Search Results (600)

Background: MS/MS spectral databases provide reference spectra for compound identification in metabolomics studies. Their utility depends on clear links among compound identifiers, chemical structures, and MS/MS evidence, yet these links are often complicated by database-specific identifiers, heterogeneous structural representations, and stereochemical specifications. Methods: Here, we present a two-layer structural key framework for linking compound identifiers and MS/MS evidence through standardized structures. Reported SMILES were standardized and converted into InChIKey-derived stereo keys and connectivity keys using a Python-based RDKit workflow. Results: As illustrated using stereoisomeric cases such as L- and D-proline, the stereo key layer preserves compound identifiers and metadata at the stereo level, whereas the connectivity key layer groups comparable MS/MS evidence at the molecular connectivity level. In a database-scale application, 217,920 HMDB compound entries were organized into 216,783 stereo keys and 196,512 connectivity keys, and 144,591 spectra from the spectrum-centered MoNA database were incorporated into the HMDB-centered framework, increasing MS/MS evidence coverage, particularly at the molecular connectivity level. Conclusions: Together, this framework links compound identifiers, standardized structures, and MS/MS evidence at the stereo and connectivity levels, providing a bidirectionally traceable system for spectral database curation without forcing connectivity-level MS/MS evidence into stereo-specific compound identities. Full article

Neurodegenerative disorders and epilepsy remain major clinical challenges, due to complex etiologies involving protein misfolding, excitotoxicity, metabolic dysregulation, and impaired cellular resilience. These unmet medical needs have stimulated interest in small-molecule modulators capable of targeting multiple pathogenic pathways. Cyclitols, a diverse family of inositol stereoisomers, play essential roles in cellular signaling and brain metabolism; among them, scyllo-inositol (SCI) has gained attention due to its distinct stereochemistry, capacity to cross the blood–brain barrier, and emerging neuroactive properties. Current pharmacokinetic data indicate that SCI exhibits dose-dependent systemic exposure, and good penetration into the central nervous system. Moreover, its supplementation seems to be well-tolerated. In experimental studies both on animals and humans, SCI has been shown to modulate amyloid-β aggregation, stabilize neuronal homeostatic pathways, and reduce network hyperexcitability, suggesting relevance for both neurodegenerative and epileptic phenotypes. Despite promising results, there is still a need for further analyses to define dosing, transporter involvement, and brain exposure thresholds. Collectively, the available data position SCI as a compelling candidate for translational development, warranting further investigation into its therapeutic window and disease-modifying potential across neurological disorders. Full article

Background/Objectives: Resistant pathogenic bacteria and fungi are a growing problem worldwide; therefore, the discovery of new active ingredients is an important challenge for which the functionalization of natural terpenes with biologically active heterocycles can provide a basis. To reach this goal, a series of 1,4-disubstituted-1,2,3-triazole conjugates was designed and synthesized starting from commercially available α-santonin. Methods: The key azido derivative intermediate was prepared according to literature procedures via Michael addition between dehydrosantonin and the TMSN₃/AcOH/Et₃N system at its highly reactive α-methylene-γ-lactone motif. Subsequently, the obtained azide was applied to regioselective Huisgen 1,3-dipolar cycloaddition reaction with a wide range of terminal alkynes bearing N-, S- and O-heterocycles. These include pyridine, pyrimidine, purine, quinoline, indol, or coumarin to afford the sesquiterpene–heterocycle chimaeras. All triazole conjugates were screened for in vitro antiproliferative activity by MTT assay against HeLa, MDA-MB231, SiHa, MCF-7 and A2780 human cancer cell lines compared with fibroblast cells (NIH/3T3) to check their cytotoxicity and antimicrobial effects on two Gram-positive (B. subtilis, S. aureus) pathogenic bacteria, two Gram-negative (E. coli and P. aeruginosa) pathogenic bacteria, and two yeasts (C. krusei and C. albicans). Results: The results indicated that most of the examined compounds expressed weak activity against human cell lines, while some of them showed moderate activity against S. aureus (up to 99% inhibition at 100 µg/mL conc.), C. krusei (up to 51% inhibition at 10 µg/mL conc.) and C. albicans (up to 52% inhibition at 10 µg/mL conc.). Conclusions: Further structural modification of the best, selective antibacterial and antifungal compounds may open the possibility to the development of effective natural sesquiterpene-based selective antimicrobial agents. Full article

Two new anthraquinone derivatives, (±)-1′-O-methyl-6-chloroaverantin (1a and 1b) and 6-chloroaverythrin (2), and one new diphenyl ether 1-((E)-but-2-en-2-yl)-3,8-dihydroxy-6-((E)-4-hydroxybut-2-en-2-yl)-4,9-dimethyl-11H-dibenzo[b,e][1,4]dioxepin-11-one (3), along with six known compounds, were isolated from the fungus Aspergillus sp. SCSIO 41331 collected from the deep-sea sediment in the cold-seep area of the South China Sea. Elucidation of planar structures was achieved via 1D and 2D NMR and mass spectrometry, whereas stereochemistry was validated through optical rotation and NOE correlations, chiral phase HPLC analysis and NMR calculation. All compounds were assessed for antitumor activity, among which compound 4 displayed moderate antiproliferative activity against HT29 cells and suppressed colony expansion. Full article

The selective detection of small, highly hydrophilic metabolites differing only in stereochemistry represents a major challenge in biosensor development. Here, we present a computational investigation to elucidate the molecular basis of the experimentally observed selectivity of a protein-based electrochemical biosensor toward myo-inositol over D-chiro-inositol. Although the two stereoisomers differ only in the orientation of a single hydroxyl group, they induce distinct dynamic effects on the protein recognition element. Molecular docking revealed comparable binding regions and similar affinity scores, indicating that selectivity does not arise from differences in binding site or docking energy. To investigate dynamic contributions, all-atom molecular dynamics simulations were performed in triplicate (3 × 100 ns) using the AMBER99SB force field and explicit TIP3P water. Trajectory analyses showed that myo-inositol forms a more persistent hydrogen bond network, resulting in reduced residue-level flexibility, more stable ligand–protein interactions, and enhanced local structural stabilization. Overall, these findings support a dynamic model of stereoselective recognition in which ligand-induced modulation of protein conformational ensembles, rather than static affinity, governs biosensor performance. This work highlights the value of molecular dynamics simulations in the rational design of biosensors targeting structurally similar analytes. Full article

An unreported bicyclic sesquiterpene acid, verruculosic acid (1), was isolated together with the previously reported labdane diterpenes, (+)-agathic acid (2a) and hypoxyterpenoid A (2b), one 3-nor-2,3-seco-labdane, penioxalicin (3), and 5-carboxyphthalide (4), from a sea grass-associated fungus, Penicillium verruculosum KUFA1509. The structures of the isolated compounds were elucidated by detailed analyses of 1D and 2D NMR and HRMS data. The absolute configurations of the stereogenic carbons in 1 and 2a were established by X-ray crystallography. The crystal structure of 2a, which was obtained for the first time, was used to prove its structure and confirm its stereochemistry. The crystal structure of 3 was also obtained; however, the value of its flack parameter does not allow us to determine the absolute configuration. Compound 2b exhibited stronger inhibitory activity than the positive control, diclofenac sodium, against LPS-induced nitric oxide (NO) production in RAW264.7 macrophages, while 1 and 2a were slightly less active than the positive control. In contrast, 3 exhibited much weaker activity than 2a. Compounds 1–4 were also assayed for antibacterial activity against reference and multidrug-resistant strains, but none exhibited antibacterial activity against the tested strains. Thus, the labdane skeleton could be considered as a potential scaffold for the development of anti-inflammatory agents through NO inhibition. Full article

Dihydromyricetin (DHM), a naturally occurring flavanonol predominantly found in medicinal plants like Ampelopsis grossedentata, has emerged as a promising source of natural antioxidants with multi-target pharmacological activities relevant to drug discovery. DHM exhibits a strong redox-modulating capacity, effectively attenuating oxidative stress and inflammation central drivers of chronic disease pathogenesis. Beyond direct radical scavenging, DHM regulates multiple redox-sensitive and kinase-mediated signalling pathways, thereby influencing key cellular processes involved in disease initiation and progression. This review synthesizes current evidence on the therapeutic potential of DHM, critically evaluating its mechanistic basis and translational prospects, with emphasis on its dual redox-driven and kinase-mediated modes of action. We detail its roles in metabolic disorders such as diabetes, obesity, and liver diseases, neuroprotection, cardio protection, and cancer prevention, focusing on the modulation of critical networks such as AMPK, PI3K/Akt, MAPK, NF-κB, and Nrf2. The interplay between these pathways underpins DHM’s efficacy across disease models. Furthermore, we highlight structure–activity relationship (SAR) analyses and molecular modelling studies that elucidate how the flavanonol scaffold, hydroxylation pattern, and stereochemistry of DHM govern its biological activities and target engagement. Key pharmacokinetic limitations, advances in extraction techniques, bioavailability challenges, and emerging formulation strategies including advanced delivery systems are discussed to address translational hurdles. Despite compelling preclinical data, the clinical translation of DHM remains constrained by limited human studies and incomplete mechanistic resolution. This review underscores the need for integrated pharmacological studies and innovative delivery approaches to translate the multifaceted promise of DHM into viable clinical interventions. Full article

Triple-negative breast cancer (TNBC) is a clinically aggressive malignancy with extremely limited effective targeted therapies. Natural products are promising alternatives for anticancer drug discovery, whereas integrated computational approaches serve as efficient tools for novel lead identification. Herein, four novel spiro-polycyclic sesquiterpene [4+2] trimers (Inubritantrimers A–D) and eight synthetic derivatives from Inula britannica L. were investigated via DFT calculations at the ωB97xD/6-311++G(2d,p) level (for geometric, electronic, spectral, and reactivity parameters), network pharmacology, molecular docking against seven core breast cancer-related targets, 500 ns all-atom molecular dynamics (MD) simulation, and MM/PBSA analysis. The results showed that the endo-type cycloaddition products had superior structural stability, with all reactions thermodynamically spontaneous (ΔG < 0). Compound 11 exhibited the most potent and balanced binding activity, with a docking free energy of −13.45 kcal/mol to MTOR; MD and MM/PBSA confirmed stable complex formation (total binding free energy −21.13 kcal/mol), driven predominantly by hydrophobic interactions. This study first established a comprehensive stereochemistry–electronic structure–property–activity relationship for this rare sesquiterpene trimer class and identified compound 11 as a promising MTOR-targeted TNBC lead. It provided a theoretical basis for developing high-efficiency, low-toxicity natural anticancer agents. Full article

Chirality has emerged as a critical determinant in the design, efficacy, and environmental behavior of modern insecticides. While a significant proportion of agrochemicals are inherently chiral, most are still commercialized as racemic mixtures, despite well-documented differences in biological activity, toxicity, and degradation pathways between enantiomers. In this review, we provide a comprehensive and critical analysis of advances in the stereoselective synthesis and resolution of chiral insecticides, with particular emphasis on neonicotinoids, pyrethroids, and oxadiazines, including indoxacarb. A systematic survey of the literature (1985–2025), including peer-reviewed articles and patents, reveals that multiple strategies have been developed to access enantiomerically enriched compounds, including asymmetric organocatalysis, transition-metal catalysis, chiral-pool approaches, biocatalytic transformations, and chromatographic resolution techniques. Among these, recent developments in photoredox catalysis, recyclable metal complexes, and enzyme-mediated processes have significantly improved enantioselectivity and scalability, bridging the gap between academic methodologies and industrial applications. Despite these advances, challenges remain in achieving cost-effective, sustainable, and universally applicable asymmetric processes. Importantly, the relationship between stereochemistry and biological performance underscores the need for integrating synthetic chemistry with toxicological and environmental studies. Future directions point toward the incorporation of green chemistry principles, continuous-flow processes, and computational tools, including machine learning and molecular modeling, to accelerate the rational design of enantiopure agrochemicals. This review highlights both the progress achieved and the critical gaps that must be addressed to realize the potential of stereoselective insecticide development fully. Full article

A novel series of hybrid tetrahydro-β-carboline (THβC)-imidazolium (IM) salts incorporating a fused diketopiperazine scaffold was designed, synthesized, and evaluated as cholinesterase inhibitors for potential application in Alzheimer’s disease. The molecular design integrates a π-conjugated THβC core with a cationic IM moiety to promote dual-site interactions within the acetylcholinesterase (AChE) active-site gorge. All compounds exhibited micromolar inhibitory activity against AChE and butyrylcholinesterase (BChE), with a pronounced preference for AChE. The most active derivative, 12d, showed an IC₅₀ value of 0.72 μM toward AChE, while compound 12c demonstrated the highest selectivity (SI = 8.4). Structure–activity relationship studies revealed that both stereochemistry and N-alkyl chain length are critical determinants of activity, with S,S-configured derivatives consistently outperforming their R,R-configured analogs. In silico ADMET analysis indicated favorable physicochemical properties and predicted central nervous system permeability, although potential hepatotoxicity highlights the need for further optimization. Molecular docking studies suggested that the most promising compound adopts a dual-binding mode, interacting with both the peripheral anionic site and catalytic active site of AChE. These results identify THβC-IM hybrids as a structurally novel and promising scaffold for the development of selective cholinesterase inhibitors, providing a basis for further optimization toward multifunctional anti-Alzheimer agents. Full article

8-Hydroxy-dihydroergotamine is the major human metabolite of the anti-migraine drug dihydroergotamine and is required, along with a stable isotope-labelled derivative, to aid metabolic studies. An efficient, scalable synthesis of the unlabelled compound is described via the coupling of dihydrolysergic acid to the tricyclic amino compound (2R,5S,8R,10aS,10bS)-2-amino-5-benzyl-10b-hydroxy-8-methoxy-2-methyltetrahydro-8H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine-3,6(2H,5H)-dione. The tricycle was obtained by a convergent synthesis combining precursors from suitably protected L-glutamic acid and L-phenylalanine, and 2-bromo-2-methylmalonic acid. For the labelled molecule, the tricyclic precursor contained a pentadeutero benzyl group derived from [2,3,4,5,6-²H₅]L-phenylalanine. Considerable experimentation was required to achieve optimal activation of dihydrolysergic acid for efficient amide formation with the tricycle’s amino function affording 8-methoxy-dihydroergotamine. The stereochemical integrity of an intermediate in this synthesis, ethyl (2R,5S,8R,10aS)-5-benzyl-10b-hydroxy-8-methoxy-2-methyl-3,6-dioxooctahydro-8H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine-2-carboxylate, was validated by crystal structure analysis. Acid-catalysed hydrolysis of 8-methoxy-dihydroergotamine gave 8-hydroxy-dihydroergotamine. Pentadeuterated 8-hydroxy-dihydroergotamine was obtained in an analogous manner from [2,3,4,5,6-²H₅]L-phenylalanine. Both 8-hydroxy-dihydroergotamine and its ²H₅-derivative were obtained as an equilibrating mixture of C-8 epimers (diastereomers), with the major isomer having (R)-configuration according to ¹H NMR analysis. The syntheses described enable the routine synthesis of 50–100 mg quantities of each target molecule. Full article

Members of the broad family of Strychnos alkaloids have been the favorite molecules for the development and evaluation of new NMR methods for many years, including the establishment of the ¹H-¹⁵N two-dimensional NMR methods. The present study is an effort to computationally evaluate the ¹⁵N chemical shift behavior of eight members of this structurally diverse group of indole alkaloids. The molecules range from relatively “simple” strychnine and brucine and their respective N-oxides to molecules as complex as vinorelbine, a synthetic analog used in cancer chemotherapy, and sungucine, a naturally occurring complex dimeric member of the family. The 20 ¹⁵N chemical shifts in this study afforded a CMAE of 2.96 ppm and an RMSD of 3.50 ppm, with the data affording a correlation coefficient, r = 0.997. Full article

Three new, previously undescribed tanzawaic acids, steckwaic acids H–J (1–3), and twenty-three known natural products (4–26) were isolated from the marine algicolous fungus Penicillium steckii SCSIO 41040. Structurally, compound 3 underwent a rare hydration reaction at the double bond of its carboxylic acid side chain. The chemical structures and stereochemistry were determined using comprehensive spectroscopic analyses, including NMR, electronic circular dichroism (ECD) calculations, and high-resolution electrospray ionization mass spectrometry (HRESIMS), and verified by literature comparison. The protective effect of tanzawaic acids on inflammatory damage to the intestinal epithelial barrier was assessed using an LPS-stimulated Caco-2/THP-1 co-culture model. Notably, immunofluorescence and Western blotting assays showed that compound 10 significantly enhanced the fluorescence signals and protein expression of ZO-1 and occludin, alleviated lipopolysaccharide (LPS)-induced intestinal barrier damage in Caco-2 cells, and contributed to the re-establishment of intestinal barrier homeostasis. Our findings demonstrate the critical role of tanzawaic acids in maintaining intestinal barrier integrity, identifying them as promising lead compounds for UC treatment. Full article

Background/Objectives: Natural compounds occupy a pharmacologically rich chemical space, characterized by abundant scaffolds, extensive functional group elaboration, and defined stereochemistry. In this context, Helichrysum italicum, a Mediterranean medicinal plant, represents a valuable source of polyphenols with multiple biological and pharmacological activities. Methods: Here, we introduce an inverse molecular docking fingerprint approach to systematically investigate eight major Helichrysum italicum polyphenols, including $\alpha$-pyrones (arzanol, ethylpyrone), flavonols (gnaphaliin, kaempferol, quercetin), and flavanones (naringenin, pinocembrin, hesperetin). More than 40,000 human protein structures from the Protein Data Bank were screened to generate target-based inverse docking score fingerprints for each compound. Results: Hierarchical clustering of these fingerprints revealed shared binding patterns among structurally related polyphenols and enabled hypothesis generation regarding potential synergistic effects. Notably, favorable interactions were identified with PPARG and CARM1, supporting therapeutic relevance in inflammation and cancer, alongside additional targets associated with neurodegeneration and bone metabolism. Conclusions: This study establishes inverse docking fingerprints as a robust, mechanism-oriented method for natural product research and highlights Helichrysum italicum polyphenols as starting points for medicinal chemistry and drug discovery. Full article

While artemisinin and its derivatives demonstrate broad antitumor potential, the stereochemical influence on the bioactivity of higher-order artemisinin assemblies remains inadequately characterized. Herein, we report the synthesis, chromatographic separation, and structural elucidation of four stereoisomeric artemisinin trimers, followed by systematic evaluation of their antitumor efficacy against MCF-7 and MDA-MB-231 breast cancer cell lines. All trimers exhibited potent cytotoxicity against MCF-7 cells (IC₅₀ < 0.09 μM), with trimer 6a (β, β, β) demonstrating robust antitumor activity in both in vitro and in vivo xenograft models. Remarkably, pronounced stereochemistry-dependent activity emerged against MDA-MB-231 cells: 6a displayed approximately 100-fold greater potency than 6b (β, β, α) and 6.6-fold superiority over gemcitabine. Mechanistic investigations revealed that 6a downregulates Cyclin D1, CDK4, and CDK6 expression, thereby inducing G0/G1 phase cell cycle arrest. These findings underscore the pivotal role of stereochemical configuration in modulating artemisinin trimer bioactivity and provide rational guidance for structure-based design of artemisinin-derived anticancer therapeutics. Full article