Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• ; Introduction The synthesis of molecules capable of mimicking the various secondary structures and key functions of proteins is a major challenge in medicinal chemistry, especially in the fields of protein–protein interactions [1][2]. Accordingly, the incorporation of heterocyclic amino acids into peptides

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• antagonist of the N-methyl-ᴅ-aspartate (NMDA) receptor to regulate excessive glutamate stimulation [27]. The β-amyloid hypothesis for AD is based on the formation of senile plaques, which are formed after the accumulation of insoluble aggregates of β-amyloid protein, primarily Aβ-42, in the brain. The gene

• for amyloid precursor protein (APP), found on chromosome 21, undergoes a mutation that causes the production of Aβ-42 instead of Aβ-40. APP, a transmembrane protein, is typically cleaved by α-secretase and γ-secretase, which leads to the formation of soluble Aβ-40. However, when cleaved by β-secretase

• and γ-secretase, it produces Aβ-42. This form misfolds, leading to the formation of insoluble protein aggregates known as senile plaques, causing toxicity [28][29]. Oxidative stress occurs when there is an imbalance between prooxidants and antioxidants in the body, leading to damage in various

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• protein sequencing by Edman degradation used to be standard practice in studying proteins but nowadays is rarely performed [39]. This is because the rules of transcription and translation are understood well enough for the sequence of a protein (its primary structure) to be predicted based on the

• recognizes and activates a specific substrate BB. Notably, the BBs are in most cases amino acids, wherein a much broader variety are used in NRP biosynthesis than the 20 canonical amino acids used in protein biosynthesis [52]. The modules are usually arranged co-linearly to the BGC sequence, which makes

• ]. It is unlikely that a Syn-BNP is able to target a specific protein or pathway, unless it in fact recapitulated key structural feature(s) of a NRP. These observations are a testament to the feasibility of this approach. This approach has also been applied to focus on NRPs with particular physical

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• ) [91]. This method manifests the synthesis of stable thioether-linked synthetic conjugates 93 and 96 displaying its efficacy via the alteration of the affibody zEGFR and the histone protein H2A. The procedure involved synthesizing the diaryliodonium salt and appraising the proficiency of oxime ligation

• chemistry on the histone H2A protein. The protein was demonstrated as the T120C mutant via site-directed mutagenesis in Escherichia coli and decontaminated by HPLC. A notable reconciliation was changing the aqueous buffer from HEPES to phosphate owing to side-product generation during the arylation in HEPES

• protein conjugate was effectively done with various hydroxylamines with the assistance of the nucleophilic catalyst 5-methoxyanthranilic acid. The resultant histone protein conjugates were functionalized with TAMRA, biotin and the cell-penetrating peptide 'penetratin' through oxime ligation, achieving

N-Glycosides of indigo, indirubin, and isoindigo: blue, red, and yellow sugars and their cancerostatic activity

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 2840–2869, doi:10.3762/bjoc.20.240

• , and Parkinson's disease, cardiovascular diseases, inflammation, AIDS and others have their origin in context with the activities of protein kinases, such as glycogen synthase kinase-3 (GSK-3β) and cyclin-dependent kinases (CDK’s). The phosphorylation of the amino acid moieties of several enzymes is

• controlled by such protein kinases. Therefore, the investigation of the influence of drugs on protein kinases plays an important role in current medicinal chemistry. Indigo naturalis is a traditional drug, derived from indigo plants, which has been used in China for centuries and also more recently against

• entirely cancelled by antioxidative pretreatment and cancer cell viability and proliferation were fully regenerated. Complete activation of cascades of caspases-3, -4, -6, -7, -8, and -9, loss of mitochondrial membrane potential, activation of proapoptotic PKCδ (protein kinase C delta), and inhibition of

Synthesis and antimycotic activity of new derivatives of imidazo[1,2-a]pyrimidines

• Dmitriy Yu. Vandyshev,
• Daria A. Mangusheva,
• Khidmet S. Shikhaliev,
• Kirill A. Scherbakov,
• Oleg N. Burov,
• Alexander D. Zagrebaev,
• Tatiana N. Khmelevskaya,
• Alexey S. Trenin and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2024, 20, 2806–2817, doi:10.3762/bjoc.20.236

• fingerprints (IFP) between the docking ligands and the protein shows that, similar to the reference ligand voriconazole, the compounds interact with the protein through hydrophobic interactions with hydrophobic residues of the protein and the formation of coordination bonds with the haem iron (Table 3). At the

• ) Superposition of docked compounds 4a–e and 5e in a CYP51 ACb. aThe amino acid residues of the protein are colored green, compound 4e is colored gold and the haem is colored grey. The heterocyclic nitrogen of compound 5e appears to be orientated towards iron and is located 2.8 Å away from it, which may indicate

• –protein interactions for voriconazole and compounds selected during docking.a Supporting Information Supporting Information File 14: General reaction procedures, compound characterization data, copies of NMR and mass spectra for all new products. Acknowledgements The research results were partially

Synthesis of fluoroalkenes and fluoroenynes via cross-coupling reactions using novel multihalogenated vinyl ethers

• Yukiko Karuo,
• Keita Hirata,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 2691–2703, doi:10.3762/bjoc.20.226

• fact, several inhibitors of the β-site amyloyd β A4 precursor protein cleaving enzyme (BACE1), which is involved in the production of β-amyloid, and fluoroalkene analogs of dipeptidyl peptidase-4 inhibitors have previously been reported [2][3]. These inhibitors possess higher drug efficacies than their

Applications of microscopy and small angle scattering techniques for the characterisation of supramolecular gels

• Connor R. M. MacDonald and
• Emily R. Draper

Beilstein J. Org. Chem. 2024, 20, 2608–2634, doi:10.3762/bjoc.20.220

Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• provide unprecedented depth of proteome coverage and the possibility to detect desired modified peptides with high sensitivity. The chemical ‘linker’ connecting an active compound–protein conjugate with a detection tag is the critical component of all chemical proteomic workflows. In this review, we

• disease [2][3]. In parallel, mass spectrometry (MS) has been crucial in many areas centered around the characterization of NPs [4]. First to annotate their often complex structures using diverse fragmentation techniques [4]. Nowadays, MS is applied for the identification of NPs’ cellular protein targets

• the desired protein coverage and robustness. Still, the critical part of the process starts with the careful design of a NP analogue and selection of the proper biological system, which may include animal models, 3D tissue-organoids, or 2D cell culture. Depending on the project aim, which typically

Cell-free protein synthesis with technical additives – expanding the parameter space of in vitro gene expression

• Tabea Bartsch,
• Stephan Lütz and
• Katrin Rosenthal

Beilstein J. Org. Chem. 2024, 20, 2242–2253, doi:10.3762/bjoc.20.192

• established itself as a successful tool in organic synthesis. A particularly fast technique for screening enzymes is the in vitro expression or cell-free protein synthesis (CFPS). The system is based on the transcription and translation machinery of an extract-donating organism to which substrates such as

• nucleotides and amino acids, as well as energy molecules, salts, buffer, etc., are added. After successful protein synthesis, further substrates can be added for an enzyme activity assay. Although mimicking of cell-like conditions is an approach for optimization, the physical and chemical properties of CFPS

• tested additives. Keywords: cell-free protein synthesis; cGAS; Escherichia coli cell-free extract; sfGFP; TX-TL; Introduction In addition to other applications such as biomanufacturing or biosensing, cell-free protein synthesis (CFPS) of enzymes has established itself as a tool for rapid screening of

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

• isolated. Nevertheless, alternariol sulfates were isolated from Alternaria sp. and alternariol-9-O-sulfate (14) turned out to be active against 23 protein kinases with IC50 values ranging from 0.22 to 8.4 µg/mL and to be cytotoxic against L5178Y cells (EC50: 4.5 µg/mL) [147]. The sulfated 9-O

• ] and Alternaria sp. [28][47][154] (Figure 8). It showed antioxidant activity with an IC50 value of 42.8 μM [153], inhibited about 90% of iNOS (inducible nitric oxide synthase) expression when applied at 20 μM, decreased the protein expression levels of pro-inflammatory cytokines (tumor necrosis factor

• -α, interleukin-6, and monocyte chemotactic protein 1), and reduced the production of NO as low as 10 μM in LPS-induced RAW264.7 cells [154]. Biosynthetic metabolization of alternariol and its 9-O-methyl ether is predominantly started with a hydroxylation in 4-position (c.f., chapter on biosynthesis

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• Supporting Information File 1). Next, we paid attention to testing the conditions we developed for the synthesis of the SO2-containing analogue 2r of potent anticancer drug enastron in gram scale (Scheme 3). Enastron is a novel dihydropyrimidine-based mitotic kinesin spindle protein KSP/Eg5 inhibitor [36

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• Ferran Nieto-Fabregat Maria Pia Lenza Angela Marseglia Cristina Di Carluccio Antonio Molinaro Alba Silipo Roberta Marchetti Department of Chemical Sciences, University of Naples Federico II, Via Cinthia 4, 80126, Italy 10.3762/bjoc.20.180 Abstract Protein–glycan interactions play pivotal roles in

• , both in free state and in complex with proteins, also with reference to the principles, methodologies, and applications of all-atom molecular dynamics simulations. Herein, we focused on the programs that are generally employed for preparing protein and glycan input files to execute molecular dynamics

• simulations and analyse the corresponding results. The presented computational toolbox represents a valuable resource for researchers studying protein–glycan interactions and incorporates advanced computational methods for building, visualising and predicting protein/glycan structures, modelling protein

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• the treatment of paroxysmal nocturnal hemoglobinuria, and CPI-637 (2), an inhibitor of both cyclic-AMP response element binding protein (CBP) and adenoviral E1A binding protein [14][15][16]. The N2-substituted indazole analogs pazopanib (3), an FDA-approved tyrosine kinase inhibitor used for the

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• ); isoquinolinone; solvent-dependence; Introduction Isoquinolinone is an important heterocyclic structure found in many natural products and biologically active compounds, including pharmaceuticals [1]. For instance, lycoricidine, found in the medicinal plant Lycoris radiata, may inhibit the MCPyV LT protein

2-Heteroarylethylamines in medicinal chemistry: a review of 2-phenethylamine satellite chemical space

• Carlos Nieto,
• Alejandro Manchado,
• Ángel García-González,
• David Díez and
• Narciso M. Garrido

Beilstein J. Org. Chem. 2024, 20, 1880–1893, doi:10.3762/bjoc.20.163

• requirements for access to γ-aminobutyric receptor type B (GABAB) [18]. Amino acids 10–12 were demonstrated [19][20][21] to act as substrates of GABAB (Scheme 3), key metabotropic receptors from the G-protein-coupled receptor superfamily responsible for CNS inhibitory synapses [22]. The authors concluded that

• solute carrier protein which is used as strategic target for blood–brain-barrier drug delivery. In general, the authors found the compounds less potent than the natural substrate ʟ-tryptophan, with exception of derivative 112 (Scheme 17). Tetrazoles: Taking advantage of using tetrazoles not as a phenyl

• -ring bioisostere, but as carboxylic acid one, Schwarz et al. [79] developed tetrazole-based pregabalin bioisosteres 113–118 (Scheme 18). The target protein α2-δ is involved in neurotransmitters release reduction, as a model of anxiety and neuropathic pain. In general, submicromolar affinities were

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• work described below, KTGS was applied to multicomponent reactions in limited cases [25]. Van der Veken et al. selected as template the protein urokinase plasminogen activator, a serine protease targeted in oncology and inhibited by imidazopyridines [26]. The main challenges of this project were the

• protein in a manner comparable to the binding mode of known imidazopyridine inhibitors. Second, the possibility that reactants could covalently modify the enzyme was ruled out by analysis of the relevant literature. Finally, appropriate building blocks displaying additional functionalities capable of

• combination of reactants was studied, but a major hurdle was found to be the imine formation step in aqueous media. Consequently, imines were first prepared as metastable adducts (with benzotriazole or p-TSA as stabilizers) and then tested with isocyanides in the presence of the template protein, involving

Discovery of antimicrobial peptides clostrisin and cellulosin from Clostridium: insights into their structures, co-localized biosynthetic gene clusters, and antibiotic activity

• Moisés Alejandro Alejo Hernandez,
• Katia Pamela Villavicencio Sánchez,
• Rosendo Sánchez Morales,
• Karla Georgina Hernández-Magro Gil,
• David Silverio Moreno-Gutiérrez,
• Eddie Guillermo Sanchez-Rueda,
• Yanet Teresa-Cruz,
• Brian Choi,
• Armando Hernández Garcia,
• Alba Romero-Rodríguez,
• Oscar Juárez,
• Siseth Martínez-Caballero,
• Mario Figueroa and
• Corina-Diana Ceapă

Beilstein J. Org. Chem. 2024, 20, 1800–1816, doi:10.3762/bjoc.20.159

• catalyze the formation of Dha-Cys or Dhb-Cys [21]. Moreover, lanPt encodes a membrane protein with two ABC transporter domains and a C39 peptidase domain. The protein cleaves the leader peptide to generate mature lanthipeptides and exports them to the extracellular environment [22]. The diversity of

• the Clostridium genus encountered 17 protein sequences associated with 12 genomes. After analyzing these genomes with AntiSMASH [3], we identified 150 different BGCs of specialized metabolites from different biosynthetic classes. The RiPPs accounted for 36% of these (54 clusters). A total of 14 BGCs

• two transporter protein peptidases, which we named CloT1 and CloT2 (Figure 2). The amino acid sequences of the C39 peptidase domain of CloT1 and CloT2, further identified as CloPt1 and CloPt2, were subjected to BLAST analysis, revealing a strong primary sequence conservation with all homologous

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• Smoothened protein (Smo protein) [7]. The HH pathway, implicated in the development and progression of various human cancers (including colorectal, brain, gastrointestinal, lung, and breast cancers), drives tumorigenesis [8]. Consequently, HH pathway inhibitors have demonstrated significant anticancer

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• biosynthetic pathway as proposed by Cox, based on bioinformatic analyses of polyketide synthase (PKS) modules and in vitro studies. Initially, highly reducing iterative polyketide synthase (HR-iPKS) SorbA forms the thioester 30 on its acyl carrier protein (ACP) domain from acetate and two units of malonyl-CoA

• reaction with biotin azide, which led to selective pull-down with streptavidin agarose and isolation of the probe–protein covalent complex. Proteomic analysis of the isolated proteins narrowed down the MaMO and MaDA candidates, including several berberine bridge enzyme (BBE)-like enzymes. This FAD-linked

• TylGI loads a methylmalonyl-CoA onto the acyl carrier protein (ACP) in module 1. The ketosynthase-like decarboxylase (KSQ) domain catalyzes the decarboxylation of the loaded methylmalonyl moiety, and subsequent modules 2 and 3 extend the carbon chain using two molecules of malonyl-CoA. The β

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• of RiPPs have a molecular weight between 1,000 and 5,000 Da. Peptide natural products exhibit high specificity and binding affinity to their corresponding targets [9][10]. The inhibition of protein–protein interactions is an emerging strategy in the development of novel therapeutics [11]. Binding to

• proteins allows peptides to disturb protein–protein interactions, which is a challenging task for small molecules. The principles of RiPP biosynthesis make the RiPP technology an ideal platform for the generation of designed peptides and allow tailored derivatisation of these peptides. The RiPP technology

• the specialised metabolism of bacteria and fungi. Each NRPS module is minimally composed of a condensation (C) domain, an adenylation (A) domain, and a peptidyl carrier protein (PCP or thiolation/T domain), and one module typically incorporates one amino acid into the final natural product. In

Polymer degrading marine Microbulbifer bacteria: an un(der)utilized source of chemical and biocatalytic novelty

• Weimao Zhong and
• Vinayak Agarwal

Beilstein J. Org. Chem. 2024, 20, 1635–1651, doi:10.3762/bjoc.20.146

• exochitinases. Genomic analysis of a marine Microbulbifer degradans 2-40 revealed three chitin depolymerases (ChiA, ChiB, and ChiC) [117]. ChiB was cloned and expressed in E. coli [22]. It is a modular protein that is predicted to contain two GH-18 catalytic domains, two polyserine domains, and an acidic repeat

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

• Yu Fan,
• Ahmed El Rhaz,
• Stéphane Maisonneuve,
• Emilie Gillon,
• Maha Fatthalla,
• Franck Le Bideau,
• Guillaume Laurent,
• Samir Messaoudi,
• Anne Imberty and
• Juan Xie

Beilstein J. Org. Chem. 2024, 20, 1486–1496, doi:10.3762/bjoc.20.132

• reversible light modulation of their activity since each isomer shows distinct structural and electronic properties [13]. Photoisomerization-induced conformational and polarity changes may allow to increase or decrease the interaction with the target protein or receptors, then modulate the drug potency on

• ][34], confirming the favorable interaction of the aryl group with the protein surface. For all compounds, no significant differences of affinities are observed between the E- and Z-isomer, with the exception of compounds 1 and 3 with para-orientation between the two aryl groups. The affinity of the E

• the known crystal structure. The extended E-isomer establishes contact through galactoside and the first aryl ring only, while the bent Z-isomer has proper conformation to wrap around the central His53 residue and to establish a more extended interaction with the protein surface. This would be in

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

• Changjun Xiang,
• Shunyu Yao,
• Ruoyu Wang and
• Lihan Zhang

Beilstein J. Org. Chem. 2024, 20, 1476–1485, doi:10.3762/bjoc.20.131

• embedded in the assembly line or not. All cis-AT PKS modules contain a ketosynthase (KS), an acyltransferase (AT), and an acyl carrier protein (ACP) to produce β-keto-intermediates, and some modules contain additional β-processing domains such as ketoreductase (KR), dehydratase (DH), and enoylreductase (ER

• 7.450 (E-INS-i option), Neighbor-Joining trees were built by Geneious Tree Builder using Jukes-Cantor distance model. Sequence logo visualization was conducted by WebLogo 3. Protein structural analysis was conducted by PyMOL. (a) Domain compositions and the products of α-, β-, γ- and δ-modules in cis-AT

Cofactor-independent C–C bond cleavage reactions catalyzed by the AlpJ family of oxygenases in atypical angucycline biosynthesis

• Jinmin Gao,
• Liyuan Li,
• Shijie Shen,
• Guomin Ai,
• Bin Wang,
• Fang Guo,
• Tongjian Yang,
• Hui Han,
• Zhengren Xu,
• Guohui Pan and
• Keqiang Fan

Beilstein J. Org. Chem. 2024, 20, 1198–1206, doi:10.3762/bjoc.20.102

• contraction reactions, yielding a benzofluorene intermediate 4 and the dimer 5, both featuring a kinamycin skeleton (Scheme 1) [11][12]. Recent investigations unveiled the catalytic activity of the O-methyltransferase-like protein AlpH, which catalyzes a unique SAM-independent coupling of ʟ-glutamylhydrazine

• demonstrate the FADH2/FMNH2-dependent nature of AlpJ-family oxygenases when utilizing 1 as the substrate. Intriguingly, these enzymes exhibit notable similarities to cofactor-independent anthrone oxygenases, exemplified by TcmH and ActVA-Orf6, in both protein sequences and structures (see Figure S1

• oxygenases. Notably, AlpJ-family oxygenases stand as a pioneering example of enzymes capable of catalyzing oxidative reactions in either an FADH2/FMNH2-dependent or -independent manner. Up to date, many oxygenases from diverse evolutionary families, featuring varied protein folds and quaternary arrangements