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

• the late-stage modification of amino acids and peptides in 2016 (Scheme 27A and B) [159]. The methodology facilitated the targeted C–H oxidative modifications in amino acids and peptides concomitant with the preservation of the α-center chirality in good yields and broad scope regarding the number of

• , several products were submitted to a subsequent metathesis mediated by Grubbs-II catalyst and a further palladium-catalyzed C=C reduction and DG-removal process, from which the desired macrocyclic peptides were obtained in good to excellent yields (Scheme 35C). Recently, again Ackermann and co-workers

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

• ; non-ribosomal peptides; polyketides; secondary metabolism; virulence; Introduction To thrive in their natural habitats all organisms from bacteria and fungi to plants and animals need access to sufficient nutritional sources and have to defend themselves against both, competitors and predators

• molecules like non-ribosomal peptides (NRP), polyketides (PK), terpenes or indole alkaloids [10][11]. The vast majority of fungal BGCs is found in the genomes of members of the Basidiomycota and Ascomycota including the genus Penicillium in which the first BGC was identified in 1990 [12][13][14

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

• biologically active small molecules and complex peptides. Keywords: bioactive molecules; 3d transition metals; late-stage functionalization; manganese catalyst; sustainable catalysis; Introduction Manganese, a 3d transition metal, allows for a potentially ideal sustainable catalytic system because of the

• active molecules and complex peptides, which are of great importance to medicinal chemists and are categorized according to the transformations involved. Review Manganese-catalyzed late-stage C–H fluorination The fluorination of organic molecules [13][14][15][16], a highly valuable synthetic

• -economical approach to several tryptophan-containing peptides with significant potential for drug discovery and medicinal chemistry. Positional selectivity was observed at the C2 position due to the presence of the pyrimidine directing group. Interestingly, alkynylative conjugation of tryptophan to a steroid

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

• the addition of GlcNAc to processed N-linked glycan structures. These include all the MGAT enzymes. 7) GalNAc-type O-glycans: O-linked glycans are attached to serine (Ser) or threonine (Thr) on peptides, where GalNAc is the root carbohydrate. This is mediated by a family of about 20 Golgi-resident

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

• , many research groups have worked on chemical modifications to the backbone and nucleobases of PNA, as well as conjugating PNA to other biomolecules (e.g., cell-penetrating peptides) [4]. The present review summarizes the most significant efforts and achievements in optimizing various aspects of PNA

• ][159][160]. Looking forward, conjugation of PNA with various delivery enhancing compounds, most notably cell-penetrating peptides (CPP) that deliver the conjugates mainly through endocytosis (Figure 11) has become one of the most promising approaches to improving cellular uptake of PNA [161][162

• covalent conjugation of PNA to delivery enhancing compounds. Cell-penetrating peptides derived from natural proteins: The initial success of PNA delivery involved PNA conjugates taken up by receptor-mediated endocytosis. Pardridge and co-workers successfully demonstrated in vivo delivery and blood-brain

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

• peptides, Tat and T7, did not increase BBB penetration above the aptamer-loaded LNPs alone. Moreover, we found that these targeted LNPs exhibit low immunogenic and low toxic profiles and that targeted LNPs can traverse the BBB to potentially deliver drugs into the target tissue. This approach highlights

• ) 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

• of LNPs through the notoriously protective BBB is to use short positively charged peptides or receptor-specific ligands, both of which have shown to be effective at increasing transport of LNPs, nucleotides, and small molecules through the BBB [9][15][16][17]. For example, the short positively

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• absorption of EDA complex in the visible-light region. In 2020, Xu and colleagues [39] proposed a visible-light-promoted alkylation reaction using Katritzky salts such as 128 and glycine derivative 127 (or glycine segments in peptides) initiated by an EDA complex. This successfully realized the simple

• synthesis of unnatural α-amino acids 129 and precise alkylation modification of peptides in the later stage (Scheme 45). Even in the presence of other amino acid residues, this protocol has excellent regio- and chemoselectivity, providing a sequence of novel corresponding dipeptides with good yield. The

[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

• diphenyldiazomethanes, available reagents carrying substituents on the phenyl rings. For example, covalent attachment of C60 to peptides is performed through a phenyl spacer, as it was demonstrated in a synthesis of fulleride 27 [89]. The latter compound was designed specifically for suppressing a HIV enzyme. The

• dimethoxymethanofullerene 7. Synthesis of fullerene monoesters and symmetric diesters 8–10 and 11–12, respectively. The synthetic route to the first fullerene–peptide conjugate 16. Synthesis of bioactive fullerene peptides 19 and 20. Synthesis of amino acid–fullerene derivatives 21 and 22. (BtOH is 1H-benzotriazol-1-ol

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

• , which involves the use of targeting ligands, such as monoclonal antibodies, antibody fragments, proteins, peptides, and other small molecules, including vitamins and carbohydrates [7][8]. The targeting ligands are coupled to the surface of the carrier to selectively target tumor cells that overexpress a

• safety [15][16][17]. Various effective receptor-binding peptides have been identified by the phage display technology [18]. The peptides can be readily prepared through solid-phase peptide synthesis (SPPS), a highly reproducible method with minimal side reactions. Many peptide–lipid conjugates

• penetrating properties, such as the transactivator of the transcription (TAT) peptide. Moreover, peptides being smaller than the antibodies generally induce a lower immunogenicity [15][16][17]. Micro- and nanocarriers are often covered by poly(ethylene glycol) (PEG) stealth coatings that significantly enhance

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

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

• and phosphonate-linked analogues of naturally occurring peptides. They are more stable than phosphonopeptides and have been widely applied as enzyme inhibitors, haptens for the production of antibodies, biological agents, and prodrugs. The synthetic strategies towards phosphonodepsipeptides are

• 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

• phosphonopeptides are peptides with a phosphonamidate bond instead of an amide bond whereas the phosphonodepsipeptides are peptides with a phosphonate linkage instead of an amide. Phosphonodepsipeptides are structurally close analogues of depsipeptides (Figure 1). In general, phosphonodepsipeptides are more stable

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

• easily handled both as free amino acids and as residues in peptides and proteins. Nonetheless, when compared to the parent proline structure, fluoroprolines possess a number of altered properties. Some properties of the amino acids in common model compounds are summarized in Table 1 and will be discussed

• compared to proline (Figure 5) [19]. Although, the difference is small, it may have an impact on the overall features of the peptides and proteins that rely on polarity. 2.4 Proline puckering In addition to the general impact of fluorination, there are some properties specifically attributed to the proline

• extended helix that attained its name from the original discovery in polymeric proline. The PII helix occurs in various proteins, and it is particularly common in proline-rich sequence fragments [100]. Studies of oligomeric peptides showed that the replacement of proline with R-Flp exerts a stabilizing

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

• increasingly prominent in 19F NMR studies owing to their improved spectral properties. Among the first perfluorinated amino acids to be reported was perfluoro-tert-butylhomoserine (8), which was synthesized by Marsh and co-workers and incorporated into a variety of antimicrobial peptides, including MSI-78, for

• , all peptides where 8 was introduced could be detected even at concentrations as low as 5 μM, demonstrating that pFtBSer is a highly sensitive tool to study binding events by way of 19F NMR chemical shift and nuclear relaxation changes. In addition to homoserine, perfluorinated analogues of both

• estrogen receptor (ER) co-activator peptides and enabled the sensitive detection of their protein–peptide interaction inhibition by the ER antagonist tamoxifen [20]. Significantly, different secondary structure conformational preferences were also found among the diastereomers of perfluoro-tert

Supramolecular polymerization of sulfated dendritic peptide amphiphiles into multivalent L-selectin binders

• David Straßburger,
• Svenja Herziger,
• Katharina Huth,
• Moritz Urschbach,
• Rainer Haag and
• Pol Besenius

Beilstein J. Org. Chem. 2021, 17, 97–104, doi:10.3762/bjoc.17.10

• rods in the range of several hundred nanometers (Figure 2B,C, and Figure S4 in Supporting Information File 1). These results thus confirm our conclusions from CD spectroscopy and prove an ionic strength-dependent β-sheet ordering in neutral or anionic sulfated dendritic peptides. Under physiological

Semiautomated glycoproteomics data analysis workflow for maximized glycopeptide identification and reliable quantification

• Steffen Lippold,
• Arnoud H. de Ru,
• Jan Nouta,
• Peter A. van Veelen,
• Magnus Palmblad,
• Manfred Wuhrer and
• Noortje de Haan

Beilstein J. Org. Chem. 2020, 16, 3038–3051, doi:10.3762/bjoc.16.253

• File 2) but may occur at the peptide portion as well [24][25][26]. Formylation is likely introduced by the exposure of the tryptic peptides to formic acid during the acid precipitation of sodium deoxycholate in the final step of the sample preparation and during subsequent storage [24]. Within the

• ). The y- and Y-fragment ions of (glyco)peptides with Cys oxidation showed a characteristic neutral loss of 107.0041 Da (C2H5O2NS), as reported for singly oxidized carbamidomethylated Cys through an elimination reaction in the gas phase (Figures S13 and S16–S18, Supporting Information File 2) [27

• ]. Peptides with Cys oxidation had a similar elution behavior as the unoxidized isomeric counterparts (with an additional hexose instead of a fucose unit), leading to a high degree of ambiguous, albeit often illogical compositions (e.g.. for the LSL cluster, Figure S16, Supporting Information File 2 and Table

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

• , Kgs. Lyngby, Denmark 10.3762/bjoc.16.248 Abstract Secondary metabolites provide Bacillus subtilis with increased competitiveness towards other microorganisms. In particular, nonribosomal peptides (NRPs) have an enormous antimicrobial potential by causing cell lysis, perforation of fungal membranes

• to understand their ecological role. Keywords: Bacillus subtilis; bacterial community; chemical ecology; Lysinibacillus fusiformis; nonribosomal peptides; surfactin; Introduction In nature, bacteria live in complex communities where they interact with various other microorganisms. Most microbial

• Bacillus spp. produce various SMs [33][34]. The most prominent and bioactive SMs are nonribosomal peptides (NRPs), of which isoforms belong to the families of surfactins, fengycins, or iturins [35][36] (Figure 1). They are biosynthesised by large enzyme complexes, nonribosomal peptide synthetases (NRPSs

Selected peptide-based fluorescent probes for biological applications

• Debabrata Maity

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

• recognition; peptide-based; Introduction Molecular recognition involving amino acids or peptides are important factors in biochemical and medicinal processes [1][2][3]. Amino acids work as biosynthetic building blocks or as signaling molecules. For example, the well-known neurotransmitters glutamate and γ

• a bound glutamate molecule [4]. Peptides often work as signaling molecules or hormones, such as small neuropetide endorphins, produced by the central nervous system to relieve stress or enhance pleasure. They produce signaling cascades in the brain by interacting with opiate receptors. Sometimes

• antibiotic, is used for the treatment of resistant bacterial infections. Its interaction with a small peptidic segment of the bacteria cell wall is a classic example of molecular recognition [6][7]. Peptides are often substrates for protease enzymes [8][9]. Enzymologists have studied the chemical principles

UV resonance Raman spectroscopy of the supramolecular ligand guanidiniocarbonyl indole (GCI) with 244 nm laser excitation

• Tim Holtum,
• Vikas Kumar,
• Daniel Sebena,
• Jens Voskuhl and
• Sebastian Schlücker

Beilstein J. Org. Chem. 2020, 16, 2911–2919, doi:10.3762/bjoc.16.240

• , Universitätsstrasse 7, 45141 Essen, Germany 10.3762/bjoc.16.240 Abstract Ultraviolet resonance Raman (UVRR) spectroscopy is a powerful vibrational spectroscopic technique for the label-free monitoring of molecular recognition of peptides or proteins with supramolecular ligands such as guanidiniocarbonyl pyrroles

• UVRR approach from peptides to proteins as binding partners for GCPs is the UV-excited autofluorescence from aromatic amino acids observed for laser excitation wavelengths >260 nm. These excitation wavelengths are in the electronic resonance with the GCP for achieving both a signal enhancement and the

• the results from density functional theory (DFT) calculations. Keywords: GCI; GCP; guanidiniocarbonyl indole; guanidiniocarbonyl pyrrole; UVRR; Raman spectroscopy; resonance Raman; Introduction Supramolecular ligands are capable to selectively bind to peptides and proteins via reversible non

Using multiple self-sorting for switching functions in discrete multicomponent systems

• Amit Ghosh and
• Michael Schmittel

Beilstein J. Org. Chem. 2020, 16, 2831–2853, doi:10.3762/bjoc.16.233

• cytosine (C) [2]. Similarly, proteins, like microtubules and actin filaments, are self-sorted on the molecular level in living cells [3]. Furthermore, the smaller molecules of life such as sugars [4], peptides, and fatty acids [5] undergo self-sorting in the construction of a cell [6][7]. The above

Nocarimidazoles C and D, antimicrobial alkanoylimidazoles from a coral-derived actinomycete Kocuria sp.: application of ¹J_C,H coupling constants for the unequivocal determination of substituted imidazoles and stereochemical diversity of anteisoalkyl chains in microbial metabolites

• Md. Rokon Ul Karim,
• Enjuro Harunari,
• Amit Raj Sharma,
• Naoya Oku,
• Kazuaki Akasaka,
• Daisuke Urabe,
• Mada Triandala Sibero and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 2719–2727, doi:10.3762/bjoc.16.222

• siderophores and modified peptides, are known from Kocuria and Micrococcus [19][20]. In our continuing investigation on secondary metabolites from marine bacteria, five alkanoylimidazoles were obtained from the culture extract of a Kocuria strain isolated from a stony coral. Alkanoylimidazoles are a new and

Enzyme-instructed morphological transition of the supramolecular assemblies of branched peptides

• Dongsik Yang,
• Hongjian He and
• Bing Xu

Beilstein J. Org. Chem. 2020, 16, 2709–2718, doi:10.3762/bjoc.16.221

• Dongsik Yang Hongjian He Bing Xu Department of Chemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA 10.3762/bjoc.16.221 Abstract Here, we report the use of an enzymatic reaction to cleave the branch off branched peptides for inducing the morphological transition of the

• assemblies of the peptides. The attachment of DEDDDLLI sequences to the ε-amine of the lysine residue of a tetrapeptide produces branched peptides that form micelles. Upon the proteolytic cleavage of the branch, catalyzed by proteinase K, the micelles turn into nanofibers. We also found that the acetylation

• of the N-terminal of the branch increased the stability of the branched peptides. Moreover, these branched peptides facilitate the delivery of the proteins into cells. This work contributes insights for the development of peptide supramolecular assemblies via enzymatic noncovalent synthesis in

Optical detection of di- and triphosphate anions with mixed monolayer-protected gold nanoparticles containing zinc(II)–dipicolylamine complexes

• Lena Reinke,
• Julia Bartl,
• Marcus Koch and
• Stefan Kubik

Beilstein J. Org. Chem. 2020, 16, 2687–2700, doi:10.3762/bjoc.16.219

• described for analytes ranging from inorganic ions over low-molecular-weight neutral and charged organic compounds, such as carboxylic acids, amino acids, and nucleotides, to larger biomolecules such as peptides and proteins [1][2][3][4][5][6][13]. All of these systems have specific areas of application

• , which should give rise to optical probes for dicarboxylates or peptides [46][47][48]. Schematic illustration of the analyte-induced crosslinking of gold nanoparticles containing a mixture of ligands of which one contains a peripheral zinc(II)–dipicolylamine unit while the other one mainly serves to

Comparative ligand structural analytics illustrated on variably glycosylated MUC1 antigen–antibody binding

• Christopher B. Barnett,
• Tharindu Senapathi and
• Kevin J. Naidoo

Beilstein J. Org. Chem. 2020, 16, 2540–2550, doi:10.3762/bjoc.16.206

• peptide conformations near the glycosylation site and at distant sites [23]. In glycopeptide enkephalin analogs, the only observed conformational effects due to O-glycosylation were on the residue of attachment and its neighboring residue [24]. While for prion peptides, the O-glycosylation (α-GalNAc) is

• -structure relative to the random coil and the effects of the glycosylation were hypothesized to relate to the conformational properties of the peptides in solution (as opposed to their equilibrium structures in solution) [25]. A comprehensive structural study of the O-glycosylation-induced changes in a

• equilibrium of the peptide backbone near the glycosylated residue for a 15-residue mucin peptide. The APDTRP fragment resembled an S-shaped bend and a clustering of low-energy conformations revealed structural similarities between glycosylated and nonglycosylated peptides [23]. The work by Movahedin et al

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

• at simple 1D proton spectra to study ligand binding to single amino acids or small peptides to introduce the basic principles and also briefly discuss ligand-detected NMR screening methods. Review One-dimensional 1H NMR spectra and basic principles to study ligand binding by NMR Simple one

• signals from the binding partner. Therefore, this approach is only suitable to study binding of hosts to small guest molecules like amino acids and short peptides. Both a shifting of the signals (chemical shift perturbation) and line broadening are indicative of binding. The chemical shift perturbation is

• supramolecular tweezers that bind to lysine or arginine, tweezers have been titrated to the free amino acids or short peptides, monitoring the Lys and Arg resonances [5][80]. While all resonances of the guest amino acid shift upon tweezer binding, the effect is most severe for the H atoms at the end of the side

The B & B approach: Ball-milling conjugation of dextran with phenylboronic acid (PBA)-functionalized BODIPY

• Patrizia Andreozzi,
• Lorenza Tamberi,
• Elisamaria Tasca,
• Gina Elena Giacomazzo,
• Marta Martinez,
• Mirko Severi,
• Marco Marradi,
• Stefano Cicchi,
• Sergio Moya,
• Giacomo Biagiotti and
• Barbara Richichi

Beilstein J. Org. Chem. 2020, 16, 2272–2281, doi:10.3762/bjoc.16.188

• range of biomolecules: amino acids [8], peptides [9], glycosides [10], nucleosides/nucleotides [11], and lipids [12]. Also, protein-based nano-bio-conjugates [13] have been prepared by ball milling, retaining the native properties of the proteins after mechanochemical synthesis. Boronic acids and their

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• report [207], Lectka and co-workers achieved selective monofluorination of the benzylic C–H bonds of phenylalanine- and tyrosine-like residues in peptides under visible-light photosensitization. After screening a variety of sensitizers, such as 1,2,4,5-tetracyanobenzene, AQN, 1,4-dicyanobenzene, 1

• was achieved with exclusive regioselectivity in peptides, with modest to moderate diastereomeric ratios of the fluorinated products (Scheme 29). With the optimum PSCat in hand, it was necessary to find a protecting group (PG) for the amine that would not undergo fluorination or oxidation when treated