Search Results (182)

Background: Daptomycin, a lipopeptide antibiotic with critical clinical applications, presents a formidable crystallization challenge due to its high conformational flexibility and complex ionization equilibrium. Current literature lacks reports on single crystals or highly crystalline powders of this molecule. This study aims to elucidate the thermodynamic and kinetic mechanisms governing daptomycin solubility and crystallization to establish a rational screening pathway. Methods: In this study, the solubility of daptomycin was systematically measured across eight pure solvents using a static gravimetric method. Molecular-level insights were obtained by integrating experimental data with the Conductor-like Screening Model for Real Solvents (COSMO-RS) and molecular dynamics (MD) simulations. Results: Solubility trends correlated strongly with solvent electrostatic and hydrogen-bonding capabilities. MD simulations revealed that the solvent’s ability to modulate conformational diversity—quantified by the number of dominant conformational clusters—is the decisive factor governing crystallization. For instance, aqueous systems exhibited strong Coulombic stabilization (−1126.61 kJ/mol). Crucially, solvents like acetone restricted daptomycin to a limited number of conformers (12 clusters), significantly lowering the nucleation barrier and yielding crystalline powders with distinct PXRD peaks. Conversely, solvents like methanol induced high conformational diversity (53 clusters), resulting exclusively in amorphous precipitates. Conclusions: The “number of conformational clusters” serves as a robust descriptor for rapidly screening crystallization solvents, effectively bridging thermodynamics and kinetics. This strategy provides a rational, reduced-trial-and-error framework for crystallizing complex, flexible macromolecules with multiple dissociation sites, moving beyond traditional trial-and-error approaches. Full article

The acid dissociation constant (pK_a) is a fundamental parameter governing the environmental fate of organic compounds. Accurate pK_a prediction remains challenging, as traditional binary Morgan fingerprints (B-MF) fail to capture stoichiometric information critical for modeling substituent effects. This study developed an interpretable machine learning framework for pK_a prediction by integrating count-based Morgan fingerprints (C-MF) with ensemble algorithms. Through systematic comparison across four algorithms (Catboost, XGBoost, GBDT, RF), C-MF consistently outperformed B-MF due to its ability to quantify functional group multiplicity. Subsequent SHAP-based recursive feature elimination (SHAP-RFE) optimized the model, identifying Catboost with only 81 features as the optimal architecture, achieving a test-set R² of 0.890 and RMSE of 1.026. SHAP analysis revealed that the model’s decisions are driven by chemically intuitive features, forming a hierarchical framework where primary ionizable sites set the baseline pK_a and electronic modifiers fine-tune it. The applicability domain, defined using the AD_SAL method, yielded high-confidence predictions (R² = 0.926). External validation on an independent open-source dataset containing 6876 acidic compounds, combined with results from AD_SAL application domain characterization, enabled accurate pK_a prediction for 390 compounds within the application domain (R² = 0.890, RMSE = 0.942). This further confirms the model’s strong generalizability. This work provides a robust and generalizable tool for high-performance pK_a prediction, with significant potential for applications in environmental risk assessment. Full article

Calcium phosphate–poly(methyl-methacrylate) composite layers have been synthetized on silicon substrates in magnetron sputtering discharge by adjusting the radio-frequency power. The electron energy distribution function measured at holder substrate position shifts to lower energies when the radio-frequency power applied to the magnetron source increases from 50 to 150 W and the poly(methyl-methacrylate) molecule dissociation is augmented. The optical emission spectral analysis indicated the dynamics of the excitation and ionization processes in the Ar–calcium phosphate–poly(methyl-methacrylate) plasma mixture, as well as the dissociation patterning of the polymer molecules. The Ca I, P I, and H_α atomic lines and CaO, PO, POH, CO, CH and C₂ molecular bands characteristic to the calcium phosphate and poly(methyl-methacrylate) decomposition were evidenced. At 150 W radio-frequency power a reduction in the polymer content in the composite layer volume was observed even if the α-CH₃ main chain and the C=O molecular bands are still present. More C-C/C-H, C-OH/C-O-C polymeric bonds were revealed at the layer surface, indicating the formation of plasma polymers. The Ca/P ratio changes from 1.72 to 1.9 at 50 to 150 W, respectively, maintaining the amorphous structure of the layers. In this power range, the transition of layer surface morphologies from grain-like to worm-like plasma polymer characteristics is connected to an increase in plasma ion density and layer thickness. Full article

The relative position of the oxime group within pharmaceutically relevant pyridinium oximes is a pivotal factor that governs their intrinsic physicochemical properties and their biological reactivity. However, studies providing in-depth, molecular-level insight into these structure–reactivity relationships are still limited. In this work, we present an integrated experimental and computational study of N-methylpyridinium-2-aldoxime chloride (PAM2-Cl), N-methylpyridinium-3-aldoxime iodide (PAM3-I), and N-methylpyridinium-4-aldoxime iodide (PAM4-I), aimed at elucidating discrete differences in their ionization behavior, electronic structure, σ-donor properties, and nucleophilicity. The crystal structure of PAM3-I was determined by X-ray diffraction. Comparative structural and spectroscopic (UV–Vis, NMR, IR) analyses elucidated the structural and electronic effects arising from the position of the oxime group. Kinetic studies of substitution reactions with aquapentacyanoferrate(II) in aqueous solution enabled the determination of pentacyano(PAM)ferrate(II) formation and dissociation rate constants, coordination modes, pK_a values of the coordinated ligands, complex stability constants, and σ-donating capabilities. The DFT-based analysis of atomic charge distribution transcended experimental limitations, offering a new perspective on electronic structure-related properties. This study presents the first side-by-side, internally consistent structure–reactivity map across PAM2, PAM3, and PAM4 isomers that triangulates crystallography, UV–Vis-derived pK_a values, substitution kinetics, and DFT descriptors in a single framework. Full article

The development of effective antioxidants has evolved from descriptive analysis toward a precise, mechanism-driven discipline targeting the molecular “redox switch”. This review synthesizes the critical advances reported since 2021, focusing on how the interplay between polyphenolic architecture and electronic descriptors, such as bond dissociation enthalpy and ionization potential, governs radical scavenging through the HAT, SET, and SPLET pathways. We evaluate the dual influence of metal coordination, where interactions can either enhance antioxidant stability through σ bond polarization or trigger pro-oxidant transitions via ligand-to-metal charge transfer. Central to this progress is the integration of computational models (DFT, QSAR) with advanced synchrotron methodologies (XAS, STXM, SR-FTIR, and SAXS), which provide element-specific validation of antioxidant behavior and subcellular oxidative mapping within complex matrices. Furthermore, we highlight how these molecular insights inform formulation engineering, specifically the development of organic nanocarriers and hybrid delivery systems, such as metal–phenolic networks, that shield therapeutic cargo from degradation and govern release in challenging physiological environments. These fundamental studies provide an essential physicochemical basis for medicine by enabling a better understanding and the rational design of antioxidant drugs, dietary supplements, and antioxidant strategies. Full article

The mechanism of charge partitioning during Coulomb explosion, especially via charge-asymmetric dissociation (CAD) pathways, remains a key question in strong-field molecular dynamics. We present an experimental and theoretical study of CAD in the heteronuclear diatomic molecule iodine bromide (IBr) driven by 800 nm femtosecond laser pulses. Using dc-sliced ion velocity map imaging, we measured the kinetic energy releases of fragment ions I^p+ (p = 1–4) and Br^q+ (q = 1–3), observing both charge-symmetric (CSD) and charge-asymmetric (CAD) dissociation channels. A unified model combining charge-resonance-enhanced ionization (CREI) with a classical over-the-barrier (COB) picture is introduced, which accounts quantitatively for the observed channels. The findings reveal the correlated electron–nuclear dynamics in IBr during Coulomb explosion, advance the understanding of strong-field dissociation in heteronuclear systems, and contribute to the analysis of ultrafast charge transfer in molecules. Full article

Fragmentation Resilience Energy Mass Spectrometry (FREMS) builds on the field of energy-resolved mass spectrometry and previously used methods, e.g., Survival Yield. It exploits breakdown energies at near “continuous” ramp (0.2% NCE increments) to offer higher resolution and a reliable method for compound differentiation, contaminant identification and structural elucidation. Implementation of FREMS involves acquiring ion breakdown/formation curves as collision energy is incrementally increased. These curves themselves can be analyzed by several means to give a single metric—Fragmentation Resilience (FR₅₀). This value has been shown to be experimentally interchangeable with the modified-Survival Yield (m-SY₅₀) and the Cross-Intersect (C-I). A full panel of testing on an LTQ-Orbitrap revealed that breakdown energies depend only on three controllable parameters—number of ions inside the ion trap, Maximum Inject time and Activation Time. A fairly linear relationship (R² > 0.95) with proposed FR₅₀, m-SY₅₀ and C-I metrics provides reliable adjustment mechanisms for these variables via calibrations. Consequently, this technique can be applied to ions produced by any atmospheric pressure ionization processes and treated as exclusively in vacuo experiments. Applications of FREMS to 4-chlorobenzylpyridinium ion revealed that under collisional activated dissociation (CAD) conditions, the rate of decomposition of precursor ion is equivalent to the rate of formation of its fragments, i.e., normalized breakdown and formation curves intersect at inflection points. Full article

Rearrangements such as the McLafferty rearrangement are common in mass spectrometry of positive ions, but rare in negative ions. The present article searched the literature for McLafferty rearrangements of negative ions formed by negative electrospray ionization (-ESI) or by negative-ion chemical ionization (NICI). McLafferty Rearrangements have been reported for negative ions formed by -ESI, yet not for anions formed by NICI in GC-MS and GC-MS/MS. This article reports for the first time a McLafferty Rearrangement of the collision-induced dissociation (CID) of precursor ions due to [M−PFB]⁻ generated by NICI in the GC-MS/MS analysis of pentafluorobenzyl (PFB) esters and thioesters of diethyl phosphates (CH₃CH₂O)₂PO₂, diethyl thiophosphates (CH₃CH₂O)₂PSO, and diethyl dithiophosphates (CH₃CH₂O)₂PS₂. Two specific product anions due to α,β-cleavages and formation of neutral losses of ethene and ethanol are formed. No McLafferty rearrangements were observed in the CID of 1-chloropropyl derivatives of these dialkyl organophosphates in the positive-ion chemical ionization (PICI) mode. McLafferty rearrangements of PFB esters of organophosphates have been observed in the EI mode. No McLafferty rearrangements were observed in the EI and NICI of diethyl fluoro phosphate, a representative of dialkyl fluoro phosphates. McLafferty rearrangements of negative ions seem to be more common than assumed so far. Full article

Lung adenocarcinoma (LUAD), the most prevalent subtype of non-small cell lung carcinoma (NSCLC), commonly metastasizes to the brain, particularly in advanced stages. Since brain metastases (BMs) are a leading cause of morbidity and mortality in LUAD patients, their early detection is critical, necessitating the identification of reliable biomarkers. Gangliosides (GGs), a class of bioactive glycosphingolipids involved in cell signaling, adhesion, and immune regulation, have emerged as promising candidates for diagnostic and therapeutic targeting in LUAD-associated brain metastases (BMLA). In this context, ion mobility spectrometry mass spectrometry (IMS-MS) was employed here to analyze GG alterations in BMLA tissues compared to healthy cerebellar control. The results revealed marked differences, including a reduction in the total number of species, altered sialylation profiles, and variations in fatty acid chain length and sphingoid base hydroxylation. GM3, a monosialodihexosylganglioside, was significantly overexpressed in BMLA, supporting its role in tumor progression via immune evasion and oncogenic signaling. Elevated levels of the brain-specific GT1 ganglioside further point to its possible role as a metastasis-associated biomarker, while the presence of asialogangliosides, absent in normal brain, suggests adaptation to the brain microenvironment. Structural modifications such as O-acetylation, fucosylation, and CH₃COO⁻ were more frequent in BMLA, being associated with aggressive tumor phenotypes. Ceramide profiles revealed increased levels of proliferative C16- and C24-ceramides and decreased pro-apoptotic C18-ceramide. Additionally, GM3(d18:1/22:0) and GD3(d18:1/16:0), identified as potential BMLA biomarkers, were structurally characterized using (−) nanoelectrospray ionization (nanoESI) IMS collision-induced dissociation tandem MS (CID MS/MS). Collectively, these findings highlight the clinical potential of GGs for early diagnosis and targeted therapy in BMLA. Full article

The rapid emergence of novel psychoactive substances (NPSs) after 2020 has created one of the most dynamic analytical challenges in modern forensic science. Hundreds of new synthetic cannabinoids, synthetic cathinones, synthetic opioids, hallucinogens, and dissociatives, appearing as hybrid or structurally modified analogues of conventional drugs, have entered the illicit market, frequently found in complex polydrug mixtures. This review summarizes recent advances in gas chromatography-mass spectrometry (GC-MS) for their detection, structural elucidation, and differentiation between 2020 and 2025 based on the ScienceDirect and Google Scholar databases. Due to its reproducible electron-ionization spectra, established reference libraries, and robustness toward complex matrices, GC-MS remains the primary tool for the separation and identification of emerging NPS. The current literature highlights significant improvements in extraction and pre-concentration procedures, derivatization strategies for thermally unstable analogues, and chromatographic optimization that enable discrimination between positional and stereoisomers. This review covers a wide range of matrices, including powders, herbal materials, vaping liquids, and infused papers, as well as biological specimens such as blood, urine, and hair. Chemometric interpretation of GC-MS data now supports automated classification and prediction of fragmentation pathways, while coupling with complementary spectroscopic techniques strengthens compound confirmation. The review emphasizes how continuous innovation in GC-MS methodology has paralleled the rapid evolution of the NPS landscape, ensuring its enduring role as a reliable, adaptable, and cost-effective platform for monitoring emerging psychoactive substances in seized materials. Full article

Background: Postoperative junctional ectopic tachycardia (JET) is a potentially life-threatening arrhythmia that may occur after congenital heart surgery, especially following tetralogy of Fallot (TOF) repair. It can cause hemodynamic instability due to atrioventricular dissociation. This study aimed to evaluate the incidence, risk factors, and outcomes of JET after TOF repair, with particular focus on management strategies and the impact of JET duration on recovery. Methods: This retrospective study included 114 pediatric patients who underwent TOF repair between 2015 and 2023. The study was approved by the institutional ethics committee (File No: 2023/09-31, Date: 10 October 2023). Postoperative JET was diagnosed based on standard electrocardiographic criteria. Perioperative variables, surgical techniques, and postoperative outcomes were analyzed. Results: JET occurred in 19 patients (16.7%). Compared with patients without JET, those with JET had higher complication rates (73.7% vs. 42.1%, p = 0.02), prolonged inotropic support, and increased mortality (15.8% vs. 2.1%, p = 0.024). Ionized calcium (p < 0.001) and pH levels (p < 0.037) were significantly lower in JET patients. Right ventricular outflow tract muscle resection was strongly associated with JET occurrence (p = 0.003). Although cardiopulmonary bypass and aortic cross-clamp times did not predict JET, both correlated with JET duration (p < 0.05). Conclusions: Postoperative JET remains a major concern following TOF repair, leading to adverse outcomes and longer recovery. Optimizing perioperative management may help reduce JET-related complications, though further multicenter prospective studies are needed to confirm these findings. Full article

This study investigates the antioxidant properties of aucubin (AU), an iridoid compound, focusing on its ability to scavenge hydroxyl radicals (^•OH) through its hydroxyl functional groups. Gaussian software was employed to model and validate the underlying antioxidant reaction mechanisms. Three primary pathways were examined: hydrogen atom transfer (HAT), sequential electron transfer-proton transfer (SET-PT), and sequential proton loss–electron transfer (SPLET). All calculations were performed using the M06-2X functional within density functional theory (DFT) at the def2-TZVP level, incorporating Grimme’s D3 dispersion correction and the implicit solvation model based on solute electron density (SMD) for water. Various thermodynamic parameters were determined to analyze and compare the antioxidant reactions, including the O-H bond dissociation energy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), electron transfer enthalpy (ETE), and proton affinity (PA) of the hydroxy groups. The results indicated that the HAT mechanism is the dominant pathway in the scavenging of ^•OH radicals by AU. The key active sites were identified as the 6-OH group in the aglycone structure and the 6′-OH group in the sugar moiety. Moreover, the polar aqueous environment promoted O-H bond homolysis to enhance the antioxidant activity. Full article

Background/Objectives: Animal and fungal sterols and stanols exhibit remarkable structural diversity, driven by variations in the number and position of C=C bonds within the steroidal tetracyclic core and side chain, along with diverse branching patterns of the latter. Similarly to phytosterols, these metabolites produce highly complex tandem mass spectra, whose interpretation has so far been limited. To address this gap, the fragmentation behavior of selected animal/fungal sterols and stanols was studied in this paper. Methods: Higher-Collisional-energy Dissociation–High-resolution tandem mass spectrometry (HCD-HRMS/MS) of protonated/dehydrated species generated via atmospheric pressure chemical ionization (APCI) was performed on structurally diverse compounds, including lathosterol, desmosterol, zymosterol, lanosterol, ergosterol, chalinasterol, and the stanols coprostanol and cholestanol. Results: Structurally diagnostic product ions originating from the side chains were unveiled, shedding light on the intramolecular migration of positive charge from the initial ionization site at C3 to alternative stable sites across the molecular structure, which is a typical mechanism also noted in cholesterol and phytosterols. In addition, characteristic fragmentation patterns related to the steroidal backbone were found and discussed for Δ⁷, Δ^5,7 and Δ⁸-sterols, and a novel elucidation of the fragmentation behavior of 4,4-dimethyl-Δ⁸-sterols, based on lanosterol as a model compound, was achieved. The relative intensities of diagnostic product ions allowed a correlation with specific structural motifs, and “cholesterol-like” and “stigmasterol-like” fragmentations pathways were recognized. These findings were integrated with prior data on cholesterol and plant sterol fragmentation acquired under identical analytical conditions. Moreover, as a proof of its relevance for novel sterol identification, MS/MS-related information was successfully applied to the identification of a positional isomer (Δ⁷) of zymosterol in baker’s yeast extract, along with typical fungal major sterols. Conclusions: The comprehensive archive of sterol/stanol fragmentations obtained by APCI-HCD-MS/MS might prove very useful for the future characterization of novel sterol/stanol species in complex matrices. Full article

Arachidonic acid (eicosatetraenoic acid) is the precursor of the eicosanoids, which include prostaglandins (PG). Methods based on GC-MS/MS are the Gold Standard for the quantitative analysis of eicosanoids in biological samples. After extraction and derivatization, biological F₂-prostaglandins are analyzed on quadrupole GC-MS/MS apparatus as pentafluorobenzyl (PFB) ester trimethylsilyl (TMS) ether derivatives, i.e., PFB-TMS. Negative-ion chemical ionization (NICI) in the ion source generates abundant anions due to [M-PFB]⁻, which are detected in the selected ion monitoring (SIM) mode. Collision-induced dissociation (CID) of [M-PFB]⁻ in the collision cell generates numerous product ions, which are suitable candidates for quantitative analyses in the selected reaction monitoring (SRM) mode. In this article, we report on investigations of gas-phase reactions of PFB-TMS derivatives of F₂-prostaglandins, which consist of PGF_2α, 8-iso-PGF_2α, and up to 62 further isomers, known as the F₂-isoprostanes. We performed a meta-analysis of previously reported CID mass spectra (32 eV) of PFB-(TMS)₃ of seven chemically closely related isomeric F₂-prostaglandins of the 15-F_2t-IsoP type. This unique dataset contains 19 product ions generated by CID of the common precursor at m/z 569 [M-PFB]⁻ in the m/z range of 150–600. All isomers produced the same product ions, which, however, greatly differed in their intensity. Principal Component Analysis (PCA) and Receiver Operating Characteristic (ROC) Analysis (ROCA) were performed. Two compounds, i.e., 8-iso-9β,11α-PGF_2α and 9α,11β-PGF_2α, and two product ions, i.e., m/z 299 [M-PFB-3×TMSOH]⁻ and m/z 215 [M-PFB-3×TMSOH-C₄H₈-C₂H₄]⁻, were noticeable. ROCA revealed the highest disagreement between PGF_2α and 8-iso-9β,11α-PGF_2α (AUC = 0.7075 ± 0.0834, p = 0.0248). PCA and ROCA are of limited value in the GC-MS/MS of closely chemically related F₂-prostaglandins. Fragmentation mechanisms were proposed for the formation of all 19 product ions generated by CID of common precursor anions due to [M-PFB]⁻. Full article