Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

• Gwendal Grelier,
• Benjamin Darses and
• Philippe Dauban

Beilstein J. Org. Chem. 2018, 14, 1508–1528, doi:10.3762/bjoc.14.128

• reaction has been extended by using a combination of 10 mol % of Cu(OTf)2, 12 mol % of 1,10-phenanthroline, and 2 equivalents of potassium phosphate, as reported by the group of Jiang (Scheme 30) [70]. Six- to eight-membered sulfur heterocycles 67 can thus be isolated from cyclic diaryl-λ3-iodanes. More

• adding 30 mol % of dimethylethylenediamine (DMEDA) and potassium phosphate to the same pot. Symmetrical diaryl-λ3-iodanes afford the diarylated indoles 80 with yields ranging from 41% to 67%. More significantly, whereas non-symmetrical diaryl-λ3-iodanes based on electron poor/rich aryl moieties do not

Design and biological characterization of novel cell-penetrating peptides preferentially targeting cell nuclei and subnuclear regions

• Anja Gronewold,
• Mareike Horn and
• Ines Neundorf

Beilstein J. Org. Chem. 2018, 14, 1378–1388, doi:10.3762/bjoc.14.116

• –S4 (Supporting Information File 1), all peptides could be successfully synthesized in high purities. First, we performed a structural analysis by diluting all peptides to a concentration of 20 μM in phosphate buffer (pH 7.0), with or without the presence of the secondary structure inducing solvent

• trifluoroethanol (TFE) [24]. As can be depicted from Figure 1, all peptides exhibited a random coil structure in phosphate buffer without TFE. In the presence of TFE, the peptides N50 and NrTP also exhibited a random coil structure, whereas N50-sC18* and NrTP-sC18* formed α-helices. This was also confirmed by the

• ; B = 0.1% TFA in acetonitrile) over 45 min and a flow rate of 6 mL·min−1. All peptides were obtained with purities >99%. CD spectroscopy All peptides were analyzed in 10 mM potassium phosphate buffer (pH 7.0) with or without the addition of TFE (1:1 dilution) using a peptide concentration of 20 µM

[3 + 2]-Cycloaddition reaction of sydnones with alkynes

• Veronika Hladíková,
• Jiří Váňa and
• Jiří Hanusek

Beilstein J. Org. Chem. 2018, 14, 1317–1348, doi:10.3762/bjoc.14.113

• -yl triflates [47] and trap them by reaction with sydnones (Scheme 2). These strain-promoted reactions proceed quickly under very mild conditions (at room temperature, in aqueous phosphate buffer with solubilizing DMSO). In a similar manner, very reactive benzynes (didehydrobenzenes) generated either

Oligonucleotide analogues with cationic backbone linkages

• Melissa Meng and
• Christian Ducho

Beilstein J. Org. Chem. 2018, 14, 1293–1308, doi:10.3762/bjoc.14.111

• , particular attention has been given to structural modifications of oligonucleotides which reduce their overall number of negative charges. One such approach is the site-specific replacement of the negatively charged phosphate diester linkage with alternative structural motifs which are positively charged at

• their oligoanionic phosphate diester backbone, severely hampers the penetration of biological barriers such as cellular membranes, thus leading to low cellular uptake. Second, unmodified ON structures are good substrates for nuclease-mediated degradation. Consequently, it is of vital importance to

• chemically modify ON structures in order to make them suitable drug candidates or chemical probes, e.g., for diagnostic purposes [6][7]. The relevance of the polyanionic phosphate diester-linked backbone to the overall function of nucleic acids has been discussed by Westheimer [8], Benner [9][10], and others

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• interactions are also augmented by a series of electrostatic and van der Waals interactions including salt bridge formation with the phosphate backbone [1]. Although, the majority of proteins recognize DNA in the major groove due, in large part, to the potential and shape complementarity, several others also

• bonding interaction between the groove floor base pairs and the amides and electrostatic stabilizing interactions between the protonated amines under physiological pH and negatively charged phosphate backbone as reported by NMR and crystallographic studies [32][33][34][35][36]. These molecules were shown

• show excellent antileukemic activity and are found to be significantly less myelotoxic than TAM against murine and human hematopoietic progenitor cells [43]. The positively charged basic amidino side chain, responsible for electrostatic interaction with negatively charged DNA phosphate backbone, was

Mechanochemistry of nucleosides, nucleotides and related materials

• Olga Eguaogie,
• Joseph S. Vyle,
• Patrick F. Conlon,
• Manuela A. Gîlea and
• Yipei Liang

Beilstein J. Org. Chem. 2018, 14, 955–970, doi:10.3762/bjoc.14.81

• )diisopropylaminophosphoramidite with a partially-protected guanosine derivative to the corresponding phosphite triester was also effected (Scheme 12). Phosphate coupling using nucleoside phosphoromorpholidates is well established [51] but the reaction times are typically in the order of days. Recent developments in this field

• ) and adenosine diphosphate ribose (ADPR) was also described. Subsequently, this methodology was applied to the preparation of a library of six ADPR carbonate derivatives in 23–68% yields (e.g., Scheme 14) and tested as sirtuin inhibitors [54]. The efficiency of phosphate coupling under mechanochemical

• of the monoester and phosphate coupling to AMP-morpholidate to be effected in one pot using LAG. Both 3′,5′- and 5′,5′- internucleoside linkages were prepared using this route. Mechanochemical transformations of nucleosides and related materials involving non-covalent bonds Dissociative processes for

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• characterized in 1966 by Wall et al. [96][97]. The main mechanism of action involves binding to the reversible complex of topoisomerase I (topo I) and the 3′-phosphate group of the DNA backbone through hydrogen bonding, resulting in accumulation of a persistent ternary complex (the cleavable complex). This

Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

• the next one are cleaved by a variety of enzymes [1]. The phosphodiester bonds of DNA are hydrolyzed, depending on the enzyme, either to a 3´- or 5´-phosphate, whereas the bonds in RNA, with few exceptions (above all RNase H-catalyzed cleavages) undergo transesterification to a 2´,3´-cyclic phosphate

• protein nucleases and ribozymes a subject of intensive mechanistic studies. pH-Rate dependency, X-ray structures, amino acid/nucleotide substitution experiments and the effect of thiosubstitution of phosphate oxygens on the binding of metal ion cofactors have given invaluable information about the

• 13.5 for an apical group [22]. For a cyclic phosphorane derived from ethylene phosphate, the first pKa value is 7.9 and the second 14.3, both values referring to an equatorial hydroxy ligand [23]. Accordingly, both neutral phosphorane and its monoanion are present in significant amount at physiological

Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

• Kartik Temburnikar and
• Katherine L. Seley-Radtke

Beilstein J. Org. Chem. 2018, 14, 772–785, doi:10.3762/bjoc.14.65

• and supramolecular complexes [10][11][12][13][14][15][16][17][18][19][20][21][22]. Nucleic acids are composed of a monomeric nucleoside unit that features an aromatic nitrogenous moiety (a nucleobase) connected to a pentose sugar, which in turn is attached to a phosphate group (Figure 1) [7]. The

Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin–GnRH-III conjugates developed for targeted drug delivery

• Sabine Schuster,
• Beáta Biri-Kovács,
• Bálint Szeder,
• Viktor Farkas,
• László Buday,
• Zsuzsanna Szabó,
• Gábor Halmos and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 756–771, doi:10.3762/bjoc.14.64

• medium for the indicated incubation time. Cells were washed two times with phosphate buffered saline (PBS) and fixed by 4% paraformaldehyde for 20 min at 37 °C. After three times washing with PBS, nuclei were stained by 4′,6-diamidine-2-phenylindole dihydrochloride (DAPI, 0.2 µg/mL, dissolved in PBS

An uracil-linked hydroxyflavone probe for the recognition of ATP

• Márton Bojtár,
• Péter Zoltán Janzsó-Berend,
• Dávid Mester,
• Dóra Hessz,
• Mihály Kállay,
• Miklós Kubinyi and
• István Bitter

Beilstein J. Org. Chem. 2018, 14, 747–755, doi:10.3762/bjoc.14.63

• recognition sites [16][18][19][33], or Zn-dipicolylamine complexes [21][23][24] attracting the negatively charged phosphate units of ATP and by π-stacking between the fluorophores of the sensors and the adenine moiety of ATP [29]. In aqueous solutions at physiological pH, the tetra-charged anionic ATP

• consists of a hydrophilic (phosphate and ribose) and a more hydrophobic part (adenine). The former ensures a good solubility of ATP in water and generates an electrostatic field around it while the latter is required for associations with similar planar hydrophobic molecules involved in the biochemical

• different concentrations are shown in Figure 3. Upon addition of ATP, a new band appears at 440 nm in the excitation spectra. This feature can be attributed to the specific intermolecular proton transfer from the hydroxy group of the flavone to the phosphate moiety of the ATP [34]. The fluorescence

Cobalt-catalyzed directed C–H alkenylation of pivalophenone N–H imine with alkenyl phosphates

• Wengang Xu and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2018, 14, 709–715, doi:10.3762/bjoc.14.60

• alkenylation reaction of pivalophenone N–H imine with an alkenyl phosphate. The reaction tolerates various substituted pivalophenone N–H imines as well as cyclic and acyclic alkenyl phosphates. Keywords: alkenylation; C–C bond formation; C–H activation; cobalt; imine; Introduction Transition-metal-catalyzed

• substrates and alkenyl electrophiles would offer a complementary approach for the C–H alkenylation [12]. In particular, C–H alkenylations by way of alkenyl C–O bond cleavage has attracted much attention because of the ready accessibility of the corresponding alkenyl electrophiles (e.g., acetate, phosphate

• Discussion The present study commenced with screening of the reaction conditions for the coupling between pivalophenone N–H imine 1a and cyclohexenyl phosphate 2a (Table 1). Thus, the reaction was performed in the presence of CoBr2 (10 mol %), ligand (10–20 mol %), and t-BuCH2MgBr (2 equiv) in THF at room

Biocatalytic synthesis of the Green Note trans-2-hexenal in a continuous-flow microreactor

• Morten M. C. H. van Schie,
• Tiago Pedroso de Almeida,
• Gabriele Laudadio,
• Florian Tieves,
• Elena Fernández-Fueyo,
• Timothy Noël,
• Isabel W. C. E. Arends and
• Frank Hollmann

Beilstein J. Org. Chem. 2018, 14, 697–703, doi:10.3762/bjoc.14.58

• exchanged against 10 mM sodium phosphate buffer, pH 5.5 by diafiltration (DV 20) and subsequently concentrated using an Amicon Ultra 15 mL centrifugal filter (MWCO 10 kDa). After centrifugation (overnight at 15,000 rpm and 4 °C), the soluble fraction was further purified using anion-exchange chromatography

• . Purification The concentrated PeAAOx solution was purified using a 58 mL Q Sepharose column (GE Healthcare). PeAAOx was eluted with a linear NaCl gradient (0–0.6 M over 6 CV) using 10 mM sodium phosphate buffer, pH 5.5. Fractions containing PeAAOx were pooled, concentrated and desalted using HiTrap desalting

• columns (GE Healthcare) and 10 mM sodium phosphate buffer, pH 5.5. The PeAAOx concentration was calculated based on the absorbance using the molar extinction coefficient of ε463 11,050 M−1 cm−1. Activity assay The activity of PeAAOx was determined by UV–vis spectroscopy, using an Agilent Cary 60 UV–vis

Enzyme-free genetic copying of DNA and RNA sequences

• Marilyne Sosson and
• Clemens Richert

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

• is the activation of the phosphate that drives what is otherwise an endergonic reaction. The other is the improved mechanistic understanding of enzyme-free primer extension that has led to a quantitative kinetic model predicting the yield of the reaction over the time course of an assay. For a

• enzyme-free primer extension assays. Whether the available template effect suffices to induce successful extension in aqueous buffer depends on the reactivity of the nucleophilic group at the primer's 3'-terminus and that of the activated phosphate of the monomer. Quantitative model To gain a better

• terminal hydroxy group of the primer has to attack the activated 5'-phosphate of the primer, most likely producing a pentavalent intermediate. Unless the leaving group finds itself in the proper apical position of the intermediate, this is followed by pseudorotation and then the release of the leaving

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• the modification in the nucleotide: the internucleosidic phosphate, the nucleobase, the sugar or the extremities of ONs. Moreover, the review provides a current and detailed account of stimuli-responsive ONs with the main goal of gene silencing. However, for some stimuli-responsive ONs reported in

• ) backbone in the replacement of the phosphate ester internucleotide linkages. This modification provides nuclease stability and favorable pharmacokinetic properties but can lead to some toxicity. In addition, the most extensively used sugar modifications are represented by the 2’-modifications: 2’-O-methyl

• (phosphate, nucleobase, sugar hydroxy groups). Reductase-responsive ONs Hypoxic conditions that are characteristic of solid tumors represent a remarkable stimulus to convert non-active prodrugs into active drugs under reductase action. Three examples of hypoxia-activated ONs have been reported thus far, with

Synthetic and semi-synthetic approaches to unprotected N-glycan oxazolines

• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 416–429, doi:10.3762/bjoc.14.30

• ][80], including those bearing mannose-6-phosphate residues [45][46]. For example as shown in Scheme 7 sequential glycosylation of the key Manβ(1–4)GlcNAc disaccharide at positions 3 and 6, using the same selectively protected manno thioglycoside donor gave a tetrasaccharide. Removal of the silyl

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

• glutarate, iPr2NEt, rt, DMF, 6 h; c) H2NCH2-cyclo[DKP-RGD] (2), PBS/MeCN or PBS/DMF (pH 7.5), overnight; d) H2NCH2-cyclo[DKP-isoDGR] (4), PBS/DMF (pH 7.5), overnight. DMAP: 4-dimethylaminopyridine; DIC: diisopropylcarbodiimide; PBS: phosphate-buffered saline; PAB: p-aminobenzyl. Synthesis of cyclo[DKP

Preparation of trinucleotide phosphoramidites as synthons for the synthesis of gene libraries

• Ruth Suchsland,
• Bettina Appel and
• Sabine Müller

Beilstein J. Org. Chem. 2018, 14, 397–406, doi:10.3762/bjoc.14.28

• . Preparation of trinucleotides in solution Over the years, a number of methodologies has been published, varying in the protecting group for the phosphate moiety being methyl [25], ethyl [26], cyanoethyl [27] or ortho-chlorophenyl [28][29], and for the 3'-OH-group being phenoxyacetyl [25], dimethoxytrityl

• for the synthesis of protected trinucleotides, as it would allow the cleavage of the trimer from the support by irradiation with UV light, without harming nucleobase and internucleotide phosphate protection. Nevertheless, photo-induced formation of byproducts may be an issue to be considered. In our

• lab, we have been developing a strategy for solid-phase trinucleotide synthesis involving a disulfide linkage to the support (CPG or polystyrene), which can be cleaved under reductive conditions without harming nucleobase and phosphate protecting groups. The disulfide bridge is generated through the

Fluorogenic PNA probes

• Tirayut Vilaivan

Beilstein J. Org. Chem. 2018, 14, 253–281, doi:10.3762/bjoc.14.17

• oligonucleotide mimics that consist of a peptide-like backbone. Although the idea of replacing the whole sugar-phosphate backbone of DNA with a completely unrelated scaffold such as peptide had been around since the 1970s [20], it was not until the 1990s that the first PNA system with an N-2-aminoethylglycine

• unique properties not observed in other classes of oligonucleotide analogues with negatively charged phosphate groups. These include the relative insensitivity of the PNA–DNA or PNA–RNA hybrids to the ionic strength of the solvent [23], and the complete stability towards nucleases as well as proteases

Polarization spectroscopy methods in the determination of interactions of small molecules with nucleic acids – tutorial

• Tamara Šmidlehner,
• Ivo Piantanida and
• Gennaro Pescitelli

Beilstein J. Org. Chem. 2018, 14, 84–105, doi:10.3762/bjoc.14.5

• surface through electrostatic interactions with the phosphate backbone. However, that is plausible only for highly positive-charged ligands (at least four net positive charges present). 3.3.4. Strong ICD (intensity of ICD band similar or stronger than the CD bands of DNA/RNA): Usually of positive sign

• between base pairs cannot be excluded on this basis. No or very small ILD: The compound is non-specifically oriented, either due to a mixed binding mode or externally bound to the phosphate backbone. 5. Vibrational circular dichroism, VCD VCD is analogous to ECD in the IR region of the electromagnetic

• stimuli [41]. Similar to the ECD case, such a correlation is often made on an empirical basis [39][40] but may be substantiated by theoretical approaches [38]. The other spectral region interesting for nucleic acids is 1250–1000 cm−1, where the stretching modes of the phosphate group are found plus some

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

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

• studied lipid A of Escherichia coli and Neisseria meningitidis contains six acyl chains (C14–C12) differently distributed across the diglucosamine backbone and two phosphate groups – one at the anomeric position of the proximal GlcN residue and the second at position 4’ of the distal GlcN moiety (Figure 2

• to the phosphate groups of lipid A alters the TLR4-mediated host immunity and accounts for the modulation of the pro-inflammatory signaling. Additionally, this modification is associated with an amplified bacterial virulence since it confers resistance to the endogenous cationic antimicrobial

• ., phosphate groups) in the molecule [65][66][67]. It has been just recently shown that TLR4 is not a sole receptor protein accountable for cellular responses induced by LPS. A number of pro-inflammatory effects such as autophagy, endocytosis and oxidative burst are induced by the LPS-mediated activation of an

Microfluidic radiosynthesis of [¹⁸F]FEMPT, a high affinity PET radiotracer for imaging serotonin receptors

• Thomas Lee Collier,
• Steven H. Liang,
• J. John Mann,
• Neil Vasdev and
• J. S. Dileep Kumar

Beilstein J. Org. Chem. 2017, 13, 2922–2927, doi:10.3762/bjoc.13.285

• no purification of the [18F]fluoroethyltosylate from the ditosylate prior to the second step. Selected results are shown in Table 2. The final product was then purified on a Phenomenex Luna column, 10 × 250 mm, 5 μm, with a mobile phase of 55% MeCN: 45% 10 mM phosphate at a flow rate of 5 mL/min. The

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

• Susanne Huhmann,
• Anne-Katrin Stegemann,
• Kristin Folmert,
• Damian Klemczak,
• Johann Moschner,
• Michelle Kube and
• Beate Koksch

Beilstein J. Org. Chem. 2017, 13, 2869–2882, doi:10.3762/bjoc.13.279

• stomach mucosa, EC 3.4.23.1, ≥250 units/mg of protein, Sigma Aldrich, St. Louis, MO, USA) were prepared at concentrations of 1 mg/mL in phosphate buffer (10 mM, pH 7.4), or in acetate buffer (10 mM, pH 4.0), respectively. For proteinase K (from tritirachium album, EC 3.4.21.64, ≥30 units/mg of protein

• after incubation for 120 min (left) and 24 h (right) with α-chymotrypsin in 10 mM phosphate buffer, pH 7.4, at 30 °C. The data shown represent the average of three independent measurements. Errors are derived from the standard deviation. Cleavage positions observed in the digestion of library peptides

Synthetic mRNA capping

• Fabian Muttach,
• Nils Muthmann and
• Andrea Rentmeister

Beilstein J. Org. Chem. 2017, 13, 2819–2832, doi:10.3762/bjoc.13.274

• of cap0 comprises three consecutive reactions targeted to nascent 5′-triphosphorylated pre-mRNAs (Figure 1). First, a 5′-triphosphatase (TPase) hydrolyzes the γ-phosphate of pre-mRNA. Next, the β-phosphate of the resulting 5′-diphosphate end is coupled to GMP to form 5′–5′-linked Gppp-RNA. The

• concentration or by digesting uncapped (i.e., triphosphorylated) RNA with a 5′-polyphosphatase which produces monophosphorylated RNA followed by 5′-phosphate-dependent exonuclease digestion. Another problem encountered with m7GpppG as initiator is elongation into the “wrong” direction, namely at the 3′-OH of

• shown to be as efficient as m7GpppG in translation inhibition assays [68]. Further modifications can be placed in the phosphate moieties. ARCA-capped RNAs substituted with a sulphur atom at the β-position were shown to be resistant to the Dcp1/2 decapping complex from S. pombe while at the same time

CF₃SO₂X (X = Na, Cl) as reagents for trifluoromethylation, trifluoromethylsulfenyl-, -sulfinyl- and -sulfonylation and chlorination. Part 2: Use of CF₃SO₂Cl

• Hélène Chachignon,
• Hélène Guyon and
• Dominique Cahard

Beilstein J. Org. Chem. 2017, 13, 2800–2818, doi:10.3762/bjoc.13.273

• was then added onto the substrate, furnishing radical intermediate 16, which was trapped by compounds 14 or 15 to form the radical copper species 17. From this intermediate, two plausible pathways were considered. First, the alkyl radical can be trapped by copper phosphate to provide the copper(III

• ) species 18. During this step, facial selectivity originated partly from hydrogen-bonding interactions between the chiral phosphate and the N–H bond adjacent to the aryl group. Ion pairing interaction in a concerted transition state probably intervened in this phenomenon as well. The final product was then

• , replacing the chiral phosphoric acid with diphenyl phosphate (Scheme 14) [20]. Liu’s research group was interested as well in 1,2-difunctionalisation of unactivated alkenes. In this context, they developed two distinct approaches allowing to perform radical-mediated 1,2-formyl- [21] or 1,2