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

• of a new chiral centre. Advances in understanding ligand–receptor interactions have facilitated the determination of optimal molecular conformations to enhance binding affinity, which can be achieved, in part, by introducing a spiro annelated ring to impart rigidity to the molecule. From a medicinal

• . Chromatographic purification was not required post-reaction. Some spiro products exhibited high binding affinity towards DNA, while others showed good cytotoxicity against different cancer cells (A545, MCF-7, HeLa, HL-60, SW480, HepG2, HT-29, and A549) with IC50 values within the micromolar range (2.18–18.54 µM

• synthesized compounds were evaluated for their DNA binding properties and screened for cytotoxicity against leukemia cancer cells (Jurkat), demonstrating IC50 values in the micromolar range (14.2 to 36.5 µM). Importantly, these derivatives exhibited minimal toxicity toward normal cells (PBMCs). Furthermore

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

• fractionated cell cultures of M. alba with 49 was followed by irradiation with 365 nm light to generate reactive carbene from diazirine. This sequence allowed the formation of covalent bonds between the synthetic probe and binding proteins. The resulting mixture was subjected to a copper-catalyzed click

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

• advance and are not recycled in the system. The amino acids are methylated either prior to tRNA binding or after. The efficiency of incorporating unnatural amino acids is lower, but Merryman and Green have demonstrated that an excess of tRNA can overcome this problem [47]. When attempting to incorporate

• biocatalytic applications. The co-crystallisation of LahSB with bound SAH provides important details about the structure–function relationship, the substrate–enzyme interaction, and the cofactor binding site (Figure 5). This structural information, including the residues involved in binding, is essential for

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

• bridges, relatively short length of the surface loops, and the increased number of Pro and Arg residues [29]. A truncated β-agarase gene without the carbohydrate-binding modules (Aga16A-ΔCBM) from the marine Microbulbifer sp. BH-1 was cloned and expressed in Escherichia coli with pH and temperature being

pKalculator: A pK_a predictor for C–H bonds

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2024, 20, 1614–1622, doi:10.3762/bjoc.20.144

• Finkelmann et al. [30][31] and Ree et al. [14], we utilize the automated approach to compute CM5 atomic charges from semiempirical tight-binding (GFN1-xTB [37]) calculations. We modify the workflow to enhance the accuracy of the computed CM5 atomic charges. Instead of generating a single random conformer, we

Supramolecular assemblies of amphiphilic donor–acceptor Stenhouse adducts as macroscopic soft scaffolds

• Ka-Lung Hung,
• Leong-Hung Cheung,
• Yikun Ren,
• Ming-Hin Chau,
• Yan-Yi Lam,
• Takashi Kajitani and
• Franco King-Chi Leung

Beilstein J. Org. Chem. 2024, 20, 1590–1603, doi:10.3762/bjoc.20.142

• applying the shear-flow method, negatively charged nanofibers of DA11 were assembled into a macroscopic soft scaffold when the solution was ejected into a shallow pool of calcium chloride solution (150 mM, Figure 4a). The high binding affinity between calcium ions and carboxylate groups enabled charge

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

• -translational modifications by specific tailoring enzymes [5][6]. This precursor peptide substrate can be subdivided into multiple segments including 1) an N-terminal leader or recognition sequence used for binding by the tailoring enzymes and 2) a core peptide that is targeted for modification by the

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

• photoswitchable tools, few photochromic lectin ligands have been developed. We have designed and synthesized several O- and S-galactosyl azobenzenes as photoswitchable ligands of LecA and evaluated their binding affinity with isothermal titration calorimetry. We show that the synthesized monovalent glycoligands

• due to stronger unfavorable entropy, they are in general of lower affinity. The validation of this proof-of-concept and the dissection of thermodynamics of binding will help for the further development of lectin ligands that can be controlled by light. Keywords: carbohydrates; glycosyl azobenzenes

• bacterial infections occur by adhesion to host tissues through receptor–ligand interaction between bacterial carbohydrate-binding proteins (lectins) and oligosaccharides at the host cell surface. Pseudomonas aeruginosa (PA), a Gram-negative, opportunistic and ubiquitous environmental bacterium, is known as

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

• binding motif can be used to predict C2-type KRs [9]. These conserved motifs have been widely used to predict the stereochemical outcome of modular cis-AT PKSs and have facilitated bioinformatics-guided structural determination of complex polyketides [12][13][14][15][16][17]. However, despite being widely

• 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

• catalytic groove. The sequence logo of C0/C1-type KRs showed that some of them possess the catalytic Y (9), but such KRs instead possess mutation in NADPH binding site (Figure S3 in Supporting Information File 1). In C2-type KRs, we found that most C2-type KRs possessed the catalytic Y (9), but some

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• proposed strategy where the metal ion acts as the binding cation template for the intramolecular desymmetrization (Scheme 15) [82]. A similar highly efficient intramolecular Cannizzaro reaction of calix[4]arene dialdehydes was observed by Galli et al. where the 1,3-distal cone 35 significantly responded to

Rhodium-catalyzed homo-coupling reaction of aryl Grignard reagents and its application for the synthesis of an integrin inhibitor

• Kazuyuki Sato,
• Satoki Teranishi,
• Atsushi Sakaue,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai,
• Hiroyuki Takeda,
• Tatsuo Kinashi and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 1341–1347, doi:10.3762/bjoc.20.118

• developing novel inhibitors of integrin function, we identified a drug candidate (10n) through high throughput screening (HTS) that inhibits the integrin complex formation, which is an important step for integrin activation. The binding inhibitor 10n was effective as IC50 of 190 μM in AlphaScreen system, and

Diameter-selective extraction of single-walled carbon nanotubes by interlocking with Cu-tethered square nanobrackets

• Guoqing Cheng and
• Naoki Komatsu

Beilstein J. Org. Chem. 2024, 20, 1298–1307, doi:10.3762/bjoc.20.113

• complexation between host molecules and SWNTs are strongly related to the molecular structures, making it possible to tune the binding affinity [8]. The host molecules we employed so far for CNT separation through molecular recognition have been developed as “nanotweezers” [9], “nanocalipers” [10] and

• square in its shape by changing anthracene in 1a to pyrene in 1b. To interpret the results of the diameter selectivity, the theoretical calculation using the semiempirical tight binding quantum chemical method GFN2-xTB was employed instead of the molecular mechanics used in our previous works, because it

• binding energy between SWNTs and the host molecules is calculated by the GFN2-xTB method, because the number of atoms is too large to use DFT methods. The binding energy Ebind is calculated by the following equation: The Ehost, ESWNTs and Ecomplex are the electronic energies of the host molecules, SWNTs

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

• ones presented here, and therefore were neglected. We used the non-covalent interactions (NCI) NCIplot analysis with the program NCIPLOT [39][40][41] to study the non-covalent interactions present in these molecules. To map local binding properties with this method, two scalar fields are used: 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

• partially localised in the nucleus of cells and, in cancer cells, become genotoxic [24]. A3A and A3H are single-domain enzymes, whereas A3B is a double-domain enzyme, in which only the C-terminal domain (CTD) has catalytic activity, and the N-terminal domain (NTD) is responsible for binding of DNA and for

• measured using the NMR-based assay (Figure 2). The results revealed that both anomers of Va do not inhibit engineered A3A mimic even at elevated concentration in comparison to a control ODN containing FdZ (IId) at pH 6.0. It is very likely that a negative charge in nucleobase Va prevents binding to the

Novel analogues of a nonnucleoside SARS-CoV-2 RdRp inhibitor as potential antivirotics

• Luca Julianna Tóth,
• Kateřina Krejčová,
• Milan Dejmek,
• Eva Žilecká,
• Blanka Klepetářová,
• Lenka Poštová Slavětínská,
• Evžen Bouřa and
• Radim Nencka

Beilstein J. Org. Chem. 2024, 20, 1029–1036, doi:10.3762/bjoc.20.91

• of HeE1-2Tyr (1), it must be considered that the synthesized ligands were significantly smaller in size. Normalization of the obtained results using the binding efficiency index (BEI) [32] suggest that both ligand types, 3a–c and 4a,b, bind more efficiently to the SARS-CoV-2 RdRp when compared to 1

Spin and charge interactions between nanographene host and ferrocene

• Akira Suzuki,
• Yuya Miyake,
• Ryoga Shibata and
• Kazuyuki Takai

Beilstein J. Org. Chem. 2024, 20, 1011–1019, doi:10.3762/bjoc.20.89

• effect, ACFs were ground in a mortar before the measurement. Results and Discussion XPS spectra acquired in a wide binding energy region for ACFs and FeCp2-ACFs-150 are shown in Figure 1. Peaks of C1s and O1s were observed in ACFs, while C1s, O1s, and Fe2p peaks appeared in the spectrum for FeCp2-ACFs

• -150. Figure 2 shows the Fe2p spectrum for FeCp2-ACFs-150 in a narrow binding energy region. The binding energies of the Fe2p peaks are similar to the reported value for FeCp2 [16]. So, the Fe2p peaks observed in FeCp2-ACFs-150 indicate the successful introduction of the FeCp2 molecule into ACFs as

• binding energy region, respectively. Table 1 shows peak positions for XPS C1s, O1s, and Fe2p peaks for ACFs and FeCp2-ACFs-150, where elemental abundances are obtained from the peak intensity. The amount of FeCp2 is calculated as 0.39 mmol in 1 g of FeCp2-ACFs-150 from the total intensity ratio of Fe2p

A Diels–Alder probe for discovery of natural products containing furan moieties

• Alyssa S. Eggly,
• Namuunzul Otgontseren,
• Carson B. Roberts,
• Amir Y. Alwali,
• Haylie E. Hennigan and
• Elizabeth I. Parkinson

Beilstein J. Org. Chem. 2024, 20, 1001–1010, doi:10.3762/bjoc.20.88

• the MMFs specifically, we have developed a chemical probe that is capable of covalently binding to natural products containing furan moieties. Molecular probes are molecules that covalently bind to a compound of interest in order to make them easier to identify from the complex milieu of the cell

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

• coelicolor [55] (Figure 8a). Further structure-based engineering of BezA successfully repurposed it to catalyze the unprecedented C6-methylation of FPP by a single residue substitution in its substrate-binding pocket [55]. Moreover, efforts have also been made to engineer the TSs to modulate their product

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• benzenes that have more than one substituent; for example, the ortho-, meta-, or para- relative substitution of a disubstituted benzene should ideally be replicated in the saturated bioisostere to ensure ligand–protein binding is conserved through the bioisosteric swap. Bioisosteres of para-substituted

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

• these homologs exist mostly as dimers in solution. Next, the heme incorporation of the isolated homologs was measured. UV–vis absorption spectra showed that each NnlA homolog exhibited characteristic Soret absorption features consistent with heme binding to the protein (Figure 3). In addition, the A412

• [32]. We sought to identify the heme binding site, but AlphaFold does not model this. However, this AlphaFold model was predicted to bind a heme cofactor by the consensus modeling tool COACH [33]. This protein–ligand model exhibited steric clashes with the heme and protein side chains (data not shown

• ), limiting the use of this model to predict the heme environment. Nevertheless, this protein–ligand model heme binding between the β-sheet and an α-helix based on similarity to the oxygen-sensing dimeric DosH protein [34]. DosH is also a heme-binding PAS-domain containing protein, further validating the

Substrate specificity of a ketosynthase domain involved in bacillaene biosynthesis

• Zhiyong Yin and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2024, 20, 734–740, doi:10.3762/bjoc.20.67

• Zhiyong Yin Jeroen S. Dickschat Kekulé-Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany 10.3762/bjoc.20.67 Abstract An isotopic labelling method was developed to investigate substrate binding by ketosynthases, exemplified by the

• glutamate decarboxylase, and incubated with BaeJ-KS2. Substrate binding was demonstrated through 13C NMR analysis of the products against the background of various control experiments. Keywords: bacillaene; biosynthesis; enzyme mechanisms; isotopes; trans-AT polyketide synthases; Introduction Polyketides

• analysed by 13C NMR, showing the presence of free 11 after the first centrifugation step (Figure 1C), but not after the last round of centrifugation (Figure 1D). Protein binding of the substrate surrogates 11 was confirmed through digestion of BaeJ-KS2 using protease K after buffer exchange. The digested

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• -binding protein (PBP) family and plays a role in chain termination and macrocyclization in the biosynthesis of surugamides. This PBP-type discrete TE was utilized in the chemoenzymatic synthesis of surugamide B with corresponding peptidyl-SNAC thioester (17b). Most recently, it was observed that SurE

New variochelins from soil-isolated Variovorax sp. H002

• Jabal Rahmat Haedar,
• Aya Yoshimura and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2024, 20, 692–700, doi:10.3762/bjoc.20.63

• structure – a linear hexapeptide with β-hydroxyaspartate and hydroxamate functional groups, serving in iron-binding coordination. Three new variochelins C–E (3–5) were characterized by varied fatty acyl groups at their N-termini; notably, 4 and 5 represent the first variochelins with N-terminal unsaturated

A myo-inositol dehydrogenase involved in aminocyclitol biosynthesis of hygromycin A

• Michael O. Akintubosun and
• Melanie A. Higgins

Beilstein J. Org. Chem. 2024, 20, 589–596, doi:10.3762/bjoc.20.51

• essential for in vivo antimicrobial activity suggesting a distinct biological function independent of ribosome binding. The hygromycin A biosynthetic gene cluster has been identified and the biosynthesis of the aminocyclitol has been proposed (Figure 1) [8][9]. Starting from glucose-6-phosphate, the pathway

• PF01408, in which Hyg17 is a member (Figure 3). PF01408 is classified as an oxidoreductase with NAD-binding Rossmann fold family and contains over 340,000 sequences. Many of the family members act as sugar dehydrogenases with diverse sugar substrates (Supporting Information File 1, Table S1). These

• then induced with 50 µL of 20 mg mL−1 thiostrepton and grown for another 24 h at 30 °C while shaking at 200 rpm. Cells were then harvested by centrifugation, resuspended in binding buffer (500 mM NaCl, 20 mM Tris pH8.0) and disrupted by sonication using a Branson Sonifier 450 (5 rounds of 3 s/3 s on

Recent developments in the engineered biosynthesis of fungal meroterpenoids

• Zhiyang Quan and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 578–588, doi:10.3762/bjoc.20.50

• they have similar substrate binding modes but different regional specificities. The rapid increase in genomic information has further expanded the number of available enzyme genes, thus increasing the potential for diversifying DMOA-derived meroterpenoid biosynthesis. Recently, a similar genome mining

• compounds (40, 43, 44, 47, 48, 50, 51, and 53–55) (Figure 7A). In addition, a structure-based mutagenesis study of SptF was performed to further amplify its catalytic potential. Firstly, the hydrophobic residues Ile63, Phe133, and Ile231, which compose the substrate binding site of SptF, were mutated. As a

• change their reaction products depending on the conformation of the terpenoid skeleton, the regiospecificity of the oxidation reaction can be modified by introducing random mutations in the substrate-binding site of αKG-dependent dioxygenase. The αKG-dependent dioxygenase AndA withdraws H-12 of