Artificial bioconjugates with naturally occurring linkages: the use of phosphodiester

• Takao Shoji,
• Hiroki Fukutomi,
• Yohei Okada and
• Kazuhiro Chiba

Beilstein J. Org. Chem. 2018, 14, 1946–1955, doi:10.3762/bjoc.14.169

• bioactivities and/or functions, which has been one of the central topics in the field of chemical biology [16][17][18][19][20][21][22][23][24][25][26]. Since peptide synthesis and oligonucleotide synthesis require different chemistries, such conjugations are typically carried out in the latter stages of the

• linkages that can be formed between native functional groups would be safe alternatives, and are known as natural conjugates such as nucleopeptides and nucleolipids [49]. We have been developing alkyl chain soluble support (ACSS)-assisted liquid-phase methods, specifically for peptide and oligonucleotide

• supported reactants would be unique alternatives that allow the use of unactivated amino acids or nucleosides. In peptide synthesis, activation of the N-terminus is rather rare, except for some recent encouraging examples [62][63][64][65][66][67][68]; however, this is not the case for oligonucleotide

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

• resulting spin-labeled palindromic duplexes could be directly investigated by PELDOR spectroscopy without further purification steps. Spin–spin distances measured by PELDOR correspond well to the values obtained from molecular models. Keywords: EPR; oligonucleotide; PELDOR; photolabile protection; TEMPO

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

• a specific protein, which leads to effective (though reversible) and selective downregulation of the protein's activity. A third option for the biological action of oligonucleotide structures is the triggering of the RNA interference mechanism by double-stranded 'small interfering' RNA (siRNA

• aspired improvement of cellular uptake, fully cationic oligonucleotide analogues might also be attractive candidate structures, as indicated by the advantageous properties of cationic cell-penetrating peptides (CPPs) [38]. However, the design of modifications of type 1–6 precludes the preparation of fully

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

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

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

• oligonucleotide is present, stacking with the base of its 5'-terminal nucleoside further adds to the attractive forces experienced by incoming monomers. This is shown schematically in Figure 5. Because downstream-binding strands favorably affect the rate and selectivity of primer extension, we have dubbed them

• ' = 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

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

• and some of them have been successful. Moreover, in the search for an alternative way to make efficient ON-based drugs, the general concept of prodrugs was applied to the oligonucleotide field. A prodrug is defined as a compound that undergoes transformations in vivo to yield the parent active drug

• group; oligonucleotide prodrugs; reduction-responsive; stimuli-responsive nucleic acids; thermolytic prodrugs; Introduction For past decades, oligonucleotide-based therapies have been widely developed using short synthetic oligonucleotides (ONs) and their chemically modified mimics as powerful tools to

• ONs definitively as a means of modifying and better improving their properties as gene silencing agents [11]. However, an alternative way to make efficient ON-based drugs is to apply the general concept of prodrugs to the oligonucleotide field. Based on the definition of a prodrug given by Albert in

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

• methods mentioned above allow the degree and localization of randomization to be adjusted to a certain degree, however, full control over mutagenesis is still rather limited. Oligonucleotide-based methods with a number of sophisticated techniques [8] are advantageous here, as they offer a better

• blocks, each of those contaminated with a "spiking mix" consisting of equal aliquots of each of the four building blocks [9][12]. The required volume of the spiking mix to achieve a desired amount of nucleotide replacements at a defined position of the oligonucleotide can be calculated, such that library

• prepared oligonucleotide libraries [14][15][25][26][28][30][31][33]. Among the described procedures the use of tert-butyldimethylsilyl [25] and 2-azidomethylbenzoyl groups [29] for 3'-O-protection stands out as being the most successful in terms of high quality trinucleotides. Both protecting groups, under

Fluorogenic PNA probes

• Tirayut Vilaivan

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

• Tirayut Vilaivan Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Road, Patumwan, Bangkok 10330, Thailand 10.3762/bjoc.14.17 Abstract Fluorogenic oligonucleotide probes that can produce a change in fluorescence signal upon binding

• . The probes usually consist of a labeled oligonucleotide strand as a recognition element together with a mechanism for signal transduction that can translate the binding event into a measurable signal. While a number of strategies have been developed for the signal transduction, relatively little

• vivo. For nucleic acids, the latter valuable information cannot be obtained by sequencing despite the tremendous advances in the field in recent years [1]. Accordingly, fluorescent oligonucleotide probes are still one of the most important tools not only for the detection of nucleic acids, but also

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

• the hydroxy group. The formed complex eliminates water and yielded the cyclization product in 75% after isolation. In an effort to increase the thermodynamic stability of oligonucleotide duplexes for antisense purposes, Lin et al. turned to size-expanded nucleobase analogues [41]. To this end they

• sodium methoxide in MeOH, which yielded the free nucleoside 15 in 71%. Standard DMTr protection furnished compound 16 which was then activated for oligonucleotide solid-phase synthesis (SPS) by phosphitylation using CEP-Cl. The total yield of tCnitro deoxyribose phosphoramidite was 0.8% over 6 steps

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

• ) of a chiral molecule can be determined [37]. Furthermore, an oligonucleotide VCD spectrum calculation was described recently [38]. 5.1. DNA VCD In VCD spectroscopy, two major spectral regions can be monitored to probe the structures of nucleic acids. In the region between 1700–1600 cm−1, the

Metal-mediated base pairs in parallel-stranded DNA

• Jens Müller

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

• duplexes so far and compares them with the corresponding base pairs in regular antiparallel-stranded DNA. In the next section, it first introduces into the concept of parallel-stranded DNA and explains different experimental approaches to enforce a parallel alignment of the complementary oligonucleotide

• strands. Review Parallel-stranded DNA In canonical DNA duplexes, the complementary oligonucleotide strands are oriented in an antiparallel fashion. From a geometrical point of view, this correlates with a cisoid orientation of the glycosidic bonds in Watson–Crick base pairs. A parallel-stranded

• orientation of oligonucleotide strands may also occur in nature, albeit in more complex topologies such as triple helices or quadruplexes [31][32]. Nonetheless, the formation of parallel-stranded DNA duplexes can be induced in various ways, leading to a variety of non-canonical DNA duplex topologies that

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

• . Confocal microscopy confirmed that 5 predominantly stains mitochondria but it also accumulates in the nucleoli of the cells. Keywords: confocal microscopy; luminescence; nucleobases; oligonucleotide binding; pyrene; X-ray; Introduction Pyrene is a planar, polycyclic aromatic hydrocarbon which shows well

• detecting markers [14], as fluorescent DNA probes [15], non-covalent binders to canonical oligonucleotide templates [16], and antiviral agents [17][18]. Notably, pyrene excimer formation in DNA template assemblies is much less efficient than in normal pyrene conjugates due to the helical twist between

• investigated towards application as fluorescent cell imaging bioprobes so far. Furthermore, self-assembly studies of pyrene–nucleobases on oligonucleotide templates have not been reported as well. The work presented herein addresses these two problems. Accordingly, in this contribution we report on the

Grip on complexity in chemical reaction networks

• Albert S. Y. Wong and
• Wilhelm T. S. Huck

Beilstein J. Org. Chem. 2017, 13, 1486–1497, doi:10.3762/bjoc.13.147

• needed that integrates the thorough appreciation of reaction rates in the design of chemical networks. Learning from the design principles applied in synthetic biology Genetic and small DNA-oligonucleotide networks provide an ideal test bed to address the basic principles of designing (bio)chemical

Synthesis of oligonucleotides on a soluble support

• Harri Lönnberg

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

• has been regarded as an approach that could combine the advantageous features of both the solution and solid-phase syntheses. The critical step of this approach is the separation of the support-anchored oligonucleotide chain from the monomeric building block and other small molecular reagents and

• oligonucleotide. Since the phosphate protecting groups are normally base-labile and the repeatedly removable 5´-O protecting group is acid-labile, the 2´-O-protection should preferably be removable under orthogonal conditions. For this purpose, numerous protecting groups have been proposed [18][19], the fluoride

• the 3´-terminal hydroxy function unprotected and, hence, available for one step conversion to a phosphoramidite building block [45]. Such phosphoramidites are widely used for the assembly of ODNs useful in protein engineering by oligonucleotide directed mutagenesis [46][47][48][49]. Cleavage of the

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

• A. Michael Downey and
• Michal Hocek

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

Towards open-ended evolution in self-replicating molecular systems

• Herman Duim and
• Sijbren Otto

Beilstein J. Org. Chem. 2017, 13, 1189–1203, doi:10.3762/bjoc.13.118

• Achieving exponential replication Pioneering work in the field of non-enzymatic self-replication has been performed by the group of von Kiedrowksi, who was the first to report on a template-directed self-replicating oligonucleotide (Figure 4) [30]. To achieve template-directed self-replication without the

• , depicted in Figure 5, an oligonucleotide template strand is immobilized via an irreversible interaction with a solid support. A complementary strand is then produced via the template-directed binding of free nucleotides from the solution. The copied strand is released from the template and is in turn

• two RNA enzymes can catalyze each other’s synthesis from a mixture of four different building blocks via template-directed reciprocal replication [45]. The RNA ligase molecule E can bind two oligonucleotide building blocks A’ and B’ and promote their ligation to form the ligase E’. The newly formed

A postsynthetically 2’-“clickable” uridine with arabino configuration and its application for fluorescent labeling and imaging of DNA

• Heidi-Kristin Walter,
• Bettina Olshausen,
• Ute Schepers and
• Hans-Achim Wagenknecht

Beilstein J. Org. Chem. 2017, 13, 127–137, doi:10.3762/bjoc.13.16

• cells. Keywords: dyes; fluorescence; nucleic acid; oligonucleotide; Introduction The “click”-type reactions [1], in particular the 1,3-dipolar cycloaddition between alkynes and azides (CuAAC) is a broadly applied strategy for postsynthetic oligonucleotide modification since both reactive groups are

• only reaction rates but improves also regioselectivity. The formation of oligonucleotide oxidation side products by Cu(I) is avoided by the use of chelating Cu(I) ligands, in particular tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) and better water-soluble derivatives [9][10]. The CuAAC

• cannot only be applied for conventional postsynthetic oligonucleotide modification in solution but also on solid phase [11] and for the introduction of multiple postsynthetic modifications [12]. The azide groups for CuAAC are typically placed onto the fluorescent dyes since azides are not compatible with

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

• , incorporated into oligonucleotides by standard solid–phase synthesis and reacted with the desired molecules on the oligonucleotide level. As amines and thiols are among the widely used groups introduced for the post-synthetic modifications, the acyclic threoninol linker (2-amino-1,3-butanediol) [14][15][16][17

• ][18][19][20][21] constitutes an attractive choice for oligonucleotide functionalization. Threoninol can be introduced in oligonucleotides via the corresponding phosphoramidite generating a ribose-free abasic site on the backbone that provides the amine group for later functionalization [22][23][24][25

• ][26][27][28]. Similarly, a thiol functionality can be introduced by substitution of the amine group of threoninol and incorporated into the oligonucleotide backbone. The amine and thiol groups can be used for further oligonucleotide functionalization reacting these sites with functional molecules like

Dinuclear thiazolylidene copper complex as highly active catalyst for azid–alkyne cycloadditions

• Anne L. Schöffler,
• Ata Makarem,
• Frank Rominger and
• Bernd F. Straub

Beilstein J. Org. Chem. 2016, 12, 1566–1572, doi:10.3762/bjoc.12.151

• ][22][23][24][25][26], nucleoside, nucleotide, and oligonucleotide chemistry [27][28][29], in fluorogenic reactions [30], and in the syntheses of dendrimers [25][31]. The detailed mechanism of this reaction and the exact role of copper(I) and the species involved in the catalytic cycle had remained

Application of Cu(I)-catalyzed azide–alkyne cycloaddition for the design and synthesis of sequence specific probes targeting double-stranded DNA

• Svetlana V. Vasilyeva,
• Vyacheslav V. Filichev and
• Alexandre S. Boutorine

Beilstein J. Org. Chem. 2016, 12, 1348–1360, doi:10.3762/bjoc.12.128

• permitted to obtain the most stable complexes of target DNA with TFO-MGB conjugates [11]. The resulting products were analyzed by 20% denaturing gel electrophoresis (PAGE) as described in [11]. For oligonucleotide HIVP products, we observed the formation of one slower migrating band on the PAGE gel with

• various yields of reactions (several examples are shown in Figure 10A). For oligonucleotides with a long linker HIVLP, except of the starting oligonucleotide, two barely resolved bands of products were observed. After purification by reversed-phase HPLC, three major peaks have been obtained; the first one

• was identified as a starting oligonucleotide, the second one – as a product 15 with only one linker 1 and the third one – as a product 16 with two linkers 1 connected to the same terminal phosphate of the hexaethylene phosphate moiety. This distribution of products has been previously observed [11][23

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• plasma and metabolic stability and no cytotoxicity. Overall, the structurally simplified 5'-deoxy muraymycin scaffold 65 may therefore be useful for further antibacterial development. It should also be noticed that it has inspired the design of a novel oligonucleotide backbone modification [116][117

Nucleic acids through condensation of nucleosides and phosphorous acid in the presence of sulfur

• Tuomas Lönnberg

Beilstein J. Org. Chem. 2016, 12, 670–673, doi:10.3762/bjoc.12.67

• higher than the parent oligonucleotide. Similar derivatives of monomeric thymidine were also detected in the fastest eluting fractions. The 80 Da difference in molecular weight could arise from capping of a free hydroxy function by a phosphate or an H-phosphonothioate group and distinguishing between

Preparation of a disulfide-linked precipitative soluble support for solution-phase synthesis of trimeric oligodeoxyribonucleotide 3´-(2-chlorophenylphosphate) building blocks

• Amit M. Jabgunde,
• Alejandro Gimenez Molina,
• Pasi Virta and
• Harri Lönnberg

Beilstein J. Org. Chem. 2015, 11, 1553–1560, doi:10.3762/bjoc.11.171

• bound 2-mercaptoethyl group was removed spontaneously giving the oligonucleotide trimer expectedly as a in fully protected 3´-(2-chlorophenyl phosphate). While the phosphate and base moiety protections remained intact, the 5´-O-(4,4´-dimethoxytrityl) group was unfortunately lost (Scheme 4). It has been

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

• able to act as hydrogelators [4]. Besides the properties of self-assembly, these conjugates are cell compatible [3][4]. Moreover, the NAS conjugates promote the proliferation of mES cells [5] and deliver the oligonucleotide into living cells [6]. Particularly, the incorporation of the functional