Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• through complementary Watson–Crick base-pairing, the sequence options of ASO lead compounds can be rationalized based on a knowledge of the endogenetic gene sequence to be targeted, thus further offering a potential against targets which are considered undruggable using conventional small-molecule drugs

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• –Crick base pairing at mixed sequences that do not have polypurine tracts is also possible, but requires chemical modifications to alter the binding properties of PNAs. These binding modes further illustrate the diversity of molecular recognition that can be achieved with PNAs. Taken together, the early

• nucleobase stacking pattern similar to that of the A-form RNA [43]. Another crystal structure of a partially self-complementary PNA–PNA duplex revealed PNA’s ability to combine the P-form Watson–Crick duplex with higher order structural features, such as reversed Hoogsteen base pairing, interstrand

• using only Watson–Crick base pairing to recognize the target [89]. As will be discussed later in this review, PNAs having guanidine (γ-GPNA) and miniPEG γ-modifications are currently among the most promising PNA derivatives explored in medicinal chemistry and preclinical studies. Anionic PNA: Anionic

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• structure with a hairpin loop and two flanking sequences [30][31]. Moreover, these nucleotides have been found to orient the additional nucleobase towards the core of the duplex to participate in Watson–Crick base pairing [32][33][34]. The incorporation of the double-headed nucleosides into oligonucleotides

• participation of both nucleobases of the double-headed nucleotides in Watson–Crick base pairing. The same group also showed that a multiple incorporation of the double-headed nucleotide is also tolerated, but the double-headed nucleotides with the present design were not suitable as triplex-forming

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• group between the sugars in DNA and RNA is at the origin of the vastly expanded fold [29][30][31][32] and functional spaces of RNA [33][34][35][36][37][38][39]. Perhaps less known is the fact that the sugar moiety in the backbone of a nucleic acid determines the base pairing priorities. For example, in

• stems from the structural incompatibility with the B-form deoxyribonucleotide-phosphate backbone. On the other hand, GNA–GNA duplexes form highly stable antiparallel duplexes that follow Watson–Crick base pairing rules [99]. GNA strands self-assemble into homochiral antiparallel right-handed ((S)-GNA

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

• Yongdong Su,
• Maitsetseg Bayarjargal,
• Tracy K. Hale and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2021, 17, 749–761, doi:10.3762/bjoc.17.65

• parallel triple-helix structure, a polypyrimidine TFO binds to dsDNA through Hoogsteen base-pairing [17], in which the cytosine bases in the TFO are protonated at the N3 atom (Figure 1B). In antisense strategies, antisense ONs (AOs) interact with RNA molecules to interfere with protein expression [18][19

• modifications, because their use in ONs led to higher ΔTm values for ON/RNA than for ON/DNA duplexes. The same modified sequences (ON1–13) were also studied in a pH-dependent Hoogsteen-type base-pairing towards the duplex D1 forming a parallel triplex [40]. As can be seen in Table 2, all parallel triplexes

Synthesis and properties of oligonucleotides modified with an N-methylguanidine-bridged nucleic acid (GuNA[Me]) bearing adenine, guanine, or 5-methylcytosine nucleobases

• Naohiro Horie,
• Takao Yamaguchi,
• Shinji Kumagai and
• Satoshi Obika

Beilstein J. Org. Chem. 2021, 17, 622–629, doi:10.3762/bjoc.17.54

• oligonucleotides [25]. Since oligonucleotides modified with 2',4'-BNA/LNA or its analog scpBNA show different nucleobase dependency [1][23], these results could be considered characteristic of the GuNA-modified oligonucleotides. Interactions between the guanidine moiety and nearby base pairing(s) might have

Using multiple self-sorting for switching functions in discrete multicomponent systems

• Amit Ghosh and
• Michael Schmittel

Beilstein J. Org. Chem. 2020, 16, 2831–2853, doi:10.3762/bjoc.16.233

• functions, for instance, to control the biological processes that eventually sustain life on our planet [1]. A well-known example is the storage of an immense amount of information in the DNA, using the algorithm of base pairing (AT and GC) between the heterocycles adenine (A), thymine (T), guanine (G) and

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

• Jonas Becher,
• Daria V. Berdnikova,
• Heiko Ihmels and
• Christopher Stremmel

Beilstein J. Org. Chem. 2020, 16, 2795–2806, doi:10.3762/bjoc.16.230

• may allow to deduce a relationship between the chain length and the binding properties. The adenine unit was supposed to establish binding interactions with the loop region of the quadruplex, namely through Watson–Crick base pairing with the complementary thymidine residues. Herein, we describe the

Extension of the 5-alkynyluridine side chain via C–C-bond formation in modified organometallic nucleosides using the Nicholas reaction

• Renata Kaczmarek,
• Dariusz Korczyński,
• James R. Green and
• Roman Dembinski

Beilstein J. Org. Chem. 2020, 16, 1–8, doi:10.3762/bjoc.16.1

• common framework for materials with potent biological properties [6][7][8][9][10]. Modification on this site of the nucleobase usually does not interfere with Watson–Crick base pairing. For example, C-5-modified pyrimidines are well tolerated by commercial polymerases [11][12]. Alkynyl modifications not

In search of visible-light photoresponsive peptide nucleic acids (PNAs) for reversible control of DNA hybridization

• Lei Zhang,
• Greta Linden and
• Olalla Vázquez

Beilstein J. Org. Chem. 2019, 15, 2500–2508, doi:10.3762/bjoc.15.243

• calculated for the unmodified PNA analogue (20). Unfortunately, no difference between isomers was observed. The potential of the functionality of our compounds could be enhanced by both changing the localization and the number of incorporated photoswitches. To try to maintain the cooperative base pairing, we

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

• ) like compounds A and B (Figure 1) [18][19]. The latter attachment does not significantly affect the natural Watson–Crick base-pairing abilities of the modified compounds. In this context, other important structural modifications in such a series include 8-vinyladenosine [20], 8-styryladenosine [13][21

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

• . The reason for the stabilization is an increased strength of the Watson–Crick base pairing and base stacking interactions due to the electronic effects of the axially oriented 2’-fluorine atom [11][12]. Additionally, FC–H···O hydrogen bonds between the 2’-fluorine and the 4’-oxygen or 5’-oxygen of the

• neighbour interactions cannot be stated at present. The base pairing selectivity of the 6’-diF-bc4,3-T was evaluated by UV-melting experiment of ON1 by inserting one of the three possible mismatches (G, C, or T) opposite the modified unit in the otherwise complementary DNA strand (Table 4). As anticipated

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

• use of therapeutic antisense oligonucleotides (AONs) [1][2][3][4]. These short, synthetic fragments bind through Watson–Crick base pairing to cellular RNA, thus modulating or silencing the gene expression through various mechanisms [5][6][7]. One mode of action is the recruitment of the endonuclease

• Watson–Crick base pairing also occurs with this modification. The thermodynamic parameters of duplex formation of ON4 and the corresponding natural sequence versus both complements were extracted from their melting curves by a known curve fitting methodology (Table S3, Supporting Information File 1) [63

• the same structural preference as in the natural reference structures (Figures S2 and S3, Supporting Information File 1). The evaluation of the base pair body parameters of the 6’F-bc4,3-DNA strand hybridized to DNA or RNA revealed the expected Watson–Crick base pairing between the two strands and the

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

• connectivity and gave an insight to the conformation. The sugar conformation (N vs S) in solution was different to that in the solid state. The macrocycles display free accessible Watson–Crick recognition sites valuable for base pairing with nucleic acids or proteins. Since the compact nucleoside macrocycles

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

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

• fully cationic α-oligonucleotides bound to single-stranded DNA and RNA targets with high affinity, with duplex stabilization being proportional to the number of cationic modifications. It was also reported that these oligonucleotides showed retained base pairing fidelity, i.e., the Tm value was

• -workers succeeded in the preparation of corresponding guanidine-linked RNA analogues [58][59], though this is not within the main scope of this review. Bruice et al. reported that oligonucleotide analogues containing the cationic DNG-modification bind to DNA with retention of base-pairing fidelity

• and triple-stranded DNG-DNA complexes, respectively. The triple-stranded DNG-DNA complex was less affected than its duplex congener though [51][60][61]. Regarding base-pairing fidelity, Bruice and co-workers have reported significantly reduced stabilities of DNG-DNA duplexes and triplexes

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

• bond between the Im nitrogen and the exocyclic amine of guanine. Dervan et al. have further developed rules for base pairing recognition of minor groove binding polyamides where antiparallel side-by-side pairings of pyrrole (py) and imidazole (Im) amino acids successfully distinguish G·C from C·G base

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

• equimolar quantities of 9-methyladenine and 1-methylthymine in an amalgam mill gave powder diffraction patterns consistent with the formation of Hoogsteen-type base-pairing (Scheme 16) [81]. No co-crystal formation was observed using 1-methylcytosine with 9-ethylguanine or other combinations which did not

• derivative (Figure 5) and its cytosine congener in an undefined "vibrator mill" at room temperature. However, above 80 °C a solid-state transition was observed in which base-pairing was inferred and upon further heating gave a smectic phase [82]. Using a mixer ball mill, Vogt and co-workers ground 5

• conditions. The capacity for stereoselective glycosidation, rapid phosphate coupling in the presence of water and also formation of specific base-pairing interactions have all been demonstrated in a ball mill and may facilitate understanding of the early appearance of life in the Hadean/Archean Eon

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

• exhibits anti-influenza activity. C-nucleoside variants of favipiravir riboside and their base pairing with uridine and cytosine. B. Synthesis of C-nucleoside variants of favirpiravir starting from D-ribonolactone. Alternative method for synthesis of 2'-substituted C-nucleosides [75]. A. Synthesis of C2

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

• this probe to include complementary base-pairing interactions. The theoretical calculations revealed the availability of multiple complex structures. The synthesis was performed using click chemistry and the nucleotide recognition properties of the probe were evaluated using fluorescence spectroscopy

• . Conclusions: The first, uracil-containing fluorescent ATP probe based on a hydroxyflavone fluorophore was synthesized and evaluated. A selective complexation with ATP was observed and a ratiometric response in the excitation spectrum. Keywords: ATP sensing; base-pairing; fluorescent probes; 3-hydroxyflavone

• [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

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

• . It involves the incorporation of nucleotides at the terminus of a primer and is directed by base pairing. The reaction occurs in aqueous medium and leads to phosphodiester formation after attack of a nucleophilic group of the primer. Two aspects of this reaction will be discussed in this review. One

• 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

• enzymes and ribozymes, relying on solely on base pairing for molecular recognition and chemical reactivity to drive the formation of phosphodiester bonds in aqueous media. This is what is usually referred to as "enzyme-free copying" (Figure 1). Studies on enzyme-free copying of genetic polymers date back

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

• 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

Fluorogenic PNA probes

• Tirayut Vilaivan

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

• specificity according to the Watson–Crick base pairing rules [22]. In fact, PNA exhibits an even higher affinity and better discrimination between complementary and mismatched nucleic acid targets than natural oligonucleotides. In addition, the uncharged peptide-like backbone of PNA contributes to several

• 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

• dT in the DNA strand with comparable affinity to that for A, and the base pairing resulted in fluorescence quenching. While the quenching of 2-AP can be useful for probing the structure and dynamics of the PNA and its DNA/RNA hybrids, the quenching effect is small and not highly specific as quenching

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

• pyrimidines, only the C5 and C6 positions are available for modifications without directly perturbing the base-pairing properties. The subtle differences between the nucleobases within a class could lead one to believe that the chemistry developed for modifications of adenine would translate easily to guanine

• % yield of 37 after TFA deprotection of the Boc group compared to the previously reported 96% [51]. The base-pairing properties of qA with T and selectivity were found to be excellent. Moreover, the melting temperature of the oligonucleotides remained close to those of unmodified sequences indicating that

• qA is an excellent adenine analogue [53]. Unfortunately, the photophysical properties of qA were not satisfactory for an internal FRET fluorophore and, thus, we moved on by modifying the quadracyclic aromatic core but leaving the advantageous base-pairing properties. To this end, we needed to develop

Metal-mediated base pairs in parallel-stranded DNA

• Jens Müller

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

• metal-based functionality. In metal-mediated base pairs, the hydrogen bonds between complementary nucleobases are replaced by coordinate bonds to one or two transition metal ions located in the helical core. In recent years, the concept of metal-mediated base pairing has found a significant extension by

• application in metal-mediated base pairing [6][7]. Structural analyses have shown that their formation is possible without major conformational changes of the nucleic acid [8], even though metal-modified nucleic acids may very well adopt non-helical topologies [9]. It is even possible to create DNA duplexes

• , even though their formation is in principle also compatible with cisoid glycosidic bonds. Hence, metal-mediated base pairs that require a transoid orientation of the glycosidic bonds may be ideally generated in a parallel-stranded double helix. This section summarizes base pairing patterns established