Liquid chromatographic enantiomer separations applying chiral ion-exchangers based on Cinchona alkaloids

Ilisz, István; Bajtai, A; Lindner, Wolfgang; Péter, Antal

doi:10.1016/j.jpba.2018.06.045

Cited by 53 publications

(33 citation statements)

References 138 publications

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“…Moreover, HPLC is an easy-to-use, versatile technique to assist synthesis in view of the wide array of chemicals detection and low implementation time, and also when integrated with flow synthesizers and high-throughput experimentation (HTE) systems. Thanks to the continuous technological advancements in the production of Chiral Stationary Phases (CSPs), HPLC-based methods have gotten faster and more effective for the enantiopurity assessment of chiral drugs [1][2][3][4][5]. To date, several hundred CSPs for HPLC applications are commercially available.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines

et al. 2020

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In the present work, we illustrate the ability of high-performance liquid chromatography (HPLC) analysis to assist the synthesis of chiral imidazolines within our medicinal chemistry programs. In particular, a Chiralpak® IB® column containing cellulose tris(3,5-dimethylphenylcarbamate) immobilized onto a 5 μm silica gel was used for the enantioselective HPLC analysis of chiral imidazolines synthesized in the frame of hit-to-lead explorations and designed for exploring the effect of diverse amide substitutions. Very profitably, reversed-phase (RP) conditions succeeded in resolving the enantiomers in nine out of the 10 investigated enantiomeric pairs, with α values always higher than 1.10 and RS values up to 2.31. All compounds were analysed with 50% (v) water while varying the content of the two organic modifiers acetonitrile and methanol. All the employed eluent systems were buffered with 40 mM ammonium acetate while the apparent pH was fixed at 7.5. Based on the experimental results, the prominent role of π-π stacking interactions between the substituted electron-rich phenyl groups outside of the polymeric selector and the complementary aromatic region in defining analyte retention and stereodiscrimination was identified. The importance of compound polarity in explaining the retention behaviour with the employed RP system was readily evident when a quantitative structure-property relationship study was performed on the retention factor values (k) of the 10 compounds, as computed with a 30% (v) methanol containing mobile phase. Indeed, good Pearson correlation coefficients of retention factors (r - log k1st = −0.93; r - log k2nd = −0.94) were obtained with a water solubility descriptor (Ali-logS). Interestingly, a n-hexane/chloroform/ethanol (88:10:2, v/v/v)-based non-standard mobile phase allowed the almost base-line enantioseparation (α = 1.06; RS = 1.26) of the unique compound undiscriminated under RP conditions.

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Section: Introductionmentioning

confidence: 99%

Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines

et al. 2020

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“…However, the mechanism of such enantiomeric separation was not fully elucidated. Hydrogen bonding, electrostatic interactions, and π-π interactions have been described as interactions arising in an anion exchange type chiral column for enantiomer separation 22 . These three interactions may contribute to the analytical systems in the present study.…”

Section: Discussionmentioning

confidence: 99%

Development of a cognitive function marker based on D-amino acid proportions using new chiral tandem LC-MS/MS systems

Kimura

Tsujimura

Tsuchiya

et al. 2020

Sci Rep

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the incidence of dementia, a clinical symptom characterized by severe cognitive decline, is increasing worldwide. Predictive biomarkers are therefore required for early identification and management. D-amino acids in the brain contribute to cognitive function and are suggested as useful biomarkers for diagnosing dementia risk. to clarify their relationship with human cognitive decline, we developed an identification method of chiral metabolomics for detecting slight differences in chiral amino acid amounts. chiral tandem liquid chromatography-tandem mass spectrometry systems were applied for sensitive and selective amino acid species along with chiral species determination based on anion and zwitterion exchange mechanisms. in a comprehensive health cohort (cross-sectional study), we measured blood chiral amino acid levels from 305 women (65-80 years old) classified into Control, Mild-cognitive-impairment (Mci), and Dementia groups using the Mini-Mental State examination. Mci exhibited higher D-pro (D-pro/(D-pro + L-pro)) proportion vs the control group, suggesting this proportion as a useful biomarker for Mci. Biomarker accuracy was improved in combination with D-Ser proportion. Receiver operating characteristics analysis of the control vs. Mci proportion obtained area under the curve (0.80) with 70% sensitivity and 84% specificity at the optimal cutoff value (0.30). Thus, dementia monitoring can be improved by including trace D-amino acids measurements. Dementia is a clinical symptom indicating a type of cognitive dysfunction that, when severe, leads to increasing dependence on others in aspects of daily living. Various types of dementia include Alzheimer (AD), cerebrovascular, Lewy body, and frontotemporal dementia. The detailed cause of onset has not yet been elucidated and no effective biomarkers are available for the early diagnosis of dementia or selection of therapeutic agents 1. The prodromal stage of dementia and mild cognitive impairment (MCI) have attracted attention in recent years as early stages of cognitive decline. It has been reported that approximately 10% of MCI converts to AD annually 2. Moreover, 14-44% of patients with MCI improve to the status of healthy elderly individuals through early interventions 3. Therefore, the early diagnosis of dementia risk and timely interventions, such as nutrition, exercise, and sleep, are desired to prevent cognitive decline in the at-risk elderly population. Current methods of diagnosis require a wide range of clinical tests including cognitive performance assessment, genetic screening, measurement of amyloid beta and tau proteins in the liquor cerebrosinalis, brain imaging, and behavioural assessments 4. Especially in recent years, numerous researchers have aimed to identify appropriate markers measurable in the blood for the early identification and management of dementia. For example, quantitative measurements of amyloid beta and its sequester protein in the blood have been developed 5-9. However, these biomarkers are difficult to apply toward practical d...

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“…Weak anion‐exchanger CSPs based on Cinchona alkaloids, and their zwitterionic ionic‐exchanger (ZWIX) version, are widely used for enantioseparation of chiral acids, amino acids and peptides . These chiral ion‐exchanger CSPs, which have been pioneered by Lindner , interact with charged analytes via long‐range ionic interactions between charged selectors and selectands (Fig.…”

Section: Cinchona Alkaloid‐based Selectorsmentioning

confidence: 99%

“…In particular, the ZWIX series contain an aminosulfonic acid‐based chiral strong cation‐exchanger moiety which forms, along with the weak anion‐exchanger site, the zwitterionic chiral selector. Consequently, in this case, two ion pairs may be formed via interactions with the anion‐ and the cation‐exchanger sites, leading to the resolution of ampholytic solutes . To displace the solutes from the ionic sites, acid and base additives are generally required as counter‐ions.…”

Section: Cinchona Alkaloid‐based Selectorsmentioning

confidence: 99%

Recent studies of docking and molecular dynamics simulation for liquid‐phase enantioseparations

et al. 2019

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Liquid‐phase enantioseparations have been fruitfully applied in several fields of science. Various applications along with technical and theoretical advancements contributed to increase significantly the knowledge in this area. Nowadays, chromatographic techniques, in particular HPLC on chiral stationary phase, are considered as mature technologies. In the last thirty years, CE has been also recognized as one of the most versatile technique for analytical scale separation of enantiomers. Despite the huge number of papers published in these fields, understanding mechanistic details of the stereoselective interaction between selector and selectand is still an open issue, in particular for high‐molecular weight chiral selectors like polysaccharide derivatives. With the ever growing improvement of computer facilities, hardware and software, computational techniques have become a basic tool in enantioseparation science. In this field, molecular docking and dynamics simulations proved to be extremely adaptable to model and visualize at molecular level the spatial proximity of interacting molecules in order to predict retention, selectivity, enantiomer elution order, and profile noncovalent interaction patterns underlying the recognition process. On this basis, topics and trends in using docking and molecular dynamics as theoretical complement of experimental LC and CE chiral separations are described herein. The basic concepts of these computational strategies and seminal studies performed over time are presented, with a specific focus on literature published between 2015 and November 2018. A systematic compilation of all published literature has not been attempted.

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Liquid chromatographic enantiomer separations applying chiral ion-exchangers based on Cinchona alkaloids

Cited by 53 publications

References 138 publications

Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines

Enantioselective HPLC Analysis to Assist the Chemical Exploration of Chiral Imidazolines

Development of a cognitive function marker based on D-amino acid proportions using new chiral tandem LC-MS/MS systems

Recent studies of docking and molecular dynamics simulation for liquid‐phase enantioseparations

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