Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting

• Lizeth Bodero,
• Paula López Rivas,
• Barbara Korsak,
• Torsten Hechler,
• Andreas Pahl,
• Christoph Müller,
• Daniela Arosio,
• Luca Pignataro,
• Cesare Gennari and
• Umberto Piarulli

Beilstein J. Org. Chem. 2018, 14, 407–415, doi:10.3762/bjoc.14.29

• is responsible for the transcription of DNA to mRNA [1][2]. Despite this strong inhibitory activity, α-amanitin exhibits only a micromolar cytotoxicity and low cellular uptake in most mammalian cells, due to its strong polarity and poor membrane permeability [2]. One notable exception are human

• , unfavorable pharmacokinetics (low tissue diffusion and low accumulation rate) and possible elicitation of immune response [6]. By conjugation to a specific cell-membrane-receptor ligand, the toxin can be delivered at the tumor site and internalized through receptor-mediated endocytosis. In 2013, Reshetnyak

• and co-workers conjugated α-amanitin to pHLIP (pH low insertion peptide) via linkers of different hydrophobicities [7]. The results indicated that pHLIP could deliver α-amanitin into cells and induce cell death in 48 h by a pH-mediated direct translocation across the membrane and cleavage of the

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• endotoxin), a complex glycolipid constituting the outer leaflet of the bacterial outer membrane. Recognition of picomolar quantities of pathogenic LPS by the germ-line encoded Toll-like Receptor 4 (TLR4) complex triggers the intracellular pro-inflammatory signaling cascade leading to the expression of

• cytokines, chemokines, prostaglandins and reactive oxygen species which manifest an acute inflammatory response to infection. The “endotoxic principle” of LPS resides in its amphiphilic membrane-bound fragment glycophospholipid lipid A which directly binds to the TLR4·MD-2 receptor complex. The lipid A

• mammalian immune cells such as macrophages, monocytes and dendritic cells [4]. LPS represents the major virulence factor of Gram-negative bacteria and is essential for bacterial survival. LPS constitutes the outer leaflet of the outer membrane of Gram-negative bacteria (Figure 1A) and possesses a complex

Binding abilities of polyaminocyclodextrins: polarimetric investigations and biological assays

• Marco Russo,
• Daniele La Corte,
• Annalisa Pisciotta,
• Serena Riela,
• Rosa Alduina and
• Paolo Lo Meo

Beilstein J. Org. Chem. 2017, 13, 2751–2763, doi:10.3762/bjoc.13.271

• , can undergo a transient period of competence after a pretreatment with calcium chloride followed by a short heat or electric shock. The addition of CaCl2 promotes the binding of pDNA to the outer membrane of Gram-negative bacteria. The Ca2+ ions both attract the negatively charged DNA backbone and

Development of a fluorogenic small substrate for dipeptidyl peptidase-4

• Futa Ogawa,
• Masanori Takeda,
• Kanae Miyanaga,
• Keita Tani,
• Ryuji Yamazawa,
• Kiyoshi Ito,
• Atsushi Tarui,
• Kazuyuki Sato and
• Masaaki Omote

Beilstein J. Org. Chem. 2017, 13, 2690–2697, doi:10.3762/bjoc.13.267

• sometimes inconvenient in terms of membrane permeability, water solubility, and inhibition of inherent interactions between the probe molecule and the target enzyme. We have developed a new OFF–ON probe with a small fluorescent core unit. The same approach was recently used to produce a fluorophore for a

What contributes to an effective mannose recognition domain?

• Christoph P. Sager,
• Deniz Eriş,
• Martin Smieško,
• Rachel Hevey and
• Beat Ernst

Beilstein J. Org. Chem. 2017, 13, 2584–2595, doi:10.3762/bjoc.13.255

• glycosides on mammalian cell surfaces. After this initial contact, they can infect host cells and form biofilms, both of which are key factors for their survival [9][27][28]. Examples of such opportunistic bacterial species binding to mannosides on host cells include Pseudomonas aeruginosa with its membrane

A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

• Marcus Baumann,
• Ian R. Baxendale and
• Fabien Deplante

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

• was phase separated. To enable the phase separation we utilised a passive membrane system based upon a modified Biotage universal separator [9]. This enabled the heavier chlorinated phase to be removed from the lower connection and for the lighter aqueous phase to be decanted from an overflow

Herpetopanone, a diterpene from Herpetosiphon aurantiacus discovered by isotope labeling

• Xinli Pan,
• Nicole Domin,
• Sebastian Schieferdecker,
• Hirokazu Kage,
• Martin Roth and
• Markus Nett

Beilstein J. Org. Chem. 2017, 13, 2458–2465, doi:10.3762/bjoc.13.242

• represent the largest group of natural products with about 60,000 different compounds being known. They occur in all three domains of life and are known to fulfill a variety of different functions, e.g., as membrane constituents, chemical attractants or feeding deterrents [1]. Over a long period, terpenoids

Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2017, 13, 2442–2457, doi:10.3762/bjoc.13.241

• measurements can be used to study ligand–protein [12] and protein–protein interactions [13]; membrane proteins [14][15][16] and membrane-associated peptides [17][18]; equilibria among conformations of RNA [19], DNA [20], and peptide nucleic acids (PNA) [21]; and many others. Particularly recent is the

Remarkable functions of sn-3 hydroxy and phosphocholine groups in 1,2-diacyl-sn-glycerolipids to induce clockwise (+)-helicity around the 1,2-diacyl moiety: Evidence from conformation analysis by ¹H NMR spectroscopy

• Yoshihiro Nishida,
• Mengfei Yuan,
• Kazuo Fukuda,
• Kaito Fujisawa,
• Hirofumi Dohi and
• Hirotaka Uzawa

Beilstein J. Org. Chem. 2017, 13, 1999–2009, doi:10.3762/bjoc.13.196

• of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba 305-8565, Japan 10.3762/bjoc.13.196 Abstract Cell-membrane glycerolipids exhibit a common structural backbone of asymmetric 1,2-diacyl-sn-glycerol bearing polar head groups in the sn-3 position. In this study, the possible

• used. From the 1H NMR analysis, the helical conformational properties around the 1,2-diacyl moiety conformed to a simple empirical rule, which permitted the proposal of a conformational diagram for 1,2-dipalmitoyl-sn-glycerols in the solution states. Keywords: cell membrane; chirality; conformation

• properties, as glycerophospholipids comprise elements of fluid membrane [5] and nanoscale vesicles called liposomes [6]. In addition, the chiral sn-glycerol backbone is composed of acyclic polyols that produce several conformers through the free rotation about each of the C–C single bonds. For example, the

β-Cyclodextrin- and adamantyl-substituted poly(acrylate) self-assembling aqueous networks designed for controlled complexation and release of small molecules

• Liang Yan,
• Duc-Truc Pham,
• Philip Clements,
• Stephen F. Lincoln,
• Jie Wang,
• Xuhong Guo and
• Christopher J. Easton

Beilstein J. Org. Chem. 2017, 13, 1879–1892, doi:10.3762/bjoc.13.183

• PAAβ-CDen alone provides insight into the factors affecting dye complexation. The rates of release of the dyes through a dialysis membrane from the three aqueous networks show a high dependence on host–guest complexation between the β-CDen substituents and the dyes as well as the structure and the

• substituent as shown by 2D 1H NOESY NMR (Figures S34–S36, Supporting Information File 1) consistent with it competing with the dyes for complexation by β-CDen. Dye release studies Dye release through a dialysis membrane with pores allowing passage of species with a molecular weight up to 3.5 kDa into an

• diffusion within the particular EO sample and its interaction with the dialysis membrane as it passes through its pores. Similar profiles characterize the release of MO and MR from PAA and adamantyl substituted PAA (Figure 12(ii) and 12(iii), respectively,) and a similar interpretation applies. However, the

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• nor did the silencing of (N)-WASP by RNA interference alter the suppression of secretory and membrane protein production by mycolactone. The angiotensin pathway was identified as a third target of mycolactones by Brodin and co-workers in 2014 [104]. It has been known for some time that mycolactone is

Chemical systems, chemical contiguity and the emergence of life

• Terrence P. Kee and
• Pierre-Alain Monnard

Beilstein J. Org. Chem. 2017, 13, 1551–1563, doi:10.3762/bjoc.13.155

• of RNAs for catalytic activity, which often requires the presence of high ion concentrations that are disruptive for the formation of primitive membrane models. Membranes composed of putatively prebiotic amphiphiles, such as single hydrocarbon chain species [20][21] may have been exemplars of such

• membrane components. Furthermore, experimental conditions are sometimes implausible from the geochemical perspective. Finally, the evolutionary continuity of the systems, which should be paramount to explain the emergence of protocellular systems and evolution towards true cells, is often neglected in

• membrane architecture, amphiphile vesicles or liposomes, became the main type of compartment models for the study of the origins of life, although other systems could also serve the very same purpose [77][78][79][80][81]. Besides the chemical continuity arguments, amphiphile bilayers offer a very fine

2-Methyl-2,4-pentanediol (MPD) boosts as detergent-substitute the performance of ß-barrel hybrid catalyst for phenylacetylene polymerization

• Julia Kinzel,
• Daniel F. Sauer,
• Marco Bocola,
• Marcus Arlt,
• Tayebeh Mirzaei Garakani,
• Andreas Thiel,
• Klaus Beckerle,
• Tino Polen,
• Jun Okuda and
• Ulrich Schwaneberg

Beilstein J. Org. Chem. 2017, 13, 1498–1506, doi:10.3762/bjoc.13.148

• heating up to 85 °C, THF up to 40 vol % tolerated) [19][24][25][26][27]. FhuA is one of the largest known outer membrane proteins consisting of 22 antiparallel β-sheets, which are connected through long extracellular loops and short periplasmic turns. After removal of the barrel-plugging “cork” domain (Δ1

• membrane of Escherichia coli (E. coli) [30]. For extraction of membrane proteins, commonly micelle-forming detergents such as sodium dodecyl sulfate (SDS), polyethylene–polyethyleneglycol (PE–PEG), sugar glycosides or polyoxyethylenes are applied [24][25][28][31][32]. SDS is an efficient detergent for

• membrane protein solubilization, but is leading to protein unfolding as a drawback. Disadvantageous of detergents is the tremendous reduction of selectivity due to denaturing the protein or the reduction of productivity by detergent micelles since hydrophobic compounds are most likely located inside the

Framing major prebiotic transitions as stages of protocell development: three challenges for origins-of-life research

• Ben Shirt-Ediss,
• Sara Murillo-Sánchez and
• Kepa Ruiz-Mirazo

Beilstein J. Org. Chem. 2017, 13, 1388–1395, doi:10.3762/bjoc.13.135

• significant part of the biochemical knowledge inherited from last century. Membrane biophysicists have also repeatedly complained about the traditional imbalance in biochemistry between the attention given to soluble enzymes over membrane proteins, whose physiological tasks have equal relevance, but are

• , developed during the twentieth century, allowed the in vitro exploration of many – both structural and dynamic – properties of supramolecular assemblies that involve, at least, three-phases (water-membrane-water) and show a striking resemblance to biomembranes, despite their much simpler composition and

• across all living domains [7], could be present at the first stages of biogenesis. Such complex membrane mechanisms were, no doubt, latecomers – highly optimized products of evolution. However, any plausible evolutionary explanation of their emergence should begin with simpler lipid compartments and with

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

Beilstein J. Org. Chem. 2017, 13, 1368–1387, doi:10.3762/bjoc.13.134

• organic solvents has offered an entirely new paradigm for the soluble-supported synthesis of oligonucleotides. The underlying idea is that on passing the reaction mixture by high pressure through a membrane, small molecules pass through the membrane, while the support is too bulky to escape through the

• nanopores of the membrane material. As a proof of concept, a 9-mer 2´-O-methyl oligoribonucleotide phosphorothioate has been synthesized [69][70]. The soluble support was 1,3,5-tris(hydroxymethyl)benzene derivatized with an eight units long PEG chain (Scheme 13), called homostar by the authors. The 3

• elongation. Ethylthiotetrazole-activated coupling (3 equiv per OH) in MeCN was followed by sulfurization with phenylacetyl disulfide in pyridine. All small molecule compounds were removed by the so-called diafiltration through a polybenzimidazole-based membrane PBI-17DBX [71][72]. In other words, the volume

BODIPY-based fluorescent liposomes with sesquiterpene lactone trilobolide

• Ludmila Škorpilová,
• Silvie Rimpelová,
• Michal Jurášek,
• Miloš Buděšínský,
• Jana Lokajová,
• Roman Effenberg,
• Petr Slepička,
• Tomáš Ruml,
• Eva Kmoníčková,
• Pavel B. Drašar and
• Zdeněk Wimmer

Beilstein J. Org. Chem. 2017, 13, 1316–1324, doi:10.3762/bjoc.13.128

• overall shape of the molecule. Further, cholesterol is one of the basic natural components of eukaryotic cells, thus some portion of construct 6 could be fixed in plasma membrane, which decreases the possibility of manifesting the known biological effects of Tb inside cells [42]. Liposome preparation and

• ), in which the construct 6 was also internalized and its distribution resembled the structure of the endoplasmic reticulum as well as partially the cell membrane. In the case of liposomes containing construct 6, intracellular uptake was detected already at 43 nM concentration after 1 h of incubation

• with U-2 OS cells (Supporting Information File 1, Figure S16), on which they were bound at the plasma membrane. After 2 h of incubation, there were two populations of cells with liposomes bound either on the plasma membrane or inside the cells (Figure 6). The intracellular localization of liposomes was

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

• saccharides. The interest in hexofuranoses is based on the arabinogalactan-rich membrane of Mycobacterium tuberculosis and other harmful microorganisms which consists of primarily Araf and Galf subunits [44]. One key step in the biosynthesis of these hexofuranoses is the isomerization of uridine 5′-diphospho

Glycoscience@Synchrotron: Synchrotron radiation applied to structural glycoscience

• Serge Pérez and
• Daniele de Sanctis

Beilstein J. Org. Chem. 2017, 13, 1145–1167, doi:10.3762/bjoc.13.114

• transporter to be determined was the one of lactose permease LacY [60]. Later on, the structures of different bacterial homologues were also solved. It is only recently that the structure of human GLUT1 was reported [61]. Nevertheless, the joint difficulty to solubilize and crystallize membrane proteins

• average particle size, distribution and shape. Different kinds of samples beside soluble proteins can be studied by this technique including nucleic acids, protein-based complexes, lipids, membrane proteins and surfactants, glycoproteins, virus, polymers and colloids [78][79]. Proteins: SAXS applied to

• biomimetic plasma membrane incorporating glycolipid rafts. The in situ chemical conversion of GD1a gangloside into its metabolic product under the action of sialidase was investigated. The outcome of the sialidase action is not limited to the creation of GM1 and AsialoGM1 gangliosides as it is accompanied by

From chemical metabolism to life: the origin of the genetic coding process

• Antoine Danchin

Beilstein J. Org. Chem. 2017, 13, 1119–1135, doi:10.3762/bjoc.13.111

• to understand the way proteins interact with membrane lipids, and our knowledge in the domain is still far from complete. There exist many models describing the operation (including ideas about the asymmetry of the bilayer, its local changes and lipid rafts). Work exploring the way proteins are

• manipulation of the electro-chemical gradient built up between the inside and the outside of the cell (in particular with the fascinating nanomotor ATP synthase [14]). Membrane components age and waste away: This implies maintenance. Finally, there are specific needs to allow for division while the role of the

• membrane differs during states of growth and non-growth. The former implies a constructive function of the membrane. Proteins are the effectors of this function with the key operation of allowing protein insertion within the membrane. Studies investigating spontaneous evolution of lipid vesicles showed

Correlation of surface pressure and hue of planarizable push–pull chromophores at the air/water interface

• Frederik Neuhaus,
• Fabio Zobi,
• Gerald Brezesinski,
• Marta Dal Molin,
• Stefan Matile and
• Andreas Zumbuehl

Beilstein J. Org. Chem. 2017, 13, 1099–1105, doi:10.3762/bjoc.13.109

• fluorescent probes are an elegant solution to this problem but it requires first the establishment of a direct correlation between the membrane surface pressure and the induced color change of the probe. Here, we analyze planarizable dithienothiophene push–pull probes in a monolayer at the air/water interface

• using fluorescence microscopy, grazing-incidence angle X-ray diffraction, and infrared reflection–absorption spectroscopy. An increase of the lateral membrane pressure leads to a well-packed layer of the ‘flipper’ mechanophores and a clear change in hue above 18 mN/m. The fluorescent probes had no

• influence on the measured isotherm of the natural phospholipid DPPC suggesting that the flippers probe the lateral membrane pressure without physically changing it. This makes the flipper probes a truly useful addition to the membrane probe toolbox. Keywords: fluorescent probes; membrane biophysics

Total syntheses of the archazolids: an emerging class of novel anticancer drugs

• Stephan Scheeff and
• Dirk Menche

Beilstein J. Org. Chem. 2017, 13, 1085–1098, doi:10.3762/bjoc.13.108

• of important cellular functions, including pH-control [17][18], membrane trafficking, protein degradation, release of neurotransmitters [18], urinary acidification [19], bone resorption [20], sperm maturation [21], cholesterol biosynthesis [22] and cytokine secretion [23]. In recent years, a key role

G-Protein coupled receptors: answers from simulations

• Timothy Clark

Beilstein J. Org. Chem. 2017, 13, 1071–1078, doi:10.3762/bjoc.13.106

• with what is already available, it reuses successful designs again and again in slightly modified forms. This is the case for the most common means of communicating across cell walls in eukaryotes, G-protein coupled receptors (GPCRs). GPCRs span the cell membrane and generally complex switching ligands

• order to obtain a complete atomistic picture of the mode of action of the GPCR. A further problem is that we need structures that correspond to the receptors in their natural surroundings as they occur and function in nature. Proteins, especially membrane-bound ones, do not necessarily crystallize in

• GPCRs. GPCRs consist of seven α-helices that span the membrane between the extra- and intracellular sides. The N-terminus is extracellular and the C-terminus intracellular. The helices are connected by three intracellular loops (IL1, H1-H2; IL2, H3-H4 and IL3, H5-H6) and three extracellular ones (EL1

Synthesis and enzymatic ketonization of the 5-(halo)-2-hydroxymuconates and 5-(halo)-2-hydroxy-2,4-pentadienoates

• Tyler M. M. Stack,
• William H. Johnson Jr. and
• Christian P. Whitman

Beilstein J. Org. Chem. 2017, 13, 1022–1031, doi:10.3762/bjoc.13.101

• . Pooled fractions were concentrated and exchanged into 20 mM KH2PO4 buffer (pH 7.3) using an Amicon Ultra filter unit (3K membrane). This procedure typically yields ≈8 mg of 4-OT estimated to be ≈95% pure. A sample was analyzed by electrospray ionization mass spectrometry (ESIMS) to verify the molecular

Glyco-gold nanoparticles: synthesis and applications

• Federica Compostella,
• Olimpia Pitirollo,
• Alessandro Silvestri and
• Laura Polito

Beilstein J. Org. Chem. 2017, 13, 1008–1021, doi:10.3762/bjoc.13.100

• family of glycosylated proteins with a high molecular weight, produced by epithelial tissues. The most studied is the membrane-bound glycoprotein MUC1, a glycoprotein with extensive O-linked glycosylation in its extracellular domain. The authors demonstrated that the multivalent presentation of MUC1

Aggregation behaviour of a single-chain, phenylene-modified bolalipid and its miscibility with classical phospholipids

• Simon Drescher,
• Vasil M. Garamus,
• Christopher J. Garvey,
• Annette Meister and
• Alfred Blume

Beilstein J. Org. Chem. 2017, 13, 995–1007, doi:10.3762/bjoc.13.99

• -C18pPhC18-PC is partially miscible with saturated phosphatidylcholines; however, closed lipid vesicles with an increased thermal stability were not found. Instead, bilayer fragments and disk-like aggregates are formed. Keywords: aggregation behaviour; bolaamphiphiles; bolalipids; membrane lipids; mixing

• in the chemical structure of those archaeal membrane lipids: the alkyl chains are connected via ether linkages in the inverse sn-2,3 configuration to the glycerol, the alkyl chains sometimes contain a varying number of cyclopentane rings or several methyl branches [2][3], and some of the archaeal

• lipids consist of two transmembrane alkyl chains (caldarchaeol-type). Especially this type of bolalipids is of great interest for applications in material sciences, biotechnology, and pharmaceuticals [10][11][12][13][14][15]. Since these bolalipids are able to span the membrane of classical phospholipid