Expanding the Role of Chiral Drugs and Chiral Nanomaterials as a Potential Therapeutic Tool.

Chirality, the property of molecules having mirror-image forms, plays a crucial role in pharmaceutical and biomedical research. This review highlights its growing importance, emphasizing how chiral drugs and nanomaterials impact drug effectiveness, safety, and diagnostics. Chiral molecules serve as precise diagnostic tools, aiding in accurate disease detection through unique biomolecule interactions. The article extensively covers chiral drug applications in treating cardiovascular diseases, CNS disorders, local anesthesia, anti-inflammatories, antimicrobials, and anticancer drugs. Additionally, it explores the emerging field of chiral nanomaterials, highlighting their suitability for biomedical applications in diagnostics and therapeutics, enhancing medical treatments.

Electrochemical chiral sensor for recognition of amino acid enantiomers with cyclodextrin-based microporous organic networks.

BACKGROUND: Chirality is a ubiquitous phenomenon in nature, but enantiomers exhibit different pharmacological activities and toxicological effects. Therefore, Chiral recognition plays a pivotal role in various fields such as life sciences, chemical synthesis, drug development, and materials science. The synthesis of novel chiral composites with well-defined loading capabilities and ordered structures holds significant potential for electrochemical chiral recognition applications. However, the design of selective and stable electrochemical chiral recognition materials remains a challenging task. RESULT: In this work, we construct a simple and rapid electrochemical sensing platform for tryptophan (Trp) enantiomer recognition using cyclodextrin-modified microporous organic network as chiral recognition agent. CD-MON with chiral microenvironment was prepared by Sonogashira-Hagihara coupling reaction of the chiral molecule heptyl-6-iodo-6-deoxyß-cyclodextrin and 1, 4-Diethynylbenzene. The adhesion of BSA makes CD-MON firmly fixed on the electrode surface, and as a chiral protein, it can improve the chiral recognition ability through synergistic effect. Chiral amino acids are in full contact with the chiral microenvironment during pore conduction of MON, and L-Trp is more stably bound to CD-MON/BSA due to steric hindrance, host-guest recognition and hydrogen bonding. Therefore, the electrochemical sensor can effectively identify tryptophan enantiomers (IL-Trp/ID-Trp = 2.02), and it exhibits a detection limit of 2.6 µM for L-Trp. UV-Vis spectroscopy confirmed the adsorption capacity of CD-MON towards tryptophan enantiomers in agreement with electrochemistry results. SIGNIFICANCE: The prepared chiral sensor has excellent stability, reproducibility (RSD = 3.7%) and selectivity, realizes the quantitative detection of single isomer in tryptophan racemic and quantitative analysis in real samples with 94.0%-101.0% recovery. This work represents the first application of MON in chiral electrochemistry which expands the application scope of chiral sensors and holds great significance in separation science and electrochemical sensing.

Remote magnetically stimulated xanthan-biochar-Fe3O4-molecularly imprinted biopolymer hydrogel toward electrochemical enantioselection of l-tryptophan.

Monitoring the levels of L-Tryptophan (L-Trp) in body fluids is crucial due to its significant role in metabolism and protein synthesis, which ultimately affects neurological health. Herein, we have developed a novel magneto-responsive electrochemical enantioselective sensor for the recognition of L-Trp based on oriented biochar derived from Loofah, Fe3O4 nanoparticles, and molecularly imprinted polydopamine (MIPDA) in xanthan hydrogel. The successful synthesis of these materials has been confirmed through physicochemical and electrochemical characterization. Various operational factors such as pH, response time, loading sample volume, and loading of active materials were optimized. As a result, the sensor exhibited an affordable linear range of 1.0-60.0 µM, with a desirable limit of detection of 0.44 µM. Furthermore, the proposed electrochemical sensor demonstrated good reproducibility and desirable selectivity for the determination of L-Trp, making it suitable for analyzing L-Trp levels in human plasma and serum samples. The development presented offers an appealing, easily accessible, and efficient strategy. It utilizes xanthan hydrogel to improve mass transfer and adhesion, biochar-stabilized Fe3O4 to facilitate magnetic orientation and accelerate mass transfer and sensitivity, and polydopamine MIP to enhance selectivity. This approach enables on-site evaluation of L-Trp levels, which holds significant value for healthcare monitoring and early detection of related conditions.

A review on the enantioselective distribution and toxicity of chiral pesticides in aquatic environment.

Chiral pesticides account for about 40% of the total pesticides. In the process of using pesticides, it will inevitably flow into the surface water and even penetrate into the groundwater through surface runoff and other means, as a consequence, it affects the water environment. Although the enantiomers of chiral pesticides have the same physical and chemical properties, their distribution, ratio, metabolism, toxicity, etc. in the organism are often different, and sometimes even show completely opposite biological activities. In this article, the selective fate of different types of chiral pesticides such as organochlorine, organophosphorus, triazole, pyrethroid and other chiral pesticides in natural water bodies and sediments, acute toxicity to aquatic organisms, chronic toxicity and other aspects are summarized to further reflect the risks between the enantiomers of chiral pesticides to non-target organisms in the water environment. In this review, we hope to further explore its harm to human society through the study of the toxicity of chiral pesticide enantiomers, so as to provide data support and theoretical basis for the development and production of biochemical pesticides.

High production of enantiopure (R,R)-2,3-butanediol from crude glycerol by Klebsiella pneumoniae with an engineered oxidative pathway and a two-stage agitation strategy.

BACKGROUND: (R,R)-2,3-butanediol (BDO) is employed in a variety of applications and is gaining prominence due to its unique physicochemical features. The use of glycerol as a carbon source for 2,3-BDO production in Klebsiella pneumoniae has been limited, since 1,3-propanediol (PDO) is generated during glycerol fermentation. RESULTS: In this study, the inactivation of the budC gene in K. pneumoniae increased the production rate of (R,R)-2,3-BDO from 21.92 ± 2.10 to 92.05 ± 1.20%. The major isomer form of K. pneumoniae (meso-2,3-BDO) was shifted to (R,R)-2,3-BDO. The purity of (R,R)-2,3-BDO was examined by agitation speed, and 98.54% of (R,R)-2,3-BDO was obtained at 500 rpm. However, as the cultivation period got longer, the purity of (R,R)-2,3-BDO declined. For this problem, a two-step agitation speed control strategy (adjusted from 500 to 400 rpm after 24 h) and over-expression of the dhaD gene involved in (R,R)-2,3-BDO biosynthesis were used. Nevertheless, the purity of (R,R)-2,3-BDO still gradually decreased over time. Finally, when pure glycerol was replaced with crude glycerol, the titer of 89.47 g/L of (R,R)-2,3-BDO (1.69 g/L of meso-2,3-BDO), productivity of 1.24 g/L/h, and yield of 0.35 g/g consumed crude glycerol was achieved while maintaining a purity of 98% or higher. CONCLUSIONS: This study is meaningful in that it demonstrated the highest production and productivity among studies in that produced (R,R)-2,3-BDO with a high purity in Klebsiella sp. strains. In addition, to the best of our knowledge, this is the first study to produce (R,R)-2,3-BDO using glycerol as the sole carbon source.

Chiral inversion induced by aromatic interactions in short peptide assembly.

Although hydrophobic interactions provide the main driving force for initial peptide aggregation, their role in regulating suprastructure handedness of higher-order architectures remains largely unknown. We here interrogate the effects of hydrophobic amino acids on handedness at various assembly stages of peptide amphiphiles. Our studies reveal that relative to aliphatic side chains, aromatic side chains set the twisting directions of single ß-strands due to their strong steric repulsion to the backbone, and upon packing into multi-stranded ß-sheets, the side-chain aromatic interactions between strands form the aromatic ladders with a directional preference. This ordering not only leads to parallel ß-sheet arrangements but also induces the chiral flipping over of single ß-strands within a ß-sheet. In contrast, the lack of orientational hydrophobic interactions in the assembly of aliphatic peptides implies no chiral inversion upon packing into ß-sheets. This study opens an avenue to harness peptide aggregates with targeted handedness via aromatic side-chain interactions.

Enzymatic Synthesis of Unprotected α,ß-Diamino Acids via Direct Asymmetric Mannich Reactions.

α,ß-Diamino acids are important structural motifs and building blocks for numerous bioactive natural products, peptidomimetics, and pharmaceuticals, yet efficient asymmetric synthesis to access these stereoarrays remains a challenge. Herein, we report the development of a pyridoxal 5'-phosphate (PLP)-dependent enzyme that is engineered to catalyze stereoselective Mannich-type reactions between free α-amino acids and enolizable cyclic imines. This biocatalyst enabled one-step asymmetric enzymatic synthesis of the unusual pyrrolidine-containing amino acid L-tambroline at gram-scale with high enantio- and diastereocontrol. Furthermore, this enzymatic platform is capable of utilizing a diverse range of α-amino acids as the Mannich donor and various cyclic imines as the acceptor. By coupling with different imine-generating enzymes, we established versatile biocatalytic cascades and demonstrated a general, concise, versatile, and atom-economic approach to access unprotected α,ß-diamino acids, including structurally complex α,α-disubstituted α,ß-diamino acids with contiguous stereocenters.

Stereodivergent Synthesis of Pyridyl Cyclopropanes via Enzymatic Activation of Pyridotriazoles.

Hemoproteins have recently emerged as powerful biocatalysts for new-to-nature carbene transfer reactions. Despite this progress, these strategies have remained largely limited to diazo-based carbene precursor reagents. Here, we report the development of a biocatalytic strategy for the stereoselective construction of pyridine-functionalized cyclopropanes via the hemoprotein-mediated activation of pyridotriazoles (PyTz) as stable and readily accessible carbene sources. This method enables the asymmetric cyclopropanation of a variety of olefins, including electron-rich and electrodeficient ones, with high activity, high stereoselectivity, and enantiodivergent selectivity, providing access to mono- and diarylcyclopropanes that incorporate a pyridine moiety and thus two structural motifs of high value in medicinal chemistry. Mechanistic studies reveal a multifaceted role of 7-halogen substitution in the pyridotriazole reagent toward favoring multiple catalytic steps in the transformation. This work provides the first example of asymmetric olefin cyclopropanation with pyridotriazoles, paving the way to the exploitation of these attractive and versatile reagents for enzyme-catalyzed carbene-mediated reactions.

Synthesis of 3,4-Disubstituted Maleimide Derivatives via Phosphine-Catalyzed Isomerization of α-Succinimide-Substituted Allenoates Cascade γ'-Addition with Aryl Imines.

3,4-disubstituted maleimides find wide applications in various pharmacologically active compounds. This study presents a highly effective approach for synthesizing derivatives of 3,4-disubstituted maleimides through the direct isomerization of α-succinimide-substituted allenoates, followed by a cascade γ'-addition and aryl imines using PR3 as a catalyst. The resulting series of 3,4-disubstituted maleimides exhibited excellent stereoselectivities, achieving yields of up to 86%. To our knowledge, the phosphine-mediated γ'-addition reaction of allenoates is seldom reported.

Preparation and study of a capillary electrochromatographic column prepared by conjugating ß-CD COFs and gold-poly glycidyl methacrylate nanoparticles.

A new enantioselective open-tubular capillary electrochromatography (OT-CEC) was developed employing ß-cyclodextrin covalent organic frameworks (ß-CD COFs) conjugated gold-poly glycidyl methacrylate nanoparticles (Au-PGMA NPs) as a stationary phase. The resulting coating layer on the inner wall of the fabricated capillary column was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), energy dispersive spectroscopy (EDS), and electroosmotic flow (EOF) experiments. The performance of the fabricated capillary column was evaluated by CEC using enantiomers of seven model analytes, including two proton pump inhibitors (PPIs, omeprazole and tenatoprazole), three amino acids (AAs, tyrosine, phenylalanine, and tryptophan), and two fluoroquinolones (FQs, gatifloxacin and sparfloxacin). The influences of coating time, buffer concentration, buffer pH, and applied voltage on enantioseparation were investigated to obtain satisfactory enantioselectivity. In the optimum conditions, the enantiomers of seven analytes were fully resolved within 10 min with high resolutions of 3.03 to 5.25. The inter- to intra-day and column-to-column repeatabilities of the fabricated capillary column were lower than 4.26% RSD. Furthermore, molecular docking studies were performed based on the chiral fabricated column and as ligand isomers of analytes using Auto Dock Tools. The binding energies and interactions acquired from docking results of analytes supported the experimental data.

Stereo flexible synthesis of the C8-C23 fragment of antarlides, androgen receptor antagonists.

A practical and efficient synthesis of the C8-C23 fragment of antarlides A-H, incorporating six stereocenters and a conjugated diene, is reported. A strategic combination of synthetic methods, including CBS reduction, Evans' aldol reaction, Keck-Maruoka allylation, and enzymatic resolution, enabled the selective introduction of these stereocenters. Furthermore, the pivotal coupling of key fragments is successfully executed through a Julia-Kocienski olefination reaction, connecting the C8-C14 and C15-C23 subunits.

Stereoselective Synthesis of meso- and l,l-Diaminopimelic Acids from Enone-Derived α-Amino Acids.

The stereoselective synthesis of meso-diaminopimelic acid (meso-DAP), the key cross-linking amino acid of the peptidoglycan cell wall layer in Gram-negative bacteria, and its biological precursor, l,l-DAP, is described. The key step involved stereoselective reduction of a common enone-derived amino acid by substrate- or reagent-based control. Overman rearrangement of the resulting allylic alcohols, concurrent alkene hydrogenation and trichloroacetamide reduction, and subsequent ruthenium-catalyzed arene oxidation completed the synthesis of each stereoisomer. The synthetic utility of this approach was demonstrated with the efficient preparation of an l,l-DAP-derived dipeptide.

Challenges encountered in the enantioselective analysis of new psychoactive substances exemplified by clephedrone (4-CMC).

In this study we report on efforts to develop an enantioselective method for the detection of the drug of abuse clephedrone (1-(4-chlorophenyl)-2-(methylamino)-1-propanone (4-chloromethcathinone, also known as 4-CMC or para-chloro-methcathinone)) and its phase-1 metabolites in human biological fluids. The major goal is not to only report results, but primarily to emphasize the various challenges encountered when developing a reliable analytical method for the detection and quantification of novel psychoactive substances (NPS) and their metabolites in the matrix of interest. Such challenges start with the lack of chemical stability of some NPS in biological matrices. Additionally, most often metabolites are unavailable in pure form to serve as analytical standards, just as deuterated standards for native drugs and metabolites are frequently not commercially available. Furthermore, if the NPS is chiral, enantiomerically pure standards with known absolute stereochemistry are required, as well as a stereochemical stability of a drug and its metabolites becomes an issue. In addition, the chirality of a NPS significantly increases the number of species to be detected in the sample and thus challenges the development of an adequate separation method. These issues are shortly addressed, and some solutions offered in this manuscript.

Stereoselective Synthesis of Baloxavir Marboxil Using Diastereoselective Cyclization and Photoredox Decarboxylation of l-Serine.

Baloxavir marboxil (1; BXM) is a potent drug used for treating influenza infections. The current synthetic route to BXM (1) is based on optical resolution; however, this method results in the loss of nearly 50% of the material. This study aimed to describe an efficient and simpler method for the synthesis of BXM. We achieved a stereoselective synthesis of BXM (1). The tricyclic triazinanone core possessing a chiral center was prepared via diastereoselective cyclization utilizing the readily available amino acid l-serine. The carboxyl moiety derived from l-serine was removed via photoredox decarboxylation under mild conditions to furnish the chiral tricyclic triazinanone core ((R)-14). The synthetic route demonstrated herein provides an efficient and atomically economical method for preparing this potent anti-influenza agent.

CSM Software: Continuous Symmetry and Chirality Measures for Quantitative Structural Analysis.

We present a comprehensive and updated Python-based open software to calculate continuous symmetry measures (CSMs) and their related continuous chirality measure (CCM) of molecules across chemistry. These descriptors are used to quantify distortion levels of molecular structures on a continuous scale and were proven insightful in numerous studies. The input information includes the coordinates of the molecular geometry and a desired cyclic symmetry point group (i.e., Cs, Ci, Cn, or Sn). The results include the coordinates of the nearest symmetric structure that belong to the desired symmetry point group, the permutation that defines the symmetry operation, the direction of the symmetry element in space, and a number, between zero and 100, representing the level of symmetry or chirality. Rather than treating symmetry as a binary property by which a structure is either symmetric or asymmetric, the CSM approach quantifies the level of gray between black and white and allows one to follow the course of change. The software can be downloaded from https://github.com/continuous-symmetry-measure/csm or used online at https://csm.ouproj.org.il.

Cooling rate uncovers epimer-dependent supramolecular organization of carbohydrate amphiphiles.

We show distinct CH-π interactions and assembly pathways for the amphiphile N-(fluorenylmethoxycarbonyl)-galactosamine and its epimer N-(fluorenylmethoxycarbonyl)-glucosamine. These differences result in the formation of supramolecular nanofibrous systems with opposite chirality. Our results showcase the importance of the carbohydrates structural diversity for their specific biointeractions and the opportunity that their ample interactome offers for synthesis of versatile and tunable supramolecular (bio) materials.

Enantioseparation of six profenoid drugs by capillary electrophoresis with bovine serum albumin-modified gold nanoparticles as quasi-stationary phases.

Profenoid drugs are a kind of common non-steroidal anti-inflammatory drugs and their chiral enantiomers often have huge differences in pharmacological activities. In this work, a novel chiral separation system by capillary electrophoresis (CE) was constructed using gold nanoparticles (AuNPs) functionalized with bovine serum albumin (BSA) as a quasi-stationary phase (QSP), and the enantioseparation of six profenoid drugs was efficiently accomplished. Under optimal chromatographic conditions, the enantioseparation performance of the AuNP@BSA-based chiral separation system was greatly improved compared with that of free BSA (Resolutions, Ibuprofen: 0.89 â†’ 8.15; Ketoprofen: 0 â†’ 10.02; Flurbiprofen:0.56 â†’ 9.83; Indoprofen: 0.88 â†’ 13.83; Fenoprofen: 0 â†’ 15.21; Pyranoprofen: 0.59 â†’ 5.34). Such high Rs are exciting and satisfying and it is in the leading position in the reported papers. Finally, through molecular docking, it was also found that the difference in binding energy between BSA and enantiomers was closely related to the resolutions of CE systems, revealing the chiral selection mechanism of BSA. This work significantly improves the CE chiral separation performance through a simple strategy, providing a simple and efficient idea for the chiral separation method.

The Development of One New Normal Phase Liquid Chromatography Method and Thermodynamic Investigation of Olodaterol Hydrochloride Enantiomer.

In order to improve and replace the enantiomer method outlined in the olodaterol hydrochloride draft monograph (From the European Pharmacopoeia forum), one new, simple, and fast enantioselective normal phase high-performance liquid chromatography chiral method was developed on polysaccharide-based Chiral MX (2) (4.6 × 250 mm, 5 µm) column. n-Hexane, ethanol, and diethylamine in the ratio of 40:60:0.1 (V/V/V) were selected as mobile phase at a flow rate of 0.8 mL/min, and the detection was performed on a photodiode array detector at 225 nm with 5 µL injection volume. The column temperature was set at 40°C for better peak shape and sensitivity. The analysis time can be shortened to 15 min, whereas the resolution between enantiomer and olodaterol was found to be even more than 10.0, which was far better than that obtained with the reported method in this draft monograph. The developed chiral method was validated in accordance with ICH Q2 (R1), including specificity, LOD&LOQ, precision, linearity, accuracy, and robustness. Thereby, the proposed method was demonstrated to be suitable for the determination of enantiomer in olodaterol hydrochloride bulk drug and drug product. Besides, the thermodynamic parameters were evaluated on the basis of Van't Hoff plots that was used to explain correlative chiral recognition mechanisms with the chiral stationary phase.

Prediction of Human Liver Microsome Clearance with Chirality-Focused Graph Neural Networks.

In drug candidate design, clearance is one of the most crucial pharmacokinetic parameters to consider. Recent advancements in machine learning techniques coupled with the growing accumulation of drug data have paved the way for the construction of computational models to predict drug clearance. However, concerns persist regarding the reliability of data collected from public sources, and a majority of current in silico quantitative structure-property relationship models tend to neglect the influence of molecular chirality. In this study, we meticulously examined human liver microsome (HLM) data from public databases and constructed two distinct data sets with varying HLM data quantity and quality. Two baseline models (RF and DNN) and three chirality-focused GNNs (DMPNN, TetraDMPNN, and ChIRo) were proposed, and their performance on HLM data was evaluated and compared with each other. The TetraDMPNN model, which leverages chirality from 2D structure, exhibited the best performance with a test R2 of 0.639 and a test root-mean-squared error of 0.429. The applicability domain of the model was also defined by using a molecular similarity-based method. Our research indicates that graph neural networks capable of capturing molecular chirality have significant potential for practical application and can deliver superior performance.