Multi-milligram resolution and determination of absolute configuration of pentedrone and methylone enantiomers

Silva, Bárbara; Pereira, José A.; Cravo, Sara; Araújo, Ana Margarida; Fernandes, Carla; Pinto, Madalena; Pinho, Paula Guedes de; Remião, Fernando

doi:10.1016/j.jchromb.2018.10.002

Cited by 28 publications

(19 citation statements)

References 49 publications

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“…values were determined using the Lux® Celullose‐2 CSP and 100% EtOH as mobile phase. This CSP was chosen due to the vast applicability and efficiency of polysaccharide‐based CSPs for different classes of chiral compounds, 47–49 including xanthone derivatives 50–52 . Good enantioselectivity, α values of 2.16 and 1.86, and resolution, Rs values of 3.38 and 2.93, were obtained for enantiomeric mixtures 3 and 4 , respectively.…”

Section: Resultsmentioning

confidence: 99%

Chiral derivatives of xanthones and benzophenones: Synthesis, enantioseparation, molecular docking, and tumor cell growth inhibition studies

Phyo¹,

Teixeira

Gonçalves

et al. 2021

Chirality

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Liquid chromatography enantioseparation and determination of enantiomeric purity of synthetized xanthone and benzophenone derivatives comprising one or more chiral moieties are reported. High enantioselectivity and resolution were observed in (S,S)‐Whelk‐O1 chiral stationary phase (CSP) for the enantiomeric mixtures of compounds comprising an aromatic ring linked to the stereogenic center(s), with α values ranging from 1.35 to 4.15 and Rs values ranging from 2.22 to 13.87. Among all the tested enantiomeric mixtures, those comprising three chiral moieties positioned in the xanthone scaffold gave the best chromatographic results. Enantiomers comprising an alkyl chain linked to the stereogenic centers were enantioseparated on a Lux® Celullose‐2 CSP. For both CSPs, the elution was performed in polar organic mode. The enantiomeric ratio (e.r.) values were always higher than 99%. Additionally, assessment of chiral recognition mechanisms on (S,S)‐Whelk‐O1 CSP was performed by molecular docking approach, which are in accordance with the chromatographic parameters. The nature and number of chiral moieties in the central aromatic scaffold of either xanthone or benzophenone derivatives are proved to be crucial for enantiorecognition. The evaluation of the growth inhibition of human tumor cell lines revealed that (S,S)‐(+)‐5 was the most potent compound, with values of GI50 of 12.83 ± 2.09 μM for A375‐C5 melanoma, 12.40 ± 1.16 μM for MCF‐7 breast adenocarcinoma, and 13.06 ± 1.29 μM for NCI‐H460 non‐small cell lung cancer. In some cases, the growth inhibitory effects demonstrated to be dependent on the stereochemistry of the compounds.

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Section: Resultsmentioning

confidence: 99%

Chiral derivatives of xanthones and benzophenones: Synthesis, enantioseparation, molecular docking, and tumor cell growth inhibition studies

Phyo¹,

Teixeira

Gonçalves

et al. 2021

Chirality

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“…Recent examples of applications at preparative scale on polysaccharide-based CSPs include: the enantioseparation of tetrahydro-α-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetic acid (TPA), a key intermediate for the synthesis of HIV protease inhibitors (enantiomeric purity of 99%) [54]; racemic coumarin derivatives [55]; isoborneol enantiomers [56]; high-affinity 5-HT7 receptor ligand (enantiomeric purity of 100%) [57]; synthetic E2F inhibitor HLM006474 (enantiomeric ratio higher than 99.5/0.5) [58]; novel pan-sigma receptor (SR) modulators, potentially useful in cancer treatment (enantiomeric excess higher than 95%) [59]; among others. Recently, we reported the enantioseparation of cathinone derivatives (amphetamine-like stimulant effects) at multi-milligram scale using the same type of CSPs (Figure 3) [60,61]. The excellent enantioresolution obtained allowed the collection of highly pure enantiomeric fractions achieving, for example, enantiomeric ratios higher than 98% for both methylone and pentedrone enantiomers [61].…”

Section: Liquid Chromatographymentioning

confidence: 98%

“…Recently, we reported the enantioseparation of cathinone derivatives (amphetamine-like stimulant effects) at multi-milligram scale using the same type of CSPs (Figure 3) [60,61]. The excellent enantioresolution obtained allowed the collection of highly pure enantiomeric fractions achieving, for example, enantiomeric ratios higher than 98% for both methylone and pentedrone enantiomers [61]. Synthetic polymers, such as polyacrylamide and the cross-linked di-allyltartardiamide, as well as brush-type CSPs (including neutral and anion exchange small molecules as chiral selectors), followed by cyclodextrin and macrocyclic antibiotic-based CSPs, are also frequently used for preparative enantioseparation purposes [27].…”

Section: Liquid Chromatographymentioning

confidence: 99%

Chiral Separations in Preparative Scale: A Medicinal Chemistry Point of View

2020

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Enantiomeric separation is a key step in the development of a new chiral drug. Preparative liquid chromatography (LC) continues to be the technique of choice either during the drug discovery process, to achieve a few milligrams, or to a scale-up during the clinical trial, needing kilograms of material. However, in the last few years, instrumental and technical developments allowed an exponential increase of preparative enantioseparation using other techniques. Besides LC, supercritical fluid chromatography (SFC) and counter-current chromatography (CCC) have aroused interest for preparative chiral separation. This overview will highlight the importance to scale-up chiral separations in Medicinal Chemistry, especially in the early stages of the pipeline of drugs discovery and development. Few examples within different methodologies will be selected, emphasizing the trends in chiral preparative separation. The advantages and drawbacks will be critically discussed.

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“…Among the developed polysaccharide-based CSPs, the 3,5-dimethylphenyl tris -phenylcarbamates of amylose and cellulose proved to have the best enantiorecognition performance [77,78,79,80]. In our group, this type of CSPs has proved to be effective for analytical as well as preparative applications [26,81,82,83,84].…”

Section: Chiral Stationary Phases: Recent Developmentsmentioning

confidence: 99%

“…LC using chiral stationary phases (CSPs) proved to be an essential tool with a wide range of applications, including preparative separation of enantiomers of diverse analytes [16,17], determination of enantiomeric composition [18,19], monitorization of asymmetric reactions [20,21], analysis of the stereochemistry of natural compounds [22,23], pharmacokinetic [24,25], forensic [26,27,28], environmental [29,30,31], and enantioselective studies [32,33], among others.…”

Section: Introductionmentioning

confidence: 99%

Chiral Stationary Phases for Liquid Chromatography: Recent Developments

et al. 2019

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The planning and development of new chiral stationary phases (CSPs) for liquid chromatography (LC) are considered as continuous and evolutionary issues since the introduction of the first CSP in 1938. The main objectives of the development strategies were to attempt the improvement of the chromatographic enantioresolution performance of the CSPs as well as enlarge their versatility and range of applications. Additionally, the transition to ultra-high-performance LC were underscored. The most recent strategies have comprised the introduction of new chiral selectors, the use of new materials as chromatographic supports or the reduction of its particle size, and the application of different synthetic approaches for preparation of CSPs. This review gathered the most recent developments associated to the different types of CSPs providing an overview of the relevant advances that are arising on LC.

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Multi-milligram resolution and determination of absolute configuration of pentedrone and methylone enantiomers

Cited by 28 publications

References 49 publications

Chiral derivatives of xanthones and benzophenones: Synthesis, enantioseparation, molecular docking, and tumor cell growth inhibition studies

Chiral derivatives of xanthones and benzophenones: Synthesis, enantioseparation, molecular docking, and tumor cell growth inhibition studies

Chiral Separations in Preparative Scale: A Medicinal Chemistry Point of View

Chiral Stationary Phases for Liquid Chromatography: Recent Developments

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