Rhodanines and related five-membered heterocycles with multiple heteroatoms have recently gained a reputation of being unselective compounds that appear as “frequent hitters” in screening campaigns ...and therefore have little value in drug discovery. However, this judgment appears to be based mostly on anecdotal evidence. Having identified various rhodanines and related compounds in screening campaigns, we decided to perform a systematic study on their promiscuity. An amount of 163 rhodanines, hydantoins, thiohydantoins, and thiazolidinediones were synthesized and tested against several targets. The compounds were also characterized with respect to aggregation and electrophilic reactivity, and the binding modes of rhodanines and related compounds in published X-ray cocrystal structures were analyzed. The results indicate that the exocyclic, double bonded sulfur atom in rhodanines and thiohydantoins, in addition to other structural features, offers a particularly high density of interaction sites for polar interactions and hydrogen bonds. This causes a promiscuous behavior at concentrations in the “screening range” but should not be regarded as a general knockout criterion that excludes such screening hits from further development. It is suggested that special criteria for target affinity and selectivity are applied to these classes of compounds and that their exceptional and potentially valuable biomolecular binding properties are consequently exploited in a useful way.
Abstract
Numerous terpenes present in essential oils (EOs) display one or more chiral centers. Within the same genus the enantiomeric ratio of these compounds can be different. Thus, the ...determination of enantiomers is a valuable tool to evaluate authenticity and quality of EOs. In here, the terpene profile of primary and commercial pine EOs was analyzed by conventional and chiral gas chromatography coupled to a flame ionization detector. The enantiomeric excess of ( ±)-α-pinene was determined and significant differences between primary and commercially available EOs were observed. Primary EOs of
Pinus sylvestris
L. showed a positive enantiomeric excess of (+)-α-pinene whereas commercial EOs labeled as
P. sylvestris
L. exhibited an enantiomeric excess of (−)-α-pinene. Thus, chiral analysis provides useful information on the authenticity of pine EOs and allows to uncover possible mislabeling, the use of the wrong herbal substance and sources of adulteration in pine oil.
α-Pinene: A never-ending story Allenspach, Martina; Steuer, Christian
Phytochemistry (Oxford),
October 2021, 2021-10-00, 20211001, Letnik:
190
Journal Article
Recenzirano
Odprti dostop
α-Pinene represents a member of the monoterpene class and is highly distributed in higher plants like conifers, Juniper ssp. and Cannabis ssp. α-Pinene has been used to treat respiratory tract ...infections for centuries. Furthermore, it plays a crucial role in the fragrance and flavor industry. In vitro assays have shown an enantioselective profile of (+)- and (−)-α-pinene for antibacterial and insecticidal activity, respectively. Recent research has used pre-validated biological structures to synthesize new chemical entities with pharmacological and herbicidal activities.
In summary, this review focuses on recent literature covering synthetic pathways of flavor compounds and scaffold hopping based on the α-pinene core domaine, as well as the (enantioselective) activities of α-pinene. Recent approaches for authenticity control of essential oils based on their enantiomeric profile are also presented.
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•Monoterpene α-pinene shows enantioselective biological activities.•The core domain of α-pinene is of high scientific value for the synthesis of new chemical entities.•Synergistic interaction of α-pinene offers a great potential in different therapeutic areas.
Gamma-hydroxybutyrate (GHB) remains a challenging clinical/forensic toxicology drug. Its rapid elimination to endogenous levels mainly causes this. Especially in drug-facilitated sexual assaults, ...sample collection often occurs later than the detection window for GHB. We aimed to investigate new GHB conjugates with amino acids (AA), fatty acids, and its organic acid metabolites for their suitability as ingestion/application markers in urine following controlled GHB administration to humans. We used LC-MS/MS for validated quantification of human urine samples collected within two randomized, double-blinded, placebo-controlled crossover studies (GHB 50 mg/kg, 79 participants) at approximately 4.5, 8, 11, and 28 h after intake. We found significant differences (placebo vs. GHB) for all but two analytes at 4.5 h. Eleven hours post GHB administration, GHB, GHB-AAs, 3,4-dihydroxybutyric acid, and glycolic acid still showed significantly higher concentrations; at 28 h only GHB-glycine. Three different discrimination strategies were evaluated: (a) GHB-glycine cut-off concentration (1 µg/mL), (b) metabolite ratios of GHB-glycine/GHB (2.5), and (c) elevation threshold between two urine samples (> 5). Sensitivities were 0.1, 0.3, or 0.5, respectively. Only GHB-glycine showed prolonged detection over GHB, mainly when compared to a second time- and subject-matched urine sample (strategy c).
Chromatographic profiles of primary essential oils (EO) deliver valuable authentic information about composition and compound pattern. Primary EOs obtained from
L. (PS) from different global origins ...were analyzed using gas chromatography coupled to a flame ionization detector (GC-FID) and identified by GC hyphenated to mass spectrometer (GC-MS). A primary EO of PS was characterized by a distinct sesquiterpene pattern followed by a diterpene profile containing diterpenoids of the labdane, pimarane or abietane type. Based on their sesquiterpene compound patterns, primary EOs of PS were separated into their geographical origin using component analysis. Furthermore, differentiation of closely related pine EOs by partial least square discriminant analysis proved the existence of a primary EO of PS. The developed and validated PLS-DA model is suitable as a screening tool to assess the correct chemotaxonomic identification of a primary pine EOs as it classified all pine EOs correctly.
As LC–MS/MS techniques are becoming more accessible even outside of highly specialized clinical laboratories, pre-analytical issues such as drug stability during specimen storage should be critically ...evaluated before implementing therapeutic drug monitoring. Our study investigated the influence of physico-chemical properties of different drugs in regard to their interaction with gel separators used in commercial available collection tubes.
Drug spiked blood samples were analyzed after storage in different commercial gel- and non-gel based serum tubes. LC–ESI–MS/MS based methods were used to determine drug concentration in serum samples.
Lipophilic compounds, defined by logP>3 and a compatibility factor>20 are prone to be efficiently and rapidly absorbed by lipophilic gel barriers inducing a significant in-vitro decrease of drug concentration over a short storage time. Our data show a relevant drop of concentration of posaconazole, sertraline and citalopram when stored in gel based tubes. Molecular descriptors such as logP, polar surface area and protein binding seem to be good predictive markers to identify gel interacting drugs.
For ease of handling and minimization of blood drawing times, we assume that tubes containing separator gel can be used for therapeutic drug monitoring of high hydrophilic drugs. In contrast lipophilic compounds showing logP higher than 3 and/or CF>20 should be critically considered and validated by extensive stability studies.
Abbreviations: logP, partition coefficient; PSA, polar surface area; TDM, therapeutic drug monitoring; ACN, acetonitrile; MeOH, methanol; IVD, in-vitro diagnostic; CF, compatibility factor
•Physico-chemical properties of drugs influence the adsorption to the gel barrier.•LogP, PSA and protein binding seems to be good predictive markers.•Drugs showing a logP>3 should be critically reviewed.•Tubes with mechanical separator can prevent interaction between drug und gel layer.
Hepatic encephalopathy is a neuropsychiatric complication of liver disease which is partly associated with elevated ammonemia. Urea hydrolysis by urease-producing bacteria in the colon is often ...mentioned as one of the main routes of ammonia production in the body, yet research on treatments targeting bacterial ureases in hepatic encephalopathy is limited. Herein we report a hydroxamate-based urease inhibitor, 2-octynohydroxamic acid, exhibiting improved in vitro potency compared to hydroxamic acids that were previously investigated for hepatic encephalopathy. 2-octynohydroxamic acid shows low cytotoxic and mutagenic potential within a micromolar concentration range as well as reduces ammonemia in rodent models of liver disease. Furthermore, 2-octynohydroxamic acid treatment decreases cerebellar glutamine, a product of ammonia metabolism, in male bile duct ligated rats. A prototype colonic formulation enables reduced systemic exposure to 2-octynohydroxamic acid in male dogs. Overall, this work suggests that urease inhibitors delivered to the colon by means of colonic formulations represent a prospective approach for the treatment of hepatic encephalopathy.
Background
Currently, an increasing demand of cannabis-derived products for recreational and medical use is observed. Therefore, the reliable and fast quantification of cannabinoids in hemp samples ...is essential for the control of product from
Cannabis sativa
, L. strains. In general, gas chromatography (GC) is the method of choice for the quantification of cannabinoids whereas this method is time consuming and the detection of acidic precursor is not feasible without derivatization.
Methods
We report the successful development and validation of an accurate and broadly applicable reversed-phase high-performance liquid chromatography (RP-HPLC) method coupled to an ultra violet (UV) detector including an optimized extraction procedure for the separation and quantification of eight different cannabinoids.
Results
The optimized method is able to separate cannabidivarin, cannabidiolic acid, cannabigerolic acid, cannabigerol, cannabidiol, cannabinol, Δ9-tetrahydrocannabinol, and tetrahydrocannabinolic acid within 10 min. For all target analytes, the %-Bias at the lower and upper calibration range varied from − 1.3 to 10.3% and from − 3.9 to 8.6%, respectively. The most suitable agent for extracting cannabis plant samples was evaluated to be a mixture of acetonitrile and water in a ratio 1:1. The extraction efficiency was more than 95% for all analytes in recreational hemp samples. Stability studies on acidic cannabinoids showed a high likeliness of decarboxylation at 100 °C and aromatization after exposure to UV light, respectively. A modified loss on drying method revealed a moisture content between 4 and 10%. The developed method was successfully applied to measure the cannabinoid content in recreational and forensic hemp samples representing broad range of cannabinoid amounts and patterns.
Conclusion
The present work proposes validated methods for the determination of cannabinoids in cannabis samples. The use of RP-HPLC-UV renders this method broadly applicable and allows the detection of acidic precursor in even less time compared to GC-based methods.
Rose oil is traditionally produced by the water distillation of
and is of high economic value due to the low essential oil yield. It is therefore a common target for adulteration, which can cause ...harm to consumers. Current standards for authenticity control only consider the analysis of major components and overlook minor quality markers as well as the enantiomeric ratio of terpenes, which have proven useful in originality determination. The aim of this study was the development of two analytical GC-FID methods for the analysis of 21 and 29 rose oil analytes including major, minor and chiral components on a DB-wax and BGB 178 30% CD (chiral) capillary column, respectively. The total run time for both methods was within 60 min. For all target analytes, the % bias at the lower and upper calibration range varied from -7.8 to 13.2% and -13.1 to 5.2% analysed on the DB-wax column and 0.5 to 13.3% and -6.9 to 7.0% analysed on the chiral column. The chiral analysis successfully separated the enantiomers (+/-)-camphene, (+/-)-rose oxide, (+/-)-linalool, (+/-)-citronellol and (+/-)-citronellyl acetate, as well as the diastereomers of citral and β-damascenone. Both methods were applied to the analysis of 10 authentic rose oil samples and the enantiomeric/diastereomeric ratios, as well as the content of major and minor components, were determined. The identity of the analysed components in the authentic samples was further confirmed by GC-MS.
Essential oils (EOs) are complex mixtures of volatile hydrocarbons with a wide range of applications in the pharmaceutical, fragrance and food industry. The composition of EOs is highly variable and ...can affect their quality and pharmaceutical efficacy. Moreover, the high economic value of EOs, such as those obtained from Rosa damascena, make falsification and misclassification a lucrative business. Consequently, adulterations can lead to serious health consequences for consumers. While current quality control methods for EOs involve analysing their chromatographic profile or comparing their Fourier transform infrared (FT-IR) spectra, these methods can be time-consuming or lack sensitivity. To address these issues, we compared state-of-the-art quality control methods, including gas chromatography flame ionization detection (GC-FID) quantification and enantiomeric ratio determination, FT-IR spectrometry with dielectric barrier discharge ionization coupled to triple quadrupole mass spectrometer (DBDI-MS), in a chemometric single- and multi-block approach.
Our results show that the best classification accuracy of 94.7% for R. damascena samples was obtained using GC-FID combined with partial least square discriminant analysis (PLS-DA). Comparatively, the enantiomeric ratios did not improve classification accuracy. In contrast, fragmentation data from DBDI-MS (Q3), which was acquired in a fraction of the analysis time and without extensive sample preparation, achieved a classification accuracy of 84.2%. We also found that combining FT-IR with parent ion DBDI-MS (Q1) data in a multi-block sequentially orthogonalized partial least squares linear discriminant analysis (SO-PLS-LDA) model improved classification accuracy, compared to their respective single-block PLS-DA models.
Overall, our study demonstrates that DBDI, as an ambient ionization method, has significant potential for high-throughput screening. When combined with MS, it can produce comparable classification accuracies to conventional methods, while offering the added benefits of speed and convenience. As such, DBDI-MS is a promising tool for EO quality control.
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•DBDI-MS is useful for fast authenticity control of essential oils.•Ease of handling represents a valuable alternative to classical GC-FID analysis.•Highest specificity was observed in the PLS-DA model on DBDI-MS fragmentation data.•SO-PLS-LDA model of FT-IR and DBDI-MS (Q1) data outperforms its single block models.
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