Chirality最新文献

We report the study of the two enantiomers of the water-soluble cryptophane 1 by Synchrotron Radiation Circular Dichroism (SRCD) in DMSO, LiOH/H₂O, NaOH/H₂O, KOH/H₂O, and CsOH/H₂O solutions. Interestingly, SRCD gives access to new Cotton bands that could not be detected with a conventional CD spectrometer. Our findings reveal that the low-lying excited states detected by SRCD spectroscopy are extremely sensitive to the concentration of the basic solution. In contrast, except for the thallium cation, the nature of the cationic species has only a little impact on the overall shape of the SRCD spectra in LiOH/H₂O (0.1 M) solution.

The objective of this study was to investigate the biotransformation characteristics and stereoselective pharmacokinetic profiles of ibuprofen (IBU) enantiomers following administration of single isomers or a racemic mixture in rats, mice, and guinea pigs. A chiral LC-MS/MS method was employed to simultaneously determine (R)-(−)-ibuprofen and (S)-(+)-ibuprofen in trace whole blood samples (5 μL). Enantiomeric inversion of IBU was assessed after separate administration of single isomers or the racemic mixture, and pharmacokinetic parameters were calculated. Results demonstrated significantly higher AUC_last values for the S-enantiomer compared to the R-enantiomer. Unidirectional enantiomeric inversion from R-IBU to S-IBU was observed in all tested species (rats, mice, and guinea pigs), with no reverse conversion detected. Notably, this study is the first to confirm strictly unidirectional enantiomeric inversion of IBU in guinea pigs. Conversion rates calculated from R-IBU and S-IBU concentrations following racemic IBU administration exhibited significant interspecies differences: 54.9 ± 5.6% (rats), 76.6 ± 5.3% (mice), and 65.6 ± 6.7% (guinea pigs). In contrast, no significant species differences were observed when conversion rates were derived from S-IBU concentrations after administration of individual enantiomers (R-IBU and S-IBU), yielding values of 65.9 ± 6.5%, 76.8 ± 21.2%, and 66.3 ± 14.4% for rats, mice, and guinea pigs, respectively.

Indoxacarb is a typical chiral pesticide composed of two enantiomers, of which only S-(+)-indoxacarb exhibits strong insecticidal activity. Growing interest in its enantioselective toxicology and metabolites has highlighted the need for more data on mammalian metabolism to assess human health risks. In this study, two new pairs of enantiomeric metabolites were identified from indoxacarb metabolism in rats: S-IN-RM493 and S-IN-RM541 derived from S-(+)-indoxacarb, and R-IN-RM493 and R-IN-RM541 derived from R-(−)-indoxacarb. To facilitate a more comprehensive risk assessment, the toxicokinetics of both metabolite pairs (IN-RM493 and IN-RM541) were evaluated in rats. The results showed that IN-RM493 was primarily formed in the stomach, which then entered the systemic circulation and was ultimately eliminated via feces. In contrast, IN-RM541 was primarily produced in the small intestine. Only a small portion of indoxacarb was converted to IN-RM541 in the small intestine, and this metabolite was poorly absorbed by the bloodstream. Consequently, IN-RM541 remained largely confined to intestinal tissues (small intestine, cecum, and large intestine) and feces. Toxicokinetic comparisons revealed that the S-enantiomeric metabolites were cleared more rapidly and accumulated less in tissues than their R-enantiomeric counterparts. This was consistent with the inherent property of S-(+)-indoxacarb, which is more easily metabolized and less prone to accumulation in vivo. Overall, S-(+)-indoxacarb demonstrates a more favorable safety profile than R-(−)-indoxacarb with respect to mammals. These findings provide valuable insights into the toxicology of indoxacarb in mammals, thereby paving the way for the informed agricultural application of its optically pure S-(+)-indoxacarb.

The resolution behavior of chiral compounds containing two carboxyl groups remains an interesting subject due to their potential for forming complex stereospecific interactions. In this study, a representative for this group of compounds, trans-1,2-cyclohexanedicarboxylic acid (CHDA) was enantiomerically separated using optically active (1S,2S)-(+)-1-(p-nitrophenyl)-2-amino-1,3-propanediol ((SS)-ANP) as a resolving agent in ethanol solvent. Remarkably, regardless of the initial molar ratio of (SS)-ANP to CHDA (ranging from 1:3 to 3:1), only a cocrystal, di-(SS)-ANP·CHDA·ethanol was obtained. When the molar ratio was adjusted to 1:2, a pair of diastereomeric salts was formed, and (RR)-CHDA freed from the less soluble diastereomeric salt exhibited an enantiomeric excess (e.e.) exceeding 85%. Upon two cycles of recrystallization of the less soluble salts, the optical purity of the freed (RR)-CHDA reached 96.5 e.e.%. To elucidate the resolution mechanism, single crystals of both the less soluble salt 2(SS)-ANP·(RR)-CHDA·ethanol and the more soluble salt 2(RR)-ANP·(RR)-CHDA·ethanol were grown and structurally analyzed. The crystallographic data revealed that the hydrogen bonding in the less soluble salt was stronger than that in the more soluble salt, enhancing the stability of the less soluble salt, 2(SS)-ANP·(RR)-CHDA·ethanol.

Odevixibat, a selective and reversible inhibitor of the ileal bile acid transporter (IBAT), received approval from the US Food and Drug Administration (FDA) in 2021 as the first therapeutic option for pruritus associated with progressive familial intrahepatic cholestasis (PFIC). In this study, a comprehensive chiral high-performance liquid chromatography (HPLC) method was developed for the enantiomeric and diastereomeric separation of Odevixibat and its stereoisomeric impurities (RS, RR, SS, and SR) using immobilized polysaccharide-based chiral stationary phases. The various chromatographic modes—including normal-phase (NP), reversed-phase (RP), and polar organic (PO)—were systematically investigated. Optimal resolution was achieved using a CHIRALPAK IA column (4.6 × 250 mm, 3 μm) with a mobile phase of n-hexane/isopropanol/methanol/trifluoroacetic acid (50:35:15:0.1, v/v/v/v) at 40°C and a flow rate of 1.0 mL/min. The method was validated according to ICH Q2(R1) guidelines. Additionally, the CHIRALPAK IM in NP mode effectively resolved closely eluting isomeric impurities, enabling preparative isolation and characterization. The optimized RP-mode method was compatible with LC–MS detection, facilitating trace-level impurity profiling on CHIRALPAK ID-3 and structural characterization of stereoisomers and process-related impurities. Thermodynamic analysis revealed entropy-driven enantioseparations, with the NP-HPLC method on CHIRALPAK IA showing more favorable interactions (ΔG° = 0.06) than the RP-HPLC system (ΔG° = 1.34). The method demonstrated excellent linearity (r² > 0.999) over the concentration range of 0.028–0.211 μg/mL, with recoveries between 87.1%–101.2% and precision within 0.8% RSD. High sensitivity was achieved, with LODs of 0.009–0.025 μg/mL and LOQs of 0.028–0.075 μg/mL. The method proved robust under deliberate variations in column temperature (±1°C), mobile phase composition (±2%), and flow rate (1.0 ± 0.1 mL min⁻¹), showing no significant change in enantioresolution. These complementary approaches are suitable for routine quality control (CHIRALPAK IA), purification (CHIRALPAK IM) process monitoring and LC–MS impurity profiling (CHIRALPAK ID-3), and regulatory submissions, supporting current good manufacturing practices (cGMP) in the development of Odevixibat.

A novel kind of framework containing axial 5-OH L-bitryptophane was synthesized under the mild reaction conditions. This synthetic strategy provides an efficient method to construct axial catalysts based on the new framework, which can be easily and economically separated from each other using silica gel column chromatography because the coupling products were atropisomers. For its promising application of the framework, eight catalysts were prepared and the relationship of the different catalytic centers on the enantioselectivity was tested using known and widely used model reactions and good enantiomeric ratios were recorded. Quantum methods were applied for the absolute configurations assignment of the new framework, the transition states (TSs) calculations for reaction mechanism study. The theoretical results agree well with the experiments. One best catalyst 8B with a 13-membered ring was found in the model reaction.

Chiral chromatography is the most sensitive technique in separation science due to the similar properties of the enantiomers, which require highly expert hands. This sort of chromatography has various limitations and issues, especially in efficient separation, detection, and reproducibility. These issues can be tackled by integrating chiral chromatography with artificial intelligence and machine learning approaches. This review article describes the present development in chiral chromatography integration with artificial intelligence and machine learning and future requirements. The most important aspects discussed in this article are the analysis of various software and models needed for integration, method development and optimization of chiral chromatography, and applications of artificial intelligence and machine learning integrated chiral chromatography in real-life samples. Besides, the challenges, recommendations, and future perspectives of artificial intelligence and machine learning integrated chiral chromatography are discussed. This article will be highly useful for applying artificial intelligence and machine learning integration in chiral chromatography in research and industrial applications.

Two previously undescribed jatrophane-type diterpenoids (1, 2) and 11 known compounds (3–13) were isolated from the whole plants of Jatropha curcas L. Their structures were elucidated using IR, HR-ESI-MS, 1D-, and 2D-NMR spectra, and the absolute configurations were established by ECD. The anti-inflammatory activity of these compounds was evaluated by inhibiting NO production in LPS-stimulated RAW264.7 macrophages, and compounds 5, 8–11, and 13 showed potent activity with IC₅₀ values ranging from 16.86 to 32.49 μM, which were comparable with that of the positive control l-NMMA (IC₅₀: 21.90 μM). The structure–activity relationships of jatrophane-type diterpenoids revealed that compounds 5 and 11 showed the most potent anti-inflammatory effects.

Pinocembrin, as a natural dihydroflavone compound, is currently in the clinical phase II research stage as a candidate new drug due to its significant therapeutic effect on stroke. However, there is no report on the systematic study of the pharmacokinetic and pharmacological activity differences of the enantiomers of pinocembrin. This study comprehensively investigated the stereoselective properties of pinocembrin enantiomers through integrated pharmacokinetic, network pharmacological and neuroprotective evaluations on HT22 cells. The results demonstrated distinct stereoselective characteristics in rat plasma between the enantiomers of pinocembrin following intravenous administration, with the plasma concentration of (+)-pinocembrin consistently being higher than that of (−)-pinocembrin. Pharmacokinetic studies of individual enantiomers administered intravenously demonstrated no evidence of stereochemical inversion between the two enantiomers of pinocembrin in either plasma or brain tissue of rats. Network pharmacology analysis revealed multiple potential therapeutic targets related to ischemic stroke pathophysiology, particularly involving apoptosis regulation and inflammatory responses. Both (+)-pinocembrin and (−)-pinocembrin exhibited protective effects against OGD/R-induced injury in HT22 cells at concentrations of 6.25–50 μM and 12.5–50 μM, respectively; however, no statistically significant difference was observed between the two enantiomers. Western blot analysis further revealed that (+)-pinocembrin significantly upregulated the Bax/Bcl-2 ratio and the p-Akt/Akt ratio, suggesting that its neuroprotective effects are mediated through modulation of apoptosis and activation of the Akt signaling pathway. These findings provide a foundation for understanding the stereoselective pharmacological properties of pinocembrin and suggest potential therapeutic applications leveraging the unique characteristics of each enantiomer for neuroprotective interventions.