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

• negatively charged phosphorus-based linkages. ASOs have the distinctive ability to bind endogenous nucleic acid targets in a sequence-specific manner, thereby inhibiting gene expression and offering opportunities for the treatment of a broad range of diseases. As ASOs interact with their RNA (or DNA) targets

• target generally are of the gapmer-design class (Figure 1), where a central segment of at least five DNA nucleotides termed the 'gap' is flanked by modified nucleotides that promote target binding and protection against exonucleolytic degradation [2]. Another class are the steric block ASOs that bind to

• containing a stretch of four DNA nucleotides in the middle, flanked by the modifications in a ´mixmer´ design, which is important for designing gapmer ASOs [31]. Another well-established method for C-5 pyrimidine modification involves the Sonogashira cross-coupling reaction between an alkyne group and a 5

A systems-based framework to computationally describe putative transcription factors and signaling pathways regulating glycan biosynthesis

• Theodore Groth,
• Rudiyanto Gunawan and
• Sriram Neelamegham

Beilstein J. Org. Chem. 2021, 17, 1712–1724, doi:10.3762/bjoc.17.119

• their tissue-specific expression, DNA binding domains, and nucleosome interaction sequences [3]. Additional factors regulating transcriptional activity include: i) cofactors and small molecules that enable TF-DNA recognition and RNA polymerase recruitment [3]; ii) chromatin modifications, such as

• sulfate chain elongation: The MECP2 (enrichment p-value = 0.037) was found to positively regulate heparan sulfate elongation. MECP2 regulates gene expression by binding to methylated promoters and then by recruiting chromatin remodeling proteins to condense DNA and repress gene expression [29][30]. MECP2

• -value = 0.035). SMAD proteins are activated by TGF-β signaling and bind to DNA to act as cofactors to recruit TFs. SMAD2 has been shown to act as a tumor metastasis suppressor in cell lines [32][33]. This TF was found to regulate GALNT1 (ρ = 0.54, RP = 1.00), which adds GalNAc to serine or threonine

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

• were brought into pure culture on PDA medium using the same culturing conditions as above. Fresh mycelium was harvested from pure cultures for molecular identification of the morphospecies. Molecular identification of endophytic fungi DNA was extracted from fresh mycelium (approximately 5 cm in

• . The samples were centrifuged for 10 min (15,000 rpm), and the upper, aqueous phase was then transferred to a new tube and DNA was precipitated in 395 µL of 100% isopropanol (−20 °C). After centrifugation (4 °C, 20 min, 15,000 rpm) the pellet was washed with 750 µL 70% ethanol, centrifuged at 15,000

• rpm (10 min), dried, and finally dissolved in 50 µL Milli-Q water (pH 6). DNA concentration and purity were determined with a NanoDrop 2000c spectrophotometer (Peqlab Biotechnology AG, Erlangen, Germany). The primer pair ITS1F and ITS4 (Supporting Information File 1, Table S2) was used to amplify the

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

• /bjoc.17.116 Abstract Peptide nucleic acid (PNA) is arguably one of the most successful DNA mimics, despite a most dramatic departure from the native structure of DNA. The present review summarizes 30 years of research on PNA’s chemistry, optimization of structure and function, applications as probes

• for innovative chemistry and biology to unlock the full potential of PNA in biomedical applications. Keywords: antisense; chemical modifications; diagnostics; peptide nucleic acid; PNA; Introduction Peptide nucleic acid (PNA) is a DNA mimic where the sugar–phosphate backbone of DNA is replaced with

• a neutral and achiral pseudopeptide backbone (Figure 1) [1]. PNA retains the natural DNA nucleobases that are connected to the amide-linked backbone through additional amide linkages. PNA was originally designed as a DNA mimic to improve the properties of triplex-forming oligonucleotides [1][2]. Two

Synthesis of 1-indolyl-3,5,8-substituted γ-carbolines: one-pot solvent-free protocol and biological evaluation

• Premansh Dudhe,
• Mena Asha Krishnan,
• Kratika Yadav,
• Diptendu Roy,
• Krishnan Venkatasubbaiah,
• Biswarup Pathak and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2021, 17, 1453–1463, doi:10.3762/bjoc.17.101

• effective against cervical cancer (HeLa cells) [8]. Moreover, γ-carbolines are known for their well-established DNA intercalating [9] and anti-Alzheimer [10] properties. The classical Graebe–Ullmann synthesis [11] of γ-carbolines, one of the very early protocols in the domain, is based on the thermal

Total synthesis of ent-pavettamine

• Memory Zimuwandeyi,
• Manuel A. Fernandes,
• Amanda L. Rousseau and
• Moira L. Bode

Beilstein J. Org. Chem. 2021, 17, 1440–1446, doi:10.3762/bjoc.17.99

• , connected by one or more unsubstituted methylene linkages, within their structure [2]. The interest in polyamines arises from the diverse roles and functions they play in biological systems [3][4]; for example, as stabilizers of RNA and DNA, secondary messengers, nutrients, antioxidants, growth factors, and

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

• of deoxyribonucleic acids (DNA) or ribonucleic acids (RNA), which contain either a purine or pyrimidine nucleobase and a furanosyl moiety of pentose sugars, 2′-deoxyribose or ribose [1][2]. Nucleotides are constituted by addition of a phosphate group at the 5′-position of the nucleosides and these

• 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

• double-headed nucleosides 4a,b were dimethoxytritylated (DMTr), phosphitylated, and incorporated into DNA oligonucleotides using the standard automated phosphoramidite method. The UV-based melting temperature (Tm) of hybrids of the modified oligonucleotides with complementary DNA strands were studied

Analogs of the carotane antibiotic fulvoferruginin from submerged cultures of a Thai Marasmius sp.

• Birthe Sandargo,
• Leon Kaysan,
• Rémy B. Teponno,
• Christian Richter,
• Benjarong Thongbai,
• Frank Surup and
• Marc Stadler

Beilstein J. Org. Chem. 2021, 17, 1385–1391, doi:10.3762/bjoc.17.97

• corresponding cultures were deposited at the mycological herbarium of Mae Fah Luang University, Chiang Rai, Thailand, accession number MFLUCC 14-0681. The DNA extraction was performed using an EZ-10 Spin Column Genomic DNA Miniprep kit (Bio Basic Canada Inc., Markham, Ontario, Canada) following the

• manufacturer’s protocol. A Precellys 24 homogenizer (Bertin Technologies, France) at 6000 rpm for 2 × 40 s was used for cell disruption. DNA regions were amplified using standard primers following our previously published protocols [13]. For both DNA regions, the PCR products were purified utilizing the Nucleo

Antiviral therapy in shrimp through plant virus VLP containing VP28 dsRNA against WSSV

• Santiago Ramos-Carreño,
• Ivone Giffard-Mena,
• Jose N. Zamudio-Ocadiz,
• Alfredo Nuñez-Rivera,
• Ricardo Valencia-Yañez,
• Jaime Ruiz-Garcia,
• Maria Teresa Viana and
• Ruben D. Cadena-Nava

Beilstein J. Org. Chem. 2021, 17, 1360–1373, doi:10.3762/bjoc.17.95

• control [7]. So far several strategies have been reported to control the WSSV, including activation of the immune system, DNA vaccines, herbal extracts, and RNA interference (RNAi) [8][9]. Among them, the RNAi technology has shown great potential to protect shrimp against the WSSV in some lab-scale

• ). Pellets with VLP-dsRNAvp28 prepared with commercial binders (Dry Oil® and NutriKelp®) are described in Supporting Information File 1. Detection of WSSV by real-time quantitative PCR. The real-time PCR (qPCR) for quantitation of WSSV was performed using DNA isolated from shrimp muscle tissue and TaqMan

• ® Fast Advanced Master Mix kit (Applied Biosystems, USA). Amplification reactions of 20 μL were prepared by mixing 23.33 ng of DNA, 0.3 μM of each primer, and 0.15 μM of TaqMan probe, and the qPCR was performed following Durand and Lightner [51] methodology. In summary, 2.0 min at 50 °C for uracil-N

A new glance at the chemosphere of macroalgal–bacterial interactions: In situ profiling of metabolites in symbiosis by mass spectrometry

• Marine Vallet,
• Filip Kaftan,
• Veit Grabe,
• Fatemeh Ghaderiardakani,
• Simona Fenizia,
• Aleš Svatoš,
• Georg Pohnert and
• Thomas Wichard

Beilstein J. Org. Chem. 2021, 17, 1313–1322, doi:10.3762/bjoc.17.91

• . mutabilis germlings were stained with SYBR Gold, a sensitive probe forming a complex with DNA with high fluorescence quantum yield [36]. In the axenic callus-like form, the nuclei of algal cells and the bacterial cells accumulated around the rhizoidal tissue and exhibited the specific fluorescence after

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

• functionality. Thus, this synthetic route represents the first successful Cu-mediated coupling reaction of berberine substrates. The DNA-binding properties of the 10-O-arylberberine derivatives with duplex and quadruplex DNA were studied by thermal DNA denaturation experiments, spectrometric titrations as well

• as CD and LD spectroscopy. Fluorimetric DNA melting analysis with different types of quadruplex DNA revealed a moderate stabilization of the telomeric quadruplex-forming oligonucleotide sequence G3(TTAG3)3. The derivatives showed a moderate affinity towards quadruplex DNA (Kb = 5–9 × 105 M−1) and ct

• DNA (Kb = 3–5 × 104 M−1) and exhibited a fluorescence light-up effect upon complexation to both DNA forms, with slightly higher intensity in the presence of the quadruplex DNA. Furthermore, the CD- and LD-spectroscopic studies revealed that the title compounds intercalate into ct DNA and bind to G4

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

• simplicity combined with the five natural bases, adenine (A), cytosine (C), guanine (G), thymine (T) and uracil (U, in RNA) belies the fact that both DNA and RNA are decorated with chemical modifications. For a catalogue of natural modifications in DNA, see https://dnamod.hoffmanlab.org/ [1], and in RNA, see

• https://iimcb.genesilico.pl/modomics/ [2]. In DNA, base modifications are much more common than those in the backbone and play a central role in epigenetics, such as, for example, the ‘fifth base’ 5-methylcytosine (5mC) [3]. In the backbone, chemical modification appears to be limited to the

Enhanced target cell specificity and uptake of lipid nanoparticles using RNA aptamers and peptides

• Roslyn M. Ray,
• Anders Højgaard Hansen,
• Maria Taskova,
• Bernhard Jandl,
• Jonas Hansen,
• Citra Soemardy,
• Kevin V. Morris and
• Kira Astakhova

Beilstein J. Org. Chem. 2021, 17, 891–907, doi:10.3762/bjoc.17.75

• ) represent an effective platform for delivering small molecules, RNA, or DNA into target cells [1]. LNPs have been successfully deployed via different administration routes in vivo to distribute cargo into target tissues [2][3][4][5][6][7][8]. By changing lipid composition [6] and/or including short peptides

• RNA aptamers as a mean to increase the specificity of LNPs for HIV-1-infected and/or target cells [31]. RNA aptamers are ideal candidates due to the lower immunogenicity profile than the DNA counterparts [30][32][33]. RNA aptamers are also highly amenable to form complex and dynamic secondary

• aptamers present an additional potential route for LNP internalization and target cell specificity. In order to assess the ability of aptamers to drive LNP internalization, short complementary Cy5-DNA oligonucleotides specific for each aptamer were used as probes to detect LNP uptake in different cells. In

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• , analgesic, etc. They form a major structural constituent of biomolecules like DNA and significant drugs like fluorouracil (65), zidovudine (66), lamivudine (67), risperidone (68), and buspirone (69, Figure 6) [65]. The biological importance of pyrimidinones like anticonvulsant (70), antiviral (71) and

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

• modifications were introduced into the DNA backbone using the Staudinger reaction between the 3’,5’-dinucleoside β-cyanoethyl phosphite triester formed during DNA synthesis and sulfonyl azides, 4-(azidosulfonyl)-N,N,N-trimethylbutan-1-aminium iodide (N+ azide) or p-toluenesulfonyl (tosyl or Ts) azide, to

• provide either a zwitterionic phosphoramidate with N+ modification or a negatively charged phosphoramidate for Ts modification in the DNA sequence. The incorporation of these N+ and Ts modifications led to the formation of thermally stable parallel DNA triplexes, regardless of the number of modifications

• incorporated into the oligodeoxynucleotides (ONs). For both N+ and Ts-modified ONs, the antiparallel duplexes formed with complementary RNA were more stable than those formed with complementary DNA (except for ONs with modification in the middle of the sequence). Additionally, the incorporation of N

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

• for the guanidine moiety because it can be easily removed under the basic conditions (ammonia/methylamine solution) used for the DNA synthesis [20]. The phosphoramidite synthesis was started from 2'-amino-LNAs 1a–c, which were rapidly prepared via the transglycosylations of 2'-amino-LNA-T [25]. First

• the middle position of 12-mer oligonucleotides (Table 1). The oligonucleotide synthesis was performed using an automated DNA synthesizer following the established synthetic method for GuNA[Me]-T-modified oligonucleotides [20]. 5-(Ethylthio)-1H-tetrazole (ETT) was used as an activator for the coupling

• , and the coupling time was extended from 40 s to 20 min for the GuNA[Me] phosphoramidites. Other conditions were the same as those used for general DNA synthesis. After the elongation, the oligonucleotides were treated with ammonia/methylamine solution (7 M NH3 in methanol/40% aqueous methylamine 1:1

Designed whole-cell-catalysis-assisted synthesis of 9,11-secosterols

• Marek Kõllo,
• Marje Kasari,
• Villu Kasari,
• Tõnis Pehk,
• Ivar Järving,
• Margus Lopp,
• Arvi Jõers and
• Tõnis Kanger

Beilstein J. Org. Chem. 2021, 17, 581–588, doi:10.3762/bjoc.17.52

• IDT codon optimization tool (to eliminate rare codons). Synthetic DNA was ordered from Twist Bioscience and inserted into pET21a backbone as one operon (see Supporting Information File 2) under the control of an IPTG-inducible tac promoter. The obtained plasmid was verified by DNA sequencing. To

• Supporting Information File 201: General material and methods for the construction of the biocatalyst as well as NMR spectra of synthesized compounds. Supporting Information File 202: DNA sequence. Funding The authors thank the Estonian Ministry of Education and Research (Grant Nos. PRG657 and PRG1031) and

Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

• packing effect has an implication on the thermostability of the triple helix [35][98][99]. In another study, fluoroprolines were incorporated in KlenTag DNA polymerase from a thermophilic organism, Thermus aquaticus [119]. The expression of the target protein was only observed with R-Flp, but not with S

• subdomain [129], T. thermohydrosulfuricus lipase [130][131][132], human ubiquitin [133], single-chain Fv format protein [134], KlenTag DNA polymerase [135], thioredoxin A [120], β2-microglobulin [136], red fluorescent protein [137][138], Pin1 WW domain [139], bacteriophage T4 fibritin C-terminal domain [106

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• their functional architecture. Such an approach typically includes the use of a variety of high-resolution proteomic tools, cryo-electron microscopy and X-ray crystallography to achieve full molecular characterization at the atomic level. However, macromolecules such as DNA/RNA and proteins are not

• IDPs upon tertiary and quaternary complex formation [79]. The Myc-Max heterodimer is a well-known oncogenic transcription factor complex able to bind to enhancer box (E-box) regions (5’-CACGTG-3’) of DNA with low-nanomolar affinity, what triggers its biological function as a transcriptional regulator

• presence of DNA, and another intrinsically disordered binding partner, breast cancer antigen 1 (BRCA1) (Figure 12). In this work the strategy employed involved the introduction of a perfluorinated [19F]3,5‐bis(trifluoromethyl)benzyl-based tag into the single cysteine residue of Myc. This modification

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

Au(III) complexes with tetradentate-cyclam-based ligands

• Ann Christin Reiersølmoen,
• Thomas N. Solvi and
• Anne Fiksdahl

Beilstein J. Org. Chem. 2021, 17, 186–192, doi:10.3762/bjoc.17.18

• ][20][21]. Simple [Au(III)–cyclam] complexes have been investigated for various biological properties [22][23][24][25][26][27][28][29]. Particularly, studies have focused on their potential in vitro anticancer properties [24][26][29], the activity against a falciparum strain [22], the in vitro DNA

Synthesis, crystal structures and properties of carbazole-based [6]helicenes fused with an azine ring

• Daria I. Tonkoglazova,
• Anna V. Gulevskaya,
• Konstantin A. Chistyakov and
• Olga I. Askalepova

Beilstein J. Org. Chem. 2021, 17, 11–21, doi:10.3762/bjoc.17.2

• [31], chemical sensors [32], DNA-intercalators [33][34] etc. Besides typical carbohelicenes, heterohelicenes, incorporating one or more heteroaromatic units in the skeleton, have also gained increasing attention [1][2][3][4][5][6][7][8][9][10][11]. The presence of heteroatoms (S, N, O, P) in the fused

Secondary metabolites of Bacillus subtilis impact the assembly of soil-derived semisynthetic bacterial communities

• Heiko T. Kiesewalter,
• Carlos N. Lozano-Andrade,
• Mikael L. Strube and
• Ákos T. Kovács

Beilstein J. Org. Chem. 2020, 16, 2983–2998, doi:10.3762/bjoc.16.248

• , whereas the remaining five were supplemented with respective B. subtilis strains by adding 10% of the final volume. The cultures were incubated at 21–23 °C and 250 rpm for 48 h. DNA was extracted from two replicates of the initial soil sample, the 12 h precultivated soil suspensions and the B. subtilis

• -treated or untreated mock communities cocultivated for 48 h. DNA extraction Environmental- and semisynthetic-community genomic DNA was extracted from either 250 mg soil or 250 µL bacterial culture, respectively, by using the DNeasy PowerSoil Pro Kit (QIAGEN) and following the manufacturer’s instructions

• . Amplification of 16S rRNA hypervariable regions V3-V4 The V3-V4 region of the 16S rRNA gene was PCR-amplified from the extracted DNA samples using Fw_V3V4 (5’-CCTACGGGNGGCWGCAG-3’) and Rv_V3V4 (5’-GACTACHVGGGTATCTAATCC-3’) primers that were tagged with short barcodes with a length of eight nucleotides, listed

Selected peptide-based fluorescent probes for biological applications

• Debabrata Maity

Beilstein J. Org. Chem. 2020, 16, 2971–2982, doi:10.3762/bjoc.16.247

• enhanced and blue-shifts after affinity/recognition in a polar solvent. Several computational studies confirmed that the spectral change is caused by the insertion of the environment-sensitive fluorophore in the hydrophobic domains/grooves of the target protein/DNA (Figure 1A). The major problem of these

• important biomolecules including nucleotides, DNA, proteins, lipids etc. in aqueous media. Fluorescent peptides have also been used for specific organelles such as lysosomes tracking. In this review, it is summarized Schmuck group’s tremendous effort in developing fluorescent peptide-based probes for

• interacts effectively with double-stranded DNA (dsDNA) as positively charged lysine residues are expected to interact with the phosphate backbone electrostatically. Upon binding to dsDNA, it undergoes a conformational change from the folded to an extended form that switches the fluorescence signal from

Synthesis of imidazo[1,5-a]pyridines via cyclocondensation of 2-(aminomethyl)pyridines with electrophilically activated nitroalkanes

• Dmitrii A. Aksenov,
• Nikolai A. Arutiunov,
• Vladimir V. Maliuga,
• Alexander V. Aksenov and
• Michael Rubin

Beilstein J. Org. Chem. 2020, 16, 2903–2910, doi:10.3762/bjoc.16.239

• imidazo[1,5-a]pyridine core is also considered to be one of the privileged pharmacophoric scaffolds and can be found in many biologically active compounds, for example, the potent antitumor agent C 1311 inhibiting topoisomerase II [4][5][6][7][8][9] or pirmagrel, a cytotoxic immunosuppressant and DNA