Isoorotamide-based peptide nucleic acid nucleobases with extended linkers aimed at distal base recognition of adenosine in double helical RNA

• Grant D. Walby,
• Brandon R. Tessier,
• Tristan L. Mabee,
• Jennah M. Hoke,
• Hallie M. Bleam,
• Angelina Giglio-Tos,
• Emily E. Harding,
• Vladislavs Baskevics,
• Martins Katkevics,
• Eriks Rozners and
• James A. MacKay

Beilstein J. Org. Chem. 2025, 21, 2513–2523, doi:10.3762/bjoc.21.193

• acid (RNA) impacts many biological processes; however, the complexities of its many roles are not completely understood. Therefore, designing tools for molecular recognition is of paramount importance. Peptide nucleic acids (PNA) show promise as a tool for selective recognition of double helical

• bonding; modified nucleobases; peptide nucleic acids; PNA–RNA triplexes; RNA recognition; Introduction RNA is a key contributor in countless biological processes. Though coding RNA has a well-known role in the central dogma of biology, most RNA is non-coding (ncRNA) and plays a multitude of roles

Discovery of cytotoxic indolo[1,2-c]quinazoline derivatives through scaffold-based design

• Daniil V. Khabarov,
• Valeria A. Litvinova,
• Lyubov G. Dezhenkova,
• Dmitry N. Kaluzhny,
• Alexander S. Tikhomirov and
• Andrey E. Shchekotikhin

Beilstein J. Org. Chem. 2025, 21, 2062–2071, doi:10.3762/bjoc.21.161

• exceptional potential as ligands targeting secondary structures of nucleic acids, particularly G-quadruplexes (G4) [21][22]. The indolo[1,2-c]quinazolin-6(5H)-one scaffold 1 exemplifies this design principle, with its rigid polycyclic framework mimicking topologies of established DNA/RNA-interactive molecules

• . Such compounds can intercalate into nucleic acids, primarily through π–π stacking interactions with nitrogenous bases. The introduction of side chains with terminal amino groups enhances binding to oligonucleotides via additional ionic interactions and hydrogen bonds. The indolo[1,2-c]quinazolin-6(5H

• new indolo[1,2-c]quinazoline derivatives to interact with nucleic acids. Since not all compounds exhibited intrinsic fluorescence, we initially performed a screening using the fluorescent intercalator displacement (FID) assay. Only compounds 7a–c showed a positive response and interaction with DNA

Synthesis of HBC fluorophores with an electrophilic handle for covalent attachment to Pepper RNA

• Raphael Bereiter and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 727–735, doi:10.3762/bjoc.21.56

• used, although often with limited success. We believe that the electrophilic warheads presented here offer an excellent balance between reactivity and selectivity for labeling of nucleic acids, and therefore, may also stimulate new designs for RNA targeting and RNA drugging. Experimental General

• fluorophores also exhibited favorable solubility compared to the other functionalizations which is a critical aspect for applications in the cell. We also note that primary alkyl halides, and in particular, the mesyloxy alkyl handles presented here, are relatively underexplored for covalent labeling of nucleic

• acids. Rather, halides with enhanced electrophilic potency, such as α-halocarbonyls [14][15][16], nitrogen (half-)mustards [17][18], or epoxides [19][20], Michael acceptors [17], carbamates [17], imidazolides [17], squarates [17], and diaziridines [17] (the latter requiring photoactivation) have been

Photocatalyzed elaboration of antibody-based bioconjugates

• Marine Le Stum,
• Eugénie Romero and
• Gary A. Molander

Beilstein J. Org. Chem. 2025, 21, 616–629, doi:10.3762/bjoc.21.49

• ) that can form covalent bonds when exposed to UV or visible light. These photoaffinity tags or crosslinkers are designed to bind to specific biomolecules, such as proteins, nucleic acids, or lipids, in a highly selective manner. The light irradiation triggers a chemical reaction, such as a bond

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• three base pairs, predominantly 5’-GGC-3’ and 5’-GGG-3’ [12][13]. Notably, a bis-phenol type unnatural analog 3, composed of the C5 deoxy A-ring bearing a phenolic hydroxy group at C8, presumably as a HB donor upon interaction with nucleic acids, exhibits superior DNA alkylation capability compared to

Chemical glycobiology

• Elisa Fadda,
• Rachel Hevey,
• Benjamin Schumann and
• Ulrika Westerlind

Beilstein J. Org. Chem. 2025, 21, 8–9, doi:10.3762/bjoc.21.2

• certainly by choice, but also by necessity. It is difficult to convey to non-glycoscientists how we still struggle with challenges that have been solved years or decades ago for proteins and nucleic acids. When molecular cloning and recombinant protein production became routine, these technologies were not

• applicable to glycans. Today, the most amazing tools in genome engineering are used to great effect to disrupt or alter the glycan biosynthetic machinery, but they still cannot be used to, for instance, mutate one glycan into another in the same manner as nucleic acids can be mutated. Methods in molecular

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• , nucleic acids, polysaccharides, and lipids. These modifications can impact the structure and biological functions of these molecules, ultimately leading to neuronal death, as observed in conditions like AD [30][31]. Recent studies highlight OS as an early event in AD pathogenesis, and mitochondria

Tandem diazotization/cyclization approach for the synthesis of a fused 1,2,3-triazinone-furazan/furoxan heterocyclic system

• Yuri A. Sidunets,
• Valeriya G. Melekhina and
• Leonid L. Fershtat

Beilstein J. Org. Chem. 2024, 20, 2342–2348, doi:10.3762/bjoc.20.200

• products and pharmacologically active molecules. For example, nucleic acids, proteins and enzymes, hormones and vitamins, essential for the functioning of a living organism, also contain nitrogen frameworks [1][2]. Besides that, nitrogen-containing compounds are widely used in medicine as antibiotics

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• , proteins, and nucleic acids. In humans and animals, they form the so-called glycocalyx, a protecting sugar coat decorating the cell surface and modulating a myriad of cell–cell interactions [1]. It is composed of branched or elongated glycan chains covalently linked to proteins or lipids, hereby

• the field of computational chemistry and bioinformatics. It is extensively used to model and simulate the dynamic behaviour of various molecular systems, including proteins, nucleic acids, lipids, and small molecules. GROMACS provides various tools for system preparation, simulation setup, and post

• interaction interfaces with other proteins, nucleic acids, lipids, small molecules, and ions, starting from a protein structure. PeSTo-Carbs is specifically trained to predict carbohydrate and cyclodextrin binding interfaces on proteins. Two different modules are available: a general model PS-G for a wide

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

Studying specificity in protein–glycosaminoglycan recognition with umbrella sampling

• Mateusz Marcisz,
• Sebastian Anila,
• Margrethe Gaardløs,
• Martin Zacharias and
• Sergey A. Samsonov

Beilstein J. Org. Chem. 2023, 19, 1933–1946, doi:10.3762/bjoc.19.144

• proteins or nucleic acids, GAGs are constantly altered by processing enzymes and thus they vary greatly in molecular mass, disaccharide unit composition, and sulfation. Based on their core structure they are categorized into six different classes, viz. heparan sulfate (HS), heparin (HP), hyaluronic acid

Insight into oral amphiphilic cyclodextrin nanoparticles for colorectal cancer: comprehensive mathematical model of drug release kinetic studies and antitumoral efficacy in 3D spheroid colon tumors

• Sedat Ünal,
• Gamze Varan,
• Juan M. Benito,
• Yeşim Aktaş and
• Erem Bilensoy

Beilstein J. Org. Chem. 2023, 19, 139–157, doi:10.3762/bjoc.19.14

• the ability to self-assemble into NPs amenable for encapsulation of an array of therapeutics (from small molecule drugs to nucleic acids) [19]. Moreover, their dense ammonium functional display furnishes their NPs with an overall positive charge and large buffering capabilities [19] at physiological

Improving the accuracy of ³¹P NMR chemical shift calculations by use of scaling methods

• William H. Hersh and
• Tsz-Yeung Chan

Beilstein J. Org. Chem. 2023, 19, 36–56, doi:10.3762/bjoc.19.4

• basis sets such as the IGLO-III [25][26] and pcS-n [27][28] basis sets with a focus on improved calculation of NMR shielding constants. Some theoretical work has been carried out on specialized phosphorus compounds that cover only a small range of chemical shifts, including nucleic acids [29][30][31][32

Ferrocenoyl-adenines: substituent effects on regioselective acylation

• Mateja Toma,
• Gabrijel Zubčić,
• Jasmina Lapić,
• Senka Djaković,
• Davor Šakić and
• Valerije Vrček

Beilstein J. Org. Chem. 2022, 18, 1270–1277, doi:10.3762/bjoc.18.133

• ], or structural motifs in xeno nucleic acids [18]. In continuation of our work on ferrocenoyl-substituted pyrimidine nucleobases [19], we report herewith a combined theoretical and experimental work on purine series. The novelty of these compounds is the carbonyl linker which connects the

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

• ][41]. The quinone–hydroquinone and quinone–semiquinone interconversions, with ROS generation, are responsible for the wide range of biological activities of menadione and its derivatives. An excess of ROS in the intracellular environment can cause harmful effects on structures such as nucleic acids

Synthesis and bioactivity of pyrrole-conjugated phosphopeptides

• Qiuxin Zhang,
• Weiyi Tan and
• Bing Xu

Beilstein J. Org. Chem. 2022, 18, 159–166, doi:10.3762/bjoc.18.17

• multiple pyrroles to phosphopeptides. In addition, pyrrole has yet to be incorporated in peptides for EISA, though oligomeric pyrroles have been extensively explored for binding nucleic acids [68]. Based on a naphthyl-capped phosphopeptide (Nap-ffpy, 1), we conjugated heteroaromatic dipyrrole or tripyrrole

Stepwise PEG synthesis featuring deprotection and coupling in one pot

• Logan Mikesell,
• Dhananjani N. A. M. Eriyagama,
• Yipeng Yin,
• Bao-Yuan Lu and
• Shiyue Fang

Beilstein J. Org. Chem. 2021, 17, 2976–2982, doi:10.3762/bjoc.17.207

• peptides, proteins and nucleic acids and to evade undesired immune responses, monodisperse PEGs are required or highly desired [12][13]. To meet the needs of monodisperse PEGs, significant efforts have been made to develop stepwise methods for their synthesis [14][15][16][17][18][19][20][21][22][23][24][25

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• ; separation of racemic nucleosides; stereoselectivity; Introduction Among all the biomolecules in an organism, nucleic acids, namely DNA and RNA, have the unique role of storing the genetic code – the nucleotide sequence that specifies the amino acid sequence of proteins that is essential for life on Earth

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

• called “heparin crisis” in 2008 [4]. In addition, the heterogeneity of naturally sourced samples poses a severe bottleneck to the molecular characterization of polysaccharides that dwarfs in comparison to other biomolecules like peptides and nucleic acids. Establishing structure–property correlations is

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

• relative to the control ON [101]. Cationic amine-functionalized group functionalities as internucleoside linkage Although previous research has highlighted the relevance of the phosphodiester-linked backbone in the overall function of nucleic acids [102][103], many researchers have still sought to change

Volatile emission and biosynthesis in endophytic fungi colonizing black poplar leaves

• Christin Walther,
• Pamela Baumann,
• Katrin Luck,
• Beate Rothe,
• Peter H. W. Biedermann,
• Jonathan Gershenzon,
• Tobias G. Köllner and
• Sybille B. Unsicker

Beilstein J. Org. Chem. 2021, 17, 1698–1711, doi:10.3762/bjoc.17.118

• mixture was incubated for 1 h at 60 °C. For separation of polysaccharides, 180 µL 5 M NaCl and 80 µL 10% CTAB were added and the mixture incubated further for 10 min at 65 °C. To extract nucleic acids by phase separation, 860 µL chloroform/isoamyl alcohol (24:1) was added and incubated on ice for 30 min

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

• modifications and various applications, to the current state of the field. We also seek insights into the key question of why PNA, despite its impressive biophysical properties, has still not entered clinical trials. The most significant difference between PNA and the natural nucleic acids is the lack of

• negative charge on PNA’s backbone. Electrostatic repulsion of the negatively charged phosphates dominates the conformational properties and structure of nucleic acids. In contrast to proteins that prefer to fold in compact structures, DNA and RNA inherently prefer extended conformations that minimize the

• ., magnesium ions), and achieve remarkably complex folded structures. Nevertheless, the electrostatic repulsion is the main force that disfavors folding and association of nucleic acids. With this consideration in mind, neutral PNA was expected to have superior binding to negatively charged nucleic acids due

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

• monomeric units polymerize to construct nucleic acids (DNA or RNA). These macromolecules preserve and express genetic information in all living cells and viruses. Modified nucleosides are a class of organic compounds which are unnatural and have an altered/substituted nucleobase and/or a modified pentose

• terminal carbons only. Double-headed nucleosides are synthetically derived nucleoside scaffolds that are known to impact significantly secondary structures in nucleic acids [29]. Some oligonucleotides containing a particular double-headed nucleotide monomer have been found to form a three-way junction

Synthesis of 10-O-aryl-substituted berberine derivatives by Chan–Evans–Lam coupling and investigation of their DNA-binding properties

• Peter Jonas Wickhorst,
• Mathilda Blachnik,
• Denisa Lagumdzija and
• Heiko Ihmels

Beilstein J. Org. Chem. 2021, 17, 991–1000, doi:10.3762/bjoc.17.81

• -DNA by terminal stacking. Keywords: berberine alkaloids; Cu-mediated coupling reactions; DNA recognition; nucleic acids; quadruplex DNA; Introduction Berberine (1a) is the most prominent member of the protoberberine family, i.e., a group of tetracyclic isoquinolinium alkaloids [1]. Like many members

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

• oligonucleotides that have been explored for gene silencing. Keywords: antisense; chemically modified oligonucleotides; crystallography; siRNA; structure; Introduction The natural nucleic acids sugar-phosphate backbone comes in two flavors, 2'-deoxyribose in DNA and ribose in RNA. However, this relative

• , replication, splicing and other fundamental processes in biological information transfer. More specifically, they can affect chemical and thermodynamic stability, folding, secondary and tertiary structure, activity and interactions between nucleic acids, proteins and receptors. Particularly, as far as

• moieties, such as a tetrose (ʟ-α-threofuranose, TNA [48]), and hexoses (e.g., hexitol, HNA [49]; altritol AtNA [50]; xylol XyNA [51]), or cyclohexene (CeNA [52]), a morpholino moiety (PMO [53]), and an acyclic, chiral glycol linker (GNA [54]), to generate so-called xeno nucleic acids (XNAs [55][56]). In