Chirality最新文献

In this research, estimation of enantioselective pharmacokinetics and biological interconversion of sotorasib were investigated. This is the first report for the novel chiral liquid chromatography–tandem mass spectrometry method for the enantioselective pharmacokinetics determination in biological matrix. Attempts were made to achieve separation in reverse phase mode with mass compatible mobile phase. The baseline chiral separation was achieved with a mobile phase consisting of acetonitrile and aqueous ammonium bicarbonate (15 mM; 95/5 v/v) on Chiralpak IC (250 × 4.6 mm, 5 μm). Positive electrospray ionization was used for monitoring multiple reactions by triple quadrupole. The developed bioanalytical method was validated for each SOT enantiomer, assessing selectivity and specificity, linearity, accuracy, precision, recovery, matrix effect, dilution integrity, and stability. The lower limit of quantification was identified as 1 ng/mL for both SOT enantiomers. The results were found to be in compliance with the bioanalytical method validation guideline. The preclinical study revealed the disparate pharmacokinetic profile between the (R) and (S)-sotorasib, after single oral administration (10 mg/kg) to rats. This is the first investigational evidence of enantioselective behavior of sotorasib in vivo. The results demonstrated that lower maximum concentration, area under curve, and higher clearance and volume of distribution for (R)-sotorasib reveal the poorer bioavailability and higher elimination rate. The study provides insights in controlling the enantiomeric impurity in quality control aspects. This research also provides a reference for clinical practice and supports further research in distomer toxicity, enantioselective drug metabolism, and drug interactions.

The present study reports the chemical investigation on the aerial parts of Cleome droserifolia yielding the related eudesmane sesquiterpene solyraterpenoid A (1) and the novel cledrone A (2) from the acetonitrile fraction of the dichloromethane extract. These compounds were separated by column chromatography, centrifugal thin layer chromatography (CTLC) followed by semipreparative reversed-phase high performance liquid chromatography (RP-HPLC). The chemical structure of these compounds was determined by mono and bidimensional NMR techniques, IR spectroscopy, and HRESIMS, while the absolute configuration was established by computational analysis of ECD spectra. Furthermore, the structure and absolute configuration of both 1 and 2 were unambiguously confirmed via single crystal X-ray diffraction (scXRD). Both compounds showed antibacterial activity against Escherichia coli and Pseudomonas aeruginosa strains, with compound 2 being more active.

Using L-cysteine capped gold nanoparticles (L-Cys-AuNPs) as a colorimetric sensor, an easy, low-cost, and highly efficient strategy for the optical chiral identification of ketoprofen enantiomers was developed. R-ketoprofen tends to rapidly adsorb onto L-Cys-AuNPs, resulting in a color change of the solution from red to purple; however, no significant change was observed upon the addition of S-ketoprofen. The potential of L-cysteine capped with AuNPs (L-Cys-AuNPs) as chiral selectors for the recognition of ketoprofen enantiomers has been investigated using UV–Vis, FESEM, FT-IR, SERS, and zeta potential. The recognition process is easily identified by the naked eye or by using a UV–Vis spectrometer. Sensors L-Cys-AuNPs revealed a good linear response to ketoprofen enantiomers in the concentration range of 8.33–33.33 μM with a relative standard deviation of 3.08%. And detection limit of 2.35 μM. The proposed method was applied to determine the ketoprofen racemic mixture in water samples and commercial tablets. This method represents easy, inexpensive, simple, and very effective methods for the recognition of ketoprofen enantiomers.

Hexahydroquinoline (HHQ) scaffold attracts great interest due to its diverse pharmacological activities. HHQ framework also includes 1,4-dihydropyridine (DHP) ring, the pharmacophore of the most popular group of drugs known as calcium channel blockers, which are frequently used in the treatment of cardiovascular conditions. In this work, we synthesized 15 HHQ-based potential calcium channel modulators (EM1–EM15) as racemic mixtures. The 15 chiral compounds were assayed on five high-efficiency liquid chromatography columns containing different small chiral selectors: derivatized β-cyclodextrin, called CDShell-RSP, WhelkoShell, and three macrocyclic glycopeptide selectors: vancomycin, VancoShell; teicoplanin, TeicoShell; and a modified macrocycle referred as NicoShell. These small chiral selectors were bonded to modern superficially porous 2.7-μm particles and packed in 10-cm columns. Small structural differences in the compounds affect their enantioselectivity. The NicoShell column was the most effective, fully separating the whole set in both the reversed-phase and normal-phase chromatographic modes. For seven compounds, the enantioresolution factor was higher than 7. The VancoShell and WhelkoShell columns could also separate the enantiomers of the entire set of chiral HHQs. The TeicoShell column was somewhat less effective, separating only 13 compounds, while the CDShell-RSP column was not as effective for these particular compounds. In the supercritical fluid chromatographic phase mode, the WhelkoShell column gave outstanding results, fully separating all 15 compounds. For nine compounds, the enantioresolution factors were higher than 5. The three macrocyclic-based chiral columns could fully separate 10 compounds. Preparative separations of these compounds will be possible using the chiral NicoShell column in reversed-phase liquid chromatography or the WhelkoShell column in supercritical fluid chromatography with minimal mobile-phase optimization.

Ensuring the enantiomeric purity of chiral pharmaceuticals is paramount for patient safety and therapeutic efficacy. Upadacitinib (UPA), a vital Janus kinase 1 (JAK-1) inhibitor for rheumatoid arthritis treatment, exemplifies this need. This study represents the development of a robust HPLC method, engineered using analytical quality by design (AQbD), for the simultaneous quantification of UPA and its enantiomeric impurity in pharmaceutical formulations. Our AQbD approach systematically optimized chromatographic separation on a Chiralpak IG column under isocratic elution using n-hexane/ethanol mixture (70:30, v/v) at a flow rate of 1.8 mL/min, UV detection at 230 nm, and a column temperature of 40 °C. Rigorous validation using accuracy profiles confirmed the method suitability. Recognizing the growing imperative for sustainable analytical practices, we further assessed the method environmental impact through comprehensive greenness metrics, while method applicability and sustainability were assessed using Blue Applicability Grade Index (BAGI) and Red-Green-Blue 12 (RGB12) algorithms, respectively. This innovation empowers pharmaceutical manufacturers with a reliable and sustainable tool to guarantee the quality and regulatory compliance of UPA formulations, ultimately contributing to safer and more effective rheumatoid arthritis therapies.

L-3,4-dihydroxyphenylalanine (L-DOPA or Levodopa) is widely used to treat Parkinson's disease, but its large-scale chemical synthesis is costly and environmentally challenging. This study investigates the enzymatic conversion of L-tyrosine to L-Dopa to enhance efficiency and yield without any potential racemization. Tyrosinase, extracted from button mushrooms, was immobilized as cross-linked enzyme aggregates (TY CLEAs), achieving an activity of 31.32 units/g. Commercially available skim milk served as a protein feeder and demonstrated antioxidant properties, helping prevent the formation of L-dopachrome as a byproduct by inhibiting the sequential oxidation of L-dopaquinone, along with ascorbic acid as a reducing agent. We evaluated the stability of TY CLEAs under varying temperatures, pH levels, and organic solvents. High productivity of 1210.95 mgL⁻¹ h⁻¹ was achieved using 10 units of enzyme at a substrate concentration of 15 mM with the use of a surfactant.

³¹P is a very attractive nucleus for nuclear magnetic resonance (NMR) analysis because of the large chemical dispersion and the simplicity of the spectra when compared with other nuclei (other than ¹⁹F). The ability to rapidly and quantitatively assay for enantiomeric excess (ee) measurements of alcohols, amines, thiols, and other chiral species using ³¹P-NMR is essential. Analysis of ee is particularly important in the pharmaceutical industry because a majority of medicinal compounds contain chiral centers, and enantiomers may possess different pharmacological activities. Although high-performance liquid chromatography (HPLC) with chiral stationary phase has become the standard method for ee determination, it can often be expensive and time consuming and requires purified samples. ³¹P-NMR offers advantages over many other nuclei as the interpretation is rapid and can have large chemical shift differences (Δδ) when comparing diastereomers. Proton decoupling avoids overlapping signals by preventing proton coupling, which could result in overlapping signals. With the rapid growth of asymmetric organocatalysis and asymmetric synthesis, the ability to quickly determine ee via phosphorus containing chiral derivatizing agents (CDAs) and chiral solvating agents (CSAs) is of utmost utility. It might be especially useful if used to determine ee directly in a reaction mixture, thereby alleviating any need for purification. This review focuses on ee determination by ³¹P-NMR.

This study has been carried out to extend the validation of an amino alcohol catalyst in the asymmetric transfer hydrogenation (ATH) of ketones. Previously, the catalyst was tested in asymmetric addition to several aromatic aldehydes with good to excellent results. After having optimized the reaction conditions and tested different amino residues, the best catalyst was tested in ATH of various aromatic ketones, leading to generally high yields (up to > 95%) and moderate to good enantioselectivities (ee 24%–69%). Moreover, considering the lack of examples of recoverable and reusable amino alcohol–based nanostructured catalysts for the ATH, the catalyst of choice was immobilized on proper functionalized superparamagnetic core–shell magnetite–silica nanoparticles and employed in an ATH reaction in semi-homogeneous phase. The obtained nanocatalyst exhibited a moderate catalytic efficiency in the ATH, that remains unchanged in the three catalytic cycles performed, even if noticeably worse than in the homogeneous counterpart.