Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

• for biological applications. The selected examples to illustrate the applications of the Atherton–Todd reaction mainly cover the past 15 years. Keywords: amphiphiles; flame retardant; lipid conjugates; organophosphorus; phosphoramidate; phosphate; Review 1. Introduction The reaction of

Synthesis of zearalenone-16-β,D-glucoside and zearalenone-16-sulfate: A tale of protecting resorcylic acid lactones for regiocontrolled conjugation

• Hannes Mikula,
• Julia Weber,
• Dennis Svatunek,
• Philipp Skrinjar,
• Gerhard Adam,
• Rudolf Krska,
• Christian Hametner and
• Johannes Fröhlich

Beilstein J. Org. Chem. 2014, 10, 1129–1134, doi:10.3762/bjoc.10.112

• natural product conjugates. Keywords: glycosylation; masked mycotoxins; resorcylic acid esters; sulfation; zearalenone; Introduction Resorcylic acid lactones (RALs, Figure 1), a compound class of benzannulated macrolides, are pharmacologically active secondary metabolites produced by a variety of

• mycotoxins, especially altered derivatives formed through conjugation to sugar moieties or sulfate, emerge after metabolization by living plants. Due to changed chemical structures and properties compared to the parent mycotoxins, these conjugates can usually not be detected applying standard analytical

• glycosylation has been reported by Grabley et al. [14]. ZEN-14-sulfate (6, Figure 2A) was first isolated from F. graminearum-inoculated rice [15] and both, the glucoside 5 and the sulfate 6, were identified as ZEN metabolites in Arabidopsis thaliana [16]. These conjugates are easily hydrolyzed back to the

Synthesis of fluorescent (benzyloxycarbonylamino)(aryl)methylphosphonates

• Michał Górny vel Górniak,
• Anna Czernicka,
• Piotr Młynarz,
• Waldemar Balcerzak and
• Paweł Kafarski

Beilstein J. Org. Chem. 2014, 10, 741–745, doi:10.3762/bjoc.10.68

• for profiling the proteolytic secretomes with the obtained profiles being useful as diagnostic tools [6][7][8]. Also conjugates of drugs with fluorescent probes have been used as so called theranostics (combination of therapeutics and diagnostics) [9][10]. Diaryl esters of α-aminoalkanephosphonic

From porphyrin benzylphosphoramidate conjugates to the catalytic hydrogenation of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin

• Marcos C. de Souza,
• Leandro F. Pedrosa,
• Géssica S. Cazagrande,
• Vitor F. Ferreira,
• Maria G. P. M. S. Neves and
• José A. S. Cavaleiro

Beilstein J. Org. Chem. 2014, 10, 628–633, doi:10.3762/bjoc.10.54

• recently synthesized porphyrin diisopropylphosphoramidate conjugates derived from 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (TPPF20). Such compounds showed a high photostability and a good capacity to generate singlet oxygen, but their solubility in water is moderate [4]. Additionally, we tried to

• conjugates 1a–c was achieved in eight minutes in 20%, 42% and 24% yields, respectively. Longer reaction times led to the formation of polysubstituted products. A significant advantage for the reaction under microwave irradiation is its applicability even in the presence of functional groups, which are prone

Preparation of new alkyne-modified ansamitocins by mutasynthesis

• Kirsten Harmrolfs,
• Lena Mancuso,
• Binia Drung,
• Florenz Sasse and
• Andreas Kirschning

Beilstein J. Org. Chem. 2014, 10, 535–543, doi:10.3762/bjoc.10.49

• introduce a thiol linker by Huisgen-type cycloaddition which can principally be utilized to create tumor targeting conjugates. In bioactivity tests, only those new ansamitocin derivatives showed strong antiproliferative activity that bear an ester side chain at C-3. Keywords: ansamitocins; antibiotics

• /ansamitocin conjugates [28] (Scheme 2). Bromo-ansamitocin 6 was obtained by mutasynthesis and was synthetically modified to the complex folic acid/drug conjugate 7. The vitamin folic acid has become a promising ligand for selectively targeting the folate receptor (FR) in cancer tissues where the FR is known

• to be overexpressed [29][30]. Folic acid has a high affinity for the FR (Kd = 10−10 M), even when conjugated to a cytotoxin such as maytansin. An important feature of these conjugates is the linker concept that connects the drug to the tumor-specific ligand. The linker is commonly designed in a way

The Flögel-three-component reaction with dicarboxylic acids – an approach to bis(β-alkoxy-β-ketoenamides) for the synthesis of complex pyridine and pyrimidine derivatives

• Mrinal K. Bera,
• Moisés Domínguez,
• Paul Hommes and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 394–404, doi:10.3762/bjoc.10.37

• light (253 nm) compound 22 shows fluorescence with a maximum intensity at 378 nm (see Supporting Information File 1 for details). The photophysical properties of structurally related pyridine–thiophene conjugates were recently investigated in detail [55][57][58]. Next, we investigated the

Total synthesis and cytotoxicity of the marine natural product malevamide D and a photoreactive analog

• Werner Telle,
• Gerhard Kelter,
• Heinz-Herbert Fiebig,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2014, 10, 316–322, doi:10.3762/bjoc.10.29

• the para-position of the phenyl ring, and also two aminoquinoline derivatives that were as cytotoxic as dolastatin 10 [3]. Antibody conjugates of monomethylauristatin E functionalized on the C-terminal side have also shown promising pharmacological profiles [20][21]. However, compound 30 is at least

Synthesis of new enantiopure poly(hydroxy)aminooxepanes as building blocks for multivalent carbohydrate mimetics

• Léa Bouché,
• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 213–223, doi:10.3762/bjoc.10.17

• resulting multivalent conjugates showed extremely high binding to P- and L-selectine [33][34]. For the planned biological testing of the corresponding aminooxepanes as components of multivalent conjugates, we required the fully deprotected compounds. Moreover, it was desirable to have additional derivatives

• such as alkynyl or azido substituents at the bicyclic skeleton will also allow further transformations such as click reactions or palladium-catalyzed couplings. We expect that the newly prepared aminooxepanes or their multivalent conjugates will have interesting properties and possibly biological

Synthesis and biological activity of N-substituted-tetrahydro-γ-carbolines containing peptide residues

• Nadezhda V. Sokolova,
• Valentine G. Nenajdenko,
• Vladimir B. Sokolov,
• Daria V. Vinogradova,
• Elena F. Shevtsova,
• Ludmila G. Dubova and
• Sergey O. Bachurin

Beilstein J. Org. Chem. 2014, 10, 155–162, doi:10.3762/bjoc.10.13

• Sciences, Severny proezd 1, Chernogolovka, 142432, Russia A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str. 28, 119991 Moscow, Russian Federation 10.3762/bjoc.10.13 Abstract The synthesis of novel peptide conjugates of N-substituted-tetrahydro-γ-carbolines

• has been performed using the sequence of the Ugi multicomponent reaction and Cu(I)-catalyzed click chemistry. The effect of obtained γ-carboline–peptide conjugates on the rat liver mitochondria was evaluated. It was found that all compounds in the concentration of 30 µM did onot induce depolarization

• of mitochondria but possessed some inhibitory effect on the mitochondria permeability transition. The original N-substituted-tetrahydro-γ-carbolines containing an terminal alkyne group demonstrated a high prooxidant activity, whereas their conjugates with peptide fragments slightly inhibited both

Synthesis of nucleotide–amino acid conjugates designed for photo-CIDNP experiments by a phosphotriester approach

• Tatyana V. Abramova,
• Olga B. Morozova,
• Vladimir N. Silnikov and
• Alexandra V. Yurkovskaya

Beilstein J. Org. Chem. 2013, 9, 2898–2909, doi:10.3762/bjoc.9.326

• , SB RAS, Institutskaya 3a, Novosibirsk 630090, Russia 10.3762/bjoc.9.326 Abstract Conjugates of 2’-deoxyguanosine, L-tryptophan and benzophenone designed to study pathways of fast radical reactions by the photo Chemically Induced Dynamic Nuclear Polarization (photo-CIDNP) method were obtained by the

• phosphotriester block liquid phase synthesis. The phosphotriester approach to the oligonucleotide synthesis was shown to be a versatile and economic strategy for preparing the required amount of high quality samples of nucleotide–amino acid conjugates. Keywords: CIDNP; nucleotide–amino acid conjugates

• model compound conjugates of the amino acid, nucleotide, and dye residues, where key participants (dye, amino acid, and nucleoside) have to be drawn together mimicking the biologically important DNA repair processes. To fulfill the requirements of the photo-induced TR CIDNP experiments, a synthetic

Charge-transfer interaction mediated organogels from 18β-glycyrrhetinic acid appended pyrene

• Jun Hu,
• Jindan Wu,
• Qian Wang and
• Yong Ju

Beilstein J. Org. Chem. 2013, 9, 2877–2885, doi:10.3762/bjoc.9.324

• ability of 2,3-dihydroxyiminooleanolic acid, adenineoleanolic acid conjugates as well as the fan-shaped C3 and molecular tweezers based on glycyrrhetinic acid [42][43][44]. In this paper, 18β-glycyrrhetinic acid–pyrene (GA-Pyrene, 3) as the electron donor, and 2,4,7-trinitrofluorenone (TNF, 4) as the

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• (1,3-dihydro-2H-isoindole-1,3-dione, 4) substitution pattern. The isoindole structure has attracted scientists for decades and can be found in several natural and pharmaceutical compounds [2][3]. A number of structures were explored over the years and promising drug conjugates such as 5–11 could be

Flow synthesis of a versatile fructosamine mimic and quenching studies of a fructose transport probe

• Matthew B. Plutschack,
• D. Tyler McQuade,
• Giulio Valenti and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2013, 9, 2022–2027, doi:10.3762/bjoc.9.238

• developed for conjugation to amines. For this reason, amine 3 was of particular interest. Likely, 3 will be a key branch-point for the synthesis of numerous biologically active conjugates and our improved production of 3 will provide significantly greater quantities of conjugates. In particular, we can now

Efficient continuous-flow synthesis of novel 1,2,3-triazole-substituted β-aminocyclohexanecarboxylic acid derivatives with gram-scale production

• Sándor B. Ötvös,
• Ádám Georgiádes,
• István M. Mándity,
• Lóránd Kiss and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2013, 9, 1508–1516, doi:10.3762/bjoc.9.172

• difference was observed between the performances of the two methods. Ferrocene-triazole conjugates play a crucial role in the labelling and detection of various systems, such as biomolecules, polymers, nanomaterials and supramolecular assemblies [70]. They also have potential applications in medicinal

• chemistry and drug discovery as biosensing probes, in immunoassays and in host–guest chemistry [71]. Ferrocene-substituted amino acids have been of significant importance in the investigation of the secondary structures of different peptides and foldamers [72]. Thus, conjugates of the azido-functionalized β

The conjugation of nonsteroidal anti-inflammatory drugs (NSAID) to small peptides for generating multifunctional supramolecular nanofibers/hydrogels

• Jiayang Li,
• Yi Kuang,
• Junfeng Shi,
• Yuan Gao,
• Jie Zhou and
• Bing Xu

Beilstein J. Org. Chem. 2013, 9, 908–917, doi:10.3762/bjoc.9.104

• covalent linkage of Phe–Phe and NSAIDs results in conjugates that self-assemble in water to form molecular nanofibers as the matrices of hydrogels. When the NSAID is naproxen (1), the resultant hydrogelator 1a forms a hydrogel at a critical concentration (cgc) of 0.2 wt % at pH 7.0. Hydrogelator 1a, also

• acting as a general motif, enables enzymatic hydrogelation in which the precursor turns into a hydrogelator upon hydrolysis catalyzed by a phosphatase at physiological conditions. The conjugates of Phe–Phe with other NSAIDs, such as (R)-flurbiprofen (2), racemic flurbiprofen (3), and racemic ibuprofen (4

• phosphatase and results in a hydrogel of 1d under physiological conditions. In addition to naproxen, we evaluate the abilities of other NSAIDs (Scheme 1) as building blocks of hydrogelators and find that the conjugates of FF and (R)-flurbiprofen (2), racemic flurbiprofen (3) or racemic ibuprofen (4) form

Peptoids and polyamines going sweet: Modular synthesis of glycosylated peptoids and polyamines using click chemistry

• Daniel Fürniss,
• Timo Mack,
• Frank Hahn,
• Sidonie B. L. Vollrath,
• Katarzyna Koroniak,
• Ute Schepers and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 56–63, doi:10.3762/bjoc.9.7

• be efficacious in the cellular delivery of oligonucleotides such as DNA [5][6][7] and RNA [8][9][10][11]. Conjugates of polyamines with aliphatic lipids or cholesterol yielding, i.e., dioctadecylaminoglycylspermine (DOGS, transfectam) are well established reagents for the transfection of DNA and

• d; (d) DBU (20.0 equiv), β-mercaptoethanol (20.0 equiv), DMF, rt, 18 h; (e) 1% TFA in CH2Cl2, rt, 10 min. Synthesis of spermine conjugates 20,21 and 24,25. 2-chlorotrityl chloride resin was used as a solid support. Synthesis of hexaalkynyl peptoids 26 and 27 on solid supports. Synthesis of a hexa

Theoretical study on β-cyclodextrin inclusion complexes with propiconazole and protonated propiconazole

• Adrian Fifere,
• Narcisa Marangoci,
• Stelian Maier,
• Adina Coroaba,
• Dan Maftei and
• Mariana Pinteala

Beilstein J. Org. Chem. 2012, 8, 2191–2201, doi:10.3762/bjoc.8.247

• increasingly large-scale expansion of this phenomenon [3]. Consequently, the development of new therapeutic conjugates able to combine new antifungal properties with water solubility of the drug has become a major direction of research in the field of antifungal therapy. In this respect, one of the expected

Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology

• Jan Anderl,
• Hartmut Echner and
• Heinz Faulstich

Beilstein J. Org. Chem. 2012, 8, 2072–2084, doi:10.3762/bjoc.8.233

• by conjugation of phallotoxins to either lipophilic or polycationic moieties, such as oleic acid, polylysine, or Tat-peptide. These conjugates were lethally toxic for cells, e.g., mouse fibroblasts or Jurkat leukemia cells, in the micromolar range. Uptake into cells starts with the attachment of the

• toxin conjugates to the plasma membrane, followed by endocytosis and, in most cases, cleavage of the toxin from the carrier. Interestingly, the internalization rate of phalloidin into cells was also significantly increased by the fluorescent moiety tetramethylrhodaminyl, as well as by high molecular

• internalization-mediating moieties and investigate the potential of their conjugates with toxins as specific inhibitors in cultured cells. The internalization-mediating moieties used in this study were either lipophilic in nature (such as oleic acid), or multicationic (such as polylysine and octarginine): two

Dimerization of a cell-penetrating peptide leads to enhanced cellular uptake and drug delivery

• Jan Hoyer,
• Ulrich Schatzschneider,
• Michaela Schulz-Siegmund and
• Ines Neundorf

Beilstein J. Org. Chem. 2012, 8, 1788–1797, doi:10.3762/bjoc.8.204

• )2 (PAD, proapoptotic domain peptide) [21] 4. All conjugates were synthesized with an enzymatic cleavage site for the peptidase cathepsin B (Gly-Phe-Leu-Gly), the expression of which is up-regulated in tumor cells [22][23], since this approach has been shown to improve intracellular release of the

• negligible for the biological testing. An exemplary HPLC chromatogram and ESI-MS spectrum is shown in Figure 5. Double conjugates were synthesized by an orthogonal protecting-group strategy involving highly acid-labile 4-methyltrityl (Mtt) protection (Scheme 1), which can be cleaved in the presence of tert

• -butyloxycarbonyl (Boc). Indeed, we did not observe concomitant deprotection of lysine side chains, which was favored by the fact that Mtt groups situated at the N-terminus are even more acid-sensitive than Nε-Mtt groups [25]. The structural analysis of the (sC18)2 conjugates by circular dichroism spectroscopy did

Modulating the activity of short arginine-tryptophan containing antibacterial peptides with N-terminal metallocenoyl groups

• H. Bauke Albada,
• Alina-Iulia Chiriac,
• Michaela Wenzel,
• Maya Penkova,
• Julia E. Bandow,
• Hans-Georg Sahl and
• Nils Metzler-Nolte

Beilstein J. Org. Chem. 2012, 8, 1753–1764, doi:10.3762/bjoc.8.200

• pathways, the synthetic chemist is free to apply all available compounds and techniques, thereby introducing even the most exotic molecular entities. The most recent and exotic additions are conjugates of metallocenes with short synthetic antimicrobial peptides [19][20][21][22] and organometallic

• activities of these RW-based synAMPs and their organometallic conjugates into perspective, two reference peptides were included, i.e., membrane-targeting gramicidin S derivative GS(K2Y2) and cell wall precursor lipid II-targeting vancomycin. For the calculations of the MIC values in µM, molecular weights of

The Amadori rearrangement as glycoconjugation method: Synthesis of non-natural C-glycosyl type glycoconjugates

• Katharina Gallas,
• Gerit Pototschnig,
• Florian Adanitsch,
• Arnold E. Stütz and
• Tanja M. Wrodnigg

Beilstein J. Org. Chem. 2012, 8, 1619–1629, doi:10.3762/bjoc.8.185

• ; carbohydrate elongation; non-natural carbohydrate conjugates; Introduction Glycoconjugates such as glycoproteins, glycopeptides, glycolipids and peptidoglycans are ubiquitous in nature [1]. They are found on cell surfaces and are responsible for processes such as cell–cell interaction, recognition and

Mannose-decorated cyclodextrin vesicles: The interplay of multivalency and surface density in lectin–carbohydrate recognition

• Ulrike Kauscher and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2012, 8, 1543–1551, doi:10.3762/bjoc.8.175

• be modified by host–guest interactions with functional guest molecules. In this article, we investigate the multivalent interaction of the lectin concanavalin A (ConA) with cyclodextrin vesicles decorated with mannose–adamantane conjugates with one, two or three adamantane units as well as one or two

• multivalent interaction with ConA, and the most efficient interaction (i.e., fastest agglutination at lowest concentration) was observed for mannose–adamantane conjugates, in which both the cyclodextrin–adamantane and the lectin–mannose interaction is inherently multivalent. Keywords: carbohydrates

• multivalent adamantane–mannose conjugates that bind to cyclodextrin vesicles. In this dynamic supramolecular system the guest molecules bind with their adamantane units to the cyclodextrin cavity, which acts as a receptor, and as a consequence the vesicle surface is covered by mannose. In turn, the mannose

Antibiotic and cytotoxic peptides

• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 1144–1145, doi:10.3762/bjoc.8.127

• the conventionally applied antibiotics. Consequently, the search for new antibiotically active compounds is of premier importance. On the other hand, highly cytotoxic peptides and peptide analogues, such as monomethyl auristatin E, are used as the “warhead” in antibody–drug conjugates for tumor

Low-generation dendrimers with a calixarene core and based on a chiral C₂-symmetric pyrrolidine as iminosugar mimics

• Marco Marradi,
• Stefano Cicchi,
• Francesco Sansone,
• Alessandro Casnati and
• Andrea Goti

Beilstein J. Org. Chem. 2012, 8, 951–957, doi:10.3762/bjoc.8.107

• for a significant multivalent effect in glycosidase inhibition. These results highlight the interest in synthesizing multivalent iminosugar-conjugates with well-defined structures. In this context, we aimed at studying the feasibility of combining the supramolecular properties of multivalent scaffolds

Building photoswitchable 3,4'-AMPB peptides: Probing chemical ligation methods with reducible azobenzene thioesters

• Gehad Zeyat and
• Karola Rück-Braun

Beilstein J. Org. Chem. 2012, 8, 890–896, doi:10.3762/bjoc.8.101

• we had to place the ligation junction next to the third amino acid serine of the SKV binding motif. In the case of the conventional NCL, we used cysteine at the ligation site, and for the auxiliary mediated ligations, we decided to introduce auxiliary-glycine-conjugates at the N-terminus, due to the

• procedures (Supporting Information File 1) [4][17]. The syntheses of the auxiliary-linked glycine conjugates 7 and 8 were accomplished by using literature protocols developed by Dawson, Offer and MacMillan [7][8] (Figure 2). The Cys-peptide 3 and the Nα-auxiliary peptides 4 and 5 were assembled on Wang resin

• for the application in ligation studies. AMPB = (aminomethylphenylazo)benzoic acid. Structure of the glycine-linked auxiliary conjugates 7 and 8. Structural differences between the trans- and the cis-state of azopeptides with a SKV PDZ binding motif. Solid-phase synthesis of the ligation-mediating