Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

• Kian Donnelly and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 232–239, doi:10.3762/bjoc.18.27

• oxadiazoles [33]. While this method provided the products in high yields, it required the use of super-stoichiometric quantities of iodine, which is potentially toxic and corrosive. This potential toxicity in combination with the requirement for the subsequent removal of excess iodine and potentially

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• permeability [1][2][3]. Hence, peptide-based drugs became of high interest because of their high selectivity combined with low toxicity. Cross-linking of side chain residues results in constrained conformations and can be used to stabilise α-helical secondary structures. This technique is called peptide

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• Togni’s reagent, is ideal because of its stability, low toxicity, and cost [148]. In terms of scope, the electronic nature of the benzoic acid had no effect on the reaction. On the other hand, only electron-rich styrene derivatives

Synthesis of new pyrazolo[1,2,3]triazines by cyclative cleavage of pyrazolyltriazenes

• Nicolai Wippert,
• Martin Nieger,
• Claudine Herlan,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2021, 17, 2773–2780, doi:10.3762/bjoc.17.187

• standardized MTT assays [41] to evaluate if the newly accessible compounds of type 5 and their precursors could become interesting target molecules for biological investigations or if the compounds show high toxicity, which might prevent their use. We monitored cytotoxicity at six different concentrations

• , characterized by two aromatic moieties at both variable positions R1 and R2. In Table S3 (Supporting Information File 1), the results for compounds 5, 9, 12, and 13 are summarized allowing the direct comparison of the toxicity of the four compound classes with respect to 5 different residues R1. The full data

• of the toxicity studies for all obtained compounds are given in Supporting Information File 1, Tables S1–S3. Comparing the 20 derivatives depicted in Figure 3 reveals that compounds of the classes 5, 9, and 12 are in general less toxic than the respective compounds of class 13, at least with respect

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

• , ʟ-nucleosides are typically endowed with lower host toxicity [11][12]. The antiviral activity and cytotoxicity in MT-4 cells showed that racemic (±)-BCH-189 (1c) possesses lower anti-HIV activity (ID50 = 0.37–1.31 µM) than AZT (ᴅ-nucleoside, ID50 = 0.0048–0.0217 µM). However, (±)-BCH-189 (1c

• higher antiviral activity and lower toxicity of the unnatural ʟ-(−)-enantiomer over the ᴅ-(−)-enantiomer. The enantiomers of natural nucleosides are known to have a greater biological activity since they possess structural and configurational similarity to naturally occurring counterparts. In turn, for

• oxathiolane nucleoside analogues, it was noticed that unnatural (−)-enantiomers have higher anti-HIV activity and lower toxicity in comparison to natural (+)-enantiomers. The activation of such analogues was established to occur preferentially by the enzymes (kinases) or by the target enzymes (polymerases

Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

• Dušan Đ. Škorić,
• Olivera R. Klisurić,
• Dimitar S. Jakimov,
• Marija N. Sakač and
• János J. Csanádi

Beilstein J. Org. Chem. 2021, 17, 2611–2620, doi:10.3762/bjoc.17.174

• . This means that a higher concentration is not as effective and that a better effect is achieved at a lower concentration of the compound, which is a good feature for an antitumor drug candidate. None of the tested compounds exhibited toxicity toward the normal cell line MRC-5. Conclusion In this work

Cryogels: recent applications in 3D-bioprinting, injectable cryogels, drug delivery, and wound healing

• Luke O. Jones,
• Leah Williams,
• Tasmin Boam,
• Martin Kalmet,
• Chidubem Oguike and
• Fiona L. Hatton

Beilstein J. Org. Chem. 2021, 17, 2553–2569, doi:10.3762/bjoc.17.171

• to its low toxicity and to control the release of compounds stored in the porous structure through one of four methods: diffusion-controlled, swelling-controlled, erosion-controlled, and stimulus-controlled [54]. A study by Koshy et al. reported a methacrylated gelatin (GelMA) cryogel implanted by

• -polymerised precursors can cause free radical damage or react with proteins in the human body containing thiols and amino groups [84]. Further toxicity research would be required for all of these cryogels to fully understand how they react in the human body as opposed to animal substitutes. However, the use

Strategies for the synthesis of brevipolides

• Yudhi D. Kurniawan and
• A'liyatur Rosyidah

Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157

• revealed various results, including toxicity to brine shrimp [9], DNA intercalation as well as antibacterial and fungal [4][9], and strong insecticidal activity against the 3rd instar larva of the cotton leaf worm Spodoptera littoralis (Biosd.) [7]. The essential oil extracted from the leaf of Hyptis

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• establishing this fact [26][27][28][29]. However, the main drawback of Hg(II) salts, as compared to other transition metal salts, is their increased toxicity [30][31]. Hg(II) salts on the other hand, are very cheap in comparison to other transition metal salts (Table 1) and one of the soft Lewis acids of the

• toxicity concerns, Hg(II) salts are cheap, stable, and versatile in terms of reactivity, making them a viable option to similar transition metal catalysts. Schematic representation of Hg(II)-mediated addition to an unsaturated bond. First report of Hg(II)-mediated synthesis of 2,5-dioxane derivatives from

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

• evaluate the changes in cellular uptake or the toxicity of the conjugated arsenic drug. Attachment of TPP onto the PISA particles however was found not to enhance the mitochondrial accumulation, but it did influence overall the biological activity of pMPC-based particles in 2D and 3D cultured sarcoma SW982

• have shown great promise as these drugs inhibit the function of mitochondria while showing overall reduced systemic toxicity. PENAO (4-(N-(S-penicillaminylacetyl)amino)phenylarsenonous acid) [2][3], a trivalent arsenical drug, was developed by Hogg and co-workers and is currently in clinical trials [4

(Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

• Luiz Claudio Ferreira Pimentel,
• Lucas Villas Boas Hoelz,
• Henayle Fernandes Canzian,
• Frederico Silva Castelo Branco,
• Andressa Paula de Oliveira,
• Vinicius Rangel Campos,
• Floriano Paes Silva Júnior,
• Rafael Ferreira Dantas,
• Jackson Antônio Lamounier Camargos Resende,
• Anna Claudia Cunha,
• Nubia Boechat and
• Mônica Macedo Bastos

Beilstein J. Org. Chem. 2021, 17, 2260–2269, doi:10.3762/bjoc.17.144

• for designing new series of substances with greater potency and less toxicity than IMT, with lesser effects for the patient. Molecular docking Validation of the molecular docking protocol was performed through redocking of the IMT complexed to the BCR-Abl-1 structure (PDB code: 3PYY) [37]. Thus, the

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• of synthetic routes for modern pharmaceuticals [21][22]. Over the past two decades, nickel has emerged as an attractive alternative to palladium due to its relative earth-abundance, less toxicity, and inexpensiveness. Despite the fact that the nickel-catalyzed cross-coupling reactions represent a

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

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• few of them become approved, due to their toxicity or other issues related to their applicability. Therefore, synthetic methodologies that facilitate the successful production of potential biologically active molecules have a relevant role in the organic synthesis research field. One of the key

• involving organochromium species generated from alkyl halides [115][116]. Whereas its toxicity has hindered the use of Cr(VI) in organic synthesis, the less toxic Cr(III) and Cr(II) salts have been exploited as plausible catalysts in organic synthesis [117][118]. A good example is a redox-neutral reaction

• toxicity of some chromium species, based on the above cited examples, by using this metal valuable biologically active molecules can be safely obtained. The correct, judicious, and optimized application of chromium-based catalysts can lead to the easier access of several drugs. Further studies in this area

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

• endogenous nucleic acid targets, thereby inhibiting the gene expression. Although ASOs have great potential in the treatment of many diseases, the search for favorable toxicity profiles and distribution has been challenging and consequently impeded the widespread use of ASOs as conventional medicine. One

• derivative group, when conjugated to the C-5 position on 2’-deoxyuridine (Table 1B, 12), improved antisense activity while reducing toxicity [39]. In addition, a 15-mer PS-ASO, modified with the C-5 tris-aminated 2’-deoxyuridine 12, improved anti-HIV activity and reduced cytotoxicity relative to the

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

• therapeutic potential of ergot alkaloids as early as 1582 and used it for abortion or to aid childbirth. The ecological significance of ergot alkaloids remains unclear, but they are assumed to be a feeding deterrent due to their toxicity and bad taste [25][26][27][28]. To trigger the synthesis of new SMs a

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• on the pyridinium nuclei, and were the first reactive, easy-to-handle fluorinating agents with wide application [28][29]. The work continued with additional disclosures until 1991 [30][31][32][33][34]. Before that, reactive fluorinating reagents were difficult to handle because of toxicity, a

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• organic synthesis. Among the 3d metals, manganese catalysts have gained increasing attention for late-stage diversification due to the sustainability, cost-effectiveness, ease of operation, and reduced toxicity. Herein, we summarize recent manganese-catalyzed late-stage C–H functionalization reactions of

• natural abundance, cost-effectiveness, and low toxicity. In addition, it presents variable oxidation states (−3 to +7), which enable diverse catalytically active manganese complexes, providing characteristic reaction profiles. Since the first pioneering manganese-mediated reaction for accessing

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

• notably lagged behind and is still limited by insufficient bioavailability and difficulties with tissue specific delivery. Relatively high doses are required to overcome poor cellular uptake and endosomal entrapment, which increases the risk of toxicity. These limitations remain unsolved problems waiting

• ]. However, the uptake of most PNA–CPP conjugates is limited by endosomal entrapment. While the uptake can be improved either by increasing the concentration of PNA–CPP conjugates or by using endosomolytic compounds (for example, chloroquine or calcium ions) this leads to toxicity that is not viable for in

• administered PNA–penetratin conjugate (3 × 10 μL of 150 μM) caused a 40% decrease in 125I-galanin binding in spinal cord sections compared to rats treated with the saline control. The PNA–peptide conjugates showed no toxicity in these studies [171]. Boffa and co-workers conjugated antigene PNA to a nuclear

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

• capsids or virus-like particles (VLPs) [30][31][32] lacking the viral genome. Their small size (20–140 nm), allows them to permeate the cell membranes without causing toxicity or immune response in the treated organisms [30][32][33][34][35][36]. In particular, the VLPs derived from plant viruses are

• [60]. The CCMV has been reported to be biocompatible in mammals, testing the wild-type virus in mice [32][61]. However, there were no studies to demonstrated non-toxicity in other species such as crustaceans and fish. Therefore, before performing the bioassays with VLP-dsRNAvp28, this study evaluated

• the toxicity of wt CCMV in healthy shrimp. The bioassay was carried out for three weeks, and the shrimp showed no symptoms of any disease or apparent abnormality when treated by IM (up to 20 µg of CCMV per shrimp). Higher doses of dsRNAvp28 (200 µg) per WSSV infected shrimp by IM injection were also

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• been also an advanced intermediate in the synthesis of alkaloids. For instance, hydrogenation of 117 yielded (+)-coniine (118), the major alkaloid extracted from poison hemlock and responsible for its toxicity, as its hydrochloride, and N-Boc protected derivative of 117 submitted to Wacker oxidation

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

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

• compared to second generation 2'-O-MOE antisense oligonucleotides [162][163]. The cEt also demonstrate an improved toxicity profile in comparison to standard LNA ASOs [162]. The arduous synthesis of the nucleoside analogues has been refined to minimize the number of needed stereochemical adjustments and

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

• ]. Clinical trial safety assessments of this formulation showed no liver toxicity and no immune stimulation, with ≈10% of trial participants experiencing mild to moderate adverse events upon administration [38]. It includes encapsulation of siRNA by a mixture of lipid components, such as an ionizable cationic

• aptamers and peptides within the LNPs or to optimize the ratio of LNPs to cells in order to reduce toxicity in any cell line tested. Discussion LNPs represent an increasingly popular modality for cargo delivery. The vast improvements in lipid design and architecture have resulted in several successful LNP

• -driven vaccines and therapeutics, including two RNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines [46], as well as an siRNA–LNP for the treatment of a transthyretin amyloidosis [36]. However, further improvements in toxicity profiles, cargo delivery, and cell or organ

[2 + 1] Cycloaddition reactions of fullerene C₆₀ based on diazo compounds

• Yuliya N. Biglova

Beilstein J. Org. Chem. 2021, 17, 630–670, doi:10.3762/bjoc.17.55

• to dementia have been demonstrated [39][40]. Moreover, it is noted that the almost nonexistent toxicity of the C60 derivatives allows to use them in living systems without negative consequences. Studies on the use of C60 derivatives in micro- and nanoelectronics are also important and very promising

• first gave ester 181 and then acid 182 (Scheme 31), the sodium and potassium salts of which are well soluble in water. The compound has antiviral and anticancer activity as well as pronounced antioxidant properties combined with low toxicity. Diarylmethanofullerene 183 was synthesized according to