Organic chemistry meets polymers, nanoscience, therapeutics and diagnostics

• Vincent M. Rotello

Beilstein J. Org. Chem. 2016, 12, 1638–1646, doi:10.3762/bjoc.12.161

• used to "pin" arginine-capped nanoparticles to oil droplets comprised of fatty acids. This trick worked remarkably well, providing ~150 nm nanocapsules. These capsules were unstable in serum however. Reaching back to our nanocomposite work, we were able to use bricks and mortar assembly of anionic

Superstructures with cyclodextrins: chemistry and applications III

• Gerhard Wenz and
• Eric Monflier

Beilstein J. Org. Chem. 2016, 12, 937–938, doi:10.3762/bjoc.12.91

• role. As exemplified in the following, CD chemistry has developed into a very attractive field of research. The cell-penetrating peptide octa-arginine was conjugated to methylated β-CD. The resulting biofunctionalized host was able to transport a porphyrin sulfonate into HeLa cells used in photodynamic

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• well as FT mass spectrometry [22]. Muraymycins have a glycyl-uridine motif, which is connected via an aminopropyl linker to a urea peptide moiety consisting of L-leucine or L-hydroxyleucine, L-epicapreomycidine (a non-proteinogenic cyclic arginine derivative) and L-valine. The uridine structure is

• between F288 and glutamic acid 287 (E287) with the peptide motif arginine-tryptophan-x-x-tryptophan (RWxxW, x represents an arbitrary amino acid) was found. Mutants F288L and E287A showed reduced or no detectable enzyme inhibition, thus indicating a secondary binding site for potential MraY inhibitors

• moiety. This led to many truncated muraymycin analogues based on the structures 7 and 8 [76]. Cbz deprotection and subsequent peptide coupling with the L-arginine-L-valine-derived urea dipeptide 9 gave various full-length muraymycin analogues 10 and 11 [76]. Some of the truncated and the full-length

Biosynthesis of α-pyrones

• Till F. Schäberle

Beilstein J. Org. Chem. 2016, 12, 571–588, doi:10.3762/bjoc.12.56

• bound substrate (Figure 25). Indeed, the exchange of this glutamate against an alanine residue resulted in an inactive version of the protein. Further an arginine residue, which could be involved in dimerization, was mutated to an aspartate. Also this mutant lost its catalytic activity, indicating that

Studies on the synthesis of peptides containing dehydrovaline and dehydroisoleucine based on copper-mediated enamide formation

• Franziska Gille and
• Andreas Kirschning

Beilstein J. Org. Chem. 2016, 12, 564–570, doi:10.3762/bjoc.12.55

• moieties present in the antibiotic myxovalargin is reported. Peptide formation is based on a copper-mediated C–N cross-coupling protocol between an acyl amide and a peptidic vinyl iodide. The presence of a neighboring arginine in the vinyl iodide posed a challenge with respect to the choice of the

• protecting group and the reaction conditions. It was found that ornithine – a suitable precursor – is better suited than arginine for achieving good yields for the C–N cross-coupling reaction. The optimized conditions were utilized for the synthesis of peptides 32, 33, 39 and 40 containing a neighboring

• cross coupling in the preparation of myxovalargin peptide fragments mainly because of the steric hindrance of β,β’-disubstituted dehydroamino acids created. Additionally, the neighboring amino acid, especially arginine or ornithine, a precursor for preparing arginine (amino acid number 9 in 1), can be

A journey in bioinspired supramolecular chemistry: from molecular tweezers to small molecules that target myotonic dystrophy

• Steven C. Zimmerman

Beilstein J. Org. Chem. 2016, 12, 125–138, doi:10.3762/bjoc.12.14

• tweezers 19 and 20 are water-soluble but tend not to self-associate [33]. This has allowed their use in a range of biomolecular recognition applications, which appear quite promising. For example, tweezer 20, also called CLR01, has been found to bind the accessible lysine and arginine groups of proteins

Multivalency as a chemical organization and action principle

• Rainer Haag

Beilstein J. Org. Chem. 2015, 11, 848–849, doi:10.3762/bjoc.11.94

• ], peptide–polymer interactions [17][18][19][20] tripodal-catecholates [21] and polycatechol–surface interactions [22] as well as multivalent organocatalyts [23]. Finally, multivalent dendritic poly(arginine/histidine)-siRNA complexes are evaluated regarding their transfection efficiency [24]. In the future

Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

• Katharina Koschek,
• Vedat Durmaz,
• Oxana Krylova,
• Marek Wieczorek,
• Shilpi Gupta,
• Martin Richter,
• Alexander Bujotzek,
• Christina Fischer,
• Rainer Haag,
• Christian Freund,
• Marcus Weber and
• Jörg Rademann

Beilstein J. Org. Chem. 2015, 11, 837–847, doi:10.3762/bjoc.11.93

• are flanked by arginine (R in one-letter-code) [16][19]. Multivalent arrangements of these monovalent ligands therefore could serve as potent inhibitors of FBP21-interactions and could be used for the inhibition of FBP21 function. As a monovalent peptide ligand the decapeptide amide GPPPRGPPPR-NH2 (P1

Impact of multivalent charge presentation on peptide–nanoparticle aggregation

• Daniel Schöne,
• Boris Schade,
• Christoph Böttcher and
• Beate Koksch

Beilstein J. Org. Chem. 2015, 11, 792–803, doi:10.3762/bjoc.11.89

• electrostatic interactions with the nanoparticles and did not trigger nanoparticle aggregation. Thus, it was concluded that the observed nanoparticle–peptide aggregate formation results from the well-defined presentation of four arginine residues in f-positions of the coiled-coil motif [32]. In the current

• . In the first two cases either three or two arginine residues were substituted with alanine, respectively; alanine is not only neutral, but is also known for its high α-helix propensity. Due to the need of an overall positive net charge of R1A3 and R2A2 to form electrostatic interactions with the

• appears with a size of 1 µm. The occurrence of two fiber species may be the result of competing interactions between arginine residues in f-position and glutamates. This can either stabilize or diminish peptide aggregation. Increasing the pH to 11 leads to a disruption of α-helical peptide fibers that

Regulation of integrin and growth factor signaling in biomaterials for osteodifferentiation

• Qiang Wei,
• Theresa L. M. Pohl,
• Anja Seckinger,
• Joachim P. Spatz and
• Elisabetta A. Cavalcanti-Adam

Beilstein J. Org. Chem. 2015, 11, 773–783, doi:10.3762/bjoc.11.87

• adhesion proteins, on the other hand, bind to multiple integrin receptors (Figure 2b) [18]. A set of receptor–ligand combinations with high-affinity interaction has even been identified. The best characterized and most widely used ligand is the arginine-glycine-aspartic acid (RGD) sequence. RGD motifs are

• present in many ECM glycoproteins, e.g., fibronectin, vitronectin and osteopontin [21], and are recognized by all five αV, two β1 (α5 and α8), and αIIbβ3 integrins [18]. More particularly, RGD binds in a pocket between the α and β subunits. The arginine residue (R) fits into a cleft in a β-propeller

Multivalent dendritic polyglycerolamine with arginine and histidine end groups for efficient siRNA transfection

• Fatemeh Sheikhi Mehrabadi,
• Hanxiang Zeng,
• Mark Johnson,
• Cathleen Schlesener,
• Zhibin Guan and
• Rainer Haag

Beilstein J. Org. Chem. 2015, 11, 763–772, doi:10.3762/bjoc.11.86

• , arginine (Arg) and histidine (His). To investigate the effects from introducing Arg and His to dPG, the resulting polyplexes of amino acid functionalized dPG-NH2s (AAdPGs)/siRNA were evaluated regarding cytotoxicity, transfection efficiency, and cellular uptake. Among AAdPGs, an optimal vector with (1:3

• residues (His) are important for safe and efficient siRNA transfection, this study indicates that AAdPGs containing higher degrees of His display lower cytotoxicity and more efficient endosomal escape. Keywords: arginine; dendritic polyglycerolamine; histidine; multivalent vector; siRNA delivery

• biomedical purposes [6] such as anti-inflammatory [10] and anticancer therapy [11][12]. Previously a number of cationic polymers like chitosan [13][14][15], PEI [16], and PAMAM [17] have been post-modified with histidine (His) or arginine (Arg) groups. The introduction of histidine groups has been beneficial

Exploring monovalent and multivalent peptides for the inhibition of FBP21-tWW

• Lisa Maria Henning,
• Sumati Bhatia,
• Miriam Bertazzon,
• Michaela Marczynke,
• Oliver Seitz,
• Rudolf Volkmer,
• Rainer Haag and
• Christian Freund

Beilstein J. Org. Chem. 2015, 11, 701–706, doi:10.3762/bjoc.11.80

• proline–arginine-rich peptides in the core splicing protein SmB/B’ and the U2-associated protein SF3B4. The interaction of FBP21 with these proteins is conferred by two WW domains that are connected by a short, 8 amino acid long linker sequence. Multivalent recognition of the proline-rich sequences (PRS

• expected from evolutionary and binding studies carried out earlier [17][18]. The sequences obtained are shown in Figure 1B. In agreement with previous findings for this group of WW domains a polyproline stretch and an arginine residue are present in most sequenced clones. Interestingly, a preference for an

• by the individual WW domains [5]. At position P4 proline can be replaced by leucine, a residue well compatible with the PPII helical conformation. Arginine is preferred at position 6 or 9, highlighting the importance of a positive charge in complex formation. Interestingly, WW1 tolerates an exchange

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

• Alan M. Jones and
• Craig E. Banks

Beilstein J. Org. Chem. 2014, 10, 3056–3072, doi:10.3762/bjoc.10.323

• analogues prepared (Scheme 23; 98–100) showed competitive binding of the native ligand with IC50’s = 32, 80, 5 µM using a radioiodinated peptide binding to the NK1 receptor in Chinese Hamster Ovary (CHO) cells (native ligand IC50 = 0.3 nM). The preparation of arginine mimetics is an ongoing challenge for

• ]. Examples of Phe7–Phe8 mimics prepared using an electrochemical approach [93]. Preparation of arginine mimics employing an electrooxidation step [96]. Preparation of chiral cyclic amino acids [20]. Two-step preparation of Nazlinine 117 using Shono flow electrochemistry [101]. Acknowledgements The authors

Molecular recognition of AT-DNA sequences by the induced CD pattern of dibenzotetraaza[14]annulene (DBTAA)–adenine derivatives

• Marijana Radić Stojković,
• Marko Škugor,
• Łukasz Dudek,
• Jarosław Grolik,
• Julita Eilmes and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2175–2185, doi:10.3762/bjoc.10.225

• in proteins which use selective binding interactions of an arginine-rich side arm inside the AT sequence minor groove to broaden the related DNA major groove, within which the protein biological action takes place [5]. However, the majority of known small molecules are not able to distinguish AT

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties

• Catalin V. Maftei,
• Elena Fodor,
• Peter G. Jones,
• M. Heiko Franz,
• Gerhard Kelter,
• Heiner Fiebig and
• Ion Neda

Beilstein J. Org. Chem. 2013, 9, 2202–2215, doi:10.3762/bjoc.9.259

• and recognizes the arginine–glycine–aspartic acid (RGD) sequence. Antagonists of this receptor are able to inhibit angiogenesis. 1,2,4-Oxadiazolebutanoic acids such as C were tested as non-peptidic analogs of αvβ3 antagonists [10]. Furthermore, substituted 1,2,4-oxadiazoles have been described as

C–C Bond formation catalyzed by natural gelatin and collagen proteins

• Dennis Kühbeck,
• Basab Bijayi Dhar,
• Eva-Maria Schön,
• Carlos Cativiela,
• Vicente Gotor-Fernández and
• David Díaz Díaz

Beilstein J. Org. Chem. 2013, 9, 1111–1118, doi:10.3762/bjoc.9.123

• composition of gelatin in terms of its amino acids content has been reported in several publications (arginine, glutamic acid, alanine, glycine, proline and hydroxyproline are the most abundant amino acids (ca. 10–25%)) [1], which makes the protein itself suitable for catalytic studies. The Henry (nitroaldol

Towards a biocompatible artificial lung: Covalent functionalization of poly(4-methylpent-1-ene) (TPX) with cRGD pentapeptide

• Lena Möller,
• Christian Hess,
• Jiří Paleček,
• Yi Su,
• Axel Haverich,
• Andreas Kirschning and
• Gerald Dräger

Beilstein J. Org. Chem. 2013, 9, 270–277, doi:10.3762/bjoc.9.33

• water-soluble protein coating, which is necessary for the cell attachment. In this paper, we disclose a strategy to strongly attach ECs to TPX 2 membranes by covalent functionalization of the chemically rather inert material with a cyclic peptide, containing the RGD (arginine-glycine-asparagine) amino

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

• derivative (8 residues) are comparable, we argue that arginine residues are more effective in mediating internalization of phalloidin than are lysine residues. For phalloidin bound to methoxy-polyethylene-glycol we found that cytotoxicity strictly depended on the molecular weight of the polymer chain (Figure

• been shown that nona-arginine is many times more efficient than Tat-peptide, suggesting that the internalization effect of Tat-peptide is mainly due to its eight cationic side chains [30]. Attachment to plasma membrane determines the rate of internalization Plasma membranes of cells in culture

• - or polycationic molecules. As already pointed out, arginine residues as in 2d are more effective than lysine residues in 2e, as 120 lysine groups are required to match the internalization increase caused by eight arginine residues. Concerning Tat-peptide, we believe that its eight cationic side

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

• variety of cargo molecules for therapy and diagnosis, as could be successfully shown for, e.g., cytostatics [1], proteins [2], oligonucleotides [3][4] and nanoparticles [5]. A common feature of CPPs is their typically high content in basic arginine and lysine residues, leading to a positive net charge of

• -293 and MCF-7 was observed. The drastically enhanced uptake of the dimer compared to the monomeric peptide is in contrast to previous studies with the TAT peptide, which is similar to sC18 with respect to the number of arginine and lysine residues and the overall charge of the peptide. Dimerization of

• exhibits significant cytotoxic effects while the monomer does not is consistent with previous studies that demonstrated the increase of membrane leakage and cytotoxicity with the number of arginine residues in oligoarginines [19] as well as increased cytotoxicity for oligomeric CPPs in general [20

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

• of small synthetic arginine and tryptophan containing peptides was prepared and analyzed for their antibacterial activity. The effect of N-terminal substitution with metallocenoyl groups such as ferrocene (FcCO) and ruthenocene (RcCO) was investigated. Antibacterial activity in different media

• , growth inhibition, and killing kinetics of the most active peptides were determined. The toxicity of selected derivatives was determined against erythrocytes and three human cancer cell lines. It was shown that the replacement of an N-terminal arginine residue with a metallocenoyl moiety modulates the

• of ~90 µM, indicating a potentially interesting therapeutic window. Both the killing kinetics and growth inhibition studies presented in this work point to a membrane-based mode of action for these two peptides, each having different kinetic parameters. Keywords: antimicrobial peptides; arginine

Antifreeze glycopeptide diastereomers

• Lilly Nagel,
• Carsten Budke,
• Axel Dreyer,
• Thomas Koop and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 1657–1667, doi:10.3762/bjoc.8.190

• arginine [11]. Tachibana et al. summarized the essential properties of AFGPs displaying significant antifreeze activity: The disaccharide must be α-glycosidically attached to every threonine; the acetylamino moiety has to be present at the C2 position; the carbohydrates must be galacto-configured; and the

Synthesis of trifunctional cyclo-β-tripeptide templates

• Frank Stein,
• Tahir Mehmood,
• Tilman Plass,
• Javid H. Zaidi and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2012, 8, 1576–1583, doi:10.3762/bjoc.8.180

• ). Standard reagents, protocols and procedures were used for deprotection (20% piperidine in NMP, 210 s, 50 °C, 20 W) and coupling (HBTU/HOBt/DIEA/NMP, 300 s, 50 °C, 20 W). Double couplings were performed for arginine. No final Fmoc deprotection step was used. After the automated peptide synthesis, the

Binaphthyl-anchored antibacterial tripeptide derivatives with hydrophobic C-terminal amino acid variations

• John B. Bremner,
• Paul A. Keller,
• Stephen G. Pyne,
• Mark J. Robertson,
• K. Sakthivel,
• Kittiya Somphol,
• Dean Baylis,
• Jonathan A. Coates,
• John Deadman,
• Dharshini Jeevarajah and
• David I. Rhodes

Beilstein J. Org. Chem. 2012, 8, 1265–1270, doi:10.3762/bjoc.8.142

• esters 4 (Scheme 1), with the exception of the synthesis of 2c in which the commercially available 4c was used as the starting material. Addition of the protected central arginine unit by diimide- or BOP-induced amide bond formation, followed by selective Fmoc removal from the respective intermediates 5

Design of a novel tryptophan-rich membrane-active antimicrobial peptide from the membrane-proximal region of the HIV glycoprotein, gp41

• Evan F. Haney,
• Leonard T. Nguyen,
• David J. Schibli and
• Hans J. Vogel

Beilstein J. Org. Chem. 2012, 8, 1172–1184, doi:10.3762/bjoc.8.130

• . Arginine residues seem to be preferred over Lys residues in short Trp- and Arg-rich AMPs obtained through combinatorial chemistry [29]. Interestingly, the gp41w-4R peptide did not show any increased antimicrobial activity despite the high content of Trp and cationic residues. Instead, the gp41w-4R peptide