Search Results (303)

Cyclodextrins (CDs) are cyclic oligosaccharides capable of forming inclusion complexes with various guest molecules, enhancing solubility, stability, and bioavailability. This review outlines the structural features of native CDs and their chemically modified derivatives, emphasizing the influence of functionalization on host–guest interactions. Synthetic approaches for CD derivatization are summarized, with attention to recent developments in stimuli-responsive systems and targeted drug delivery. Analytical techniques commonly employed for characterizing CD complexes, such as spectroscopy, thermal analysis, and molecular modeling, are briefly reviewed. Applications in pharmaceutical formulations are discussed, including inclusion complexes, CD-based conjugates, and nanocarriers designed for solubility enhancement, controlled release, and site-specific delivery. Special consideration is given to emerging multifunctional platforms with biomedical relevance. The regulatory status of CDs is addressed, with reference to FDA- and EMA-approved formulations. Safety profiles and toxicological considerations associated with chemically modified CDs, particularly for parenteral use, are highlighted. This review presents an integrative perspective on the design, characterization, and application of CD-based systems, with a focus on translational potential and current challenges in pharmaceutical development. Full article

The bis-thiourea chiral solvating agent (CSA) BTDA enables the NMR-based determination of absolute configuration in N-3,5-dinitrobenzoyl (DNB) amino acid derivatives without requiring covalent derivatization. A reliable trend of the sense of nonequivalence and absolute configuration is found in both ¹H and ¹³C NMR spectra. A dual-enantiomer approach, using (R,R)- and (S,S)-BTDA, generates diastereomeric complexes with the enantiopure substrate, and distinct spatial arrangements are reflected in consistent and interpretable Δδ values. The observed chemical shift differences correlate reliably with the stereochemistry of the chiral center and are further supported by ROESY (Rotating-frame Overhauser Enhancement SpectroscopY) experiments and binding constants’ measurements, confirming the formation of stereoselective non-covalent complexes. This methodology extends the logic of Mosher’s analysis to solvating agents and remains effective even in samples containing single pure enantiomers of the amino acid derivative. The BTDA-based dual-CSA system thus represents a robust, non-derivatizing strategy for stereochemical assignment by NMR, combining operational simplicity with broad applicability to DNB derivatives of amino acids with free carboxyl function. Full article

Background: Hydroxyl and amino compounds play a significant role in defining the flavor and quality of sauce-flavor Baijiu, yet their comprehensive analysis remains challenging due to limitations in detection sensitivity. In this study, we developed a novel bromine isotope labeling approach combined with ultra-high performance liquid chromatography–high-resolution mass spectrometry (UHPLC-HRMS) to achieve high-coverage profiling of these compounds in sauce-flavor Baijiu. Methods: The method employs 5-bromonicotinoyl chloride (BrNC) for rapid (30 s) and mild (room temperature) labeling of hydroxyl and amino functional groups, utilizing bromine’s natural isotopic pattern (Δm/z = 1.998 Da) for efficient screening. Annotation was performed hierarchically at five confidence levels by integrating retention time, accurate mass, and MS/MS spectra. Results: A total of 309 hydroxyl and amino compounds, including flavor substances (e.g., tyrosol and phenethyl alcohol) and bioactive compounds (e.g., 3-phenyllactic acid), were identified in sauce-flavor Baijiu. The method exhibited excellent analytical performance, with wide linearity (1–4 orders of magnitude), precision (RSD < 18.3%), and stability (RSD < 15% over 48 h). When applied to sauce-flavor Baijiu samples of different grades, distinct compositional patterns were observed: premium-grade products showed greater metabolite diversity and higher contents of bioactive compounds, whereas lower-grade samples exhibited elevated concentrations of acidic flavor compounds. Conclusions: These results demonstrate that the established method is efficient for the comprehensive analysis of hydroxyl and amino compounds in complex food matrices. The findings provide valuable insights for quality control and flavor modulation in sauce-flavor Baijiu production. Full article

A 3D-printed device was designed and printed by a stereolithographic technique (SLA) and coated with a highly selective solid phase extraction resin for on-site diclofenac extraction from wastewater, avoiding the transport and treatment of large volumes of samples in the laboratory. The best results in terms of chemical and mechanical resistance were obtained with Rigid 10K resin. The “stick-and-cure” impregnation technique was used to coat the 3D-printed device with Oasis^® HLB resin. The coated 3D-printed device can be reused up to eight times without losing extraction efficiency. The eluent and derivatization reagent volumes were optimized by a multivariate design. The proposed method allowed for the extraction and determination of diclofenac by PTV-GC-MS, achieving methodological detection and quantification limits of 0.019 and 0.055 μg L⁻¹, respectively, with a preconcentration factor of 46. The analysis time was 23 min per sample. To validate the proposed methodology, addition/recovery tests were carried out in different wastewater samples, obtaining recoveries above 90%. The methodology was applied at the wastewater treatment plant (WWTP) of Calvià (Mallorca, Spain), finding diclofenac in concentrations of 15.39 ± 0.07 μg L⁻¹ at the input of the primary decantation process, 4.48 ± 0.03 μg L⁻¹ at the output of the secondary decantation, and 0.099 ± 0.001 μg L⁻¹ at the output of the tertiary treatment, demonstrating the feasibility of the on-site extraction method in monitoring diclofenac over a wide concentration range. Finally, a greenness index of 0.58 for the proposed on-site sample preparation was achieved according to the AGREEprep metrics, making it an eco-friendly alternative for diclofenac monitoring. Full article

Organophosphorus (OP) pesticides are a class of chemicals that are extensively used worldwide. The exposure to and use of organophosphates can be assessed by analyzing their metabolites and degradation products, such as dialkyl phosphate (DAP), dialkyl thiophosphate (DATP), and dialkyl dithiophosphate (DADTP). However, since these metabolites/hydrolysis products can result from the metabolism or breakdown of several organophosphorus pesticide families, they serve as nonspecific biomarkers and do not indicate the specific pesticide involved in exposure. In an earlier study, chemical derivatization using N-(2-(bromomethyl)benzyl)-N,N-diethylethanaminium bromide (CAX-B) was described to improve the signal intensity of numerous organophosphorus (OP) acids in liquid chromatography tandem mass spectrometry (LC-ESI-MS/MS) analysis. In the present study, CAX-B was employed to derivatize a set of seven phenolic compounds corresponding to the complementary portion of OP pesticides. The derivatization process using CAX-B was performed in acetonitrile with potassium carbonate at 50 °C for 30 min. LC-Orbitrap-ESI-MS/MS was used to analyze the resulting phenol derivatives and their fragmentation patterns were studied. Notably, the derivatized phenols were markedly more sensitive than the underivatized phenols when LC-ESI-MS/MS was used in MRM technique, without being affected by the sample matrix (soil or plant extracts). This derivatization technique aids in identifying OP pesticides, offers insights into their subfamily, and pinpoints a specific compound through the analysis of corresponding phenol derivative. Full article

Background/Objective: Avapritinib is an orally bioavailable tyrosine kinase inhibitor and was approved by the FDA in 2020 for gastrointestinal stromal tumor treatments. Although avapritinib is known to be chiral, its stereochemistry was initially established randomly. This study aims to develop a definitive method for determining avapritinib’s absolute configuration and propose a universal methodology for stereochemical characterization of flexible chiral drugs. Methods: The absolute configuration of avapritinib was determined through an integrated approach combining chiral resolution, chiroptical spectroscopy and synthetic validation. Enantiomeric separation was achieved via chiral liquid chromatography, followed by comprehensive chiroptical characterization including electronic circular dichroism (ECD), specific optical rotation and optical rotatory dispersion. Conformational analysis and density functional theory (DFT) calculations correlated experimental spectra with theoretical predictions, facilitating definitive configurational assignment. The stereochemical determination were further verified through ECD derivatization and chemical synthesis. Finally, the enantiomers’ kinase inhibition profiles against c-KIT D816V were quantitatively assessed. Results: Two enantiomers of avapritinib were resolved via chiral HPLC and a Chiralpak IG column. Through combined experimental ECD spectra and time-dependent DFT calculations employing the core extraction method, the levo-isomer was unambiguously determined as S configuration. This stereochemical assignment was confirmed by p-cyanobenzaldehyde derivatization and de novo synthesis. Biological evaluation revealed (S)-(−)-avapritinib exhibited superior c-KIT D816V inhibitory activity compared to its (R)-(+)-counterpart, a finding corroborated by molecular docking studies elucidating their differential target interactions. Conclusions: This study advances avapritinib stereochemical understanding and establishes a definitive protocol for its absolute configuration assignment, serving as a paradigm for flexible chiral drug characterization. Full article

The quality of persimmon wine is closely related to various compounds, including polysaccharides. Polysaccharides are an essential class of macromolecules that modulate the wine’s chemical and physical characteristics by influencing the colloidal state or interacting with other compounds through non-covalent bonds. Polyphenols, on the other hand, exhibit antioxidant properties and effectively neutralize free radicals. This study employed Luotian sweet persimmons and Brassica napus (rapeseed) as core ingredients for producing functional fermented wine. Using GC-MS, rapeseed polysaccharides were subjected to trifluoroacetic acid hydrolysis and then derivatized via silylation for qualitative analysis of their monosaccharide composition. Molecular docking and molecular dynamics simulations were performed to provide molecular-level insights into the interactions between D-glucopyranose from rapeseed polysaccharides and quercetin, a polyphenol present in persimmon wine. The objective was to explore the binding mechanisms of these compounds during fermentation and to assess how these molecular interactions in-fluence the wine’s flavor and stability. In addition, volatile flavor compounds in two types of persimmon wine (pure persimmon wine and oleoresin-enriched persimmon wine) were qualitatively and quantitatively analyzed using headspace solid-phase microextraction (SPME) combined with gas chromatography–mass spectrometry (GC-MS). The results reveal that D-glucopyranose forms hydrogen bonds with quercetin, modulating its redox behavior and thereby enhancing the antioxidant capacity of persimmon wine. The results from four in vitro antioxidant assays, including DPPH, ABTS, FRAP, and vitamin C analysis, demonstrate that the addition of rapeseed flowers improved the antioxidant activity of persimmon wine. HS-SPME-GC-MS analysis revealed that esters, alcohols, and aldehydes were the primary components contributing to the aroma of persimmon wine. Persimmon wines with varying levels of oleoresin addition exhibited significant differences in the contents of key compounds, which subsequently influenced the aroma complexity and flavor balance. In conclusion, these findings provide reliable data and a theoretical foundation for understanding the role of rapeseed flower in regulating the aroma profile of persimmon wine. These findings also offer theoretical support for a deeper understanding of the fermentation mechanisms of persimmon wine while providing practical guidance to optimize production processes, ultimately improving both product flavor and stability. This study fills a critical academic gap in understanding microscopic molecular interactions during fermentation and offers a novel perspective for innovation in the fermented food industry. Full article

Background: KRAS-G12D mutations drive 20–50% of pancreatic/biliary cancers yet remain challenging to target due to GTP-pocket conservation and high cellular GTP levels. While allosteric inhibitors targeting the SWII pocket (e.g., MRTX1133) show promise, limited chemical diversity and paradoxical cellular/enzymatic activity relationships necessitate the exploration of novel scaffolds. This study aims to develop KRAS-G12D inhibitors and PROTACs to offer a selection of new chemical entities through systematic structure–activity optimization and evaluate their therapeutic potential through PROTAC derivatization. Methods: Eleven compounds featuring heterocyclic cores (pyrimidine/pyrido[4,3-d]pyrimidine/5,6,7,8-tetrahydroprodo[3,4-d]pyrimidine) were designed via structure-based drug design. Antiproliferative activity against KRAS-G12D (Panc1), KRAS-G13D (HCT116) and wild-type (A549) cells was assessed using the CCK-8 assay. KRAS-G12D enzymatic inhibition was measured using a GTPase activity assay. Molecular docking simulations (Sybyl 2.0; PDB:7RPZ) elucidated binding modes. Two PROTACs were synthesized from lead compounds by conjugating E3 ligase linkers. All the novel inhibitors and PROTACs were characterized by means of NMR or HRMS. Results: Compound 10c demonstrated selective anti-proliferation in Panc1 cells (IC₅₀ = 1.40 μM) with 4.9-fold greater selectivity over wild-type cells, despite weak enzymatic inhibition (IC₅₀ > 10 μM). Docking revealed critical hydrogen bonds between its protonated 3,8-diazabicyclo[3.2.1]octane moiety and Asp12/Gly60. The enzymatic inhibitor 10k showed potent KRAS-G12D inhibition (IC₅₀ = 0.009 μM) through homopiperazine-mediated interactions with Glu92/His95. Derived PROTACs 26a/b exhibited reduced potency (IC₅₀ = 3–5 μM vs. parental 10k: 2.22 μM), potentially due to impaired membrane permeability. Conclusions: Eleven novel KRAS-G12D inhibitors with a seven-membered ring pharmacophore were synthesized. Compound 10c showed strong anti-proliferative activity, while 10k exhibited potent enzymatic inhibition. Two PROTACs were designed but showed no clear advantage over 10k. This study provides valuable insights for KRAS-targeted drug development. Full article

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited therapeutic options. Leonotis ocymifolia is a shrub widely used in traditional medicine to alleviate cancer-related symptoms. In a search to find safe and efficacious therapeutic agents from medicinal plants, Leonotis ocymifolia was studied to find compounds with anticancer activity against TNBC. Methods: Compounds from Leonotis ocymifolia were characterized using spectroscopic data such as IR, 1D and 2D NMR, and MS spectrometry and evaluated for cytotoxic activity against triple-negative breast cancer (HCC70), hormone receptor-positive breast cancer (MCF-7), and non-tumorigenic mammary epithelial cell lines (MCF-12A). Results: A previously unreported bis-spirolabdane, 13S-nepetaefolin (1), together with five known labdane diterpenoids, namely nepetaefolin (2), dubiin (3), nepetaefuran (4), leonotin (5), and leonotinin (6), from the genus Leonotis were isolated. Overall, the labdane diterpenoids showed selective activity toward triple-negative breast cancer cells (HCC70). Of the compounds extracted, 13S-nepetaefolin demonstrated the greatest cytotoxic activity with an IC₅₀ of 24.65 µM (SI = 1.08) against HCC70 cells; however, it was equally cytotoxic to non-tumorigenic MCF-12A breast cells (IC₅₀ of 26.55 µM), whereas its isomer (2) showed no activity. This suggests that stereochemistry might have an effect on the cytotoxic activity of the bis-spirolabdane diterpenoids. All the compounds (1–6) demonstrated adsorption, distribution, metabolism, and excretion properties (ADME), while leonotin (5) and leonotinin (6) exhibited lead-like properties and high synthetic accessibility scores. Conclusions: The findings from this study warrant further investigation of L. ocymifolia for potential triple-negative breast cancer (TNBC) therapeutic agents, including potential chemical derivatization of bis-spiro labdane diterpenoid (1) to improve selectivity to TNBC over non-cancer cells. Full article

Chromatography–mass spectrometry typically requires a time-consuming and costly pretreatment to detect illegal additives in cosmetics. Retinoic acid is classified as a prohibited additive in cosmetics by the European Union and China. Therefore, a rapid and convenient method is needed for its detection. In this study, a method for detecting retinoic acid using Reactive Paper Spray Ionization Mass Spectrometry was developed. N′-dimethylpiperazine was used as the derivatization reagent due to its ability to react with carboxyl functional groups at room temperature. Our results indicate that the derivatized retinoic acid compounds obtained using this method exhibited good linearity within the range of 0.0005~0.1 μg·mL⁻¹, achieving a limit of detection of 0.107 ng·mL⁻¹. Full article

β-glucan, a promising drug candidate for immuno-antitumor therapy, holds tremendous potential for clinical applications. However, the absence of highly sensitive quantitative methods for polysaccharides, attributed to their complicated chemical structures and susceptibility to endogenous interference, has posed significant challenges for their clinical development. Here, we report a highly sensitive and reliable analytical strategy for quantifying β-1, 3/1, 6-glucan derived from Durvillaea antarctica (BG136) in various biological matrices. This approach integrates targeted depolymerization and derivatization, followed by oligosaccharide isomer fingerprinting using ultra-high-performance liquid chromatography-triple quadrupole tandem mass spectrometry (UHPLC-MS/MS). The absolute quantification of BG136 relied on the abundance of the structure-specific trisaccharide (Glc-β1, 6-Glc-β1, 3-Glc) generated. This methodology not only facilitates prototype-based BG136 administration but also exhibits remarkable sensitivity. Following method optimization and validation, we successfully explored the in vivo fate of BG136 across multiple models, including cellular uptake and release kinetics, as well as preclinical and clinical pharmacokinetics. These achievements provide insight into the “black box” of BG136 from administration to elimination in vivo. This work marks the first practical application of this strategy in complex biological matrices, offering methodological support for the successful execution of the BG136 Phase I clinical trial. Full article

Non-volatile organic acids (NVOAs) are essential to the flavor profile of Baijiu. However, the low levels and diversity of NVOAs in Baijiu make their isolation, annotation, and quantification challenging. In this study, a well-established pipeline combining chemical derivatization, isotope labeling, and high-resolution mass spectrometry with a three-tier annotation process was used to quantify NVOAs in three typical flavor types of Baijiu with high coverage and confidence. The results revealed the annotation of 56, 145, and 1277 NVOAs in Baijiu at tier 1, tier 2, and tier 3 levels, respectively. Among them, a total of 166 high-confidence NVOAs were first reported in Baijiu. Furthermore, multivariate statistical analyses indicated that abundant NVOAs could potentially be used as biomarkers to distinguish between different flavor types of Baijiu. This study provides a powerful tool for the qualification and quantification of NVOAs in Baijiu. The results will greatly expand the understanding of NVOAs in Baijiu. Full article

Current research demonstrates the expanding therapeutic potential of heparin derivatives in oncology, extending beyond traditional anticoagulation mechanisms. This systematic analysis examines the structural characteristics, molecular mechanisms, and therapeutic applications of heparin-based compounds in malignancy treatment. The essential antithrombin binding pentasaccharide sequence has enabled development of specialized molecular variants, particularly fractionated heparins and their non-anticoagulant counterparts. These agents exert antineoplastic effects via multiple pathways, particularly through modulation of heparanase enzymatic activity and specific protein–glycosaminoglycan interactions. Evidence from pivotal clinical trials (FRAGMATIC, MAGNOLIA, GASTRANOX) confirms efficacy in managing cancer-associated thrombosis while indicating potential enhancement of chemotherapeutic outcomes. The preparation methods utilize enzymatic cleavage reactions and selective chemical derivatization to generate structurally modified heparins exhibiting unique molecular characteristics and biological activities. Analysis of the glycosaminoglycan analog dociparstat sodium reveals significant activity in myeloid malignancies, mediated by specific interference with CXCL12/CXCR4 signaling cascades. Significant challenges remain in manufacturing scale-up, analytical validation, and long-term safety assessment. Future studies must address dose optimization, combination strategies, and controlled clinical trials to determine the full therapeutic potential of these compounds in clinical oncology. Full article

Hair care products that have oxidative hair dye ingredients have been widely used to permanently change hair color for the characteristic and younger appearance of people and/or their companion animals. In the European Union and the Republic of Korea, these ingredients have been carefully used or prohibited for cosmetic products according to their genotoxic potential. There is a growing demand for reliable quantification methods to monitor oxidative hair dye ingredients in hair care products. However, accurately quantifying oxidative dyes in cosmetic samples is challenging due to their high reactivity and chemical instability under both basic and ambient conditions. For this reason, for the quantification methods, elaborate sample preparation procedures should be accompanied by chemical derivatization to avoid chemical reactions between hair dye ingredients, before instrumental analysis. Therefore, this study utilized a gas chromatography–mass spectrometry (GC-MS) method combined with in situ chemical derivatization to quantify 26 oxidative hair dye ingredients in hair care products. In situ derivatization using acetic anhydride provided the characteristic [M-CH₂CO]⁺ ions at m/z (M-42), produced by the loss of a ketene from the hair dye ingredient derivatives. These characteristic ions can be used to establish a selective ion monitoring (SIM) mode of GC-MS. The established method was successfully applied to hair dye products (n = 13) and hair coloring shampoos (n = 12). Most products contained unintended hair dye ingredients including catechol without labeling. It was cautiously speculated that these unintended hair dye ingredients might be caused by biodegradation due to various enzymes in natural product extracts. This study presents a reliable GC-MS method with in situ derivatization to quantify 26 oxidative hair dye ingredients in hair care products, addressing challenges related to their chemical instability. This method is crucial for public health and regulatory compliance. Full article

The dysregulation of fatty acid (FA) metabolism is linked to various brain diseases, including Alzheimer’s disease (AD). Mass spectrometry imaging (MSI) allows for the visualization of FA distribution in brain tissues but is often limited by low detection sensitivity and high background interference. In this work, we introduce a novel on-tissue chemical derivatization method for FAs using Girard’s Reagent T (GT) as a derivatization reagent combined with 2-chloro-1-methylpyridinium iodide (CMPI) as a coupling reagent and triethylamine (TEA) to provide a basic environment for the reaction. This method significantly enhances the detection sensitivity of FAs, achieving a 1000-fold improvement over traditional negative ion mode analysis. Our method enabled us to observe a notable depletion of oleic acid in the corpus callosum of AD mouse model brain tissue sections compared to wild-type control brain tissue sections. The reliability of our method was validated using LC-MS/MS, which confirmed the presence of eight distinct GT-labeled FAs across various tissue locations. This approach not only improves FA detection in brain tissues but also has the potential to provide a deeper understanding of FA dynamics associated with AD pathogenesis. Full article