Absolute content determination by quantitative NMR (qNMR) spectroscopy: a curious case of aldosterone

Singh, Neeraj; Taibon, Judith; Pongratz, Stephan; Geletneky, Christian

doi:10.1039/d1ra03472c

Cited by 9 publications

(5 citation statements)

References 21 publications

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“…suggesting the presence of an aldehyde at position 18 which, due to the proximity of the 11hydroxy group, forms an hemiacetal and a bicyclical acetal [21,28,29]. Once X-ray crystallography and NMR became available, it was shown that aldosterone in crystal form is the bicyclical acetal [30] (Fig 1 ), while in solution it is a mixture of the readily interconverted hemiacetal and bicyclical acetal forms [29,31].…”

Section: Isolation and Chemical Characterization Of Adrenal Cortical ...mentioning

confidence: 99%

“…Reichstein, who had isolated 50 mg of the steroid, demonstrated that oxidation of the steroid yielded a γ-lactone [21,[26][27][28], suggesting the presence of an aldehyde at position 18, which, due to the proximity of the 11β-hydroxy group, forms a hemiacetal and a bicyclic acetal [21,28,29]. Once X-ray crystallography and NMR became available, it was shown that aldosterone in crystal form is the bicyclic acetal [30] (▶ Fig 1 ), while in solution, it is a mixture of the readily interconverted hemiacetal and bicyclic acetal forms [29,31]. The parent structure of an aldehyde in position 13 drawn in many publications has never been confirmed in solution or solid state due to the very high reactivity of the -CHO group at C-13 with the 11β-hydroxy (forming a hemiacetal) and the 11β-hydroxy, the -CHO group at C-13, and 20-keto which form the more stable bicyclic acetal.…”

Section: Isolation and Chemical Characterization Of Adrenal Cortical ...mentioning

confidence: 99%

“…The contaminants present included dimers, aldosterone acetal, and aldosterone-γ-lactone. The use of different sources of aldosterone as standards for its quantification has significant repercussions in precision and reproducibility between laboratories [29].…”

Section: Isolation and Chemical Characterization Of Adrenal Cortical ...mentioning

confidence: 99%

“…There were several possibilities for the position of the second hydroxy group. Reichstein, who had isolated 50 mg of the steroid, demonstrated that oxidation of the steroid yielded a γ-lactone [21,[26][27][28], suggesting the presence of an aldehyde at position 18, which, due to the proximity of the 11β-hydroxy group, forms a hemiacetal and a bicyclic acetal [21,28,29]. Once X-ray crystallography and NMR became available, it was shown that aldosterone in crystal form is the bicyclic acetal [30] (▶ Fig 1 ), while in solution, it is a mixture of the readily interconverted hemiacetal and bicyclic acetal forms [29,31].…”

Section: Isolation and Chemical Characterization Of Adrenal Cortical ...mentioning

confidence: 99%

“…The synthesis of aldosterone made it available for studies and the design of multiple methods for its measurement [32][33][34]. A recent quantitative NMR study of aldosterone samples from two commercial sources that were at least 95 % pure by liquid chromatography with tandem mass spectrometric (LC-MS-MS) demonstrated by quantitative 1 HNMR that in the purest sample, the diastereomers are in a tautomeric equilibrium of the bicyclic acetal 18 R,20 S and 18 S,20-oxo in a proportion of 3:4 [29]. 1 HNMR showed that this sample was 93.8 % pure, while the other was only 81.85 % pure.…”

Section: Isolation and Chemical Characterization Of Adrenal Cortical ...mentioning

confidence: 99%

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An Abbreviated History of Aldosterone Metabolism, Current and Future Challenges

Gómez-Sánchez

2023

Exp Clin Endocrinol Diabetes

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The initial isolation of adrenal steroids from large quantities of animal adrenals resulted in an amorphous fraction resistant to crystallization and identification that had potent effects on electrolyte transport. Aldosterone was eventually isolated and identified in the fraction and was soon shown to cause hypertension when in excess. The autonomous and excessive production of aldosterone, primary aldosteronism, is the most common cause of secondary hypertension. Aldosterone is metabolized in the liver and kidney and its metabolites conjugated with glucuronic acid for excretion. The most common liver metabolite is 3,5-tetrahydroaldosterone-3-glucuronide; that of the kidney is aldosterone-18-oxo-glucuronide. Their values, especially the aldosterone-18-oxo-glucuronide, are commonly used for the diagnosis of primary aldosteronism because they provide and integrated value of the total daily production of aldosterone. Conversion of aldosterone to 18-oxo-glucuronide is impeded by drugs, like some common NSAIDS that compete for UGT2B7, the most important glucuronosyltransferase for aldosterone metabolism. Tetrahydroaldosterone is the most abundant metabolite and most reliable for the diagnosis of primary aldosteronism, but is not commonly measured.

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Section: Isolation and Chemical Characterization Of Adrenal Cortical ...mentioning

confidence: 99%

Section: Isolation and Chemical Characterization Of Adrenal Cortical ...mentioning

confidence: 99%

Section: Isolation and Chemical Characterization Of Adrenal Cortical ...mentioning

confidence: 99%

Section: Isolation and Chemical Characterization Of Adrenal Cortical ...mentioning

confidence: 99%

Section: Isolation and Chemical Characterization Of Adrenal Cortical ...mentioning

confidence: 99%

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An Abbreviated History of Aldosterone Metabolism, Current and Future Challenges

Gómez-Sánchez

2023

Exp Clin Endocrinol Diabetes

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Quantitative NMR in Quality Control

Liu

2024

Quality Control of Chinese Medicines

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An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of aldosterone in human serum and plasma

Taibon

Santner

Singh

et al. 2023

Clinical Chemistry and Laboratory Medicine (CCLM)

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Objectives An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC MS/MS)-based candidate reference measurement procedure (RMP) for aldosterone quantification in human serum and plasma is presented. Methods The material used in this RMP was characterized by quantitative nuclear magnetic resonance (qNMR) to assure traceability to SI Units. For liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis a two-dimensional heart cut LC approach, in combination with an optimal supported liquid extraction protocol, was established for the accurate analysis of aldosterone in human serum and plasma in order to minimize matrix effects and avoid the co-elution of interferences. Assay validation was performed according to current guidelines. Selectivity and specificity were assessed using spiked serum; potential matrix effects were examined by a post column infusion experiment and the comparison of standard line slopes. An extensive protocol over 5 days was applied to determine precision, accuracy and trueness. Measurement uncertainty was evaluated according to the Guide to the Expression of Uncertainty in Measurement (GUM), for which three individual sample preparations were performed on at least two different days. Results The RMP allowed aldosterone quantification within the range of 20–1,200 pg/mL without interference from structurally-related compounds and no evidence of matrix effects. Intermediate precision was ≤4.7% and repeatability was 2.8–3.7% for all analyte concentrations. The bias ranged between −2.2 and 0.5% for all levels and matrices. Total measurement uncertainties for target value assignment (n=6) were found to be ≤2.3%; expanded uncertainties were ≤4.6% (k=2) for all levels. Conclusions The RMP showed high analytical performance for aldosterone quantification in human serum and plasma. The traceability to SI units was established by qNMR content determination of aldosterone, which was utilized for direct calibration of the RMP. Thus, this candidate RMP is suitable for routine assay standardization and evaluation of clinical samples.

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Absolute content determination by quantitative NMR (qNMR) spectroscopy: a curious case of aldosterone

Abstract: 1D/2D-NMR based extensive analyses of the real structure of aldosterone, elucidating the plausible diastereomeric hemiacetal/hemiketal tautomers and a qNMR based method of absolute content determination.

Cited by 9 publications

References 21 publications

An Abbreviated History of Aldosterone Metabolism, Current and Future Challenges

An Abbreviated History of Aldosterone Metabolism, Current and Future Challenges

Quantitative NMR in Quality Control

An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) for the quantification of aldosterone in human serum and plasma

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