762/bjoc.14.260

• clinical infections. In S. aureus, virulence is mainly mediated by quorum sensing, a bacterial cell-to-cell communication system based on the secretion of signal molecules [9][10][11]. The natural product hamamelitannin (1) has been identified as a non-peptide analogue of RIP (RNAIII-inhibiting protein

Synthesis of mono-functionalized S-diazocines via intramolecular Baeyer–Mills reactions

• Miriam Schehr,
• Daniel Hugenbusch,
• Tobias Moje,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2018, 14, 2799–2804, doi:10.3762/bjoc.14.257

• functionalization such as cross coupling, peptide coupling or further functionalization. The photoswitchable properties of the S-diazocines 1–5 were investigated using UV–vis and NMR spectroscopic methods. The photostationary states (PSS), half-lives (t1/2) and absorption maxima (λmax) were recorded in acetone and

• precursors for the incorporation in photopharmacophores using cross-coupling, peptide coupling or further functionalization methods such as nucleophilic substitution reaction of the benzyl alcohol 5. The yield determining steps prior to the Baeyer–Mills reaction are the formation of the hydroxylamine with

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

• successfully designed and demonstrated a novel continuous process for assembling targeting ligands, peptidic spacers, fluorescent tags and a chelating core for the attachment of cytotoxic molecules, radiotracers, nanomaterials in a standard Fmoc solid-phase peptide synthesis in high yield and purity. The

• differentially protected Fmoc-Lys-(Tfa)-OH plays a vital role in attaching fluorescent tags while growing the peptide chain in an uninterrupted manner. The methodology is versatile for solid-phase resins that are sensitive to mild and strong acidic conditions when acid-sensitive side chain amino protecting

• tag; Fmoc-Lys-(Tfa)-OH; prostate cancer and ovarian cancer; solid-phase peptide synthesis; Introduction The understanding of cell processes is indispensable to devise new strategies for diagnosis and treatment of cancer and inflammatory diseases through targeted drug delivery techniques [1]. The

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

• attachment of a cell-penetrating peptide sequence [58]. One additional class, which did show cellular activity, was based on a catechol scaffold [59]. In analogy to the successful discovery of PqsD inhibitors starting from known FabH-targeting compounds (vide supra), ligands of another enzyme with high

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

• Kaiserslautern, Amerikastraße 1, 66482 Zweibrücken, Germany Research Group of Peptide Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, Pázmány Péter sétány 1/A, 1117 Budapest, Hungary Eötvös Loránd University, Faculty of Science, Institute of Chemistry, Pázmány Péter sétány 1/A, 1117 Budapest

• , Hungary 10.3762/bjoc.14.226 Abstract Background: Peptide hormone-based targeted tumor therapy is an approved strategy to selectively block the tumor growth and spreading. The gonadotropin-releasing hormone receptors (GnRH-R) overexpressed on different tumors (e.g., melanoma) could be utilized for drug

• approaches to diminish this kind of cytotoxic effects on healthy tissues is the employment of drug delivery systems directed specifically to cancer cells. The chemotherapeutic drug targeting is often based on the receptors for certain peptide hormones that are preferentially expressed by cancer cells. The

Synergistic approach to polycycles through Suzuki–Miyaura cross coupling and metathesis as key steps

• Sambasivarao Kotha,
• Milind Meshram and
• Chandravathi Chakkapalli

Beilstein J. Org. Chem. 2018, 14, 2468–2481, doi:10.3762/bjoc.14.223

• interests include: organic synthesis, green chemistry, development of new synthetic methods for unusual amino acids, peptide modifications, cross-coupling reactions, and metathesis. Currently, he occupies the Pramod Chaudhari Chair Professor in Green Chemistry. Milind P. Meshram was born in Amravati