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

• than the corresponding phosphonopeptides because the phosphonate bond is more inert than a phopshonamidate bond. Phosphonodepsipeptides are widely used as enzyme inhibitors [6][7][8][9][10], haptens for inducing catalytic antibodies [11][12], and produgs [8][9][13]. They have potential applications as

• -diazoalkylphononates can be readily prepared from the corresponding 1-aminoalkylphosphonates via nitrosation with amyl nitrite. Conclusion Phosphonodepsipeptides are phosphorus analogues of depsipeptides. They are more stable than the corresponding phosphonopeptides and have been widely used as enzyme inhibitors

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

• hydroxylating enzyme in E. coli has been previously achieved [36][37]. Bacterial prolyl hydroxylases have been characterized, and they are able to oxidize proline and analogous structures in recombinantly expressed proteins [38]. Nonetheless, we are still missing evidences of natural posttranslational

• example, the volume difference between Pro and Dfp is smaller than the difference between Val and Ile. It is therefore not surprising that Flp and Dfp can in principle be recognized as proline by natural enzyme binding pockets. The successful experimental incorporation of fluoroprolines into proteins

• based on the recognition of fluoroprolines by the native enzyme aminoacyl-tRNA synthetase (vide infra) proves this assumption. 2.2 Local polarity Another important feature of fluoroprolines is their local electrostatic potential (local polarity). In proline, position 4 contains a positive surface

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• TFMK moiety is a proven effective metal chelator in various enzyme inhibitors (Figure 1b) [58][59][60][61][62][63][64][65]. Several useful methods exist for preparing trifluoromethyl ketones [66][67], such as the direct trifluoromethylation of esters by the Ruppert–Prakash reagent (Me3SiCF3) [68][69

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• was sought. The possibility to exploit the use of an enzyme to derivatize benzyl alcohol into an easily separable species was an intriguing opportunity. To integrate such a biocatalyzed transformation into the continuous Curtius rearrangement process, immobilized CALB, a robust hydrolase enzyme was

• immobilized CALB enzyme is reported. This approach enabled the chemoselective derivatization of benzyl alcohol into the readily removable benzyl butyrate thus simplifying the final purification stages. The resulting Cbz-carbamates were furthermore elaborated into derivatives of β-amino acids via biphasic flow

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• 78 was incubated in the presence of IPP and the enzyme prenyltransferase, a rate of 5.1 × 10−4 nmol⋅min−1⋅mg−1 was measured for the condensation reaction (Scheme 24), which is to be compared to a value of 7.4 × 102 nmol⋅min−1⋅mg−1 observed for the condensation involving IPP and geranyl pyrophosphate

Regioselective chemoenzymatic syntheses of ferulate conjugates as chromogenic substrates for feruloyl esterases

• Olga Gherbovet,
• Fernando Ferreira,
• Apolline Clément,
• Mélanie Ragon,
• Julien Durand,
• Sophie Bozonnet,
• Michael J. O'Donohue and
• Régis Fauré

Beilstein J. Org. Chem. 2021, 17, 325–333, doi:10.3762/bjoc.17.30

• , France 10.3762/bjoc.17.30 Abstract Generally, carbohydrate-active enzymes are studied using chromogenic substrates that provide quick and easy color-based detection of enzyme-mediated hydrolysis. For feruloyl esterases, commercially available chromogenic ferulate derivatives are both costly and limited

• ; hydrolysis; lipase; transesterification; Introduction The development of “white biotechnology” is underpinned by advances in enzyme discovery and engineering, areas that are being driven by metagenomics and in vitro-directed enzyme evolution. These techniques procure massive discovery or the creation of new

• enzyme-encoding sequences, filling up databases with a wealth of information. However, while resolving an early step in the discovery pipeline, these techniques progressively create a new bottleneck regarding enzyme characterization. Therefore, there is a pressing need to extend the enzymologist’s

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

• and complex biomolecules, such as enzymes. In a recent study exemplifying this application, 19F NMR has been employed to investigate the metabolism of carnitine. In animals, carnitine is biosynthesised from trimethyllysine in four enzyme-catalysed steps, which involves in the last step the action of

• the γ-butyrobetaine hydroxylase enzyme (hBBOX) (Figure 5a–c). As the fluorine shift of the metabolised product is distinctively different from the shift of the precursor, by producing a novel fluoromethyl analogue of the γ-butyrobetaine substrate (GBBNF) Rydzik et al. were able to monitor carnitine

• biosynthesis through hBBOX-catalysed GBBNF hydroxylation, both in vitro and in cell lysates [43]. Moreover, by using a competitive substrate for the enzyme, inhibition experiments could be directly employed to determine the IC50 values in the basis of fluoride release, and the extent of GBBNF turnover

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

• enantioselective functional group interconversions on prochiral or racemic difluorocyclopropane and difluorocyclopropene derivatives have provided important ways of obtaining enantiomerically pure cyclopropanes. The key reactions in this context are the enzyme-catalyzed formation and hydrolysis of esters and the

Insight into functionalized-macrocycles-guided supramolecular photocatalysis

• Minzan Zuo,
• Krishnasamy Velmurugan,
• Kaiya Wang,
• Xueqi Tian and
• Xiao-Yu Hu

Beilstein J. Org. Chem. 2021, 17, 139–155, doi:10.3762/bjoc.17.15

• also discussed. Keywords: host–guest chemistry; macrocycles; noncovalent interactions; supramolecular photocatalysis; Introduction Enzyme-catalyzed reactions are often carried out fantastically in nature via noncovalent interactions of a substrate [1][2]. Inspired by these natural processes, chemists

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

• complexes, with most of the complexes being homooligomeric complexes [58]. In fact, an analysis done in the BRENDA enzyme database [59] shows that there are more homooligomeric complexes than expected [60]. PPIs in homooligomeric complexes are usually difficult to predict using computational measures

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

• , enzyme inhibition, or disruption of bacterial protein synthesis. This knowledge was primarily acquired in vitro when B. subtilis was competing with other microbial monocultures. However, our understanding of the true ecological role of these small molecules is limited. In this study, we have established

• 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

• biological applications. Review Nucleoside triphosphates detection Nucleoside triphosphates play crucial roles in several biological processes including energy transduction, cellular respiration, enzyme catalysis, and signaling [35][36][37][38]. They are the most targeted anionic species because of their

• 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

• heparin stabilizes the tetrameric structure, without its tryptase dissociates into inactive monomers. The reported cationic ligand binds at the rim of anionic residues around the entrance of the central pore, blocks the access to the active sites, and inhibits enzyme activity. Schmuck et al. reported a

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

• cellular environment. Keywords: acetylation; branched peptides; enzyme; nanostructures; N-terminal; responsive; self-assembly; Introduction Peptides, being able to self-assemble to exhibit emergent properties and functions [1][2][3][4][5], have received considerable attentions recently. For example

• in a polymeric hydrogel for a responsiveness to thermolysin [35]. Dong et al. reported the branching of an oligopeptide via a cysteine linkage to result in multivalence [37]. During our studies on enzyme-instructed self-assembly (EISA) [38][39][40] of branched peptides for hydrogelation [32], we

• serendipitously found that an enzyme-responsive branched peptide was able to deliver small molecules or proteins to mitochondria efficiently in a cell-specific manner [33]. The branched peptide, which bears FLAG-tag as the branch [32], forms micelles. Certain proteases on the mitochondria of certain cells cleave

Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

• Yuvixza Lizarme-Salas,
• Alexandra Daryl Ariawan,
• Ranjala Ratnayake,
• Hendrik Luesch,
• Angela Finch and
• Luke Hunter

Beilstein J. Org. Chem. 2020, 16, 2663–2670, doi:10.3762/bjoc.16.216

• to different levels of flexibility within the enzyme active sites. A third possibility is that the analog 2 adopts different conformations upon binding to AChE vs BACE-1, since the microenvironments within the enzymes’ active sites could be different (e.g., more/less polar), the “correct” binding

• geometry of 2 might be favoured in AChE but not in BACE-1. These possibilities all remain speculative in the absence of high-resolution structural data of the enzyme–ligand complexes. Conclusion A threo-difluorinated piperine analog (2) was successfully synthesised through a stepwise route. The

A consensus-based and readable extension of Linear Code for Reaction Rules (LiCoRR)

• Benjamin P. Kellman,
• Yujie Zhang,
• Emma Logomasini,
• Eric Meinhardt,
• Karla P. Godinez-Macias,
• Austin W. T. Chiang,
• James T. Sorrentino,
• Chenguang Liang,
• Bokan Bao,
• Yusen Zhou,
• Sachiko Akase,
• Isami Sogabe,
• Thukaa Kouka,
• Elizabeth A. Winzeler,
• Iain B. H. Wilson,
• Matthew P. Campbell,
• Sriram Neelamegham,
• Frederick J. Krambeck,
• Kiyoko F. Aoki-Kinoshita and
• Nathan E. Lewis

Beilstein J. Org. Chem. 2020, 16, 2645–2662, doi:10.3762/bjoc.16.215

• Rules Linear Code was first used to represent reaction rules in 2009. A reaction network, specifying glycans with condensed IUPAC and Linear Code, was trained on mass spectrometry abundance to learn biosynthetic enzyme activities [10]. Their reaction rules table contained four features: enzyme, reactant

• insights into the glycosylation types. Some models of glycan synthesis generated reaction rule tables with an additional column Enzyme Commission number (EC number) [7][16][37]. The EC number system is a numerical classification scheme for enzyme-catalyzed reactions that provides an unambiguous accession

• substrate code to be replaced by a new substring to form the product code. In addition, there can be constraint and adjustment substrings whose presence or absence within the substrate string either restricts which glycans can be substrates of a particular enzyme or modifies the reaction rate parameters

Anion exchange resins in phosphate form as versatile carriers for the reactions catalyzed by nucleoside phosphorylases

• Julia N. Artsemyeva,
• Ekaterina A. Remeeva,
• Tatiana N. Buravskaya,
• Irina D. Konstantinova,
• Roman S. Esipov,
• Anatoly I. Miroshnikov,
• Natalia M. Litvinko and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2020, 16, 2607–2622, doi:10.3762/bjoc.16.212

• for new variants of nucleoside synthesis using nucleoside phosphorylases, since they indicated a complex dependence of the efficiency of enzyme-mediated phosphorolysis and nucleoside synthesis on a number of different factors (see [41][42], and the works cited therein). Thus, e.g., in our work on the

• phosphorolysis of Ara-U and thymidine in 5 mM K-phosphate buffer (pH 7–8) at room temperature was tested at different quantities of UP and TP, respectively, and it was found that an almost complete phosphorolysis ended after 10–25 h employing about 1,000 IU of the enzyme per 1 mmol of substrate (Figure 1

• reaction mixture followed by silica gel column chromatography gave KR in 61% yield of 98.0% purity according to HPLC. We have earlier noticed that the enzyme-mediated reaction of analogs of natural purine bases with PF-1Pis (Ba2+) proceeded much faster and resulted in a high conversion yield in Tris·HCl

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

• protein in unlabeled minimal media by simply adding the isotope-labeled amino acid, without the need for auxotrophic strains or metabolic enzyme inhibitors [108]. The assignment of all Lys residues, beyond the assignments available from classic uniform 15N- and 13C-labeling, was achieved by specific 15N

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

Tools for generating and analyzing glycan microarray data

• Akul Y. Mehta,
• Jamie Heimburg-Molinaro and
• Richard D. Cummings

Beilstein J. Org. Chem. 2020, 16, 2260–2271, doi:10.3762/bjoc.16.187

• , all concentration plots, and a model structure. The software was designed to be useful for lectin and enzyme analysis. It has been used to discover fine specificities of lectins (AAL, SNA) and glycosidase enzymes (α1-2-fucosidase and an α2-3,6,8-neuraminidase) [45]. 3. SignalFinder-Microarray: Status

Azo-dimethylaminopyridine-functionalized Ni(II)-porphyrin as a photoswitchable nucleophilic catalyst

• Jannis Ludwig,
• Julian Helberg,
• Hendrik Zipse and
• Rainer Herges

Beilstein J. Org. Chem. 2020, 16, 2119–2126, doi:10.3762/bjoc.16.179

• of sugars [6], enzyme mimics [7], and the utilization of intermolecular cooperative effects [8] are further applications of photoswitchable catalysis. Particularly interesting and close to our approach is an early work by Inoue et al. who achieved control of the transformation of CO2 and 1,2

Access to highly substituted oxazoles by the reaction of α-azidochalcone with potassium thiocyanate

• Mysore Bhyrappa Harisha,
• Pandi Dhanalakshmi,
• Rajendran Suresh,
• Raju Ranjith Kumar and
• Shanmugam Muthusubramanian

Beilstein J. Org. Chem. 2020, 16, 2108–2118, doi:10.3762/bjoc.16.178

• ][22][23][24][25][26]. Some oxazoles play a significant role in biological properties such as TRPV1 antagonistical activity, antifungal, analgesic, anti-inflammatory, antiproliferative, antileukemia, anticancer [27][28][29][30][31][32] and enzyme inhibitory activities [33][34][35][36][37][38][39][40

The biomimetic synthesis of balsaminone A and ellagic acid via oxidative dimerization

• Sharna-kay Daley and
• Nadale Downer-Riley

Beilstein J. Org. Chem. 2020, 16, 2026–2031, doi:10.3762/bjoc.16.169

• with shikimic acid, feature the dimerization of monomeric phenolic precursors by a laccase enzyme, a single-electron enzyme complex within macro-organisms which facilitates oxidative dimerization through phenolic coupling [19]. In the case of balsaminone A (4), lawsone (6) is methylated to ether 7

• which undergoes reduction to the dihydroxynaphthalene 8. This is then dimerized by the copper-rich enzyme to quinone arenol 9, which, following intramolecular cyclization, affords balsaminone A (4, Scheme 1). Similarly, the biosynthetic precursor of ellagic acid (5), gallic acid (10), undergoes

Synthesis, docking study and biological evaluation of ᴅ-fructofuranosyl and ᴅ-tagatofuranosyl sulfones as potential inhibitors of the mycobacterial galactan synthesis targeting the galactofuranosyltransferase GlfT2

• Marek Baráth,
• Jana Jakubčinová,
• Zuzana Konyariková,
• Stanislav Kozmon,
• Katarína Mikušová and
• Maroš Bella

Beilstein J. Org. Chem. 2020, 16, 1853–1862, doi:10.3762/bjoc.16.152

• substrate of mycobacterial galactofuranosyltransferase GlfT2 in the transition state, we evaluated these compounds by computational methods, as well as in an enzyme assay for the possible inhibition of the mycobacterial galactan biosynthesis. Our data show that despite favorable docking scores to the active

• decaprenyl-P-P-GlcNAc-Rha, (glycolipid 2, GL2), which serves as a lipid carrier for arabinogalactan polymerization [7][8]. The latter enzyme, GlfT2, extends the product of GlfT1-catalyzed reaction, decaprenyl-P-P-GlcNAc-Rha-Galf2 (glycolipid 4, GL4), producing the lipid-linked galactan polymer [8]. Both

• enzymes require an activated sugar donor uridine diphosphate (UDP)-Galf, which is synthesized from UDP-galactopyranose (UDP-Galp) by the enzyme UDP-Galp mutase [9] (Supporting Information File 1, Figure S1). The recently published GlfT2 X-ray structure with a UDP donor part [10] was used in the reaction

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• –H activations, visible-light-induced photocatalysis, electrosynthesis, enzyme catalysis, and others. Each of these techniques aims at accessing complex molecules while limiting ecological footprint. Over the last decade, the metal-catalyzed C–H activation established itself as one of the most

Microwave-assisted efficient one-pot synthesis of N²-(tetrazol-5-yl)-6-aryl/heteroaryl-5,6-dihydro-1,3,5-triazine-2,4-diamines

• Moustafa Sherief Moustafa,
• Ramadan Ahmed Mekheimer,
• Saleh Mohammed Al-Mousawi,
• Mohamed Abd-Elmonem,
• Hesham El-Zorba,
• Afaf Mohamed Abdel Hameed,
• Tahany Mahmoud Mohamed and
• Kamal Usef Sadek

Beilstein J. Org. Chem. 2020, 16, 1706–1712, doi:10.3762/bjoc.16.142

• specific biological target such as a receptor or an enzyme. A promising strategy that overcomes the classical one-target, one-molecule approach is the design of stable chemical hybrid molecules which are a combination of two biologically active scaffolds acting at different targets [20][21][22][23][24