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Chiral drugs are very complex substances since individual enantiomers may differ in pharmacological and toxic effects, making it necessary to analyze enantiomers separately. In this study, we investigated the chiral differentiation of two ezetimibe enantiomers (i.e., SRS-EZM and RSR-EZM) and their mechanisms in complex with β-cyclodextrins (CDs) and metal ions as the auxiliary ligands. For this purpose, two complementary approaches have been employed: electrospray-tandem mass spectrometry (ESI-MS/MS) with collision induced dissociation (CID) and molecular modeling methods, including density functional theory (DFT) calculations and molecular dynamics (MD) simulations. The results showed a good agreement between experimental and theoretical data. It was demonstrated that SRS-EZM can be easily distinguished from RSR-EZM by applying CID in ESI-MS/MS. SRS-EZM is likely to form a more stable complex with β-CD and metal ions, and thus the [SRS-EZM]-Cu-[β-CD] cluster is more energetically difficult to separate from the SRS-EZM molecule compared with RSR-EZM. Such a difference may be attributed to the interactions between the drug molecule and the metal ion, as well as the cavity shape changes of the β-CDs upon complexation with molecular guests. Therefore, enantiomers in chiral drug can be recognized as ternary complexes of metal-analyte-β-CD by ESI-MS/MS with CID. [ABSTRACT FROM AUTHOR]

Chirality is one of the key factors affecting the medicinal efficacy of compounds. In addition to central chirality, sterically hindered chiral axes commonly appear in drugs and the resulting chirality is known as atropisomerism. With developments in medicinal chemistry, atropisomerism has attracted increasing attention. This review discusses the classification, biological activity, pharmacokinetics, toxicity and side effects of atropisomers, and can serve as a reference in the research and development of potential chiral drugs. [ABSTRACT FROM AUTHOR]

[Display omitted] • Developing a crystallization-based chiral resolution approach for RS-Ofloxacin with diastereomeric cocrystal formation. • Providing a detailed characterization of diastereomeric cocrystal formation using melting point data, FTIR, and PXRD analyses. • Utilizing capillary electrophoresis for the effective separation of diastereomeric cocrystals of RS-Ofloxacin:L-Glutamic acid. • Increasing the enantiomeric purity of RS-Ofloxacin, achieving significant enantiomeric excess (61.82% ee) of the more potent S-enantiomer. • Demonstrating the scalability and adaptability of diastereomeric cocrystal formation for chiral resolution in pharmaceutical applications. Chiral drugs often exhibit significant differences in pharmacological activity between their enantiomers, highlighting the importance of effective chiral separation to enhance therapeutic efficacy and safety. Despite advances in this field, efficient methods for enantiomer separation remain a critical demand, especially for drugs like RS-Ofloxacin (RS-OFX), a chiral fluoroquinolone antibiotic. For RS-OFX, the S-enantiomer exhibits significantly higher potency—approximately 8–128 times greater—than the racemic mixture. This highlights the need to accurately separate the enantiomers. This study presents a new cocrystallization-based method for the precise and economical chiral separation of RS-OFX using amino acids by utilizing the formation of diastereomeric cocrystals. L-Glutamic acid (L-Glu) was identified as an appropriate coformer during the screening of potential coformers; consequently, diastereomeric cocrystals of R-OFX:L-Glu and S-OFX:L-Glu were successfully obtained. Melting point data, Fourier-Transform Infrared Spectroscopy (FTIR), and Powder X-Ray Diffraction (PXRD) analyses all confirmed the existence of a new solid state, revealing significant modifications in the crystal structure indicative of cocrystal formation. Capillary electrophoresis (CE) was employed to quickly identify the most suitable solvent mixture for the separation of the diastereomeric pair. The diastereomeric cocrystals exhibited distinct solubility profiles in various solvent mixtures, allowing effective chiral separation through evaporative crystallization in methanol:chloroform (50:50, v/v) mixture, yielding 61.82% enantiomeric excess (ee) of the more active S-OFX:L-Glu. The results of this study suggest that the chiral resolution of racemic APIs through diastereomeric cocrystal formation with amino acids has the potential for scalability and adaptability in other APIs. This approach has the potential to be a valuable tool for the pharmaceutical industry in improving the efficiency of producing enantiopure pharmaceuticals. [ABSTRACT FROM AUTHOR]

Due to the chiral uniformity of proteins and carbohydrates, the basic building blocks of living matter, the mirror symmetry characteristics of drugs are of exceptional importance for medicinal chemistry. In this work, we present a new synthesis of the mono-enantiomeric chiral drug prenalterol 1 based on the symmetry-breaking phenomenon, namely, the spontaneous resolution of 4-hydroxyphenyl glycerol ether 2. The single crystal X-ray diffraction method was used to investigate both rac- and (S)-1 as well as (R)-2. A feature of the main crystal-forming supramolecular motif (SMM) for diol 2 is the participation of three different molecules representing different types of hydroxyl groups in the formation of its repeating unit. The type of prenalterol SMM, as in the case of the related drugs propranolol 3 and pindolol 4, appears to be a chirality driven property, and is dictated by the enantiomeric composition of the crystals. In single-enantiomeric forms, infinite one-dimensional chains are realized, organized around helical axes, while in racemates, zero-dimensional cycles are realized, organized around inversion symmetry elements. The results obtained again demonstrate the influence of the chiral polarization of a substance not only on the general (selection of a space group), but also on particular characteristics of matter crystal organization, namely selection of a specific SMM. [ABSTRACT FROM AUTHOR]

Asymmetric homogeneous hydrogenation under high pressure in continuous flow was achieved with a slug flow reactor. High hydrogen pressure enabled iridium-catalyzed asymmetric hydrogenation of acetophenone with a turn-over-frequency (TOF) of up to 274,000 h−1. An operando infrared tool was used to provide in-situ monitoring of the reaction. The effect of gas-liquid ratio and speed of slug flow in the microchannel were studied. The multi-step flow synthesis of active pharmaceutical ingredients, in which asymmetric hydrogenation is a key step, was successfully demonstrated, with subsequent reactions carried out under longer residence times within a cascade of CSTRs. [ABSTRACT FROM AUTHOR]

A terahertz (THz) all-dielectric metasurface with crescent cylinder arrays for chiral drug sensing has been demonstrated. Through the multipole expansion method, we theoretically found that breaking the symmetry of the metasurface can excite higher-order resonance modes and provide stronger anisotropy as well as enhanced sensitivity for the surroundings, which gives a better sensing performance than lower-order resonance. Based on the frequency shift and transmittance at higher-order resonance, we carried out the sensing experiments on (R)-(−)-ibuprofen and (S)-(+)-ibuprofen solution on the surface of this metasurface sensor. We were able to monitor the concentrations of ibuprofen solutions, and the maximum sensitivity reached 60.42 GHz/mg. Furthermore, we successfully distinguished different chiral molecules such as (R)-(−)-ibuprofen and (S)-(+)-ibuprofen in the 5 μL trace amount of samples. The maximum differentiation was 18.75 GHz/mg. Our analysis confirms the applicability of this crescent all-dielectric metasurface to enhanced sensing and detection of chiral molecules, which provides new paths for the identification of biomolecules in a trace amount. [ABSTRACT FROM AUTHOR]

Chiral drugs are very complex substances since individual enantiomers may differ in pharmacological and toxic effects, making it necessary to analyze enantiomers separately. In this study, we investigated the chiral differentiation of two ezetimibe enantiomers (i.e., SRS-EZM and RSR-EZM) and their mechanisms in complex with β-cyclodextrins (CDs) and metal ions as the auxiliary ligands. For this purpose, two complementary approaches have been employed: electrospray-tandem mass spectrometry (ESI-MS/MS) with collision induced dissociation (CID) and molecular modeling methods, including density functional theory (DFT) calculations and molecular dynamics (MD) simulations. The results showed a good agreement between experimental and theoretical data. It was demonstrated that SRS-EZM can be easily distinguished from RSR-EZM by applying CID in ESI-MS/MS. SRS-EZM is likely to form a more stable complex with β-CD and metal ions, and thus the [SRS-EZM]-Cu-[β-CD] cluster is more energetically difficult to separate from the SRS-EZM molecule compared with RSR-EZM. Such a difference may be attributed to the interactions between the drug molecule and the metal ion, as well as the cavity shape changes of the β-CDs upon complexation with molecular guests. Therefore, enantiomers in chiral drug can be recognized as ternary complexes of metal-analyte-β-CD by ESI-MS/MS with CID.

A luminescent double recognition nanoprobe is described as a new strategy for the selective determination of chiral molecules. C-dots/Ir/Au fluorescent nanoparticles, synthesised under hydrothermal conditions, are used as a high-performance probe in combination with a molecularly imprinted polymer (MIP) and calix[6]arene as a double recognition element. Thiolated calix[6]arene is grafted on C-dots/Ir/Au as the first recognition element, which then forms a host–guest complex with the target molecule levodopa (L-DOPA). Subsequently, an MIP is prepared on the C-dots/Ir/Au (MIP/C-dots/Ir/Au) by chemical polymerisation. After the removal of L-DOPA, double recognition imprinting cavities are formed. The fluorescence intensity at 478 nm of the nanoprobe is effectively quenched by adsorption of L-DOPA on MIP/C-dots/Ir/Au, which provides a method for L-DOPA determination. Owing to the double recognition strategy, this method has excellent selectivity which can effectively avoid interference from enantiomer D-DOPA, and a imprinting factor of 7.1 is obtained for L-DOPA. This accurate and reliable method, with a wide linear range (5 × 10−10 to 1.2 × 10−7 mol L−1) and a low limit of detection (1.45 × 10−10 mol L−1), was successfully applied to the determination of L-DOPA in real samples, giving standard recoveries of 89.7–110.0%. Thus, the proposed sensing method provides a viable approach for the determination of a single enantiomer. [ABSTRACT FROM AUTHOR]

A terahertz (THz) all-dielectric metasurface with crescent cylinder arrays for chiral drug sensing has been demonstrated. Through the multipole expansion method, we theoretically found that breaking the symmetry of the metasurface can excite higher-order resonance modes and provide stronger anisotropy as well as enhanced sensitivity for the surroundings, which gives a better sensing performance than lower-order resonance. Based on the frequency shift and transmittance at higher-order resonance, we carried out the sensing experiments on (R)-(−)-ibuprofen and (S)-(+)-ibuprofen solution on the surface of this metasurface sensor. We were able to monitor the concentrations of ibuprofen solutions, and the maximum sensitivity reached 60.42 GHz/mg. Furthermore, we successfully distinguished different chiral molecules such as (R)-(−)-ibuprofen and (S)-(+)-ibuprofen in the 5 μL trace amount of samples. The maximum differentiation was 18.75 GHz/mg. Our analysis confirms the applicability of this crescent all-dielectric metasurface to enhanced sensing and detection of chiral molecules, which provides new paths for the identification of biomolecules in a trace amount.

Racemic metoprolol is a selective ß1-blocker, which is used in cardiovascular disease treatment. It has been found that (S)-metoprolol has a higher affinity to bind the ß-adrenergic receptor compared to (R)-metoprolol. Moreover, the regulatory authorities' high market demand and guidelines have increased the preference for single enantiomer drugs. In this work, the lipase-catalyzed kinetic resolution of racemic metoprolol was performed to obtain the desired enantiomer. The type of lipase, acyl donor, and solvent were screened out. This was achieved by Candida antarctica B lipasecatalyzed transesterification of racemic metoprolol in hexane and vinyl acetate as the solvent and an acyl donor, which gave maximum conversion of (S)-metoprolol (XS) of 52%, enantiomeric excess of substrate, (ees) of 92% and product (eeP) of 90% with enantiomeric ratio (E) of 62. This method can be considered as green chemistry, which can be applied to produce other enantiopure beta-blockers. [ABSTRACT FROM AUTHOR]

A novel enantioselective synthesis of (R)‐cinacalcet with 99% enantiomeric excesses (ee) has been achieved. The main strategies of the approach include a gram‐scale cobalt‐catalysed asymmetric cross‐coupling of racemic ester with arylzinc reagent, Hoffman‐type rearrangement of acidamide, the amidation of chiral amine, and improving the ee of chiral amide from 87% to 99% via recrystallization. [ABSTRACT FROM AUTHOR]

Here, we describe a study of screen characterization of aptamers targeting the chiral drug ephedrine using the non-immobilized graphene oxide (GO) SELEX. The improved method of long and short chains was here used to prepare the ssDNA library. The Resonance Rayleigh Scattering (RRS) method was first used to monitor the screening process. Through high-throughput sequencing, the genetic sequence data of 90,487 aptamers were obtained. Through the analysis of the parameters of free energy value and secondary structure prediction model of high repeatability sequence, the 10 candidate sequences were identified. Finally, a best-fit aptamer named EP08 was identified by combining the dissociation experiment. The binding affinity and binding mechanism of the aptamer and target were analyzed using an isothermal titration colorimetry (ITC) experiment and circular dichromatic (CD) experiment. The binding affinity (Kd) of the EP08 aptamer to ephedrine is approximately 2.86 ± 0.24 μM. This novel DNA aptamer will help in the future development of a new method for the identification and detection of chiral drug ephedrine. • This was the first time that Resonance Rayleigh Scattering (RRS) detection was introduced into the screening process. • The improved method of long and short chains was here used to prepare the ssDNA library. • The binding affinity and binding mechanism of the aptamer and target were analyzed using an isothermal titration colorimetry (ITC) experiment and circular dichromatic (CD) experiment. [ABSTRACT FROM AUTHOR]

Graphical abstract Schematic representation of pixelated-polarization-camera-based polarimetry system for optical rotation sensing. Highlights • A pixelated-polarization-camera-based polarimetry system was developed to detect the optical rotation of the chiral material. • The concise light path provides a convenient way, and the random error and the systematic error of the system are very low. • The sensor could achieve real-time, wide-range, high-accuracy and high-resolution detection. • The pixelated-polarization-camera-based polarimetry sensor has a higher accuracy and resolution than existing methods. Abstract Chirality is an essential consideration in the field of life sciences and pharmaceutical industry because most biomolecules and pharmaceuticals are chiral, and optical rotation measurement is a simple and efficient means for identification, purity test and content detection of chiral materials. However, there are some drawbacks in existing methods, such as small measurement range, non-real-time performance, low measurement accuracy and resolution. This paper presents a novel system to implement optical rotation measurement, and pixelated polarization cameras and Stokes parameters are employed in the system. The polarization information of linearly polarized incident light can be recorded and extracted by a pixelated polarization camera and Stokes parameters respectively. Experiments demonstrate that the proposed system has the necessary advantages for optical rotation measurement, such as real time, wide range (− 90 ° to + 90 °), high accuracy (1 × 1 0 − 4 °) and high resolution (± 6 × 1 0 − 6 °). Thus, this measurement system has great practical prospects in the hospital clinical diagnosis, chemical research, sugar production and pharmaceutical industry. [ABSTRACT FROM AUTHOR]

1.Itraconazole (ITZ), an antifungal azole derivate is a chiral drug that consists of four cis-diastereoisomers ((+)-2R,4S,2′R-ITZ-A; (+)-2R,4S,2′S-ITZ-B; (-)-2S,4R,2′S-ITZ-C and (-)-2S,4R,2′R-ITZ-D) which may differ in their pharmacokinetics and pharmacodynamics. 2.As ITZ is known as a CYP3A4 inhibitor causing severe drug-drug interaction, the inhibitory potencies of its individual optical isomers towards nine drug-metabolising cytochrome P450 (including CYP3A, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1), were investigated. 3.All ITZ diastereoisomers dose-dependently inhibited CYP3A activity in both used assays, midazolam and testosterone hydroxylation. The Ki values were assessed: for testosterone ITZ-A/0.085 µM; ITZ-B/0.91 µM, ITZ-C/0.20 µM and ITZ-D/0.022 µM; for midazolam ITZ-A/0.44 µM; ITZ-B/0.48 µM, ITZ-C/1.56 µM and ITZ-D/3.48 µM. The enzyme activity of CYP2C19 was moderately inhibited (IC50 30-53 µM), but in this case without large differences between the individual optical isomers. 4.The significant differences between diastereoisomers were presented. Antifungal potency of ITZ stereoisomers also differs so the potential enantiopure preparations of ITZ was not of interest. [ABSTRACT FROM AUTHOR]

Abstract: Chiral molecules are of great importance in the life science since individual enantiomers may differ in biological activity, mechanism, and toxicity, making it necessary to explore efficient chiral analysis methods. Chromatography approaches are often used to differentiate enantiomers while mass spectrometry (MS) was thought to be blind in chiral analysis. With the development of MS technique, it began to play a more and more crucial part in chiral observation. In this review, we will give a detailed introduction of the analysis methods related to MS for chiral drugs, including its mechanism, applications, and future development. [ABSTRACT FROM AUTHOR]

For many years, studies focused on developing new natural or synthetic compounds with antineoplastic activity have attracted the attention of researchers. An interesting group of such compounds seem to be those with both lactone moiety and an aromatic ring which, in addition to antimicrobial or antiviral activity, also exhibit antitumor properties. The study shows antitumor activity of two enantiomeric trans isomers of 5-(1-iodoethyl)-4-(2′,5′-dimethylphenyl)dihydrofuran-2-one. Our aim was to determine their antitumor activity manifested as an ability to induce apoptosis in selected canine cancer cell lines as well as to evaluate differences in their strength depending on the configuration of their stereogenic centers. The enantiomers (+)-(4 R ,5 S ,6 R )- 1 and (−)-(4 S ,5 R ,6 S )- 2 were found to induce classical caspase-dependent apoptosis through downregulation of the expression of anti-apoptotic proteins Bcl-xL and Bcl-2. Although the mechanism of apoptosis induction was the same for both enantiomers, they differed in their strength, as stronger antineoplastic activity in vitro was exhibited by isomer (+)-(4 R ,5 S ,6 R )- 1 . [ABSTRACT FROM AUTHOR]

A novel, concise, and efficient enantioselective synthesis of (S)-preclamol (87% ee, 51% total yield) has been developed. The key steps of this synthetic approach included cobalt-catalyzed asymmetric catalytic cross-coupling of α-bromo ester with arylzinc and the reduction of chiral ester to diol with a tertiary carbon atom. Moreover, it was demonstrated that our enantioselective Negishi cross-coupling was a powerful tool to construct stereogenic benzylmethyl center in chiral drugs on a gram scale. [ABSTRACT FROM AUTHOR]

In this study molecular imprinting technology was employed to prepare a specific affinity sorbent for the resolution of Ephedrine, a chiral drug. The molecularly imprinted polymer (MIP) was prepared by non-covalent molecular imprinting with either (+) or (-)-Ephedrine ((R∗,S∗)-2-(methylamino)-1-phenylpropan-1-ol) as the template. Methacrylic acid and ethylene glycol di-methacrylate were copolymerized in the presence of the template molecule. The bulk polymerization was carried out in chloroform with 2,2′-azobisisobutyronitrile as the initiator, at 5°C and under UV radiation. The resulting MIP was ground into powders, which were slurry packed into analytical columns. After removal of template molecules, the MIP-packed columns were found to be effective for the resolution of (±)-Ephedrine racemates. The separation factor for the enantiomers ranged between 1.3 and 2.1 when the column was packed with MIP prepared with (+)-Ephedrine as the template. A separation factor ranging from 1.3 to 2.6 could be achieved from the column packed with MIP, prepared with (-)-Ephedrine as the template. Although the separation factor was higher with that previously obtained from reversed-phase column chromatography following derivatization with a chiral agent, elution peaks were broader due to the heterogeneity of binding sites on the MIP particles and the possible non-specific interaction.

A chiral method using capillary electrophoresis was developed for the separation of the four stereoisomers of a new chiral substance currently undergoing drug development as single enantiomer. After the selection of highly sulfated β-CD as chiral selector, an exhaustive study on the influence of several experimental variables on the resolution was performed, being the substitution degree of the CD a very decisive factor. Run time and resolutions were about 20 min and higher than 2.0, respectively. The method was validated in terms of selectivity, linearity, accuracy, precision, and limits of detection and quantitation according to the requirements of the International Conference on Harmonisation for the determination of the chiral purity of a drug substance. The usefulness of the method was demonstrated in the control of stereoisomeric impurities in raw material as well as in the determination of the chiral stability of the drug in the solid state and in dosage forms used in safety assessment. Finally, the chiral method was used to investigate the possible in vivo inversion in biological samples. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor inhibitors are of importance in cancer therapy and possibly in the management of pain. Herein, we report a structure-activity relationship study with 29 new 6-aryl-furo[2,3- d ]pyrimidin-4-amines, involving modification of the 4-amino group and 6-aryl function. The EGFR activity was especially dependent on having a chiral 4-benzylamino group with correct stereochemistry. Molecular dynamics indicate this to be due to favourable cation-π interactions. The most active inhibitor identified, equipotent to Erlotinib, was substituted with ( R )-1-phenylethylamine at C-4 and a N 1 , N 1 -dimethyl-1,2-diamine group in para position of the 6-aryl moiety. These new furopyrimidines had a different off-target kinase profile when compared to Erlotinib, and also possessed high activity towards Ba/F3 EGFR L858R reporter cells. Further, comparing the EGFR data of the furo[2,3- d ]pyrimidin-4-amines with that of the corresponding thieno- and pyrrolopyrimidines concludes the furopyrimidine scaffold to be highly useful for development of new epidermal growth factor receptor antagonists. [ABSTRACT FROM AUTHOR]

Novel angiotensin II receptor type 1 (AT 1 ) blockers bearing 6-substituted carbamoyl benzimidazoles with a chiral center were designed and synthesized as the first step to develop new antihypertensive agents and understand their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [ 125 I] Sar 1 Ile 8 -Ang II, which was specifically bound to human AT 1 receptor. Radioligand binding assays revealed nanomolar affinity in several compounds under study. The IC 50 values of nine ligands were higher than those of Losartan. The screening of decreased blood pressure in spontaneous hypertensive rats displayed that compound 8S (IC 50 = 5.0 nM) was equipotent with Losartan, whereas compounds 13R (IC 50 = 7.3 nM), 14R (IC 50 = 6.3 nM), and 14S (IC 50 = 3.5 nM) were slightly ahead of Losartan, and the most significant activity was demonstrated by compound 8R (IC 50 = 1.1 nM). Candidate 8R was identified for its excellent efficacy in antihypertension and fairly low toxicity based on plasma analyses, toxicology studies, and chronic oral tests. Finally, compound 8R exhibited strong and multiple interactions with target active sites of the theoretical AT 1 receptor model in docking study. [ABSTRACT FROM AUTHOR]

The current work reports an extended theoretical study from our previous experimental work for the enantioselective extraction of amlodipine enantiomers in a biphasic recognition chiral extraction system (BRCES) consisting of hydrophobic D-diisopropyl tartrate dissolved in organic phase (n-decanol) and hydrophilic hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous phase (acetate buffer) which preferentially recognize the R-enantiomer and S-enantiomer, respectively. The calculations were simulated using a semi-empirical PM3 method as a part of the Gaussian09 software package and were used to optimize the structures of the hosts, guests, and host-guest complexes in the gas phase without any restrictions. It was found that HP-β-CD has the strongest recognition ability among the three β-CD derivatives studied, namely HP-β-CD, hydroxyethyl-β-cyclodextrin (HE-β-CD), and methylated-β-cyclodextrin (Me-β-CD), due to the large interaction energies (Ecomp = -14.3025 kcal/ mol), while D-diisopropyl tartrate has the strongest ability among the four tartaric acid derivatives studied namely; L-diisopropyl tartrate, D-diisopropyl tartrate, L-diethyl tartrate, and D-diethyl tartrate ( Ecomp = -5.9964 kcal/ mol). The computational calculations for the enantioselective partitioning of amlodipine enantiomers rationalized the reasons for the different behaviors for this extraction. The present theoretical results may be informative to scientists who are devoting themselves to developing models for their experimental parts or for enhancing the hydrophobic drug solubility in drug delivery systems. [ABSTRACT FROM AUTHOR]

Four chiral drugs were enantioseparated by native beta-cyclodextrin (β-CD) and negatively charged carboxymethyl-beta-cyclodextrin (CM-β-CD) using capillary electrophoresis coupled with electrochemiluminescence detection (CE-ECL). Using 50 mM pH 5.5 Tris–H 3 PO 4 with 10 mM CM-β-CD as a running buffer, high resolution efficiency could be obtained. With the help of isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR) and molecular modeling, the chiral recognition mechanism was comprehensively investigated. Thermodynamic parameters data from ITC revealed that CM-β-CD exhibited stronger binding affinity with analytes than β-CD, and that the driving forces of CM-β-CD responsible for chiral recognition were mainly electrostatic interactions between negatively charged CM-β-CD and positively charged analytes. In addition, from both a macroscopic and microscopic point of view, the results of NMR and molecular modeling investigation adequately confirm the conclusion by comparing the stereochemical structures of complexes. Combination of ITC, NMR and molecular modeling techniques not only can assist CE to investigate the chiral discrimination mechanism, but also can predict and guide CE enantioseparation efficiency conversely. [ABSTRACT FROM AUTHOR]

ABSTRACT DNA-based chiral selectors are constructed to discriminate ofloxacin enantiomers through metal-ion anchoring on a special DNA double helix that contains successive GC pairs. The effects of metal ions involving Mg2+, Ni2+, Cu2+, Ag+, and Pt2+ were studied on the regulation of DNA chiral discrimination towards ofloxacin enantiomers. It is shown that DNA-Cu(II) complexes exhibit the highest at the [Cu2+]/base ratio of 0.1. The enantiomeric excess can reach 59% in R-enantiomer after being adsorbed by the RET-Cu(II) complex. recognition of ofloxacin enantiomers on the double helix is tunable via external stimulus, providing a programmable desorption process to regenerate DNA. This DNA-based chiral selector exhibits excellent reusability without apparent loss of after three cycles of adsorption and desorption. Chirality 26:249-254, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Highlights: [•] Supercritical fluid chromatography (SFC) in pharmaceutical analysis. [•] SFC has widespread applications in pharmaceutical analysis and enantioseparation. [•] Chiral stationary phases (CSPs) were developed for the separation of chiral drugs. [•] SFC offers advantages over HPLC (e.g., using smaller amounts of toxic solvents). [•] SFC meets the requirements of Green Analytical Chemistry rules. [ABSTRACT FROM AUTHOR]

Effectiveness of chiral drugs is very well established against several lethal diseases. The demand of chiral drugs is increasing day by day. Besides this, the racemization of some chiral drugs is also found in biological as well as in environmental matrices. The analysis of chiral drugs has become a necessary Research and Development Unit task for any analytical scientist, pharmaceutical institute or pharma industry considering not only the specific role of these drugs for better and suitable treatment of any lethal disease but also for their occurrence and fate in environmental matrices. The present article highlights the importance, bioactivities, occurrence and fate of chiral drugs in environment. [ABSTRACT FROM AUTHOR]

Abstract: Chiral recognition based on enantioselective sensors is superior to conventional chromatographic enantioseparation techniques in terms of simplicity and rapidity. Normally, highly specific enantioselective receptors are used for the fabrication of enantioselective sensors. However, to date there only limited number of highly specific chiral selectors are reported, which greatly confines the development of enantioselective sensors. Herein, we demonstrate the feasibility of using relatively weak chiral selectors to construct an enantioselective biosensor for accurate chiral discrimination of enantiomers. The detection of racemic mixture of (R)- and (S)-1,2,3,4-Tetrahydro-1-naphthylamine (TNA) was demonstrated as an example. The sensor was made up of a dual-channel microfluidic chip. One channel of the chip was modified with human serum albumin (HSA), which was reported to be a weak chiral selector for TNA; while the other channel was modified with a monoclonal anti-TNA antibody, which was a non-enantioselective TNA receptor. A portable localized surface plasmon resonance (LSPR) detection system was integrated with the microfluidic chip to accomplish the signal collection. Our investigation revealed that the combination of LSPR responses obtained from the two channels can be used for quantitative discrimination of the (R)- and (S)-TNA. The limit of detection was found to be 150nM for (R)-TNA and 100nM for (S)-TNA. The feasibility of use relatively weak chiral selectors could potentially promote the development of various enantioselective sensors. [Copyright &y& Elsevier]

Abstract: Bovine serum albumin (BSA) anchored on the surface of magnetic Fe3O4 nanoparticles (MNPs) were prepared using electrostatic adsorption and studied as a new magnetically chiral selector for the separation of chiral drug enantiomers. It is indicated that the immobilized BSA molecules on the magnetic nanoparticles using electrostatic adsorption retain their stereoselective recognition with site II-binding drug ibuprofen at pH 7.0 and site I-binding drug ofloxacin at pH 9.0, with a optimal loading of 467mg BSA per gram of MNPs. For racemic ibuprofen and ofloxacin, single-stage adsorption gives an enantiomeric excess of 13% and 14%, and the multi-stage operation enhances the chiral performance providing the ee value of 54% and 39% respectively. As increasing the initial ee of enantiomeric mixtures, Δee levels of 50%, 35% and 16% for stronger binder ibuprofen, as well as 31%, 17% and 13% for weaker binder ofloxacin are achieved under the same operational conditions. Depending upon the eutectic point of racemic compound, a hybrid process involving the enrichment of one enantiomer using BSA–PDDA–MNPs followed by subsequent crystallization is proposed to obtain the enantiomer with higher optical purity. [Copyright &y& Elsevier]

Abstract: A screen of aryloxy aminopropanol organocatalysts derived from the β-blocker inhibitor S-timolol determined the most active catalyst of asymmetric α-hydroxylation of β-keto esters. (R)-1-(tert-butylamino)-3-(3,4,5-trimethoxyphenoxy) propan-2-ol (3k) was the most effective derivative, enantioselectively catalyzing α-hydroxylation of β-keto esters using tert-butyl hydroperoxide as the oxidant in hexane to afford the corresponding products in excellent yield and with good enantioselectivity (up to 96% yield, 88% ee). [Copyright &y& Elsevier]

Abstract: Burkholderia cepacia lipase was immobilized on superparamagnetic nanoparticles using three different methodologies (adsorption, chemisorption with carboxibenzaldehyde and chemisorption with glutaraldehyde) and employed in the kinetic resolution of a chiral drug precursor, (RS)-2-bromo-1-(phenyl)ethanol, via enantioselective acetylation reaction. An excellent improvement of lipase catalytical performance was observed. Free B. cepacia lipase gave the ester (S)-2 with poor E-value <30, and after its immobilization to magnetic nanoparticles the E-value was up to >200. The effect of several reaction parameters in the kinetic resolution was studied. The best results for kinetic resolution were obtained using vinyl acetate as acetyl donor and toluene as solvent, typically yielding the ester in high enantiomeric excess (>99%) and E-value (E >200). Of the three tested immobilization methods, chemisorption with glutaraldehyde was the best one in terms of temperature stability and yield product. [Copyright &y& Elsevier]

Abstract: This review provides a brief overview on chirality as a structural characteristic of pharmaceuticals. This property has received very little attention in the field of environmental analysis, despite the fact that many drugs are marketed as racemates. The review covers the different methodologies commercially available on chiral liquid chromatography (LC) columns to provide good resolving power. It also reviews recent results obtained in chiral analysis of drugs and their metabolites with an array of modern mass-spectrometric analyzers coupled to an LC system that provides high selectivity and sensitivity. It further covers the occurrence and the fate of chiral drugs in the environment. [Copyright &y& Elsevier]

Abstract: The present work illustrates possibilities of column-coupling capillary electrophoresis (CE-CE) combined with chiral selector (2-hydroxypropyl-β-cyclodextrin, HP-β-CD) and fiber-based diode array detection (DAD) for the direct quantitative enantioselective determination of trace drug (amlodipine, AML) in biological multicomponent ionic matrices (human urine). Capillary isotachophoresis (ITP) served as an ideal injection technique in CE-CE. Moreover, the ITP provided an effective on-line sample pretreatment prior to the capillary zone electrophoresis (CZE) separation. Enhanced separation selectivity due to the combination of different separation mechanisms (ITP vs. CZE–HP-β-CD) enabled to obtain pure zones of the analytes, suitable for their detection and quantitation. The DAD, unlike single wavelength UV detection, enabled to characterize the purity (i.e. spectral homogeneity) of the analytes zones. A processing of the raw DAD spectra (the background correction and smoothing procedure) was essential when a trace analyte signal was evaluated. Obtained results indicated pure (i.e. spectrally homogeneous) zones of interest confirming effective ITP–CZE separation process. The proposed ITP–CZE–DAD method was characterized by favorable performance parameters (sensitivity, linearity, precision, recovery, accuracy, robustness, selectivity) and successfully applied to an enantioselective pharmacokinetic study of AML. [Copyright &y& Elsevier]

Abstract: The interaction between the chiral drug of propranolol (PPL) and α1-acid glycoprotein (AGP, orosomucoid) has been first studied by fluorescence spectrophotometry. The fluorescence intensity of PPL increased due to the addition of AGP into PPL. The equation of Scatchard was employed to calculate the association constant and binding site number of the two enantiomers with AGP. The association constant is 2.62×105 M−1 for R-PPL and 8.57×105 M−1 for S-PPL and the binding site number is 0.41 for R-PPL and 1.17 for S-PPL at 17°C respectively. The method of thermodynamics was applied to determine the binding type of S-PPL with AGP. The results suggested that the binding type is mainly van der waals force or hydrogen bond. At last the effect of three metal cations on the association constant and the binding site number of S-PPL with AGP was examined. [Copyright &y& Elsevier]

Abstract: Background:: Amlodipine, a dihydropyridine calcium channel antagonist, is prescribed for the management of angina and hypertension. It is used therapeutically as a racemic mixture, composed of S- and R-enantiomers, but its calcium channel-blocking effect is confined to S-amlodipine; R-amlodipine has 1000-fold less activity than its S-enantiomer. Objective:: The objective of this study was to compare the pharmacokinetic and pharmacodynamic properties and safety profiles of a newly developed amlodipine formulation, composed wholly of S-amlodipine, with those of the conventionally prescribed racemic formulation. Methods:: This randomized, open-label, 2-period, comparative, crossover study was conducted with healthy volunteers at the Gil Medical Center and Gachon Medical School, Incheon, Korea. Male subjects, aged 20 to 50 years, were eligible to participate if their weight was within 20% of ideal body weight and if they were judged by physicians to be healthy. All subjects were randomly assigned in a 1:1 ratio to 1 of 2 treatment sequences: (1) a single dose of the test amlodipine formulation (S-enantiomer amlodipine 5 mg PO) (Lodien™ [Hanlim Pharmaceutical Co., Seoul, Korea]) in the first study period, followed by a single dose of the reference amlodipine formulation (racemate 10 mg PO) (Norvasc® [Pfizer Pharmaceuticals Korea Ltd., Seoul, Korea]) in the second study period, or (2) a single dose of the reference formulation in the first study period, followed by a single dose of the test formulation in the second period. A 3-week washout occurred between study periods. Blood samples for pharmacokinetic analysis of S-amlodipine were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, 72, 96, 120, 144, and 168 hours after drug administration. Pharmacodynamic variables (ie, systolic and diastolic blood pressure and heart rate) were measured at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, and 72 hours after administration. Safety profiles were also assessed. Hematology, biochemistry, electrocardiography, and urinalysis were performed at baseline and end of study. Adverse events were monitored throughout the study period. Pharmacokinetic characteristics were compared using noncompartmental analysis. Pharmacokinetic equivalence was concluded if the geometric mean ratios of the plasma Cmax and AUC were within the predetermined range of 80% to 125%. Results:: Twenty-six healthy Korean male volunteers were screened and 18 subjects (mean [SD] age, 23.4 [1.5] years [range, 21–26 years]; mean [SD] weight, 69.3 [6.8] kg [range, 60-88 kg]) were enrolled and completed the study. The plasma concentration-time profiles of S-amlodipine were comparable after administration of both formulations. The mean (SD) values for Cmax AUC from time 0 to the last available measurement (AUClast), and AUC from 0 to infinity (AUC0−∞) for the reference formulation (3.0 [0.6] ng/mL, 151.4 [35.7] ng - h/mL, and 175.3 [45.1] ng - h/mL, respectively) did not differ significantly from those for the test formulation (3.1 [0.6] ng/mL, 139.7 [40.3] ng - h/mL, and 161.7 [43.8] ng - h/mL, respectively). The calculated 90% Cls for the corresponding ratios of log*transformed Cmax, AUCO0−∞, and AUClast were 97.56% to 112.51%, 86.31% to 98.74%, and 83.46% to 100.04%, respectively, which met the predetermined criteria for pharmacokinetic equivalence. Despite the single administration, significant changes in maximal blood pressure and heart rate were observed after drug administration for both formulations, compared with baseline values (all, P < 0.001). However, no significant differences were observed between the 2 formulations in terms of pharmacodynamic profiles, and no clinically relevant changes were observed for either formulation with respect to physical examination, hematology, biochemistry, electrocardiography, or urinalysis. Neither formulation caused any serious adverse events. Conclusions:: Two amlodipine formulations were found to be equivalent in terms of the pharmacokinetics of S-amlodipine. The newly developed formulation, comprised of only S-amlodipine, had pharmacodynamic profiles comparable to those of the conventional racemic amlodipine formulation in these healthy Korean male subjects. Both formulations were well tolerated. [Copyright &y& Elsevier]

Abstract: Sample solubility in the mobile phase and enantioselectivity are key factors in chiral preparative chromatography. In the search for a high throughput process for production of pure enantiomers, the rational design of the mobile phase and the selection of a suitable chiral stationary phase (CSP) are essential. However, one may sometimes be faced with the incompatibility between the CSP and the preferential eluent for sample solubility. Such a limitation may be circumvented by using an immobilized CSP such as CHIRALPAK® IA. In this manuscript, the chiral separation of a Ca-sensitizing drug (EMD 53986) is optimized on CHIRALPAK® IA in terms of sample solubility, enantioselectivity and preparative productivity. The approaches for method optimization and the impact of sample solubility on productivity are discussed. The preparative potential of CHIRALPAK® IA is also demonstrated. [Copyright &y& Elsevier]

Finding the right chiroptical tool to reliably assign the stereochemistry of bioactive compounds is a hot topic in spectroscopy, attracting a broad and growing interest of the Organic Analytical and Medical Chemistry Society. Since these molecules' three-dimensional (3D) structure directly governs their biological properties, the absolute configuration (AC) must be established with the highest possible degree of certainty. Such a reliable AC assignment is achieved using one or a combination of two or more suitable techniques selected from a range of chiroptical methods. Due to the undeniable benefits of using chiroptical methods to determine the structure of bioactive compounds effectively, we will highlight key issues related to selecting the appropriate technique(s) and the state-of-the-art level of their application based on a diverse pool of bioactive compounds. Our review will strengthen the holistic approach to chiroptical methods and enhance their correct use for a wide range of chiral compounds. • Analytical aspects of circular dichroism (CD) spectroscopies in the proper assignment of stereochemistry. • State-of-the-art measurement possibilities within CD spectroscopy. • Applications of CD techniques in the analysis of chiral active pharmaceutical ingredients (APIs). • Future perspectives of CD in probing bioactive compounds. [ABSTRACT FROM AUTHOR]