A photochemical C=C cleavage process: toward access to backbone N-formyl peptides

• Haopei Wang and
• Zachary T. Ball

Beilstein J. Org. Chem. 2021, 17, 2932–2938, doi:10.3762/bjoc.17.202

• -formyl amide products have unique properties and reactivity, but are difficult or impossible to access by traditional synthetic approaches. Keywords: formyl peptide; nitroaryl compound; nitroso compound; olefin cleavage; photocleavage; Findings The photochemistry of nitroaromatic functional groups has

• , which leads to formyl products from formal oxidative cleavage of a C=C bond. Our interest in vinylogous analogues of 2-nitroaryl photoreactive groups stems from studies into alkenylboronic acid reagents for Chan–Lam-type modification of peptide backbone N–H bonds, directed by a proximal histidine

• ) provide entry into similar photo-uncaging chemistries for amide release. Figure 1C shows an example of this concept applied to a peptide substrate. Reaction of the peptide i with an alkenylboronic acid reagent iv in the presence of a copper(II) salt in water provides access to the backbone N–H

GlycoBioinformatics

• Kiyoko F. Aoki-Kinoshita,
• Frédérique Lisacek,
• Niclas Karlsson,
• Daniel Kolarich and
• Nicolle H. Packer

Beilstein J. Org. Chem. 2021, 17, 2726–2728, doi:10.3762/bjoc.17.184

• article by Barnett et al. [2] uses molecular dynamics to show that O-linked glycosylation alters peptide conformation, which influences the binding of the peptides to antibodies, despite the fact that glycans are not directly involved in the binding. Another molecular modeling article by Fogarty et al. [3

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

• ammonolysis in methanol affords compound 1c. The silylation of 1c with TBDPSCl was carried out, and then coupling reaction with tert-Boc-Met-Leu-Phe-OH in the presence of DCC and HOBt provided compound 98. The tert-Boc protecting group was further removed in formic acid, and the resulting nucleoside peptide

Adjusting the length of supramolecular polymer bottlebrushes by top-down approaches

• Tobias Klein,
• Franka V. Gruschwitz,
• Maren T. Kuchenbrod,
• Ivo Nischang,
• Stephanie Hoeppener and
• Johannes C. Brendel

Beilstein J. Org. Chem. 2021, 17, 2621–2628, doi:10.3762/bjoc.17.175

• bonding moieties are either urea-based or peptide-based (i.e., phenylalanine) units, the dodecyl chains act as hydrophobic shields to induce the amphiphilic assembly in water and prevent the surrounding water from interfering with the hydrogen bonds in the interior [29]. Attaching a hydrophilic PEO chain

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

• injecting through a conventional needle [18]. Gelatin was chosen for its inherent peptide sequences that facilitate cell adhesion and enzymatic degradation. Gelatin is also low cost and safe to use in human testing as shown in a work done by Nichol et al. [77]. The bulk mechanical behaviour, structure, and

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

• ]. PENAO triggers cell apoptosis by targeting the ANT protein, which is located in the mitochondria. More specifically, PENAO binds to the thiols located on the ANT peptide loops Cys57 and Cys257, which results in the formation of stable cyclic dithioarsinite complexes [5]. Arsenic drugs do not only bind

Catalyzed and uncatalyzed procedures for the syntheses of isomeric covalent multi-indolyl hetero non-metallides: an account

• Ranadeep Talukdar

Beilstein J. Org. Chem. 2021, 17, 2102–2122, doi:10.3762/bjoc.17.137

• ability of the products. Up to >80% inhibition of the amyloid-β peptide aggregates were achieved with these compounds, with the highest activity found for the 4-N-methylpiperidyl derivative. Ethers The synthesis of the bis(indol-6-yl) ether 175 was performed by Chai in 2017. Their protocol used a Cu(OAc)2

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• hydroquinolinone, chromene, piperidine, peptide, lipid, and glycoside moieties (Scheme 2). Bojanowski and co-workers developed a methodology to synthetize 3,4-dihydrocoumarins 10 through a decarboxylative and dearomatizative cascade reaction [33]. This reaction was carried out using coumarin-3-carboxylic acids 8

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

• full agonists (54 and 55, Scheme 20A) [139]. Ackermann and co-workers presented a manganese(I)-catalyzed C–H allylation, installing α,β-unsaturated esters in peptide analogues bearing indole motifs (Scheme 22B) [140]. Starting with tryptophan, the enantioselective allylation reaction afforded the

• amino acids and peptide scaffolds compatible with the transformation. The late-stage oxidation of proline 76 to 5-hydroxyproline furnished interesting intermediates, giving access to relevant motifs in peptide chemistry (Scheme 27C). Sesquiterpenes are known to present complex polycyclic structures with

• C-2 position of indole derivatives bearing peptide units in the C-3 position (Scheme 35A). This process led to several activated products in good yields, including one whose basic structure is already known to present important biological activities (106) [187] (Scheme 35B). Still in this work

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

• improved liver targeting [22][23] and ASO–glucagon-like peptide-1 (GLP1) conjugation for improved delivery to pancreatic β-cells [24]. Previously, Menzi et al. reviewed the impact of cationic modifications and conjugations for ONs and siRNAs biophysical and biological activities until 2015 [25]. In this

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

• known and span the whole range of secondary metabolite classes. Table 1 provides an overview of the major secondary metabolites from A. fumigatus and lists their ecological roles as well as their impact on virulence. Gliotoxin Gliotoxin (GT, 5) is the non-ribosomal peptide (NRP) derived

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

• alkynylations of bioactive structural motifs are rare [63]. In 2017, the Ackermann group disclosed a late-stage Mn(I)-catalyzed C–H alkynylation of various complex peptide scaffolds [64]. As shown in Scheme 9, manganese(I) catalysis remarkably resulted in racemization-free alkynylation, representing a step

• , demonstrating significant bioorthogonality in manganese(I) catalysis. The robustness of the method bears significance for further synthetic applications, such as “Click” chemistry or N-functionalization. Moreover, as shown in Scheme 9B, the manganese(I) catalysis regime enabled peptide macrocyclization (see 25f

• cyclic peptide motif (Scheme 11). Dipeptide substrate 26f decorated with a Morita–Baylis–Hillman carbonate underwent the intramolecular C–H allylation process to yield cyclic peptide 28f under dilute reaction conditions. This macrocyclization strategy introduces an exocyclic olefin motif onto the cyclic

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

• matched DNA duplex [136]. Bong and co-workers used melamine as a Janus-wedge nucleobase (KM, Figure 9) to organize two identical strands of oligothymidine DNA tracts (or oligouridine RNA tracts) on a peptide template to form peptide−DNA(RNA) triplex structures [137]. This approach was applied to induce

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

• transformation in this case. After several failed attempts, a procedure typically used for Boc deprotection in peptide synthesis utilizing TFA and triisopropylsilane was successfully used. Product purification furnished the desired enantiomer of pavettamine as a TFA salt (28). The presence of TFA was evident in

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

• CCMV (data not shown). Furthermore, these VLPs can be chemically modified with a peptide or using protein engineering, to express on its external surface to better recognize (target) the WSSV infected cells increasing the antiviral therapy efficiency. Because new viral outbreaks are the primary threat

Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• critical for the identification of functional groups, being the equivalent of what next became IR spectroscopy. Schiff himself had contributed to this development with the discovery of the sulfite-decolorized fuchsine test for aldehydes and with the popularization of the biuret test for peptide bonds. It

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• of aromatic aldehydes with acetone were performed in flow using a solid-supported heterogeneous peptide catalyst. The H-Pro-Pro-Asp-NH-resin 69 which was prepared using Fmoc/t-Bu chemistry and assembled onto a TantaGel® polymeric support, then packed into a column reactor (Scheme 10). Optimisation of

• , the (S)-enantioselectivity could be reversed by inversion of stereochemistry at the terminal proline moiety of the supported peptide. Ötvös’ protocol highlights some of the key advantages of this immobilisation approach, i.e., improved reaction kinetics over batch (higher effective catalyst loading

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

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

• arguably the most radical alternative nucleic acid pairing system, peptide nucleic acid (PNA), the sugar-phosphate backbone is replaced by an amide-based, neutral and achiral scaffold that allows cross-pairing with both DNA and RNA as well as formation of double- and triple-stranded species [57]. Despite

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

• LNPs that can cross the BBB, we developed and assessed two approaches. The first was centered on the BBB-penetrating trans-activator of transcription (Tat) peptide or the peptide T7, and the other on RNA aptamers targeted to glycoprotein gp160 from human immunodeficiency virus (HIV) or C-C chemokine

• charged peptide Tat has previously been demonstrated to be effective as an excipient species to increase the uptake through the negatively charged BBB [9][18]. Tat (sequence: H-YGRKKRRQRRR-NH2) is an arginine-rich short cell-penetrating peptide derived from the natural nuclear Tat protein of HIV-1 [19][20

• ]. The HIV-1 Tat protein itself has been shown to traverse the BBB by acting as a cell-penetrating peptide [9][20]. Other small positively charged molecules used for BBB penetration include transferrin and corresponding peptide derivatives or analogs that act as ligands for the transferrin receptor. The

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

• of natural ONs, such as peptide nucleic acids (PNA) [20], locked nucleic acids [21] (LNA, also known as bridged nucleic acids (BNA) [22]) and phosphorothioate (PS) ONs [23][24] have been evaluated for antigene/antisense applications, however, each of the analogues did not meet all the requirements

[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

• the main characteristics of C60 stimulated a great interest in the application of fullerenes in medical chemistry. Of the fullerene-based biologically significant molecules, amino acid derivatives are of particular interest. In fact, Prato and co-workers synthesized and characterized the first peptide

• amphiphilic C60 derivatives. Treatment of 14 with oxalyl chloride gives reactive acid chloride 15. Acylation of the presynthesized (ʟ-Ala-Aib)2-ʟ-Ala-OMe peptide with compound 15 gives the expected fullerene–peptide conjugate 16 (Scheme 8). A somewhat modified version for the synthesis of peptidofullerenes is

• given in Scheme 9 [87]. On this pathway for the synthesis of conjugates 19 and 20, acid 18 is cross-linked with a peptide component using a milder carbodiimide method via the starting methanofullerene 17. Similar to Scheme 8, fullerene adducts 21 and 22 with glycine and phenylalanine, respectively, were

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

• synthesis of 2'-amino-LNA (Figure 1) functionalized with a peptide or sugar at the N2'-position, with the aim of modulating the physicochemical properties and specific organ distributions of the therapeutic oligonucleotides [13][14]. A more favorable example is the covalent attachment of a guanidine moiety

Synthesis and physicochemical evaluation of fluorinated lipopeptide precursors of ligands for microbubble targeting

• Masayori Hagimori,
• Estefanía E. Mendoza-Ortega and
• Marie Pierre Krafft

Beilstein J. Org. Chem. 2021, 17, 511–518, doi:10.3762/bjoc.17.45

• Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan 10.3762/bjoc.17.45 Abstract Ligand-targeted microbubbles are focusing interest for molecular imaging and delivery of chemotherapeutics. Lipid–peptide conjugates (lipopeptides) that feature alternating

• . By contrast, the hydrocarbon lipopeptide led to microbubbles with a larger mean diameter and a significantly lower stability. Keywords: adsorption at fluid interfaces; drug delivery; microbubble targeting; molecular imaging; monolayer; perfluoroalkylated lipopeptide; solid-phase peptide synthesis

• particular cell surface receptor [7][9][10][11][12][13][14]. To this aim, ligand–lipid conjugates have been developed in research and preclinical development for liposome targeting for decades. In particular, peptide ligands offer significant advantages, including efficient synthesis routes, versatility, and

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• phosphonodepsipeptides with C-1-hydroxyalkylphosphonic acids. Keywords: alkylation; mimetic; multicomponent condensation; peptide; phosphonopeptide; phosphonodepsipeptide; phosphonylation; Introduction Both, phosphonopeptides and phosphonodepsipeptides are phosphorus analogues of peptides [1][2][3][4][5]. The

• acids and hydroxy esters through phosphonochloridates as in situ-generated intermediates. To prepare an antigen to induce monoclonal catalytic antibodies capable of catalyzing peptide-bond formation reactions, the phosphonodepsidipeptide 39 was synthesized via the coupling of the hydroxy analog of

• , another library of phosphonodepsipeptides 78 was prepared (Scheme 12) [27]. Synthesis of γ-phosphonodepsipeptides γ-Phosphonodepsipeptides 79 have been prepared from N-Cbz-ʟ-glutamic acid (80) and diethyl 2-hydroxyglutarate (84). To prepare phosphorus analogues of γ-glutamyl peptide, the starting N-Cbz-ʟ