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

• pentose sugar and the nucleobase are connected by a carbon–nitrogen bond that is adjacent to the sugar oxygen resulting in an hemiaminal ether bond, also known as the glycosidic bond. Because of their key role in many biological processes, modifications to the nucleoside structure have been widely

• the glycosidic bond is stable under physiological conditions, cleavage of the bond is common and is highly dependent on the nature of the nucleobase and local pH. In addition, the rate of glycosidic bond cleavage is higher for purines than pyrimdines [38][39][40][41][42][43][44]. Moreover, 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

• a uracil nucleobase to the known 4’-dimethylamino-hydroxyflavone fluorophore. Results: The complexation of this scaffold with ATP is already known. The complex is held together by stacking and electrostatic interactions. To achieve multi-point recognition, we designed the uracil-appended version of

• way to enhance the selectivity. Since ATP has one adenine nucleobase, a simple uracil/thymine unit appended to a neutral chemosensor operating mainly through π-interaction could be a good model for investigation. We selected DMHF as the fluorophore and core scaffold because of its easy synthesis and

• on the detailed investigation of the supramolecular structure of the DEHF∙ATP (4’-diethylaminohydroxyflavone) complex (see below), we envisioned the uracil group to be appended on the A ring in close proximity to the nucleobase. In addition, some flexibility was required to obtain the proper

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

• an RNA primer by one nucleotide. B = nucleobase, LG = leaving group. Oligomerization of the 2-methylimidazolide of guanosine-5'-monophosphate on a poly(C) template. Structures of backbone linkages produced in enzyme-free primer extension reactions: the phosphoramidate of a 3'-amino-2',3

• ' = nucleobase). Interactions attracting the incoming nucleotide to the extension site. Besides base pairing via hydrogen bonding to the templating base, stacking interactions with neighboring bases of primer and a possible downstream-binding helper oligonucleotide, as well as help of solvophobic effects

• the dissociation constant (Kd). It takes into account the rate of hydrolysis with the corresponding rate constant (kh), the binding equilibrium for the hydrolyzed monomer that acts as inhibitor (Kdh), and it assumes a single rate-limiting chemical step (kcov); B, B' = nucleobase = OH for RNA. Binding

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

• may be attached at different positions of the ON: the internucleotide linkage, the ribose, the nucleobase, or the 5’ or 3’ extremities. For simplicity, each section corresponding to one class of stimulus has been divided into sub-sections related to the site of the modification in the ON when the

• (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

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

• ), which after the synthesis was cleaved with a 5% solution of 25% aqueous ammonia in methanol, or with 20% pyridine in methanol [20]. Combined with phosphotriester chemistry for trimer assembly, this treatment did not cause damage of the phosphotriester linkages and the nucleobase N-acyl groups. Using

• 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

• duplexes by various mechanisms, such as groove binding or intercalation. This fluorescent label may be a stand-alone entity (referred to as a tethered label) or combined with a nucleobase that integrates the base pairing and the fluorescence sensing in a single event. The latter strategy should allow a

• base via a rigid linker that disfavors such intercalation [175][176]. PNA probes carrying fluorescent nucleobases There are three major strategies to introduce fluorescent nucleobases into oligonucleotides or PNA probes. These are (i) the extension of conjugation in the natural nucleobase, (ii

• ) appending a fluorophore onto a natural nucleobase and (iii) the use of unnatural, intrinsically fluorescent nucleobases. They can be divided into fluorescent nucleobases capable of hydrogen bond formation, which can form specific base pairs with canonical nucleobases, and those that cannot (i.e., universal

Fluorescent nucleobase analogues for base–base FRET in nucleic acids: synthesis, photophysics and applications

• Mattias Bood,
• Sangamesh Sarangamath,
• Moa S. Wranne,
• Morten Grøtli and
• L. Marcus Wilhelmsson

Beilstein J. Org. Chem. 2018, 14, 114–129, doi:10.3762/bjoc.14.7

• , SE-412 96 Gothenburg, Sweden 10.3762/bjoc.14.7 Abstract Förster resonance energy transfer (FRET) between a donor nucleobase analogue and an acceptor nucleobase analogue, base–base FRET, works as a spectroscopic ruler and protractor. With their firm stacking and ability to replace the natural nucleic

• , our group took this progress one step further and introduced base–base FRET [14], where the donor and acceptor molecules are nucleobase analogues [15][16]. With the donor and acceptor molecules rigidly stacked in the base-stack of the nucleic acid (Figure 1c) this approach provides highly accurate

• orientation information and has the potential to increase the structure and dynamics information obtained in a nucleic acid FRET experiment. Later Asanuma et al. introduced base-stacked aromatic moieties [17], not working as nucleobase analogues, which also can be used to provide information about orientation

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

• stock solution of polynucleotides would be about 0.01 M. It is calculated as nucleobase/mol by using the molar extinction coefficient at the maximum of the wavelength absorbance (as defined by the supplier). In addition, dissolving polynucleotides is not an instantaneous process and usually takes

• exciton coupling mechanism determines the ECD spectra of polynucleotides, Figure 6 reports the case of guanine quadruplexes (G-quadruplexes) which are easy to analyze because of the presence of a single type of nucleobase and a rigid structure [23]. The ECD spectrum is dominated by the degenerate exciton

Metal-mediated base pairs in parallel-stranded DNA

• Jens Müller

Beilstein J. Org. Chem. 2017, 13, 2671–2681, doi:10.3762/bjoc.13.265

• Ag(I)-mediated base pairs formed from a d(CC) dinucleotide indicates significantly tilted nucleobases, leading to a conformation in-between cisoid and transoid [65]. Such an arrangement was later found in the crystal structure of an Ag(I) complex of the model nucleobase 1-hexylcytosine as well as in

• a non-canonical DNA structure [9][66]. Pyrrolocytosine (PC) represents a fluorescent analogue of cytosine that still retains the base pairing properties of its parent nucleobase [67]. Accordingly, its application in metal-mediated base pairing was probed, too. An initial report on the MePC–Ag(I)–C

• adenine which was shown to bind transition metal ions better than its parent nucleobase [74]. Accordingly, its propensity to engage in metal-mediated base pairing was investigated in detail. As it turned out, εA is capable of simultaneously binding two metal ions with an almost parallel alignment of the N

Pyrene–nucleobase conjugates: synthesis, oligonucleotide binding and confocal bioimaging studies

• Artur Jabłoński,
• Yannic Fritz,
• Hans-Achim Wagenknecht,
• Rafał Czerwieniec,
• Tytus Bernaś,
• Damian Trzybiński,
• Krzysztof Woźniak and
• Konrad Kowalski

Beilstein J. Org. Chem. 2017, 13, 2521–2534, doi:10.3762/bjoc.13.249

• Chemistry, Biological and Chemical Research Centre, University of Warsaw, Żwirki and Wigury 101, 02-089 Warszawa, Poland 10.3762/bjoc.13.249 Abstract Fluorescent pyrene–linker–nucleobase (nucleobase = thymine, adenine) conjugates with carbonyl and hydroxy functionalities in the linker were synthesized and

• chromophores [19][20][21]. This helical twist was evidenced by circular dichroism, in particular a strong bisignate Cotton effect for the DNA-templated pyrene assemblies [19][20]. Figure 1 shows selected examples of pyrene-modified nucleic acids and nucleosides. On the other hand, pyrene–nucleobase conjugates

• of the general structure pyrene–spacer–nucleobase (Figure 1) have been investigated to a lesser extent than their oligomeric counterparts. A literature survey shows that pyrene–thymines A1 and A2 (Figure 1) were utilized as selective fluorescent chemosensors for Hg(II) ions [19][22]. The molecular

Enzymatic separation of epimeric 4-C-hydroxymethylated furanosugars: Synthesis of bicyclic nucleosides

• Neha Rana,
• Manish Kumar,
• Vinod Khatri,
• Jyotirmoy Maity and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2017, 13, 2078–2086, doi:10.3762/bjoc.13.205

• Vorbrüggen coupling of tetraacetylated sugar derivatives 7a,b and 12a,b: synthesis of acetylated nucleosides 8 and 13. Similar as described in [18] to a stirred solution of compound 7a,b (3.0 g, 5.97 mmol) and nucleobase uracil (1.0 g, 8.9 mmol) in anhydrous acetonitrile (25 mL), N,O-bis(trimethylsilyl

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

• , and a nucleobase, 8-oxoguanine, serving as recyclable electron donor to trigger the redox cleavage of the precursor molecule, [71] was also found to be enhanced by the presence of pre-formed fatty acid vesicles. In aqueous media, both parts of the photochemical catalyst needed to be covalently linked

Effect of uridine protecting groups on the diastereoselectivity of uridine-derived aldehyde 5’-alkynylation

• Raja Ben Othman,
• Mickaël J. Fer,
• Laurent Le Corre,
• Sandrine Calvet-Vitale and
• Christine Gravier-Pelletier

Beilstein J. Org. Chem. 2017, 13, 1533–1541, doi:10.3762/bjoc.13.153

• epigenetic modulators [9] or chemical tools [10][11]. Furthermore, they represent central monomers for oligonucleos(t)ide synthesis [12][13][14][15][16][17]. In the past decades, chemical modifications of these crucial building blocks have been extensively studied, both on the nucleobase itself and on the

• numerous approaches, this 5′ stereogenic center comes from the chiral pool and the nucleobase is introduced under Vorbrüggen conditions [20][21][22][23][24][25][26]. It can also be created directly on the nucleoside, either by functionalization of an alkene at C-5’ [27][28][29][30][31][32] or by the

Nucleophilic displacement reactions of 5′-derivatised nucleosides in a vibration ball mill

• Olga Eguaogie,
• Patrick F. Conlon,
• Francesco Ravalico,
• Jamie S. T. Sweet,
• Thomas B. Elder,
• Louis P. Conway,
• Marc E. Lennon,
• David R. W. Hodgson and
• Joseph S. Vyle

Beilstein J. Org. Chem. 2017, 13, 87–92, doi:10.3762/bjoc.13.11

• and nucleoside substrate (e.g., the leaving group [11] or nucleobase protection [12]) are therefore often required. We anticipated that some of these issues could be ameliorated through mechanochemical mixing of reactants and substrates, with diverse solubility profiles, using minimal or no added

Facile synthesis of a 3-deazaadenosine phosphoramidite for RNA solid-phase synthesis

• Elisabeth Mairhofer,
• Elisabeth Fuchs and
• Ronald Micura

Beilstein J. Org. Chem. 2016, 12, 2556–2562, doi:10.3762/bjoc.12.250

• consistent with the structure of the desired ß-N9 isomer 4, indicated by strong ROEs of the nucleobase C3-H with ribose C3’-H, C2’-H and C1’-H (see Supporting Information File 1). The benzoyl groups of nucleoside 4 were then cleaved with methylamine in ethanol and water to furnish the free c3A nucleoside 5

DNA functionalization by dynamic chemistry

• Zeynep Kanlidere,
• Oleg Jochim,
• Marta Cal and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2016, 12, 2136–2144, doi:10.3762/bjoc.12.203

• template-directed selection of one nucleobase from the reaction mixture with the amine or thiol functional group was investigated [44][45][46][47]. In our studies, dynamic chemistry is applied for post-synthetic functionalization of the threoninol based modified oligonucleotides in a reversible manner

• , we generated the libraries of reversibly interconverting building blocks – dynamic combinatorial libraries (DCL) (Figure 1). The abasic strand and its complementary template strand are spontaneously assembled into a double helix through Watson–Crick base-pairing and the incoming nucleobase monomer

• benefits from the hydrogen bonding recognition by the respective nucleobase in the template strand. The reversible attachment generates a dynamic system that enables the combinatorial screening of the best bound nucleobase by allowing a rapid and continuous exchange between the threoninol site and the set

Synthesis of the C8’-epimeric thymine pyranosyl amino acid core of amipurimycin

• Pramod R. Markad,
• Navanath Kumbhar and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2016, 12, 1765–1771, doi:10.3762/bjoc.12.165

• , antiviral, antibacterial and antifungal [2]. Peptidyl nucleosides in which the sugar part is in the furanose form are common, however, the sugar framework in the pyranose form, with a nucleobase and a peptide linker at either ends, are rare in nature. A few examples of this category are amipurimycin and

•  1) that involves (a) a unique pyranosyl amino acid ring skeleton with a hydroxy group and a branched 1,2-dihydroxyethyl side chain at C3’, (b) a glycosidic β-linked purine nucleobase, and (c) a five-membered cis-pentacin framework coupled to C6’ via the N-terminus of an amino acid [5]. The absolute

• of 1 is not known. The reported methodologies are mainly focused on construction of the exigent central pyranosyl amino acid fragment with or without the C3’-branched chain and nucleobase, frequently using carbohydrate substrate [6][7][8][9][10][11][12][13][14][15]. In a non-carbohydrate approach

Beta-hydroxyphosphonate ribonucleoside analogues derived from 4-substituted-1,2,3-triazoles as IMP/GMP mimics: synthesis and biological evaluation

• Tai Nguyen Van,
• Audrey Hospital,
• Corinne Lionne,
• Lars P. Jordheim,
• Charles Dumontet,
• Christian Périgaud,
• Laurent Chaloin and
• Suzanne Peyrottes

Beilstein J. Org. Chem. 2016, 12, 1476–1486, doi:10.3762/bjoc.12.144

• -containing derivatives are biologically interesting (Figure 1) [7]. In addition, molecular docking studies have been performed and highlighted the importance of three binding areas within the active site of the protein: a hydrophobic clamp (Phe157, His209 and Tyr210) interacting with the nucleobase, a

• ) [7], we were interested in studying the effect of replacing the nucleobase by a 1,2,3-triazole moiety, linked to various substituents, with the aim to retain or modulate essential elements for enzyme recognition. Indeed, the assembly of the triazole ring with various substituents confers to the final

• compound high flexibility. Initially reported by K. Seley-Radtke’s group, the replacement of the nucleobase by a “flexi-moiety” where the imidazole ring and a six-membered heterocycle is linked through a C–C bond lead to new derivatives behaving as nucleosides and even as enzyme inhibitors [11][12][13

The role of alkyl substituents in deazaadenine-based diarylethene photoswitches

• Christopher Sarter,
• Michael Heimes and
• Andres Jäschke

Beilstein J. Org. Chem. 2016, 12, 1103–1110, doi:10.3762/bjoc.12.106

• in which a purine nucleobase represented one of the aryl rings of the photoswitch (Figure 1B). Importantly and different from most other approaches towards photoswitchable nucleic acids, the nucleobase constituted an active part of the photoswitch (rather than an appendage), changing its bonding and

Interactions between 4-thiothymidine and water-soluble cyclodextrins: Evidence for supramolecular structures in aqueous solutions

• Vito Rizzi,
• Sergio Matera,
• Paola Semeraro,
• Paola Fini and
• Pinalysa Cosma

Beilstein J. Org. Chem. 2016, 12, 549–563, doi:10.3762/bjoc.12.54

• DIMEB CD/S4TdR inclusion complexes were studied (see Figure S1D, Supporting Information File 1), a very important effect was observed when the 6-H proton, directly linked to the double bond of the nucleobase, was considered. The 6-H proton appeared to be significantly downfield shifted, with others

Effective in silico prediction of new oxazolidinone antibiotics: force field simulations of the antibiotic–ribosome complex supervised by experiment and electronic structure methods

• Jörg Grunenberg and
• Giuseppe Licari

Beilstein J. Org. Chem. 2016, 12, 415–428, doi:10.3762/bjoc.12.45

• flexibility of the U2620 (U2585 in Escherichia coli) moiety has already been discussed elsewhere [20]. Nevertheless, due to our simulation, there is no hydrogen bond between this nucleobase and the morpholine ring. The absence of a second hydrogen bond in our simulations (which is indeed observed for

• . Comparing our simulated bioactive conformation of linezolid with that from linezolid bound to Haloarcula marismortui (code 3CPW), we find a value of 0.70 RMSD, again pointing to the quality of our ribosomal model. Interestingly the nucleobase G2540 (U2505 in Escherichia coli) undergoes a profound

• conformational change during the Monte Carlo scan. While in the solid state structure from Haloarcula marismortui this nucleobase is oriented away from linezolid, due to our simulation the nucleobase approaches linezolid interacting through a new H-bond (relaxed force constant: of 0.23 N/cm) between the NH2

Synthesis and evaluation of the biostability and cell compatibility of novel conjugates of nucleobase, peptidic epitope, and saccharide

• Dan Yuan,
• Xuewen Du,
• Junfeng Shi,
• Ning Zhou,
• Abdulgader Ahmed Baoum,
• Khalid Omar Al Footy,
• Khadija Omar Badahdah and
• Bing Xu

Beilstein J. Org. Chem. 2015, 11, 1352–1359, doi:10.3762/bjoc.11.145

• .11.145 Abstract This article reports the synthesis of a new class of conjugates containing a nucleobase, a peptidic epitope, and a saccharide and the evalution of their gelation, biostability, and cell compatibility. We demonstrate a facile synthetic process, based on solid-phase peptide synthesis of

• proteolytic stabilities of the conjugates depend on the functional peptidic epitopes. We found that TTPV is proteolytic resistant and LGFNI is susceptible to proteolysis. In addition, all the conjugates are compatible to the mammalian cells tested. Keywords: biocompatibility; biostability; nucleobase

• ; peptidic epitope; saccharide; Introduction This article describes the synthesis and evaluation of a new class of molecular conjugates that consist of a nucleobase, a peptidic epitope, and a saccharide. Nucleobases, amino acids, and saccharides are part of the unified building blocks of life [1] because

NAA-modified DNA oligonucleotides with zwitterionic backbones: stereoselective synthesis of A–T phosphoramidite building blocks

• Boris Schmidtgall,
• Claudia Höbartner and
• Christian Ducho

Beilstein J. Org. Chem. 2015, 11, 50–60, doi:10.3762/bjoc.11.8

• . In comparison, the introduction of positive charges into the nucleic acid scaffold has found less attention. Positively charged units were attached to the 2'-hydroxy group or the nucleobase as a compensation for the presence of negative charges in the phosphate backbone [25][26][27][28][29]. In

• was observed (particularly for DNA/RNA duplexes). Further experiments with native counterstrands bearing one nucleobase mismatch were performed, and duplex structures were studied by CD spectroscopy. Overall, we found that NAA-modified DNA oligonucleotides (i) formed stable duplexes with complementary

• nucleosyl amino acid and protecting group manipulations in order to obtain both 6'-epimers of 9 dependent on the choice of the hydrogenation catalyst [38]. Here, we report on further studies directed towards a possible synthesis of 9 without 3-(N-BOM)-protection of the thymine nucleobase. In the case of the

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

• cage-like bis-phenanthridinium derivatives (Scheme 16; general structure 7), with a rigid structure allowing accommodation of only one nucleobase, showed pronounced ss-RNA over ds-RNA/DNA selectivity [60], whereas more flexible cyclic (6) and acyclic analogues (5) [61] revealed opposite preference

• phenanthridine ring (Scheme 23). The phenanthridinium–nucleobase conjugates did not show targeted selectivity toward complementary nucleotides in aqueous medium due to the strong competition of bulk water with the expected hydrogen bonds [70][71]. Fortuitously, the hydrophobic environment within the common DNA

• aromatic stacking and hydrogen-bonding interactions [73][74]. At variance to phenanthridinium–nucleobase conjugates (Scheme 23), which were not able to differentiate among mononucleotides, some bis-phenanthridinium–nucleobase conjugates provided a more convenient binding site for the nucleobase. For

Regio- and stereoselective synthesis of new diaminocyclopentanols

• Evgeni A. Larin,
• Valeri S. Kochubei and
• Yuri M. Atroshchenko

Beilstein J. Org. Chem. 2014, 10, 2513–2520, doi:10.3762/bjoc.10.262

• aminoglycosides [7], and nucleosides containing 9H-purin-6-amine as a nucleobase portion. High levels of stereoselectivity have been observed in substrate-controlled diastereoselective epoxidation of cyclic alkenes with O- and N-allylic directing groups [20][21]. Several 3-substituted diastereomeric epoxides have