Electrophilic oligodeoxynucleotide synthesis using dM-Dmoc for amino protection

• Shahien Shahsavari,
• Dhananjani N. A. M. Eriyagama,
• Bhaskar Halami,
• Vagarshak Begoyan,
• Marina Tanasova,
• Jinsen Chen and
• Shiyue Fang

Beilstein J. Org. Chem. 2019, 15, 1116–1128, doi:10.3762/bjoc.15.108

• instability of the adduct under acidic conditions during ODN synthesis [7]. In recent years, applications of ODNs have extended to emerging areas such as nanotechnology [8][9], antisense drug development [10][11][12], DNA damage and repair [13][14], DNA methylation and demethylation [15][16][17][18], DNA

• –protein interactions [19][20], CRISPR genome editing [21][22][23], DNA data storage [24][25], synthetic biology [26], bioconjugation [27] and others [28][29][30]. These applications frequently require modified ODNs that contain a wide variety of functional groups including those that cannot survive known

• MerMade 6 DNA/RNA synthesizer. The dT-Dmoc-CPG (4) was used as the solid support. Detritylation was carried out under standard conditions suggested by the synthesizer manufacturer for 1 µmol synthesis. The 0.1 M acetonitrile solutions of phosphoramidite monomers 3a–c and the commercially available 5'-DMTr

Photochemical generation of the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) radical from caged nitroxides by near-infrared two-photon irradiation and its cytocidal effect on lung cancer cells

• Ayato Yamada,
• Manabu Abe,
• Yoshinobu Nishimura,
• Shoji Ishizaka,
• Masashi Namba,
• Taku Nakashima,
• Kiyofumi Shimoji and
• Noboru Hattori

Beilstein J. Org. Chem. 2019, 15, 863–873, doi:10.3762/bjoc.15.84

• strong DNA-damaging activity [65], they play important roles as anticancer therapeutic agents [66]. Among the free radicals, nitroxides including the TEMPO radical have unique properties, where they can act not only as radical scavengers, but also as anticancer agents [67]. Due to the unique properties

An improved synthesis of adefovir and related analogues

• David J. Jones,
• Eileen M. O’Leary and
• Timothy P. O’Sullivan

Beilstein J. Org. Chem. 2019, 15, 801–810, doi:10.3762/bjoc.15.77

• cause nephrotoxicity [7]. The mode of action of adefovir has been widely studied and involves the inhibition of viral replication by the termination of DNA synthesis [8][9][10]. Although adefovir was described in 1986 for the first time by Holý, De Clercq and co-workers, it is still actively employed in

Synthesis and fluorescent properties of N(9)-alkylated 2-amino-6-triazolylpurines and 7-deazapurines

• Andrejs Šišuļins,
• Jonas Bucevičius,
• Yu-Ting Tseng,
• Irina Novosjolova,
• Kaspars Traskovskis,
• Ērika Bizdēna,
• Huan-Tsung Chang,
• Sigitas Tumkevičius and
• Māris Turks

Beilstein J. Org. Chem. 2019, 15, 474–489, doi:10.3762/bjoc.15.41

• for this type of molecules. Traditionally, fluorescent purine nucleoside analogs were recognized as valuable fluorescent probes for DNA and RNA research [17]. This paved a way for development of various adenosine and guanosine analogs which in many cases contained an additional substituent at C(8

• ] have been actively studied for their fluorescent properties. Among others, also azole containing compounds of type E [28] and F [29] have been described. Similarly, to purine derivatives also 7-deazapurines are used in DNA labeling [30]. On the other hand, modified purines have found also applications

• in the cytoplasm. The representative fluorescent image of the labeled MCF-7 cells with compound 9 is shown in Figure 8 (for other examples see Figure S82 in Supporting Information File 1). Based on the recent investigation of metabolic labelling of DNA [30][56] by deaza-7-ethenyl-2'-deoxyguanosine

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

• reactions can be integrated in the toolbox of chemical proteomics. Recently, following a similar strategy, Lu et al. reported on-DNA RCM and CM, an application potentially useful to generate DNA-encoded libraries for hit identification and target validation [90]. Substrates appended to oligonucleotides

• the activities of 7 different DNA-tethered substrates for RCM. Good conversions were achieved in water mixtures (40% t-BuOH) at room temperature after 1 hour of reaction. However, these reactions are not catalytic as they require 150 equivalents of the G-III catalyst. The same conditions were tested

• developed (e.g., protein modification, on-DNA metathesis, directed evolution of artificial metalloenzymes, etc.) and are paving the way to future interesting applications. Some of the most representative catalysts for aqueous metathesis. a) Well-defined ruthenium catalysts. b) Catalysts bearing ammonium

Synthesis, biophysical properties, and RNase H activity of 6’-difluoro[4.3.0]bicyclo-DNA

• Sibylle Frei,
• Adam K. Katolik and
• Christian J. Leumann

Beilstein J. Org. Chem. 2019, 15, 79–88, doi:10.3762/bjoc.15.9

• -DNA (6’-diF-bc4,3-DNA). The difluorinated thymidine phosphoramidite building block was synthesized starting from an already known gem-difluorinated tricyclic glycal. This tricyclic siloxydifluorocyclopropane was converted into the [4.3.0]bicyclic nucleoside via cyclopropane ring-opening through the

• oligonucleotides hybridized to complementary DNA or RNA disclosed a significant destabilization of both duplex types (ΔTm/mod = −1.6 to −5.5 °C). However, in the DNA/RNA hybrid the amount of destabilization could be reduced by multiple insertions of the modified unit. In addition, CD spectroscopy of the

• oligonucleotides hybridized to RNA showed a similar structure than the natural DNA/RNA duplex. Furthermore, since the structural investigation on the nucleoside level by X-ray crystallography and ab initio calculations pointed to a furanose conformation in the southern region, a RNase H cleavage assay was

Selective ring-opening metathesis polymerization (ROMP) of cyclobutenes. Unsymmetrical ladderphane containing polycyclobutene and polynorbornene strands

• Yuan-Zhen Ke,
• Shou-Ling Huang,
• Guoqiao Lai and
• Tien-Yau Luh

Beilstein J. Org. Chem. 2019, 15, 44–51, doi:10.3762/bjoc.15.4

• properties [1][2][3]. To illustrate this, polynorbornenes and polycyclobutenes are readily obtained from the corresponding monomeric norbornene and cyclobutene derivatives under various conditions. Symmetrical DNA-like double stranded ladderphanes are conveniently synthesized from bisnorbornene [4][5][6][7

New standards for collecting and fitting steady state kinetic data

• Kenneth A. Johnson

Beilstein J. Org. Chem. 2019, 15, 16–29, doi:10.3762/bjoc.15.2

• is so much slower than chemistry, the initial weak substrate binding and the conformational change are the primary determinants of specificity. DNA polymerase fidelity DNA polymerases provide ideal model systems to study enzyme specificity because fidelity is high and physiologically relevant, and

• the alternate substrates are well known. Moreover, it is easy to perform single turnover kinetic measurements to examine steps leading up to the chemical reaction by mixing an enzyme DNA complex with only one nucleoside triphosphate. Recent work on DNA polymerase fidelity has shown that the rate of

• must also define specificity. However, that would be wrong. An additional experiment was required to measure the rate of substrate release using dideoxy-terminated DNA to allow the conformational change but prevent chemistry. This experiment allowed the measurement of the rate of enzyme reopening to

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

• (T4P) are surface-exposed fibers that mediate many functions in both Gram-positive and Gram-negative bacteria, including motility, adhesion to host cells, biofilm formation, DNA uptake, and protein secretion [120][121][122][123][124][125][126][127][128]. Mtb expresses T4P that appear by electron

Thermophilic phosphoribosyltransferases Thermus thermophilus HB27 in nucleotide synthesis

• Ilja V. Fateev,
• Ekaterina V. Sinitsina,
• Aiguzel U. Bikanasova,
• Maria A. Kostromina,
• Elena S. Tuzova,
• Larisa V. Esipova,
• Tatiana I. Muravyova,
• Alexei L. Kayushin,
• Irina D. Konstantinova and
• Roman S. Esipov

Beilstein J. Org. Chem. 2018, 14, 3098–3105, doi:10.3762/bjoc.14.289

• ΔEcoRI-B int::(lacI::PlacUV5::T7 gene1) i21 Δnin5. Plasmid vector: pET 23a+, pET 23d+ (Merck Millipore, USA, MA). Enzymes: NdeI, XhoI, NcoI, T4 DNA-ligase (Thermo Scientific, USA, MA), Encyclo-polymerase (Eurogen, Russia). The protein concentration was determined by the Bradford method [17], using BSA as

• a standard. Protein purity was determined by electrophoresis in a polyacrylamide gel under denaturing conditions [18]. Cloning and creation of producer strain: Genes TT_RS08985 and TT_RS06315, encoding TthHPRT and TthAPRT, respectively, were amplified on the genomic DNA template of the T

6’-Fluoro[4.3.0]bicyclo nucleic acid: synthesis, biophysical properties and molecular dynamics simulations

• Sibylle Frei,
• Andrei Istrate and
• Christian J. Leumann

Beilstein J. Org. Chem. 2018, 14, 3088–3097, doi:10.3762/bjoc.14.288

• unsaturated 6’-fluoro[4.3.0]bicyclo nucleotides (6’F-bc4,3-DNA). Two 6’F-bc4,3 phosphoramidite building blocks (T and C) were synthesized starting from a previously described [3.3.0]bicyclic sugar. The conversion of this sugar to a gem-difluorinated tricyclic intermediate via difluorocarbene addition followed

• phosphoramidite building blocks into oligonucleotides was achieved with tert-butyl hydroperoxide as oxidation agent. Thermal melting experiments of the modified duplexes disclosed a destabilizing effect versus DNA and RNA complements, but with a lesser degree of destabilization versus complementary DNA (ΔTm/mod

• = −1.5 to −3.7 °C). Molecular dynamics simulation on the nucleoside and oligonucleotide level revealed the preference of the C1’-exo/C2’-endo alignment of the furanose ring. Moreover, the simulation of duplexes with complementary RNA disclosed a DNA/RNA-type duplex structure suggesting that this

Repurposing the anticancer drug cisplatin with the aim of developing novel Pseudomonas aeruginosa infection control agents

• Mingjun Yuan,
• Song Lin Chua,
• Yang Liu,
• Daniela I. Drautz-Moses,
• Joey Kuok Hoong Yam,
• Thet Tun Aung,
• Roger W. Beuerman,
• May Margarette Santillan Salido,
• Stephan C. Schuster,
• Choon-Hong Tan,
• Michael Givskov,
• Liang Yang and
• Thomas E. Nielsen

Beilstein J. Org. Chem. 2018, 14, 3059–3069, doi:10.3762/bjoc.14.284

• experiments, transcriptomic profiling showed upregulation of the recA gene, which is known to be important for DNA repair, implicating that cisplatin could interfere with DNA replication in P. aeruginosa. Cisplatin treatment significantly repressed the type III secretion system (T3SS), which is important for

• modifications. Generally, PAO1 cells were cultivated either with (1.5 μM) or without cisplatin. The cells were harvested at the early-stationary phase (after approximately 8 h cultivation). Total RNA was extracted with an RNeasy Protect Bacteria Mini Kit with on-column DNase digestion (Qiagen). A Turbo DNA-free

• . aeruginosa as compared to cisplatin (Figure 1). Mode of action The growth inhibitory effects of cisplatin on both eukaryotic cells and microbial cells are attributed to the interactions of Pt(II) in cisplatin with DNA [28][29][30]. To reveal the growth arresting mechanisms and overall impact of cisplatin on

Ring-closing-metathesis-based synthesis of annellated coumarins from 8-allylcoumarins

• Christiane Schultze and
• Bernd Schmidt

Beilstein J. Org. Chem. 2018, 14, 2991–2998, doi:10.3762/bjoc.14.278

• ). Angelicin (3a, also named isopsoralen), for instance, is an angular furanocoumarin from Psoralea corylifolia [11][12] that is moderately cytotoxic [13] and exhibits anti-oxidative activity [14], but is significantly less phototoxic than the linear isomer psoralen, due to its inability to cross link DNA [15

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

• regulation of gene expression, DNA replication, signal transduction, virulence, etc. and therefore represent potential fruitful targets for antibacterial drug discovery. Recently, scientific efforts have helped towards the understanding and the deciphering of the protein-interaction networks (PINs) that

• antimicrobial molecules are presented below. β-Sliding clamp Sliding clamps are prokaryotic ring-shaped proteins that secure DNA polymerases to the DNA template and slide along the double helix, enabling enzyme activity at a specific region of the DNA and increasing the rapid and processive DNA synthesis [52

• ][53][54]. The β-clamp interacts with many different proteins such as several polymerases (e.g. I, II, III, IV, V and DnaE) and other proteins involved in DNA replication including DNA ligase and the replication regulatory protein Hda, all of which contain the conserved binding pentapeptide motif QL(S

Non-native autoinducer analogs capable of modulating the SdiA quorum sensing receptor in Salmonella enterica serovar Typhimurium

• Matthew J. Styles and
• Helen E. Blackwell

Beilstein J. Org. Chem. 2018, 14, 2651–2664, doi:10.3762/bjoc.14.243

• proteins consist of two domains: a larger N-terminal ligand-binding domain (LBD) connected to a smaller C-terminal DNA-binding domain (DBD). In 2006, the structure of the EHEC SdiA LBD was solved by NMR in the presence and absence of AHL and demonstrated increased folding and structure upon ligand binding

• sufficiently high to productively bind to the LuxR-type receptor protein. AHL binding typically promotes receptor homodimerization and binding to DNA at various promoters to activate transcription of QS-controlled genes, often including luxI and luxR (thereby autoinducing the QS system). B) Compounds

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

• spontaneous mutations in genes encoding for the target protein. For example, certain mutational changes within DNA gyrase will lead to lowered susceptibility for fluoroquinolones [15]. Other examples are mutants leading to efflux pump overexpression [15]. If the resistance determinant is located on a

• (HIF-1) signaling pathways and, thus, down-regulate host innate immune systems [36][37]. Other PQS-related metabolites have been shown to have additional effects. HQNO, for example, induces autolysis and release of extracellular DNA thereby promoting biofilm formation and increasing meropenem tolerance

• interaction, e.g., protein–protein or protein–DNA/RNA interaction, while the exact molecular mechanism remains unclear. Even though Zender et al. were not able to attenuate PA virulence via blockage of PqsE, important new insights on this target were made. The discovery that pathoblockers targeting PqsE

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• that, in addition to antimicrobial resistance, forms biofilms, a complex matrix of extracellular polysaccharides, polypeptides and DNA, which act as an additional protective barrier [30]. P. aeruginosa employs two lectins for biofilm formation and host–cell adhesion: proteins LecA and LecB [31][32

• DNA [63]. Recently, inhibitors of the clostridial collagenase were discovered that showed high selectivity for the bacterial enzyme over related host metalloproteases [64]. It is hoped that continued research in this area will lead to a complementary class of antivirulence drugs against Clostridium

Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

• Gergő Mótyán,
• László Mérai,
• Márton Attila Kiss,
• Zsuzsanna Schelz,
• Izabella Sinka,
• István Zupkó and
• Éva Frank

Beilstein J. Org. Chem. 2018, 14, 2589–2596, doi:10.3762/bjoc.14.236

• cancer selectivity. Since the molecular site of action of the tested compounds is not known, cisplatin (a clinically used DNA-binding anticancer agent) was applied as the reference. The results indicated that the 3β-acetates 6a–j exhibited weak or only modest antiproliferative activities, typically

Impact of Pseudomonas aeruginosa quorum sensing signaling molecules on adhesion and inflammatory markers in endothelial cells

• Carmen Curutiu,
• Florin Iordache,
• Veronica Lazar,
• Aurelia Magdalena Pisoschi,
• Aneta Pop,
• Mariana Carmen Chifiriuc and
• Alina Maria Hoban

Beilstein J. Org. Chem. 2018, 14, 2580–2588, doi:10.3762/bjoc.14.235

• deficient strains differ in size and stability of the structure, being more flexible due to the production of QS-regulated extracellular DNA [8], which acts as a stabilizer of three-dimensional biofilm structure [8]. In patients with cystic fibrosis, the growth of bacteria in biofilm determines aggravation

Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

• Nicholas G. Jentsch,
• Jared D. Hume,
• Emily B. Crull,
• Samer M. Beauti,
• Amy H. Pham,
• Julie A. Pigza,
• Jacques J. Kessl and
• Matthew G. Donahue

Beilstein J. Org. Chem. 2018, 14, 2529–2536, doi:10.3762/bjoc.14.229

• integration of viral DNA into host cell chromatin (Figure 1) [7][8][9]. In contrast to the FDA approved integrase strand transfer inhibitors (INSTIs) dolutegravir, elvitegravir, and raltegravir, arylquinolines 1 and 2 bind to a non-catalytic site of integrase (NCINI) via allosteric binding inhibition

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

• of conjugates requires their receptor-mediated internalization and the lysosomal degradation, while Dau could diffuse through the plasma membrane and exerts its antitumor activity by intercalating directly to DNA. Furthermore, it was previously demonstrated that the smallest Dau-containing fragment

• (H-Lys(Dau=)-OH)) formed via lysosomal degradation of this type of conjugates had a lower binding affinity to DNA, than the free drug [35]. The two-fold higher intracellular fluorescence intensity of Dau was accompanied by almost two-fold higher cytotoxic activity compared to the conjugates. By

• cell cycle phases was analyzed by measurements of relative DNA contents of individual cells by flow cytometry after propidium iodide (Sigma-Aldrich, St. Louis, MO, USA) staining. The effects of conjugates and Dau on cell cycle phase distribution of A2058 cells are shown in Figure 4. The apoptotic

Nucleoside macrocycles formed by intramolecular click reaction: efficient cyclization of pyrimidine nucleosides decorated with 5'-azido residues and 5-octadiynyl side chains

• Jiang Liu,
• Peter Leonard,
• Sebastian L. Müller,
• Constantin Daniliuc and
• Frank Seela

Beilstein J. Org. Chem. 2018, 14, 2404–2410, doi:10.3762/bjoc.14.217

• analysis of the cyclic ketones muscone and civetone [1]. Other classical examples are cyclic peptides such as valinomycin and cyclic oligosaccharides like cyclodextrins [2][3][4]. The literature has been recently reviewed [5]. Also, oligonucleotides form cyclic structures commonly existing in plasmid DNA

• macrocyclic systems [18][19][20][21][22][23][24][25]. DNA mimics with triazole linkages were constructed [26][27]. The click reaction was used to generate a cyclic ADP-ribose second messenger mimic [28]. Modelling studies using MM+ energy minimization showed that pyrimidine nucleosides are useful synthons for

• ’-azido-2’,5’-dideoxycytidine 2. Earlier, the nucleoside precursor 1 was used for DNA cross-linking and labelling [36]. The unprotected nucleoside 1 was treated with equimolar amounts of carbon tetrabromide and triphenylphosphine and a five-fold excess of sodium azide to obtain the azide derivative 2 (37

Synthesis of new p-tert-butylcalix[4]arene-based polyammonium triazolyl amphiphiles and their binding with nucleoside phosphates

• Vladimir A. Burilov,
• Guzaliya A. Fatikhova,
• Mariya N. Dokuchaeva,
• Ramil I. Nugmanov,
• Diana A. Mironova,
• Pavel V. Dorovatovskii,
• Victor N. Khrustalev,
• Svetlana E. Solovieva and
• Igor S. Antipin

Beilstein J. Org. Chem. 2018, 14, 1980–1993, doi:10.3762/bjoc.14.173

• the p-tert-butylthiacalix[4]arene platform with 1,3-alternate conformation having polyammonium binding sites. They were shown to effectively interact with calf thymus DNA causing a 4-fold compaction of the latter [25]. Related macrocycles containing two cationic imidazolium fragments demonstrated a

A hemicryptophane with a triple-stranded helical structure

• Augustin Long,
• Olivier Perraud,
• Erwann Jeanneau,
• Christophe Aronica,
• Jean-Pierre Dutasta and
• Alexandre Martinez

Beilstein J. Org. Chem. 2018, 14, 1885–1889, doi:10.3762/bjoc.14.162

• Watson–Crick base pairing, DNA can also organize in a triple helical fashion [1]. These three-stranded structures of DNA naturally occur and play important roles in regulating gene function and DNA metabolism. Collagen, the most abundant protein in animals, also adopts a triple helical structure: three

Synthesis of 9-arylalkynyl- and 9-aryl-substituted benzo[b]quinolizinium derivatives by Palladium-mediated cross-coupling reactions

• Siva Sankar Murthy Bandaru,
• Darinka Dzubiel,
• Heiko Ihmels,
• Mohebodin Karbasiyoun,
• Mohamed M. A. Mahmoud and
• Carola Schulzke

Beilstein J. Org. Chem. 2018, 14, 1871–1884, doi:10.3762/bjoc.14.161

• pH-sensitive light-up probe. Photometric and fluorimetric titrations of duplex and quadruplex DNA to 9-(arylethynyl)benzo[b]quinolizinium derivatives revealed a significant binding affinity of these compounds towards both DNA forms with binding constants of Kb = 0.2–2.2 × 105 M−1. Keywords: DNA

• ligands; fluorescence; heterocycles; Pd-mediated couling reactions; quinolizinium; Introduction Polycyclic cationic hetarenes are a paradigm of DNA-binding ligands whose association with the nucleic acid may affect the biological activities of the DNA [1][2][3][4]. For example, a DNA-bound heterocyclic

• ligand may interfere with DNA–enzyme recognition events, which are essential for DNA-based cellular processes, e.g., gene replication or transcription [1]. To this end, it was shown that DNA-binding ligands may operate as chemotherapeutic anticancer, antiviral or antibacterial drugs, for example as