Rotaxanes with integrated photoswitches: design principles, functional behavior, and emerging applications

• Jullyane Emi Matsushima,
• Khushbu,
• Zuliah Abdulsalam,
• Udyogi Navodya Kulathilaka Conthagamage and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2345–2366, doi:10.3762/bjoc.21.179

• Michael addition taking place at the active site (C=C−C=N+) in the merocyanine unit in the presence of sulfite ions, resulting in color changes from red to green. This work represents a substantial advancement in the development of rotaxane-based fluorescent probes, providing highly sensitive and

Enantioselective radical chemistry: a bright future ahead

• Anna C. Renner,
• Sagar S. Thorat,
• Hariharaputhiran Subramanian and
• Mukund P. Sibi

Beilstein J. Org. Chem. 2025, 21, 2283–2296, doi:10.3762/bjoc.21.174

• from α-halocarbonyl compounds as in the previous report. In this case, radical formation from the alkyl iodide was accomplished through photoexcitation of a charge-transfer complex of the substrate and flavin in the active site of the enzyme (a mutated ene-reductase). Subsequent 5-exo-trig or 6-exo

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

• production of jet fuel precursors through the electrocatalytic highly selective coupling reaction of furfural and levulinic acid. The Ni2+ species serves as the active site for the coupling process (Scheme 53) [181]. A similar strategy involving phenolic compounds and furfural allowed the production of

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• that all ligands consistently interacted with Cys200 and Ser242, key residues in the enzyme's active site, underscoring their critical role in ligand stabilization. In addition to hydrogen bonding, extensive van der Waals interactions were observed, particularly involving residues such as Thr190

• ellipsoids at the 30% probability level. The intramolecular hydrogen bond is shown as red dashed line. The bioavailability radar of studied compounds 5a–e. The interactions of potential drugs 5a–c in the active site of enzyme iNOS. The interactions of potential drugs 5d and 5e and control drug (DEX) in the

• active site of enzyme iNOS. Synthesis of 4-[1-(4-methoxybenzyl)amino]ethylidene-1,5-disubstituted pyrrolidine-2,3-diones 3a–e. Synthesis of 4-(1-methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones 5a–e. Proposed mechanism for the reaction between 4-[1-(4-methoxybenzyl)amino]ethylidene-1,5

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

• enzyme, and the hydroxy group of 57 interacts with catalytic aspartate residues in the active site. The fluorinated pepstatin analogue 58 was predicted to be pre-organised into the bent conformation and hence be a more potent inhibitor than 57. Compound 58 was indeed found to be more potent than 57

Beyond symmetric self-assembly and effective molarity: unlocking functional enzyme mimics with robust organic cages

• Keith G. Andrews

Beilstein J. Org. Chem. 2025, 21, 421–443, doi:10.3762/bjoc.21.30

• active site (binding a substrate in an orientation that directs internally catalyzed reactivity) [347][348]. The examples of cavities with functionality discussed above, from Cram’s “full serine protease model” [87], to MOCs with flexible peripheral groups [349], to frameworks with internal proline

• between a simple, highly symmetrical, often hydrophobic pocket of a typical coordination cage host system and the complex, highly unsymmetrical and largely polar environment of an enzyme active site is a moot point… [since]… the mechanisms which an enzyme utilizes to accelerate chemical reactions are in

Advances in the use of metal-free tetrapyrrolic macrocycles as catalysts

• Mandeep K. Chahal

Beilstein J. Org. Chem. 2024, 20, 3085–3112, doi:10.3762/bjoc.20.257

• recognition, and supramolecular assemblies [9][10][11][12][13]. There are numerous examples of using metalloporphyrins as artificial photosynthesis models, enzyme mimics, and catalysts for various organic transformations, where a metal center acts as an active site [14][15][16][17]. However, metal-free (or

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

• ][53][54][55][56][57]. The exception is the 10 residues that constitute the A domain active site, whose high variability creates binding pockets of varying shapes and sizes. These residues therefore dictate substrate BB specificity of an A domain and are referred to as the nonribosomal code (in analogy

• offloading step always entails the same chemical reaction, wherein nucleophilic attack is promoted by the catalytic triad of a TE via general base catalysis. This is likely why traditional mechanistic studies that focused on the enzyme active site failed to work out how TEs control NRP topology. A priori

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

• an improved water solubility or ability to pass the cell membrane or by an improved recognition of the drug in the active site of the receptor. In contrast to indirubin-N-glycosides, indigo-N-glycosides are relatively unstable and not highly active against cancer, except for the natural products

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

• )-enantiomer of 5e and therefore, these compounds were classified as inactive. The docking results are shown in Table 3. Compounds 4a–e bind to the active site of CYP51 with affinities ranging from −7.7 to −8.8 kcal/mol and compound 5e has a much higher affinity of −5.4 kcal/mol. Therefore, we assume that the

• Tanimoto coefficient calculated from the MACCS descriptors for the selected compounds is <0.5, indicating that the chemical structure of compounds 4a–e and 5e is significantly different from voriconazole. The three-dimensional position of the selected compounds in the active site of the enzyme is shown in

• ]pyrimidines. Key correlations observed in the NOESY and HMBC spectra of the products 4d and 5d. Structures of imidazo[1,2-a]pyrimidines selected for docking and voriconazole selected for comparison. (A) Position of the (S)-isomer of compound 4e in the active site of CYP51 after molecular dockinga. (B

Factors influencing the performance of organocatalysts immobilised on solid supports: A review

• Zsuzsanna Fehér,
• Dóra Richter,
• Gyula Dargó and
• József Kupai

Beilstein J. Org. Chem. 2024, 20, 2129–2142, doi:10.3762/bjoc.20.183

• showed that the activity of a difunctional organocatalyst in lactose hydrolysis was improved 5.2-fold by immobilisation on different solid supports that mimic the active site channels of enzymes [113]. In a solid-supported system, the solvent can exert a different influence on the catalytic activity

• organocatalyst also depend on the density of catalytic sites on the support surface, as well as the nature and length of the linker [8]. Additionally, the linker itself could serve as a competitive active site. In the case of enantioselective catalysis, the linker could promote the formation of racemic products

• , leading to lower stereoselectivity. Moreover, in catalyst co-polymerisation, the organocatalyst might be enclosed within the inner part of the polymer bead, rendering it inaccessible for reactants, or the repeating unit of the polymer could act as a competitive active site. On the other hand, in some

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

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

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

• sets, BLAST of subsets, comparison of MIBiG sets, active site finder, RREF finder, Pfam Cluster analysis, GO term annotation based on Pfam, and analysis with TIGRFam. Precursor peptide analysis After identifying the lanthipeptide BGCs from the genomes of the Clostridium genus, BGCs containing all genes

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

• the core, the precursor is cleaved and the MT domain is presumably degraded without catalysing any further methylating reactions [98]. The OphMA fusion functions as a homodimer, with the active site of the interlocking dimers modifying the substrate peptide (Figure 7) [99]. The MT domain of OphMA is

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

• . coli from a marine Microbulbifer sp. ALW1 [59]. Enzyme structure and site-directed mutagenesis led to the identification of key residues in the enzyme active site that participated in the hydrolytic activity [59]. Carbohydrate esterases Carbohydrate esterases (CEs) catalyze the O- or N-deacylation of

Mining raw plant transcriptomic data for new cyclopeptide alkaloids

• Draco Kriger,
• Michael A. Pasquale,
• Brigitte G. Ampolini and
• Jonathan R. Chekan

Beilstein J. Org. Chem. 2024, 20, 1548–1559, doi:10.3762/bjoc.20.138

• in 1998 [18]. This domain is typically around 300 amino acids in length and has a conserved CHX10CHX25-27CHX25-26CH motif which comprises the active site of the burpitide cyclase. The resulting number of stand-alone transcripts from this filtering step were mapped onto a cladogram of the 647 species

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

• the active site resides, and a structural subdomain (KRS) with a truncated Rossmann fold that lacks NADPH binding sites and solely provides structural support by forming a heterodimer with KRC [24][25][26]. In δ-modules, an ER domain is inserted between KRS and KRC. Phylogenetic analyses of KRC and

Stability trends in carbocation intermediates stemming from germacrene A and hedycaryol

• Naziha Tarannam,
• Prashant Kumar Gupta,
• Shani Zev and
• Dan Thomas Major

Beilstein J. Org. Chem. 2024, 20, 1189–1197, doi:10.3762/bjoc.20.101

• formation of (6,6) vs (5,7) is rooted in very slight changes in mechanism (protonation at C1 vs C10), it is of interest to understand whether there is a systematic difference in energy. In cases where enzymes use pathways with high-energy intermediates, the enzyme active site must in some way direct the

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• inhibition of APOBEC3A was observed for modified DNAs. Although this shows that the negative charge is poorly accommodated in the active site of CDA and APOBEC3, the synthetic route reported here provides opportunities for the synthesis of other derivatives of phosphapyrimidine riboside for potential

• A3A and A3B offers a potent strategy to suppress cancer evolution and prolong efficacy of existing anticancer therapies [19][38][39]. Despite of the low sequence identity, CDA and A3 share a similar overall structural topology and a close structural homology for the Zn2+-containing active site. Since

• been synthesised in the past and evaluated as inhibitors targeting the active site of CDA. THU (Ia) [45][48], zebularine (Z, IIa) [47][49][50] and 5-fluorozebularine (FZ, IIb) [47][51] as well as diazepinone riboside (IIIa) [42][43][44][52] were among the most potent compounds (Figure 1B). THU (Ia

Enhancing structural diversity of terpenoids by multisubstrate terpene synthases

• Min Li and
• Hui Tao

Beilstein J. Org. Chem. 2024, 20, 959–972, doi:10.3762/bjoc.20.86

• properties (Figure 4c) [45]. Notably, one tetrahydrofuranoterpenoid 59 is also formed as a major product in the BcBoT2 reaction, despite the low sequence similarity between these sesqui-TSs, which could be explained by similar active-site conformations to stabilize prenyl substrates. Similarly, limonene

Activity assays of NnlA homologs suggest the natural product N-nitroglycine is degraded by diverse bacteria

• Kara A. Strickland,
• Brenda Martinez Rodriguez,
• Ashley A. Holland,
• Shelby Wagner,
• Michelle Luna-Alva,
• David E. Graham and
• Jonathan D. Caranto

Beilstein J. Org. Chem. 2024, 20, 830–840, doi:10.3762/bjoc.20.75

• orthologous protein sequences and could facilitate NNG hydrolysis in the active site (Figure S4, Supporting Information File 1). The function of these residues are being investigated. There are also several nearby conserved basic residues. The significance of these residues will be further discussed below

• may occur non-enzymatically or is catalyzed within the NnlA active site. However, an imine product has not yet been observed and further investigations of the NNG degradation mechanism are needed. Given the potential widespread presence of NnlA, it is possible that NnlA could mediate previously

• formation of propionate 3-nitronate (P3N) as a conjugate base (Scheme 2) [39]. It is P3N that directly reacts with a cysteine in the ICL1 active site, forming a thiohydroxamate adduct that inhibits ICL1 turnover [40]. Additionally, the nitronate form of nitro acids has been proposed to behave as a

Development of a chemical scaffold for inhibiting nonribosomal peptide synthetases in live bacterial cells

• Fumihiro Ishikawa,
• Sho Konno,
• Hideaki Kakeya and
• Genzoh Tanabe

Beilstein J. Org. Chem. 2024, 20, 445–451, doi:10.3762/bjoc.20.39

• of the GrsA A-domain with ʟ-Phe and AMP revealed that the 2′-OH of the adenosine skeleton is oriented toward the outside of the active site of the GrsA A-domain, suggesting that chemical modification at the 2′-OH group of the adenosine skeleton would be tolerated [16] (Figure 2b). Moreover, these

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

Unraveling the role of prenyl side-chain interactions in stabilizing the secondary carbocation in the biosynthesis of variexenol B

• Moe Nakano,
• Rintaro Gemma and
• Hajime Sato

Beilstein J. Org. Chem. 2023, 19, 1503–1510, doi:10.3762/bjoc.19.107

• several terpene compounds with prenyl side chains have been reported, it remains unclear whether these prenyl side chains are located inside or outside the active site during the cyclization process. Therefore, we searched for conformations in which the side chain is closer to the carbocation center and

• computational models in the future. Furthermore, future research is expected to determine whether there is space in the enzyme active site for these prenyl side chains to fold and approach the reaction center, as seen in X-ray crystallographic analysis. Experimental All calculations were carried out using the