Search Results (284)

Perezone, a sesquiterpene quinone, was the first natural product isolated in crystalline form on the American continent in 1852. It is commonly found in the roots of herbs from the Acourtia species (formerly Perezia). This molecule, along with its synthetic isomer isoperezone, exhibits antineoplastic effects, among others. In this study, an enzymatic reaction (green chemistry) was employed to oxidize the C12−C13 double bond of perezone and isoperezone. This method proved to be more effective than traditional toxic chemical oxidants. As result, epoxides were obtained, followed by acetonides, diols, and esters. All compounds were successfully synthesized and characterized using standard spectroscopic techniques. In breast cancer cell tests, the isoperezone acetonide showed the highest cytotoxicity, with an IC₅₀ of 8.44 µM. Additionally, a computational study was performed at the DFT (B3LYP) level of theory, indicating that the geometrical and energy differences between 6-R and 6-S stereoisomers are 0.5 kcal/mol, and the spectroscopic and electronic properties aligned with the experimental data. Finally, molecular docking revealed binding energies of −8.14 kcal/mol for 6-R and −8.04 kcal/mol for 6-S, with a hydrogen bond of 2.9 Å involving the His121 residue. A chemoinformatic prediction was also conducted to compare cytotoxicity results. Full article

Antibiotic stereoisomers as components of medicines are typically characterized by different biological activities. Because pharmaceuticals can include a racemic mixture of stereoisomers, monitoring of all forms is required. One contaminant of food products, antibiotic ofloxacin (OFL), as a chiral compound, has two enantiomers—the biologically active S-isomer and less active R-isomer. In this study, a sensitive immunochromatographic test system for simultaneous enantiospeсific detection of the two OFL isomers was developed for the first time. For this, polyclonal antibodies were produced, and conditions for a double lateral flow immunoassay (LFIA) were selected and optimized so that the cross-reactivity with another enantiomer was negligible. The LFIA was performed in a competitive format with gold nanoparticles as a label for secondary antibodies. The achieved LODs/cutoffs were 0.001/10 and 0.007/30 ng/mL for S-OFL and R-OFL detection, respectively; the assay procedure took only 15 min. A double LFIA was performed to detect S-OFL and R-OFL in milk with minimal sample pretreatment; the recoveries were 85–95%. The developed test system is an effective tool for the selective detection of both isomers of OFL, allowing for the avoidance of false negative results. This immunochromatographic approach can be promising for the control of other optically active food toxicants. Full article

The mixture of enantiomers in pharmaceuticals can lead to adverse effects, as demonstrated by thalidomide, where one enantiomer exhibited therapeutic properties while the other was teratogenic. Currently, efforts are focused on developing efficient catalysts capable of selectively producing a single stereoisomer, particularly in the synthesis of neuropharmaceuticals and NSAIDs. In this context, a new chiral catalyst was synthesized, featuring a palladium core and the dipeptide L-lysine-glycine as a ligand. The catalyst was characterized using various spectroscopic techniques and exhibited enantiomeric excesses of up to 40% in aldol reactions. Additionally, it efficiently promoted Heck cross-coupling reactions, indicating its potential catalytic versatility. Full article

The control of crystal form in chiral active pharmaceutical ingredients (APIs) is a critical challenge in pharmaceutical development, as differences in solid-state structure can significantly influence physical properties and manufacturing performance. Troglitazone, a molecule with two chiral centers, exists as four stereoisomers (RR, SS, RS, SR) that crystallize as two enantiomeric pairs: RR/SS and RS/SR. This study aims to elucidate the relationship between solution-state molecular interactions and crystallization behavior of these diastereomeric pairs. Antisolvent crystallization experiments were conducted for both mixed solutions containing all four isomers and solutions of individual pairs. Crystallization kinetics were monitored by HPLC, and the resulting solids were characterized by PXRD, DSC, TG, and microscopic observation. Nucleation induction times were determined over a range of supersaturation levels. To probe intermolecular interactions in solution, NOESY and targeted NOE NMR experiments were performed, and the results were compared with crystallographic data. The RS/SR crystals(H-form) consistently exhibited shorter induction times and faster crystallization rates than the RR/SS crystals (L-form), even under conditions where RR/SS solutions were more supersaturated. In mixed solutions, H-form crystallized preferentially, with L-form either remaining in solution or being incorporated into H-form crystals as a solid solution. NOESY and NOE analyses revealed intermolecular proximities between protons that are distant in the molecular structure, indicating the presence of ordered aggregates in solution. These aggregates were more structurally compatible with the H-form than with the L-form crystal lattice, as supported by crystallographic distance analysis. The results demonstrate that differences in nucleation kinetics between troglitazone diastereomers are closely linked to solution-state molecular arrangements. Understanding these relationships provides a molecular-level basis for the rational design of selective crystallization processes for chiral APIs. Full article

Levoglucosenone (LGO) smoothly undergoes microwave-assisted hetero-Diels–Alder reactions with thiochalcones in THF solution at 60 °C. The studied reactions are completed after 10 min, and the expected tricyclic 2,3-dihydro-4H-thiopyran derivatives are formed in a highly regio- and moderately stereoselective manner via competitive exo- and endo-attacks of the 1-thiadiene moiety onto the activated C=C bond of dienophile LGO. Although eight isomers are possible, only the formation of exo,exo- (major) and exo,endo- (minor) cycloadducts was observed. In most cases, isomeric products were separated by preparative layer chromatography and identified by means of spectroscopic methods. Some of the cycloadducts were obtained as single crystalline solids, and X-ray analyses enabled unambiguous confirmation of their structures. In order to explain the observed selectivity of the studied hetero-Diels–Alder reactions, DFT studies were carried out to determine the thermodynamic and kinetic properties of all regio- and stereoisomers. The results of these calculations predict the preferred formation of the two experimentally observed isomers. In addition, remarkable details on the electronic structure of E-1,3-diphenylprop-2-en-1-thione and on involved and hypothetical transition states could be elucidated. Full article

The discovery of Asgard archaea has reshaped our understanding of eukaryotic origins, supporting a two-domain tree of life in which eukaryotes emerged from Archaea. Building on this revised framework, we propose the Pre-prokaryotic Organismal Lifeforms Existing Today (POLET) hypothesis, which suggests that relic pre-prokaryotic life forms—termed POLETicians—may persist in deep, anoxic, energy-limited environments. These organisms could represent a living bridge to the RNA world and other origin-of-life models, utilizing racemic oligoribonucleotides and peptides, non-enzymatic catalysis, and mineral-assisted compartmentalization. POLETicians might instead rely on radical-based redox chemistry or radiolysis for energy and maintenance. These biomolecules may be racemic or noncanonical, eluding conventional detection. New detection methods are required to determine such life. We propose generalized nanopore sequencing of any linear polymer—including mirror RNAs, mirror DNAs, or any novel genetic material—as a potential strategy to overcome chirality bias in modern sequencing technologies. These approaches, combined with chiral mass spectrometry and stereoisomer-resolved analytics, may enable the detection of molecular signatures from non-phylogenetic primitive lineages. POLETicians challenge the assumption that all life must follow familiar biochemical constraints and offer a compelling extension to our search for both ancient and extant forms of life hidden within Earth’s most extreme environments. Full article

In this article, an efficient and straightforward protocol for the construction of complex dispirocyclic skeletons via regioselective intramolecular Michael addition is presented. Diverse dispirocyclic compounds were synthesized under mild and transition-metal-free conditions with good to excellent yields. Most stereoisomers were conveniently separated by column chromatography, and their relative configurations were identified by single-crystal X-Ray diffraction of representative compounds. A scale-up experiment validated the practicality of this method. In an in vitro assay, some dispirocyclic compounds exhibited potent cytotoxicity with an IC₅₀ value of 10⁻⁶ mol/L. Full article

The reaction of either the L (2S3R) or D (2R3S) enantiomers of H₂N-C*H(R)CO₂⁻ (R = -C*H(OH)CH₃ or -C*H(OH)CH(CH₃)₂) and the L (2S) or D (2R) enantiomers of H₂N-C*H(C(CH3)₂OH)CO₂⁻ with imidazole-4-carboxaldehyde and nickel(II) acetate in methanol yields a single stereoisomer of an oxazolidine. There is retention of chirality on ring positions 4 and 5 (if C_β is chiral) of the oxazolidine, C_α and C_β of the parent amino acid, and transfer of chirality to the newly generated stereogenic centers, ring positions 3, the amino acid nitrogen atom, N_AA, and 2, the aldehyde carbon atom, C_ald. Specifically, when C_α has an S configuration, both N_AA and C_ald are formed as R. Likewise, a C_α which is R results in both N_AA and C_ald being formed as S. For example, the reaction of L threonine (C_α is S and C_β is R) with 4-imidazolecarboxaldehyde in the presence of nickel(II) gives the facial Λ NiL₂, where L is (2R, 3R, 4S, 5R) 4-carboxylato-5-methyl-2-(4-imidazolyl)-1,3-oxazolidine. The same reaction with D threonine produces the enantiomeric Δ complex of (2S, 3S, 4R, 5S) 4-carboxylato-5-methyl-2-(4-imidazoyl)-1,3-oxazolidine. The high stereospecificity is thought to be based on the fused three-ring structure of the characterized nickel complexes in which the hydrogen atoms of C_α, N_AA, and C_ald must be cis to one another. Identical reactions occur with 2-pyridine carboxaldehyde and LT or DT. In contrast, the reactions of L allo threonine (2S3S) and the primary alcohols, L or D serine, give the conventional meridionally coordinated aldimine product. Full article

The stability of collagen, the most abundant protein in humans and many animals, is related to the hydroxylation of L-proline, a post-translational modification occurring at carbon 3 and 4 on its pyrrolidine ring. Collagens of different origins have shown different proline hydroxylation levels, making hydroxyprolines useful biomarkers in structure characterizations. The presence of two chiral carbon atoms, 3-hydroxyproline and 4-hydroxyproline, results in eight stereoisomers (four pairs of enantiomers) whose quantitation in collagen hydrolysates requires enantioselective analytical methods. Capillary electrophoresis was applied for the separation and quantitation of the eight stereoisomers of 3- and 4-hydroxyproline and D,L-proline in collagen hydrolysates. The developed method is based on the derivatization with the chiral reagent (R)-(-)-4-(3-Isothiocyanatopyrrolidin-yl)-7-nitro-2,1,3-benzoxadiazole, enabling the use of a light-emitting diode-induced fluorescence detector for high sensitivity. The separation of the considered compounds was accomplished in less than 10 min, using a 500 mM acetate buffer pH 3.5 supplemented with 5 mM of heptakis(2,6-di-O-methyl)-β-cyclodextrin as the chiral selector. The method was fully validated and showed the adequate sensitivity for the application to samples of collagen hydrolysates. The analysis of samples extracted from chicken Pectoralis major muscles affected by growth-related myopathies showed different stereoisomer patterns compared to those from the unaffected control samples. Full article

A novel and general approach to the practical ROMP polymerization of cinchona alkaloid derivatives providing novel hybrid materials having quinine attached on a poly(norbornene-5,6-dicarboxyimide) matrix is presented. The concept involves an easy modification of quinine (in general, any cinchona alkaloid) toward clickable 9-azide that reacts with N-propargyl-cis-5-norbornene-exo-2,3-dicarboxylic imide in Cu(I)-catalyzed Huisgen cycloaddition (click chemistry). The resulting monomers undergo a controllable ROMP reaction that leads to novel polymers of a desired length and solubility. This sequence allows for the facile preparation of a regularly decorated polymeric material having one quinine moiety per single mer of the polymer chain inaccessible using typical immobilization methods. A poly(norbornene-5,6-dicarboxyimide) type of polymeric matrix was selected due to the high reactivity of the exo-norbornene motif in Ru(II)-catalyzed ROMP and its chemical and thermal stability as well as convenient, scalable access from inexpensive cis-5-norbornene-exo-2,3-dicarboxylic anhydride (‘one-pot’ Diels–Alder reaction of dicyclopentadiene and maleic anhydride). An appropriate combination of a Grubbs catalyst, Ru(II) (G1, G2), and ROMP conditions allowed for the efficient synthesis of well-defined soluble polymers with mass parameters in the range Mn = 2.24 × 10⁴ – 2.26 × 10⁴ g/mol and Mw = 2.90 × 10⁴–3.05 × 10⁴ g/mol with good polydispersity, Đ_M = 1.32–1.35, and excellent thermal stability (up to 309°C T_d10). Spectroscopic studies (NMR and electronic circular dichroism (ECD)) of these products revealed a linear structure with the slight advantage of a trans-configuration of an olefinic double bond. The resulting short-chain polymer discriminates mandelic acid enantiomers with a preference for the (R)-stereoisomer in spectrofluorimetric assays. This concept seems to be rather general with respect to other molecules dedicated to incorporation into the poly(norbornene-5,6-dicarboxyimide) chain. Full article

The Bacillus horneckiae-like strain 2011SOCCUF3 was isolated from the marine sponge Spongia officinalis and its metabolome was studied for secondary metabolites with antimicrobial activity. Culturing in the presence of Diaion HP-20 resin and purifying the culture extract identified cyclo-phenylalanine-proline (cyclo-(Phe-Pro)), a 2,5-diketopiperazine (2,5-DKP), isolated as a major metabolite. Further, LCMS analysis of the extract showed the presence of two isomers of the molecule in the culture broth. To confirm the stereochemistry of the isomers observed in the natural extract, all four stereoisomers of cyclo-(Phe-Pro) were synthesised. NMR and LCMS studies identified the presence of both cis- and trans-cyclo-(Phe-Pro) isomers. Stability and epimerisation studies on synthetic isomers and the effect of culturing conditions suggested that the less stable cis isomer was naturally produced, which epimerised in culture broth. Full article

Crohn’s disease is an inflammatory bowel disease (IBD) that currently lacks satisfactory treatment options. Therefore, new targets for new drugs are urgently needed to combat this disease. In the present study, we investigated the transcriptomics-based mRNA expression of intestinal biopsies from patients with Crohn’s disease. We compared the mRNA expression profiles of the ileum and colon of patients with those of healthy individuals. A total of 72 genes in the ileum and 33 genes in the colon were differentially regulated. Among these, six genes were overexpressed in both tissues, including IL1B, TCL1A, HCAR3, IGHG1, S100AB, and OSM. We further focused on OSM/oncostatin M. To confirm the responsiveness of intestinal tissues from patients with Crohn’s disease to oncostatin M inhibition, we examined the expression of the oncostatin M using immunohistochemistry in patient biopsies as well as in kindlin-1^−/− and kindlin-2^−/− knockout mice, which exhibit an inflammatory bowel disease (IBD) phenotype, and found strong oncostatin M expression in all samples examined. Next, we conducted a drug-repurposing study using the supercomputer MOGON and bioinformatic methods. A total of 13 candidate compounds out of 1577 FDA-approved drugs were identified by PyRx-based virtual drug screening and AutoDock-based molecular docking. Their lowest binding energies (LBEs) ranged from −10.46 (±0.08) to −8.77 (±0.08) kcal/mol, and their predicted inhibition constants (pK_i) ranged from 21.62 (±2.97) to 373.78 (±36.78) nM. Ecamsule has an interesting stereostructure with two C₂-symmetric enantiomers (1S,4R-1′S,4′R and 1R,4S-1′R,4′S) (1a and 1b) and one meso diastereomer (1S,4R-1′R,4′S) (1c). These three stereoisomers showed strong, albeit differing, binding affinities in molecular docking. As examined by nuclear magnetic resonance and polarimetry, the 1S,4R-1′S,4′R isomer was the stereoisomer present in our commercially available preparations used for microscale thermophoresis. Ecamsule (1a) was chosen for in vitro validation using recombinant oncostatin M and microscale thermophoresis. Considerable dissociation constants were obtained for ecamsule after three repetitions with a K_d value of 11.36 ± 2.83 µM. Subsequently, we evaluated, by qRT-PCR, the efficacy of ecamsule (1a) as a potential drug that could prevent oncostatin M activation by inhibiting downstream inflammatory marker genes (IL6, TNFA, and CXCL11). In conclusion, we have identified oncostatin M as a promising new drug target for Crohn’s disease through transcriptomics and ecamsule as a potential new drug candidate for Crohn’s disease through a drug-repurposing approach both in silico and in vitro. Full article

Novel peptides based on common amino acid building blocks may serve as possible drug candidates; however, their flexible structures may require stabilization via the incorporation of conformational constraints. The insertion of unusual amino acids is a feasible option that may provide improved pharmacokinetic and pharmacodynamic properties of such peptide-type drugs. The stereochemical purity of these kinds of building blocks must be verified by an efficient separation technique, such as high-performance liquid chromatography. Here, we present and discuss the results of the stereoselective separation mechanism of ß-methylated phenylalanine (ß-MePhe), tyrosine (ß-MeTyr), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (ß-MeTic), and cyclohexylalanine (ß-MeCha) together with non-methylated Phe, Tyr, Tic, and Cha applying Cinchona alkaloid-based chiral stationary phases (CSPs). The studied zwitterionic CSPs acting as ion exchangers provided optimal performance in the polar ionic mode when methanol or a mixture of methanol and acetonitrile was utilized as the mobile phase together with organic acid and base additives. It was found that the basicity of small amines applied as mobile phase additives did not directly influence the chromatographic ion exchange concept. However, the size of the amines and their concentration led to a reduced retention time following the principles of ion exchange chromatography. On the basis of a systematic study of the effects of the eluent composition on the chromatographic behavior, important structure–retention and enantioselectivity relationships could be revealed. Through a temperature study, it has become evident that the composition of the eluent and the structure of analytes markedly affect the thermodynamic properties. Full article

Background/Objectives: Hypertensive disorders of pregnancy are a leading cause of pregnancy-related deaths in the United States, accounting for 7% of maternal mortality. Labetalol and nifedipine are the first-line drugs for the management of hypertension in pregnancy, but there are little data guiding the choice of one drug over the other. The current pilot longitudinal study aims to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of labetalol stereoisomers throughout pregnancy and postpartum. Methods: This is a single-center clinical study recruiting up to 40 pregnant individuals ≥ 18 years of age at the time of enrollment, taking labetalol as per the standard of care. The exclusion criteria include any pathophysiology impacting the PK of labetalol, e.g., liver failure. Maternal plasma, urine, amniotic fluid, cord blood, and breast milk will be collected, and labetalol stereoisomers will be measured using a validated LC-MS/MS assay. Heart rate and blood pressure will be measured as the PD endpoints. These may be assessed throughout a participant’s dosing interval at scheduled PK study visits, which will occur every 6–10 weeks during pregnancy, at delivery, during the 1st week postpartum, and up to 20 weeks postpartum. The primary aim is to characterize the PK and PD of labetalol during pregnancy and in the postpartum period. The secondary aim is to determine the extent of breast milk excretion of and infant exposure to labetalol from breast milk. The data will be analyzed using population PK modeling to evaluate the PK/PD relationship and ultimately develop trimester-specific dosing recommendations. Results/Conclusions: To our knowledge, this is the first study aiming to characterize the PK of labetalol stereoisomers across pregnancy and postpartum, utilizing individual stereoisomer data to evaluate the PK/PD relationship, and collecting postpartum samples, including breast milk, to model infant exposure to labetalol through breast milk. This study will provide important PK/PD data and knowledge which will be combined with large multi-center clinical trial data to develop trimester-specific dosing regimens for anti-hypertensive agents. Full article

In low-resource and point-of-care settings, traditional PCR often faces challenges of poor sample preparation, adverse environmental conditions, and long assay times. We have previously described a laboratory-based instrument to achieve “adaptive” PCR, a PCR thermocycling control system that replaces preset cycling times and temperatures with the optical monitoring of added L-DNA stereoisomers matching the sequences of the reaction primers and target. These L-DNA biosensors directly monitor DNA hybridization, compensating for ambient environmental conditions and poor sample preparation. This report describes instrument simplifications and a comparative evaluation of both direct photothermal and plasmonic laser heating to reduce the assay time to 15 min. Instrument performance was assessed using a split sample design to compare reaction performances of 1370 and 808 nm adaptive PCR heating modalities to a standard PCR instrument. Both the novel 1370 nm direct heating and the 808 nm plasmonic method achieved target amplification similar to the traditional PCR system within 15 min. However, a major disadvantage of 808 nm heating was nanorod optical interference that reduced the fluorescence signal from PCR probes and optical cycling components. Further characterization of the 1370 nm direct heating method found comparable limits of detection of 10⁰ copies/µL and reaction efficiencies of approximately 2 for both the 1370 nm system and the traditional PCR instrument. These results suggest that a field-deployable PCR instrument design incorporating both adaptive optical control and 1370 nm laser heating can achieve 15 min sample assay times without sacrificing analytical sensitivity. Full article