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

Synthesis and photophysical studies of a multivalent photoreactive Ru^II-calix[4]arene complex bearing RGD-containing cyclopentapeptides

• Sofia Kajouj,
• Lionel Marcelis,
• Alice Mattiuzzi,
• Adrien Grassin,
• Damien Dufour,
• Pierre Van Antwerpen,
• Didier Boturyn,
• Eric Defrancq,
• Mathieu Surin,
• Julien De Winter,
• Pascal Gerbaux,
• Ivan Jabin and
• Cécile Moucheron

Beilstein J. Org. Chem. 2018, 14, 1758–1768, doi:10.3762/bjoc.14.150

• . Barton et al. demonstrated in 1990 that [Ru(bpy)2(dppz)]2+ behaves as a light-switch for DNA [5]: this complex is not luminescent in water but upon intercalation within the DNA base pairs stack, the complex luminescence is restored. Derivatives of [Ru(bpy)2(dppz)]2+ and complexes bearing similar aromatic

• planar ligands were developed to probe specific sites of DNA, such as mismatches [6][7][8], abasic sites [9] or G-quadruplexes [10][11]. Aside photosensors, photoreactive complexes able to damage biological targets were also developed. These complexes are mainly used to induce damages in cancerous cells

• upon light irradiation. Two types of photooxidative damages can be induced: (i) by photosensitization of singlet oxygen and subsequent generation of highly reactive oxygen species (ROS) (type I photosensitization) or (ii) by direct oxidative electron transfer to biological molecules such as DNA or

Glycosylation reactions mediated by hypervalent iodine: application to the synthesis of nucleosides and carbohydrates

• Yuichi Yoshimura,
• Hideaki Wakamatsu,
• Yoshihiro Natori,
• Yukako Saito and
• Noriaki Minakawa

Beilstein J. Org. Chem. 2018, 14, 1595–1618, doi:10.3762/bjoc.14.137

• ” (i.e., DNA makes RNA makes proteins). The latter make up the cell walls of microorganisms and also play a role in transmitting information on the cell surface, whose interactions with proteins are a starting point for signal transduction into cells [1]. Since both types of polymers are essential for

Drug targeting to decrease cardiotoxicity – determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells

• Livia Polgár,
• Eszter Lajkó,
• Pál Soós,
• Orsolya Láng,
• Marilena Manea,
• Béla Merkely,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 1583–1594, doi:10.3762/bjoc.14.136

• the DNA of the cancer cells. Methotrexate is an antimetabolite that inhibits the folate metabolism of tumor cells. All three drugs have a great number of adverse effects; doxorubicin and daunorubicin are especially known for their cardiotoxicity, leading to cardiomyopathy and heart failure [18][19

Phosphoramidite building blocks with protected nitroxides for the synthesis of spin-labeled DNA and RNA

• Timo Weinrich,
• Eva A. Jaumann,
• Ute M. Scheffer,
• Thomas F. Prisner and
• Michael W. Göbel

Beilstein J. Org. Chem. 2018, 14, 1563–1569, doi:10.3762/bjoc.14.133

• could be incorporated by unmodified standard procedures into four different self-complementary DNA and two RNA oligonucleotides. After photochemical removal of the protective group, elimination of formic aldehyde and spontaneous air oxidation, the nitroxide radicals were regenerated in high yield. The

• oligonucleotides by phosphoramidite building blocks [27][28][29][30][31][32][33][34][35][36][37][38][39][40]. However, some degradation of the spin labels inevitably will occur. Nitroxide labeled DNA strands of the general structures 2 and 4 have been prepared by this way [30][34][37]. In recent years, we have

• have been successfully used in PELDOR experiments to determine the distance between two spins [8][25][43]. The apparent usefulness of such building blocks has prompted us in the present study to extend the protection strategy from amidite 6 to its DNA analog 5 and to adenosine derivatives 7 and 8

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

• . Therefore, HeLa and MCF-7 cells were exposed to the chemotherapeutic drug doxorubicin (DOX) that is already clinically applied in cancer therapy [37]. Doxorubicin interacts with DNA by intercalation and thereby inhibits the macromolecular biosynthesis [38]. Instead of covalent conjugation of the drug, we

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

• motifs, and nucleosyl amino acid (NAA)-derived modifications. The synthesis and properties of the corresponding oligonucleotide analogues are described. Keywords: backbone modifications; cations; DNA; oligonucleotides; zwitterions; Introduction Oligonucleotides have the unique ability to bind

• and binds to double-stranded DNA to form a triple helix. The triple helix is not a substrate for the transcription machinery, and hence, RNA biosynthesis (and therefore protein formation) is blocked. In the antisense pathway [3], the ON binds to single-stranded mRNA in the cytoplasm, thus furnishing a

• duplex structure (usually a DNA–RNA heteroduplex) which cannot undergo ribosomal protein biosynthesis. Alternatively, the DNA–RNA heteroduplex can be a substrate for RNAse H-mediated degradation of the mRNA strand. This way, catalytic amounts of the ON can mediate the efficient cleavage of mRNA encoding

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

• carrier of genetic information, the DNA double helix interacts with many natural ligands during the cell cycle, and is amenable to such intervention in diseases such as cancer biogenesis. Proteins bind DNA in a site-specific manner, not only distinguishing between the geometry of the major and minor

• grooves, but also by making close contacts with individual bases within the local helix architecture. Over the last four decades, much research has been reported on the development of small non-natural ligands as therapeutics to either block, or in some cases, mimic a DNA–protein interaction of interest

• . This review presents the latest findings in the pursuit of novel synthetic DNA binders. This article provides recent coverage of major strategies (such as groove recognition, intercalation and cross-linking) adopted in the duplex DNA recognition by small molecules, with an emphasis on major works of

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

• exploited grinding to facilitate disaggregation of DNA from tightly bound proteins through selective denaturation of the latter. Despite the wide application of ball milling to amino acid chemistry, there have been limited reports of mechanochemical transformations involving nucleoside or nucleotide

• : specifically, solid solutions, cocrystals, polymorph transitions, carbon nanotube dissolution and inclusion complex formation. Keywords: DNA; green chemistry; mechanochemistry; nucleoside; nucleotide; Introduction Several definitions of mechanochemistry have been attempted since Ostwald included it as one of

• DNA and RNA isolation The lack of free-volume within double-stranded DNA at low hydration levels leads to limited ice formation even under cooling in liquid air [57]. In contrast, cold denaturation of globular proteins at such temperatures is almost ubiquitous [58]. Furthermore, large conformational

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

• kinases. Gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP) are the active metabolites which inhibit processes required for DNA synthesis [91]. The incorporation of dFdCTP into DNA during polymerization, which causes DNA polymerases unable to proceed, is the major mechanism by which

• sugar moiety. The difference between Dau and Dox is a hydroxy group substituted at the C-14 carbon atom on Dox providing an extra conjugation site for ester linkage (Figure 6). The mechanism of action of anthracyclines is based on their intercalation to DNA inhibiting the macromolecular biosynthesis

• . Furthermore, they stabilize the topoisomerase II DNA complex preventing the transcription. They may also increase quinone type free radical production, however, this plays a role rather in their cytotoxic side effects. Daunorubicin is mainly used in the treatment of leukemia [95] while doxorubicin in the cure

Local energy decomposition analysis of hydrogen-bonded dimers within a domain-based pair natural orbital coupled cluster study

• Ahmet Altun,
• Frank Neese and
• Giovanni Bistoni

Beilstein J. Org. Chem. 2018, 14, 919–929, doi:10.3762/bjoc.14.79

• importance for regulating molecular properties like polarizability [1] and in various biochemical processes, including protein folding [2] and stability [3], replication of DNA and RNA [4], enzyme catalysis [5], proton relay mechanism [6], and drug delivery [7]. Energy decomposition analysis (EDA) schemes

Development of novel cyclic NGR peptide–daunomycin conjugates with dual targeting property

• Andrea Angelo Pierluigi Tripodi,
• Szilárd Tóth,
• Kata Nóra Enyedi,
• Gitta Schlosser,
• Gergely Szakács and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 911–918, doi:10.3762/bjoc.14.78

• ]. It is well known from our previous studies that not only the free Dau but also Dau containing metabolites like Dau=Aoa-Gly-OH bind to DNA efficiently resulting in antitumor activity. The exchange of the Lys in the cycle simplified the cyclization step and due to the avoidance of the Fmoc cleavage in

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

• studies with small molecular phosphodiesters. Keywords: Cleavage; DNA; kinetics; mechanism; RNA; Introduction Nucleic acids are polymeric diesters of phosphoric acid that store and transfer biological information. In biological systems, the diester linkages bridging 3´-O of one nucleoside to the 5´-O of

• 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

• that is rapidly hydrolyzed to 2´- and 3´-phosphates (Figure 1). In the absence of any catalyst, the 3´,5´-phosphodiester linkages are remarkably stable under physiological conditions. The half-life for the hydrolysis of an individual phosphodiester bond in DNA has been estimated to be 30 million years

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

• stability, ii) altered hydrogen bonding motifs, and iii) altered molecular recognition properties [25][29][37][58]. Because of these changes, C-nucleosides have been useful in the study of RNA and DNA processing enzymes, as well as drug design efforts and novel supramolecular structures [12][29][59

• endothelial cells and RSV with low cytotoxicity towards Huh-7, HEp-2 and MT4 cells. Moreover, the triphosphate of 4 selectively inhibits, HCV RdRp and RSV RdRp over human RNA Pol II and DNA polymerases (α, β, γ) [65]. The 2'-Me compound 7 as its triphosphate (TP) shows anti-HCV activity in replicon assays [77

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

• (Dox), daunorubicin (Dau) or epirubicin are frequently used anticancer drugs. Their mode of action is based on a planar ring system which is important for intercalation into DNA [10]. In this way, anthracyclines can affect a broad range of DNA processes leading to an inhibited synthesis of

• macromolecules such as mRNA and DNA [10][11]. More precisely, anthracyclines act as topoisomerase II toxins inhibiting DNA transcription and replication. They stabilize a DNA topoisomerase-II intermediate in which the DNA strands are separated and a specific tyrosine residue of the topoisomerase II is covalently

• linked to the DNA by formation of a tyrosine phosphodiester [10][11][12]. Moreover, anthracyclines provide a beneficial auto-fluorescence allowing the performance of fluorescence based studies like confocal laser scanning microscopy (CLSM) and fluorescence-activated cell sorting (FACS) to investigate the

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

• ; nucleotide recognition; Introduction Nucleotides play essential roles in various physiological processes, such as energy transportation [1], DNA synthesis [2] and cell signaling events [3]. Especially, adenosine-5’-triphosphate (ATP) is vital, since it is the main energy source in living systems [4]. The

• [45], however, none of them are the result of rational design. Base pairing is a well-known phenomenon in the double helix structure of DNA since the work of Watson and Crick. It is also known that the cohesion of the double strand is provided by the efficient π-stacking interaction [46]. Adding

Volatiles from the xylarialean fungus Hypoxylon invadens

• Jeroen S. Dickschat,
• Tao Wang and
• Marc Stadler

Beilstein J. Org. Chem. 2018, 14, 734–746, doi:10.3762/bjoc.14.62

• transcribed spacer (ITS) DNA sequences and homology comparisons [38][39][40]. In fact, the ITS is not regarded species- or even genus-specific in Xylariales and the phylogenies based on this DNA locus have led to rather ambiguous results. It should be interesting to find out in the future which other species

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

• Marilyne Sosson Clemens Richert Institute of Organic Chemistry, University of Stuttgart, 70569 Stuttgart, Germany 10.3762/bjoc.14.47 Abstract The copying of short DNA or RNA sequences in the absence of enzymes is a fascinating reaction that has been studied in the context of prebiotic chemistry

• successful modeling of the reaction, the strength of the template effect, the inhibitory effect of spent monomers, and the rate constants of the chemical steps have to be determined experimentally. While challenges remain for the high fidelity copying of long stretches of DNA or RNA, the available data

• suggest that enzyme-free primer extension is a more powerful reaction than previously thought. Keywords: base pairing; DNA; enzyme-free primer extension; nucleotides; oligonucleotides; replication; RNA; Introduction Replication of genetic information is critical for all living systems. In the cell, this

Mannich base-connected syntheses mediated by ortho-quinone methides

• Petra Barta,
• Ferenc Fülöp and
• István Szatmári

Beilstein J. Org. Chem. 2018, 14, 560–575, doi:10.3762/bjoc.14.43

• ). Rokita et al. focused on generating o-QMs and used them as cross-linking and DNA alkylating agents. Starting from Mannich base 56 and transforming it by a number of synthetic steps, they were managed to elaborate a process that provides easy access to o-QM precursors containing a broad array of linkers

• mostly examined from the point of view of their application as DNA alkylating agents. One of the first examples was reported by Kearney et al. in 1996 about preformulation studies of the antitumor agent topotecan [91]. The antitumor activity of the compound could be explained by its degradation to highly

• , mutagenous properties were also shown. Freccero et al. examined the photogeneration by laser flash photolysis and reactivity of naphthoquinone methides as well as their activity as purine selective DNA alkylating agents [93]. Farrell et al. studied the mechanism of the cytotoxic action of naphthoquinone

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

• strategies include antisense oligonucleotides (AONs), ribozymes, DNAzymes, small interfering RNAs (siRNAs) and micro RNAs (miRNAs) that specifically target the complementary mRNA sequence of the relevant undesired gene before translation. AONs are single-stranded DNA of 15 to 25 nucleotides in length that

• bind to mRNA targets through Watson–Crick base pairing and form a RNA/DNA duplex [4]. This can result in either mRNA cleavage mediated by RNase H or mRNA translational arrest through steric blocking. Another strategy for gene inhibition involves ribozymes [5] and DNAzymes [6], which are nucleic acid

• normal cells. A nitrobenzyl (NB) group has also been introduced at O6 of a guanine to modulate the conformational properties of a G-quadruplex structure-forming single-stranded DNA [28]. The dGNB phosphoramidite was synthesized and incorporated into the sequence of a thrombin-binding DNA aptamer (TBA, at

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

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

• on soluble polymers, and their use as synthons in standard DNA synthesis. Keywords: gene library; protein engineering; soluble support; synthesis; trinucleotide; Introduction Protein engineering is a highly actual research area with a number of potential applications [1][2][3][4]. The construction

• generation of protein mutant libraries and high throughput screening processes to select for variants with improved traits. Protein mutant libraries are produced from gene libraries, which are generated by random mutagenesis at DNA level. Often polymerase chain raction (PCR)-based methods like error-prone

• PCR are used for this purpose as well as recombinant methods like DNA shuffling and related strategies [6][7]. One of the major challenges in gene library production is to generate libraries with a high number of promising candidates to enhance the chance of selecting functional protein variants. The

Fluorogenic PNA probes

• Tirayut Vilaivan

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

• attention has been paid to the recognition element. Peptide nucleic acids (PNA) are DNA mimics with several favorable properties making them a potential alternative to natural nucleic acids for the development of fluorogenic probes, including their very strong and specific recognition and excellent chemical

• the principle, showcase state-of-the-art technologies and update recent developments in the areas of fluorogenic PNA probes during the past 20 years. Keywords: DNA; fluorescence; molecular beacons; molecular probes; oligonucelotides; RNA; Review Introduction The development of molecular probes that

• -free format. One of the landmark developments in this area is the DNA molecular beacon – a double-labeled hairpin DNA that can change its fluorescence in response to the conformational change induced by binding with the complementary nucleic acid target (Figure 1) [3][4]. While a number of signal