Post-functionalization of drug-loaded nanoparticles prepared by polymerization-induced self-assembly (PISA) with mitochondria targeting ligands

• Janina-Miriam Noy,
• Fan Chen and
• Martina Stenzel

Beilstein J. Org. Chem. 2021, 17, 2302–2314, doi:10.3762/bjoc.17.148

• nanoparticles without TPP have been reported earlier [42]. This figure was adapted with permission from [42], Noy et al., Direct Comparison of Poly(ethylene glycol) and Phosphorylcholine Drug-Loaded Nanoparticles In Vitro and In Vivo, Biomacromolecules 2020, 21, 2320–2333. Copyright 2020 American Chemical

• Nanoparticles In Vitro and In Vivo, Biomacromolecules 2020, 21, 2320–2333. Copyright 2020 American Chemical Society. This content is not subject to CC BY 4.0. Synthesis of TPP-based PISA particles based on zwitterionic 2-methacryloyloxyethyl phosphorylcholine (PPM-NP4-TPP) and poly(oligo ethylene glycol methyl

Constrained thermoresponsive polymers – new insights into fundamentals and applications

• Patricia Flemming,
• Alexander S. Münch,
• Andreas Fery and
• Petra Uhlmann

Beilstein J. Org. Chem. 2021, 17, 2123–2163, doi:10.3762/bjoc.17.138

• , the developed GA-polyHMPA initially exhibits UCST responsiveness, but can subsequently be slowly biodegraded to a fully water-soluble polymer (polyHMPA) via hydrolysis. Initial in vivo studies of a sustained release of either a hydrophilic model protein or a hydrophobic dye entrapped within the

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

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

• observed (75). The cationic phosphoramidate variant termed DEED was originally tested for its triplex-forming capabilities. The authors found that ONs containing the DEED modification were more capable at forming triplexes under conditions that approximated the magnesium, pH, and potassium levels found in

• vivo [108]. A later study conducted by Weeks and co-workers reported that a TFO modified with the DEED modification could efficiently inhibit the expression of plasmid DNA injected into Xenopus oocytes [111]. The study demonstrated that a sufficiently long mismatch-free DNA target needed to be present

Natural products in the predatory defence of the filamentous fungal pathogen Aspergillus fumigatus

• Jana M. Boysen,
• Nauman Saeed and
• Falk Hillmann

Beilstein J. Org. Chem. 2021, 17, 1814–1827, doi:10.3762/bjoc.17.124

• ACAT2 and renders it inactive [173]. In vivo, PPPA-mediated ACAT2 inhibition was shown to protect the mice from atherosclerosis, ACAT2 enzyme mediates in lipid metabolism and is localized in the liver and intestines [174]. Furthermore, PPPA was also shown to exhibit insecticidal properties against

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

• therapeutics. While many modifications have improved on PNA’s binding affinity and specificity, solubility and other biophysical properties, the original PNA is still most frequently used in diagnostic and other in vitro applications. Development of therapeutics and other in vivo applications of PNA has

• folding in compact structures and aggregation in concentrated solutions [13]. Other bottlenecks for in vivo applications of PNA have been poor cellular uptake and unfavorable pharmacokinetics [14][15][16]. Unmodified PNAs are not taken up by eukaryotic cells in vitro and are cleared rapidly (within 10–30

• extensive studies reviewed below, PNA still needs innovative chemistry to break through in clinic and other in vivo applications. Review PNA binding modes to DNA and RNA PNA was originally designed with an expectation to improve the binding properties of negatively charged triplex-forming oligonucleotides

Recent advances in the application of isoindigo derivatives in materials chemistry

• Andrei V. Bogdanov and
• Vladimir F. Mironov

Beilstein J. Org. Chem. 2021, 17, 1533–1564, doi:10.3762/bjoc.17.111

• [120]. At the same time, in vivo experiments have shown the high efficiency of low-molecular-weight isoindigo 71 in oxygen sensitization for cancer therapy [121]. Therein, a high value (84%) of the singlet oxygen quantum yield was obtained. Conclusion To summarize, it can be concluded that isoindigo is

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

• ) encapsidates the dsRNA of 563 bp, are shown to silence the WSSV glycoprotein VP28 (dsRNAvp28). In experimental challenges in vivo, the VLPs- dsRNAvp28 protect shrimp against WSSV up to 40% by oral administration and 100% by IM. The novel research demonstrates that plant VLPs, which avoid zoonosis, can be

• . Through in vivo bioassays, the antiviral efficacy of VLPs is assessed by intramuscular injection and per os, in Penaeus vannamei infected with WSSV. To our knowledge, this is the first report where an oral VLPs are administered to treat infected shrimp against viruses. This is a novel technique in

• ®, Europe) [47]. This inoculum solution is referred to as the 1:10 dilution. The in vivo experiments were immediately initiated after preparing the inoculums. Simultaneously, uninfected shrimp or free WSSV were parallel-used under the same procedure as a negative control (WSSV-negative). Viral inoculum

Structural effects of meso-halogenation on porphyrins

• Keith J. Flanagan,
• Maximilian Paradiz Dominguez,
• Zoi Melissari,
• Hans-Georg Eckhardt,
• René M. Williams,
• Dáire Gibbons,
• Caroline Prior,
• Gemma M. Locke,
• Alina Meindl,
• Aoife A. Ryan and
• Mathias O. Senge

Beilstein J. Org. Chem. 2021, 17, 1149–1170, doi:10.3762/bjoc.17.88

• [18], the conformation of the porphyrin core can play a key role in the binding of small molecules or on its efficiency as an organocatalyst as demonstrated by Roucan et al. [19]. With the continuing interest in nonplanar porphyrins [20] and their relevance for the in vivo functioning of porphyrin

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

• production of proteins, enzymes and receptors that may be inhibited by small-molecule and antibody therapeutics. However, native RNA oligonucleotides do not possess sufficient metabolic stability for in vivo applications. Therefore, chemical modification is absolutely essential to re-engineer RNA into a

• acyclic nucleic acid backbone is of interest as a prospective evolutionary precursor of RNA [100]. Furthermore, GNA analogues with N2' → P3' phosphoramidate linkages have been studied as a potential alternative genetic system and they have been incorporated into siRNA duplexes to increase in vivo potency

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

• lipid, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and PEG-lipid, each with an essential role in the design (Figure 1). These lipids promote the effective distribution of the LNP in vivo as well as aid in effective cargo release from the endosome [1][37]. To this end, we herein

• average sizes of 57.3 nm and 91.9 nm, respectively, as well as a more negative ZP (−11 mV and −9.4 mV, respectively, Table 2). These ZP values indicate that complexation leads from a neutral to anionic LNP product [39], a property that typically confers with low to no cytotoxicity in vivo [40]. Further

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

• transfection reagent, whereas, N+ONs remain concentrated in vesicles within the cytoplasm. These results indicate that both N+ and Ts-modified ONs are promising for various in vivo applications. Keywords: cell uptake; charge neutral modification; DNA; modified phosphates; Staudinger reaction; Introduction

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

• (ASOs) modified with 2',4'-bridged nucleic acid/locked nucleic acid (2',4'-BNA/LNA; Figure 1) are now widely used for gene regulation in vitro and in vivo because 2',4'-BNA/LNA greatly increases the affinity toward the target RNAs, thus enhancing the efficacy of the modified ASOs [1][2][3][4][5][6

• ]. The S-cEt-modified ASOs displayed a higher nuclease resistance and lower hepatotoxicity in in vivo experiments than the corresponding 2',4'-BNA/LNA-modified ASOs [9]; the reduction in hepatotoxicity might be a sequence-dependent phenomenon. Currently, a number of S-cEt-modified ASOs with low

• hepatotoxicity have been confirmed to be effective for gene regulations in vivo [10][11]. We previously developed amido-bridged nucleic acids (AmNA[R]s) (Figure 1), in which the N-alkyl substituent groups were found to modulate nuclease resistance and hepatic distributions [12]. Wengel’s group reported the

Menthyl esterification allows chiral resolution for the synthesis of artificial glutamate analogs

• Kenji Morokuma,
• Shuntaro Tsukamoto,
• Kyosuke Mori,
• Kei Miyako,
• Ryuichi Sakai,
• Raku Irie and
• Masato Oikawa

Beilstein J. Org. Chem. 2021, 17, 540–550, doi:10.3762/bjoc.17.48

• analysis by NMR, conformational calculation, and X-ray crystallography. A mice in vivo assay showed that (2R)-MC-27, with a six-membered oxacycle, is neuroactive, whereas the (2S)-counterpart is inactive. It was also found that TKM-38, with an eight-membered azacycle, is neuronally inactive, showing that

• intracerebroventricular injection, and the seven-membered oxacycle (2R)-IKM-154 (5) is weakly hypoactive [4]. In 2015, we reported the synthesis and evaluation of the six-membered oxacyclic analog MC-27 in the racemic form, (rac)-4, which was shown to be weakly hypoactive in vivo [5]. In the present study, we synthesized

• of the heterotricyclic skeleton of menthyl esters 10 (2R) and 21*/21 would have enabled configurational analysis based on NOESY data and conformational calculations. The mice in vivo assay in the present study showed that, as for MC-27 (4), the (2R)-isomer is the neuroactive enantiomer. It is again

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

• auxotrophic E. coli in media with hyperosmotic sodium chloride concentrations [75]. To obtain high in vivo concentrations of the proline analogue, they took advantage of the phenomenon that proline and similar solutes actively accumulate in cells in response to the hyperosmotic shock in bacteria [76]. This

• S-Flp may preclude the production of proteins with this substrate as the in vivo expression of enzymes with oligoproline stretches might be completely suppressed with this analogue (vide infra). Chin and co-workers reported the directed evolution on ribosomes that yielded a variant (dubbed as O-d2d8

• diversity of complications that could hinder protein studies with fluoroprolines. On the other hand, in the presence of R-Flp, the folded and fully active PWA enzyme was isolated, clearly demonstrating the ability of this analog to abolish the ribosome stalling issues in vivo. This is in full agreement with

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

• static entities, for which also complementary dynamic and targeted local site-specific conformational information is needed to fulfil our understanding on how these assemblies perform their biological role and function in vivo. It is in this regard that 19F NMR has proven to be a valuable analytical tool

• investigated in detail [59][76], as well as the kinetics of α-Syn oligomerization and fibril formation both in vitro [60][75] and in vivo [77][78]. In these more recent studies, incorporation of 4-tfmF residues using amber-suppressing codons at various positions was shown to be more advantageous as a 19F

• atoms within the probe results key in providing a much more superior spectral enhancement, proving successful in enabling to monitor the conformational changes experienced within the DNA/RNA strains upon G-quadruplex formation both in vitro and in vivo. In addition, these novel probes have the extra

Molecular basis for protein–protein interactions

• Brandon Charles Seychell and
• Tobias Beck

Beilstein J. Org. Chem. 2021, 17, 1–10, doi:10.3762/bjoc.17.1

• –protein complex formation. Finally, we will give a brief account of some examples for higher-order protein complexes and the PPIs involved. Review Characterisation methods for PPIs Particular PPIs can be relatively difficult to study since in vivo, any particular protein is present amongst a plethora of

• characterisation of the binding reaction. Computational methods are used to predict PPIs and interfaces. The advantage of performing in silico experiments includes narrowing down the number of the binding partners to be tested in vitro or in vivo. Computational methods include supervised machine learning, where

• recognize and interact with another partner protein among hundreds or thousands of other biomolecules [45]. Consequently, it was hypothesised that a long-range electrostatic guide or force is involved in bringing molecules together to interact non-covalently in vivo [46]. This is backed up by the fact that

Metal-free nucleophilic trifluoromethylselenolation via an iodide-mediated umpolung reactivity of trifluoromethylselenotoluenesulfonate

• Kevin Grollier,
• Alexis Taponard,
• Arnaud De Zordo-Banliat,
• Emmanuel Magnier and
• Thierry Billard

Beilstein J. Org. Chem. 2020, 16, 3032–3037, doi:10.3762/bjoc.16.252

• , Institut Lavoisier de Versailles, 78035 Versailles Cedex, France CERMEP-In vivo imaging, Groupement Hospitalier Est, 59 Bd Pinel, 69677 Lyon, France 10.3762/bjoc.16.252 Abstract We report herein a practical method to generate CF3Se− (and RFSe−) anions from shelf-stable reagents under iodide activation

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

• back to different growth rates among the present species. A substantial shift in the community compositions was observed between in vivo and in vitro communities since the majority of the genera present in the in vitro communities was below the detection limit in the soil sample. However, during the 12

• ]. Such pure NRP supplementations in various concentrations would allow exploring their effects on bacterial community assembly. Furthermore, in vivo experiments could reveal the impact of NRPs on microbial communities in complex natural systems, similar to the study from Chowdhury et al. from 2013 [59

Selected peptide-based fluorescent probes for biological applications

• Debabrata Maity

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

• to perform FRET in vitro and in vivo, particularly in living cells [30]. FRET-based peptide probes are heavily used for ratiometric fluorescence detection of biomolecules. Pyrene-functionalized oligonucleotides and locked nucleic acids (LNAs) are considerably used for targeting nucleic acids [31

• serine protease of human mast cells and is known to be involved in the pathogenesis of asthma and other allergic and inflammatory disorders [48][49][50]. The structure of the enzyme is tetramer, composed of four identical subunits arranged in two different orientations, around a central pore. In vivo

NMR Spectroscopy of supramolecular chemistry on protein surfaces

• Peter Bayer,
• Anja Matena and
• Christine Beuck

Beilstein J. Org. Chem. 2020, 16, 2505–2522, doi:10.3762/bjoc.16.203

• [8][9][10][11][12], and inhibit enzyme function [13] in vitro, they also exhibit interesting effects in vivo like the reversal of Alzheimer plaques in mice [14], tumor inhibition [15], and reduction of HIV infectivity [16], all while showing almost no toxic side effects [14][17]. In calixarenes with

• 1H,15N-BEST-TROSY titration of a truncated survivin (residues 1–120) construct revealed one distinct interaction at the Asp and Glu-rich histone H3 binding site. This ligand was also able to inhibit the survivin-H3 interaction, which is important for cell division, in vitro and in vivo and reduce

Synthesis of 1,4-benzothiazinones from acylpyruvic acids or furan-2,3-diones and o-aminothiophenol

• Ekaterina E. Stepanova,
• Maksim V. Dmitriev and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2020, 16, 2322–2331, doi:10.3762/bjoc.16.193

• toxicity testing in vivo. The authors also thank the Ural Research Institute of Phthisiopulmonology (Yekaterinburg, Russia) and Clinical Phthisiopulmonological Medical Center (Krasnokamsk, Russia) for performing antitubercular assays in vitro. Funding This work was supported by the Ministry of Science and

Selective preparation of tetrasubstituted fluoroalkenes by fluorine-directed oxetane ring-opening reactions

• Clément Q. Fontenelle,
• Thibault Thierry,
• Romain Laporte,
• Emmanuel Pfund and
• Thierry Lequeux

Beilstein J. Org. Chem. 2020, 16, 1936–1946, doi:10.3762/bjoc.16.160

• biological and physiological properties and can enhance the half-life of drugs in vivo [1][2][3][4]. During the last decade, fluorinated nucleoside analogues have received increasing interest, as is illustrated by the two pharmaceutical leads gemcitabine (I) and sofosbuvir (II), potent anticancer or

Synthesis of Streptococcus pneumoniae serotype 9V oligosaccharide antigens

• Sharavathi G. Parameswarappa,
• Claney L. Pereira and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2020, 16, 1693–1699, doi:10.3762/bjoc.16.140

• ManpNAc were synthesized using a convergent [2 + 3] glycosylation strategy. The antigens we prepared will be employed in serological studies using glycan arrays and immunological studies in vivo to probe the significance of the acetate group for immunogenicity and antigenicity. Streptococcus pneumoniae 9V

Synthesis, antiinflammatory activity, and molecular docking studies of bisphosphonic esters as potential MMP-8 and MMP-9 inhibitors

• Abimelek Cortes-Pacheco,
• María Adelina Jiménez-Arellanes,
• Francisco José Palacios-Can,
• José Antonio Valcarcel-Gamiño,
• Rodrigo Said Razo-Hernández,
• María del Carmen Juárez-Vázquez,
• Adolfo López-Torres and
• Oscar Abelardo Ramírez-Marroquín

Beilstein J. Org. Chem. 2020, 16, 1277–1287, doi:10.3762/bjoc.16.108

• antiinflammatory activity of these compounds has been gaining attention. In our previous work, we synthesized and in vivo evaluated the bisphosphonic esters 1 and 2, finding a moderate edema inhibition upon oral and topical administration on BALB/c mice. Thus, in this work, the bioisosteric replacement of an amide

• ]. Specifically, bisphosphonates act as osteoclast resorption inhibitors, augmenting the bone density and preventing osteoporosis [4]. Moreover, some bisphosphonates have gained attention as potential antiinflammatory agents by in vitro and in vivo assays [5][6][7][8]. Additionally, bisphosphonates have been

• describe the enzyme inhibitor site binding modes [16][17][18]. Thus, in this work, the bisphosphonates 3–6 were synthesized by a two-step method and then evaluated through two in vivo acute inflammation models in BALB/c mice. Furthermore, the acute toxicity was determined for these derivatives, and