Enantiomeric purity determination of acetyl-l-carnitine by NMR with chiral lanthanide shift reagents

Kagawa, Miyuki; Machida, Yoshio; Nishi, Hiroyuki; Haginaka, Jun

doi:10.1016/j.jpba.2005.06.005

Cited by 16 publications

(4 citation statements)

References 16 publications

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“…Acetylated carnitine is localized within mitochondria where it acts as a sink for excess acetate and therefore maintains adequate levels of free coenzyme A (CoA-SH) (39). The proton MR signal at 3.24 ppm represents the N-trimethyl moiety and therefore is a composite of a total cellular carnitine; acetyl carnitine is distinguished by an acetyl-methyl group $2.1 ppm (40). The absence of a prominent peak at 2.1 ppm (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cardiac effects of MDMA on the metabolic profile determined with ¹H‐magnetic resonance spectroscopy in the rat

Perrine¹,

Michaels²,

Ghoddoussi³

et al. 2008

NMR in Biomedicine

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Despite the potential for deleterious (even fatal) effects on cardiac physiology, 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) abuse abounds driven mainly by its euphoric effects. Acute exposure to MDMA has profound cardiovascular effects on blood pressure and heart rate in humans and animals. To determine the effects of MDMA on cardiac metabolites in rats, MDMA (0, 5, or 10 mg/kg) was injected every 2 h for a total of four injections; animals were sacrificed 2 h after the last injection (8 h drug exposure), and their hearts removed and tissue samples from left ventricular wall dissected. High resolution magic angle spinning proton magnetic resonance spectroscopy (1H-MRS) at 11.7 T, a specialized version of MRS aptly suited for analysis of semi-solid materials such as intact tissue samples, was used to measure the cardiac metabolomic profile, including alanine, lactate, succinate, creatine, and carnitine, in heart tissue from rats treated with MDMA. MDMA effects on MR-visible choline, glutamate, glutamine, and taurine were also determined. Body temperature was measured following each MDMA administration and serotonin and norepinephrine (NE) levels were measured by high pressure liquid chromatography (HPLC) in heart tissue from treated animals. MDMA significantly and dose-dependently increased body temperature, a hallmark of amphetamines. Serotonin, but not NE, levels were significantly and dose-dependently decreased by MDMA in the heart wall. MDMA significantly altered the MR-visible profile with an increase in carnitine and no change in other key compounds involved in cardiomyocyte energy metabolomics. Finally, choline levels were significantly decreased by MDMA in heart. The results are consistent with the notion that MDMA has significant effects on cardiovascular serotonergic tone and disrupts the metabolic homeostasis of energy regulation in cardiac tissue, potentially increasing utilization of fatty acid metabolism. The contributions of serotonergic signaling on MDMA-induced changes in cardiac metabolism remain to be determined.

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Section: Discussionmentioning

confidence: 99%

Cardiac effects of MDMA on the metabolic profile determined with ¹H‐magnetic resonance spectroscopy in the rat

Perrine¹,

Michaels²,

Ghoddoussi³

et al. 2008

NMR in Biomedicine

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“…Unfortunately, all the studied chromatographic analyses led to failure as no signs of enantiomeric separations for (±)- 10 were obtained. Therefore, we decided to investigate enantiomeric separation conditions applying a common NMR methodological approach, which assumes the use of a lanthanide-like chiral shift reagent (CSR) such as europium(III) tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate [Eu(hfc) 3 ] [ 84 – 86 ]. To our disappointment, the desirable enantiomeric shift difference magnitudes and enhanced spectral resolution for the studied (±)- 10 were not achieved.…”

Section: Resultsmentioning

confidence: 99%

First chemoenzymatic stereodivergent synthesis of both enantiomers of promethazine and ethopropazine

Borowiecki¹,

Paprocki²,

Dranka³

2014

Beilstein J. Org. Chem.

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SummaryEnantioenriched promethazine and ethopropazine were synthesized through a simple and straightforward four-step chemoenzymatic route. The central chiral building block, 1-(10H-phenothiazin-10-yl)propan-2-ol, was obtained via a lipase-mediated kinetic resolution protocol, which furnished both enantiomeric forms, with superb enantioselectivity (up to E = 844), from the racemate. Novozym 435 and Lipozyme TL IM have been found as ideal biocatalysts for preparation of highly enantioenriched phenothiazolic alcohols (up to >99% ee), which absolute configurations were assigned by Mosher’s methodology and unambiguously confirmed by XRD analysis. Thus obtained key-intermediates were further transformed into bromide derivatives by means of PBr3, and subsequently reacted with appropriate amine providing desired pharmacologically valuable (R)- and (S)-stereoisomers of title drugs in an ee range of 84–98%, respectively. The modular amination procedure is based on a solvent-dependent stereodivergent transformation of the bromo derivative, which conducted in toluene gives mainly the product of single inversion, whereas carried out in methanol it provides exclusively the product of net retention. Enantiomeric excess of optically active promethazine and ethopropazine were established by HPLC measurements with chiral columns.

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“…The enantiomeric purity of acyl-l-carnitine was determined by 500 MHz 1 H NMR employing fast diastereomeric interaction with chiral shift reagents such as chiral lanthanide-camphorato {[Eu(hfc) 3 ], [Pr(hfc) 3 ]} or chiral samarium-pdta shift reagents. The LOD of the determination was 0.5% for the D-enantiomer [171].…”

Section: Process Impurities: Configurational Isomers Epimers and Enan...mentioning

confidence: 94%

Pharmaceutical impurities and degradation products: Uses and applications of NMR techniques

Maggio

Calvo

Vignaduzzo

et al. 2014

Journal of Pharmaceutical and Biomedical Analysis

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Enantiomeric purity determination of acetyl-l-carnitine by NMR with chiral lanthanide shift reagents

Cited by 16 publications

References 16 publications

Cardiac effects of MDMA on the metabolic profile determined with ¹H‐magnetic resonance spectroscopy in the rat

Cardiac effects of MDMA on the metabolic profile determined with ¹H‐magnetic resonance spectroscopy in the rat

First chemoenzymatic stereodivergent synthesis of both enantiomers of promethazine and ethopropazine

Pharmaceutical impurities and degradation products: Uses and applications of NMR techniques

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Enantiomeric purity determination of acetyl-l-carnitine by NMR with chiral lanthanide shift reagents

Cited by 16 publications

References 16 publications

Cardiac effects of MDMA on the metabolic profile determined with 1H‐magnetic resonance spectroscopy in the rat

Cardiac effects of MDMA on the metabolic profile determined with 1H‐magnetic resonance spectroscopy in the rat

First chemoenzymatic stereodivergent synthesis of both enantiomers of promethazine and ethopropazine

Pharmaceutical impurities and degradation products: Uses and applications of NMR techniques

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Product

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Cardiac effects of MDMA on the metabolic profile determined with ¹H‐magnetic resonance spectroscopy in the rat

Cardiac effects of MDMA on the metabolic profile determined with ¹H‐magnetic resonance spectroscopy in the rat