Electrosynthesis methods and approaches for the preparative production of metabolites from parent drugs

Gül, Turan; Bischoff, Rainer; Permentier, Hjalmar P.

doi:10.1016/j.trac.2015.01.016

Cited by 36 publications

(24 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Comprehensive overviews about oxidative metabolic phase I reactions and their mimicry by EC have been published by Jurva et al 11 and Johansson et al 12 Apart from the EC/MS setup, EC recently gained attention in electrosynthetic applications for the generation of metabolite standards. [13][14][15] Reference materials are needed for the quantification and identification of metabolites, for toxicological studies, and for the complete structure elucidation of the metabolites. 10,16 Conventionally, metabolite standards are either synthesized via an organic de novo synthesis in a bottom-up approach or by a top-down approach utilizing biomimetic systems like liver microsomes or enzymes on a preparative scale.…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, the porous WE is often subjected to electrode fouling processes, which lead to a deactivation of the WE surface and thereby to decreasing conversion efficiencies over time. 14 Electrode fouling is also known in other types of electrochemical applications and has been studied thoroughly. 26,27 The resulting deactivation can be counteracted by flushing with different solvents and electrochemical cycling, 14 but due to the cell design, an exchange of deactivated WEs is difficult and expensive.…”

Section: Introductionmentioning

confidence: 99%

“…One of those approaches is scaling up electrochemical metabolism mimicry to the preparative scale. This top‐down approach allows the fast, easy, and controlled synthesis of metabolites from their parent compounds, and the purely instrumental approach grants a simple implementation and clean‐up procedure 10,14,15 . Due to the synthesis starting with the parent compound in this approach, isotopically labeled metabolite standards can easily be synthesized from isotopically labeled precursors, which are often already available for drug candidates.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Development of an electrochemical flow‐through cell for the fast and easy generation of isotopically labeled metabolite standards

Göldner

Fangmeyer

Kärst

2021

Drug Testing and Analysis

View full text Add to dashboard Cite

In drug development, metabolite standards of new chemical entities are required for a comprehensive safety evaluation. Stable isotope-labeled internal metabolite standards at the milligram scale, which are difficult and expensive to synthesize in common bottom-up approaches, are necessary for metabolite quantification using liquid chromatography/mass spectrometry. A preparative electrochemical flowthrough cell is presented here as a powerful tool for the cheap and straightforward synthesis of milligram amounts of isotopically labeled metabolite standards. The developed cell scales up established, so-called "coulometric" electrochemical cells.Problems like electrode fouling and cross contamination between syntheses are addressed by the use of exchangeable working electrodes. The applicability of the developed cell for the synthesis of metabolite standards is demonstrated using isotopically labeled acetaminophen as a model system for the generation of a biologically relevant phase II metabolite.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Development of an electrochemical flow‐through cell for the fast and easy generation of isotopically labeled metabolite standards

Göldner

Fangmeyer

Kärst

2021

Drug Testing and Analysis

View full text Add to dashboard Cite

show abstract

“…The synthesis and isolation of metabolites is a distinct issue. Since the conventional approach of obtaining metabolites assumes organic synthesis, some modern techniques such as biosynthesis, enzymatic methods, and electrochemical (EC) synthetic reactions are particularly gaining attention [35][36][37][38][39][40]. In this context, the photocatalytic transformation of drugs in order to further metabolite isolation seems to become a promising tool.…”

Section: Introductionmentioning

confidence: 99%

Mimicking of Phase I Metabolism Reactions of Molindone by HLM and Photocatalytic Methods with the Use of UHPLC-MS/MS

et al. 2020

View full text Add to dashboard Cite

Establishing the metabolism pathway of the drug undergoing the hepatic biotransformation pathway is one of the most important aspects in the preclinical discovery process since the presence of toxic or reactive metabolites may result in drug withdrawal from the market. In this study, we present the structural elucidation of six, not described yet, metabolites of an antipsychotic molecule: molindone. The elucidation of metabolites was supported with a novel photocatalytical approach with the use of WO3 and WS2 assisted photochemical reactions. An UHPLC-ESI-Q-TOF combined system was used for the registration of all obtained metabolite profiles as well as to record the high resolution fragmentation spectra of the observed transformation products. As a reference in the in vitro metabolism simulation method, the incubation with human liver microsomes was used. Chemometric comparison of the obtained profiles pointed out the use of the WO3 approach as being more convenient in the field of drug metabolism studies. Moreover, the photocatalysis was used in the direction of the main drug metabolite synthesis in order to further isolation and characterization.

show abstract

“…Electrochemistry (EC) is a relatively new and innovative approach to supporting drug discovery [3]. EC is an alternative method to study drug metabolism and toxicities in early phases by mimicking phase I metabolism [7][8][9][10]. Crucially, most marketed drugs (including pro-drugs) show electroactivity at solid electrodes [4,11].…”

Section: Introductionmentioning

confidence: 99%

Voltammetric Behaviour of Drug Molecules as a Predictor of Metabolic Liabilities

et al. 2020

View full text Add to dashboard Cite

Electron transfer plays a vital role in drug metabolism and underlying toxicity mechanisms. Currently, pharmaceutical research relies on pharmacokinetics (PK) and absorption, distribution, metabolism, elimination and toxicity (ADMET) measurements to understand and predict drug reactions in the body. Metabolic stability (and toxicity) prediction in the early phases of the drug discovery and development process is key in identifying a suitable lead compound for optimisation. Voltammetric methods have the potential to overcome the significant barrier of new drug failure rates, by giving insight into phase I metabolism events which can have a direct bearing on the stability and toxicity of the parent drug being dosed. Herein, we report for the first time a data-mining investigation into the voltammetric behaviour of reported drug molecules and their correlation with metabolic stability (indirectly measured via t½), as a potential predictor of drug stability/toxicity in vivo. We observed an inverse relationship between oxidation potential and drug stability. Furthermore, we selected and prepared short- (<10 min) and longer-circulation (>2 h) drug molecules to prospectively survey the relationship between oxidation potential and stability.

show abstract

Electrosynthesis methods and approaches for the preparative production of metabolites from parent drugs

Cited by 36 publications

References 79 publications

Development of an electrochemical flow‐through cell for the fast and easy generation of isotopically labeled metabolite standards

Development of an electrochemical flow‐through cell for the fast and easy generation of isotopically labeled metabolite standards

Mimicking of Phase I Metabolism Reactions of Molindone by HLM and Photocatalytic Methods with the Use of UHPLC-MS/MS

Voltammetric Behaviour of Drug Molecules as a Predictor of Metabolic Liabilities

Contact Info

Product

Resources

About